Frontiers in Neuroendocrinology 35 (2014) 347–369

Contents lists available at ScienceDirect

Frontiers in Neuroendocrinology
journal homepage: www.elsevier.com/locate/yfrne

Review

Gender differences in autoimmune disease

S.T. Ngo a,b,1, F.J. Steyn a,1, P.A. McCombe b,c,⇑
a
School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia
b
University of Queensland Centre for Clinical Research, University of Queensland, Herston, Queensland, Australia
c
Department of Neurology, Royal Brisbane & Women’s Hospital, Herston, Queensland, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Autoimmune diseases are a range of diseases in which the immune response to self-antigens results in
Available online 2 May 2014 damage or dysfunction of tissues. Autoimmune diseases can be systemic or can affect specific organs
or body systems. For most autoimmune diseases there is a clear sex difference in prevalence, whereby
Keywords: females are generally more frequently affected than males. In this review, we consider gender differences
Autoimmunity in systemic and organ-specific autoimmune diseases, and we summarize human data that outlines the
Gender prevalence of common autoimmune diseases specific to adult males and females in countries commonly
Sex differences
surveyed. We discuss possible mechanisms for sex specific differences including gender differences in
Immune system
immune response and organ vulnerability, reproductive capacity including pregnancy, sex hormones,
genetic predisposition, parental inheritance, and epigenetics. Evidence demonstrates that gender has a
significant influence on the development of autoimmune disease. Thus, considerations of gender should
be at the forefront of all studies that attempt to define mechanisms that underpin autoimmune disease.
Ó 2014 Published by Elsevier Inc. Open access under CC BY-NC-ND license.

1. Introduction 1.1. Autoimmunity and autoimmune disease – key considerations for

Autoimmune disease, first recognized by Ian Mackay and
Macfarlane Burnet, is characterized by the failure of an organism
to tolerate its own cells and tissues, resulting in an aberrant
immune response by lymphocytes and/or antibodies (Mackay
and Burnet, 1963). This leads to pathological changes and dysfunc-
tion of the tissue that is the target of the self-directed immune
response. Autoimmune diseases can be systemic or can affect
specific organs or body systems including the endocrine, gastro-
intestinal and liver, rheumatological, and neurological systems. In
this review, we discuss systemic and organ-specific autoimmune
diseases. In general there is a greater prevalence of autoimmune
disease in females than males, although there are exceptions. To
demonstrate sex differences in autoimmune disease, we summa-
rize human data to provide an overview of the prevalence in males
and females of common autoimmune diseases in countries
commonly surveyed. We then discuss possible mechanisms for
sex specific differences.
⇑ Corresponding author at: University of Queensland Centre for Clinical Research,
University of Queensland, Herston, Queensland, Australia. Fax: +61 7 38327447.
E-mail address: pamela.mccombe@uq.edu.au (P.A. McCombe).
1
Authors contributed equally.
sexual dimorphism
Autoimmune diseases comprise a range of diseases in which the
immune response to self-antigens results in damage or dysfunction
of tissues (Mackay and Burnet, 1963). Criteria have been developed
that allow a disease to be classified as autoimmune (Rose and
Bona, 1993). These criteria include the identification of a target
antigen, the presence of antibodies and/or T cells in the target
organ, and the transfer of disease to animals by cells or antibodies
(Rose and Bona, 1993; Witebsky et al., 1957). The immune system
is comprised of multiple cell types of a single lineage. Collectively,
these cells contribute to acquired and innate immunity. Interac-
tions between acquired and innate immune function may aggra-
vate autoimmune responses. A strong inflammatory component,
with infiltration of tissue with macrophages and lymphocytes, is
associated with many organ-specific autoimmune diseases, such
as in rheumatoid arthritis (RA) and multiple sclerosis (MS). Non-
inflammatory conditions like myasthenia gravis (MG) are anti-
body-mediated, although there may be some minor lymphocyte
infiltration. Systemic lupus erythematosus (SLE) is another impor-
tant antibody-mediated disease.
The origin of autoimmune disease is a disruption of immune
tolerance of self-antigens. This is thought to occur in genetically
susceptible individuals after exposure to environmental triggers
(Mackay, 2001). Autoimmune diseases are strongly associated with

http://dx.doi.org/10.1016/j.yfrne.2014.04.004
0091-3022/Ó 2014 Published by Elsevier Inc. Open access under CC BY-NC-ND license.
348 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
human leukocyte antigen (HLA) genes through mechanisms that
could involve genetic variability in the immune response and
genetic variability in the ability to present antigens (Gough and
Simmonds, 2007). Modern genetic studies of autoimmune diseases
such as MS, type I diabetes (T1D) and inflammatory bowel disease
(IBD) have shown that many other genes, each with small effect,
also contribute to genetic susceptibility to autoimmunity
(Australia and New Zealand Multiple Sclerosis Genetics, 2009;
Barrett et al., 2009; Khor et al., 2011). At times autoimmune dis-
eases run in families (Bias et al., 1986; McCombe et al., 1990). This
was once thought to indicate an autosomal dominant inheritance,
but it is now thought to be due to the interaction of common genes
(Clayton, 2009). However, what is often overlooked is that a very
significant component of the genetic contribution to autoimmunity
is gender, with the presence or absence of a Y chromosome influ-
encing the risk for autoimmune disease.
Environmental factors also predispose to autoimmune disease.
This is well illustrated by twin studies, where the risk of develop-
ing autoimmune disease cannot be solely explained by genetics.
For example, in MS there is greater concordance in monozygotic
than dizygotic twins, indicating that genetic factors are important
(Willer et al., 2003). However, the concordance in monozygotic
twins is incomplete, suggesting a role for environmental factors.
In a study from Finland, it was shown that the concordance of
MS in dizygotic twins has increased in two decades, with this rapid
increase again suggesting a significant role for environmental fac-
tors (Kuusisto et al., 2008). Possible environmental factors that
predispose to autoimmunity include exposure to infectious agents
and to dietary components (Lamb et al., 2008; Pender and Greer,
2007), exposure to chemicals, xenobiotics or toxins (Rieger and
Gershwin, 2007), stress (Rieger and Gershwin, 2007), or reduced
exposure to factors that protect from the development of autoim-
mune diseases (e.g. sunlight during childhood and adulthood)
(Fraser et al., 2003; Ponsonby et al., 2005). Different exposure or
response to these environmental factors could contribute to gender
differences in autoimmunity.
2. Sexual dimorphism in autoimmune diseases – prevalence
and consequence
2.1. Effect of gender on the prevalence of autoimmune diseases
For most autoimmune diseases there are clear sex differences in
prevalence whereby females are generally more frequently
affected than males (Eaton et al., 2007). This gender bias can be
modest, as is seen in MS (Bentzen et al., 2010; Cheng et al.,
2009; El Adssi et al., 2012; Hadjimichael et al., 2008; McCombe,
2003; Osoegawa et al., 2009; Pandit and Kundapur, 2014;
Ramagopalan et al., 2013), or strong, as is seen in primary biliary
cirrhosis (PBC) (Amarapurkar and Patel, 2007; Eaton et al., 2007;
Harada et al., 2013; McNally et al., 2011; Shen et al., 2009; Sood
et al., 2004). Importantly, prevalence between males and females
may be changing. For example, the predominance of MS in females
is increasing; initial early reports suggest equal prevalence in
males and females (Buckley, 1954), by the 1980’s prevalence was
approximately 2:1 (female:male) (Confavreux et al., 1980), and
recent reports suggest prevalence in some instances of up to 3:1
(female:male) (Ramagopalan et al., 2013). Such a rapid change is
likely to be due to environmental factors. To provide a more
detailed assessment of the current status of gender bias in autoim-
mune diseases, we summarize adult data from recent studies,
focusing predominantly (when possible) on the United States
(USA), England, France, Denmark, Japan, China, India, and Australia.
Measures are further categorized based on systemic, endocrine,
gastrointestinal, neurological or rheumatological diseases (Fig. 1).
Data highlight the very high (9:1) gender bias toward females
for systemic autoimmune diseases including SLE (Chiche et al.,
2012; Eaton et al., 2007; Feldman et al., 2013; Li et al., 2012;
Ramagopalan et al., 2013) and Sjögren’s syndrome (SS) (Eaton
et al., 2007; Misra et al., 2003; Nannini et al., 2013; Ramagopalan
et al., 2013; Seror et al., 2013; Tsuboi et al., 2013; Xiang and Dai,
2009), occurring independent of country of assessment. By con-
trast, some neurological diseases (including MG (Guptill et al.,
2011; Guy-Coichard et al., 2008; Huang et al., 2013; Pedersen
et al., 2013; Ramagopalan et al., 2013; Singhal et al., 2008;
Suzuki et al., 2011) and Guillain–Barré syndrome (GBS)
(Alshekhlee et al., 2008; Chen et al., 2014; Dhadke et al., 2013;
Eaton et al., 2007; Mitsui et al., 2013)) had a near equal prevalence
in males and females, although recent data suggest a greater prev-
alence of GBS in males in Asian countries including Japan (Mitsui
et al., 2013), China (Chen et al., 2014) and India (Dhadke et al.,
2013). In our recent study of GBS in Australia, there was a male
preponderance (Blum et al., 2013). However, in MS, the most com-
mon neurological autoimmune disease, females accounted for two
thirds of all cases (Bentzen et al., 2010; Cheng et al., 2009; El Adssi
et al., 2012; Hadjimichael et al., 2008; McCombe, 2003; Osoegawa
et al., 2009; Pandit and Kundapur, 2014; Ramagopalan et al., 2013).
Again, this occurred mostly independent of country of assessment.
The prevalence of endocrine related autoimmune diseases pre-
dominantly favored females (including Grave’s Disease (GD)
(Carle et al., 2011; Gaujoux et al., 2006; Guo et al., 2013;
Phitayakorn et al., 2013) and Hashimoto’s thyroiditis (HT)
(Ramagopalan et al., 2013; Zhang et al., 2012)). This was not the
case for T1D (Anderson et al., 2012; Bhadada et al., 2011; Eaton
et al., 2007; Kawasaki and Eguchi, 2004; Menke et al., 2013), where
prevalence was equal in males and females. This varied somewhat
between countries, and prevalence slightly favored males in the
USA (Menke et al., 2013) and Denmark (Eaton et al., 2007), but
females in Japan (Kawasaki and Eguchi, 2004) and Australia
(Speight et al., 2012). Prevalence for rheumatological autoimmune
diseases varied greatly between countries, however trends
remained the same. For ankylosing spondylitis (AS), prevalence
favored males in the USA (Reveille, 2011), England (Ramagopalan
et al., 2013), China (Xiang and Dai, 2009), India (Aggarwal and
Malaviya, 2009), and Australia (Oldroyd et al., 2009). For RA prev-
alence greatly favored females, with reports ranging from 66% to
86% dominance (Biver et al., 2009; Li et al., 2012; Myasoedova
et al., 2011; Pedersen et al., 2011; Ramagopalan et al., 2013;
Yamanaka et al., 2013). Of the gastrointestinal diseases that we
studied, PBC showed a strong female dominance (values ranging
from 80% to 100%), regardless of country (Amarapurkar and Patel,
2007; Eaton et al., 2007; Harada et al., 2013; McNally et al.,
2011; Shen et al., 2009; Sood et al., 2004). While celiac disease
was generally female dominant (60% to 80% incidence), an excep-
tion was the recent observations by Nijhawan et al. (2013) that
found a 60% incidence for adult males (Nijhawan et al., 2013). A
similar rate of prevalence in male children was reported
(Bhattacharya et al., 2013). Incidence of ulcerative colitis (UC)
and Crohn’s disease (CD) in males and females did not vary greatly
by country, and generally did not favor females or males
(Gathungu et al., 2012; Jain et al., 2012; Jess et al., 2007; Nerich
et al., 2006; Ng et al., 2013; Ramagopalan et al., 2013; Zhao
et al., 2013). Of interest, Asakura et al. (2009) showed a deviation
in this trend, with 70% CD subjects in Japan being male (Asakura
et al., 2009). The studies detailed above do not consider severity
of symptoms.
2.2. Effect of gender on the severity of autoimmune diseases
As well as prevalence varying with gender, the severity of
autoimmune diseases, meaning the severity of symptoms and the
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369 349

Fig. 1. Prevalence of autoimmune disease in USA, England, France, Denmark, Japan, China, India, and Australia. There is a very high gender bias toward females for systemic
diseases including systemic lupus erythematosus (Chiche et al., 2012; Eaton et al., 2007; Feldman et al., 2013; Li et al., 2012; Ramagopalan et al., 2013) and Sjögren’s
syndrome (Eaton et al., 2007; Misra et al., 2003; Nannini et al., 2013; Ramagopalan et al., 2013; Seror et al., 2013; Tsuboi et al., 2013; Xiang and Dai, 2009). Neurological
diseases including myasthenia gravis (Guptill et al., 2011; Guy-Coichard et al., 2008; Huang et al., 2013; Pedersen et al., 2013; Ramagopalan et al., 2013; Singhal et al., 2008;
Suzuki et al., 2011) and Guillain–Barré syndrome (Alshekhlee et al., 2008; Chen et al., 2014; Dhadke et al., 2013; Eaton et al., 2007; Mitsui et al., 2013) have near parity
distribution between males and females, although recent data suggests a greater prevalence of Guillain–Barré syndrome in males in Japan (Mitsui et al., 2013), China (Chen
et al., 2014) and India (Dhadke et al., 2013). In Australia, there is a male preponderance in Guillain–Barré syndrome (Blum et al., 2013). For multiple sclerosis, females account
for two thirds of all cases (Bentzen et al., 2010; Cheng et al., 2009; El Adssi et al., 2012; Hadjimichael et al., 2008; McCombe, 2003; Osoegawa et al., 2009; Pandit and
Kundapur, 2014; Ramagopalan et al., 2013). The prevalence of endocrine related diseases predominantly favors females (including Grave’s Disease (Carle et al., 2011; Gaujoux
et al., 2006; Guo et al., 2013; Phitayakorn et al., 2013) and Hashimoto’s thyroiditis (Ramagopalan et al., 2013; Zhang et al., 2012)). Prevalence is near parity for type 1 diabetes
(Anderson et al., 2012; Bhadada et al., 2011; Eaton et al., 2007; Kawasaki and Eguchi, 2004; Menke et al., 2013), although prevalence slightly favors males in the USA (Menke
et al., 2013) and Denmark (Eaton et al., 2007), or females in Japan (Kawasaki and Eguchi, 2004) and Australia (Speight et al., 2012). Prevalence for rheumatological diseases
varies between countries, however trends remained the same. For ankylosing spondylitis, prevalence favors males in the USA (Reveille, 2011), England (Ramagopalan et al.,
2013), China (Xiang and Dai, 2009), India (Aggarwal and Malaviya, 2009), and Australia (Oldroyd et al., 2009). For rheumatoid arthritis, prevalence greatly favors females
(Biver et al., 2009; Li et al., 2012; Myasoedova et al., 2011; Pedersen et al., 2011; Ramagopalan et al., 2013; Yamanaka et al., 2013). Primary biliary cirrhosis shows a strong
female dominance (Amarapurkar and Patel, 2007; Eaton et al., 2007; Harada et al., 2013; McNally et al., 2011; Shen et al., 2009; Sood et al., 2004). Celiac disease is generally
female dominant, although prevalence seems to favor males in India (Nijhawan et al., 2013). Incidence of ulcerative colitis (UC) and Crohn’s disease (CD) in males and females
does not vary greatly by country, and generally does not favor females or males (Gathungu et al., 2012; Jain et al., 2012; Jess et al., 2007; Nerich et al., 2006; Ng et al., 2013;
Ramagopalan et al., 2013; Zhao et al., 2013), although a deviation in this trend is seen in Japan (Asakura et al., 2009).

degree of disability, may also differ between males and females.
However, compared to prevalence, this is not easily defined. The
effect of gender on severity varies among autoimmune diseases.
For example, psoriasis is more severe in males (Sakai et al.,
2005). Men develop autoimmune hepatitis at a younger age and
have high relapse rates, but also have better prognosis than women
(Al-Chalabi et al., 2008). By contrast, the clinical course in CD is
more severe in girls (Gupta et al., 2007), whereas in diseases like
RA, gender does not necessarily predict outcome (Courvoisier
et al., 2008). In MS, disease severity, measured as disability pro-
gression, appears to be greater in males (Runmarker and
Andersen, 1993; Weinshenker et al., 1991). A recent study demon-
strates greater disease severity in male SLE patients; male patients
were more likely to suffer renal and cardiovascular co-morbidities
350 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
while female patients were more likely to suffer from urinary tract
infections, hypothyroidism, depression, esophageal reflux, asthma,
and fibromyalgia (Crosslin and Wiginton, 2011).
2.3. Effect of gender on the pathological features of autoimmune
disease
Gender differences are reported in the T cell and antibody
responses that occur in autoimmune disease. In MS for instance,
females tend to secrete higher levels of IFNc in response to prote-
olipid protein (PLP) peptides when compared to control females
and males with MS (Pelfrey et al., 2002), and increased T-cell reac-
tivity occurs at a higher frequency (Greer et al., 2004). On the other
hand, a small study in SLE patients report that the IgM and IgG
reactivity to dsDNA Ro and La follows no gender bias (Ferreira
et al., 2005). In diabetes, females have higher levels of antibodies
to glutamic acid decarboxylase (Lindholm et al., 2004).
There are no systematic studies of the effects of gender on the
histopathological features of autoimmune disease, but it has been
suggested that autoimmune disease in males is young onset, with
acute inflammation and autoantibodies, while in females autoim-
mune disease is either acute onset and non-inflammatory and/or
associated with chronic pathology (Fairweather et al., 2008). Much
remains to be studied in this area.
2.4. Effect of gender on survival in autoimmune disease
Autoimmune diseases are generally not considered to be fatal,
but in many diseases, reduced life expectancy can be demon-
strated, compared to the general population. The measure of this
is the standarized mortality rate (SMR), which compares the
observed mortality in a group with that expected in that popula-
tion. This has been well studied in MS where survival duration is
greater for women than men. However, when survival is consid-
ered and adjusted relative to general mortality rates, females with
MS have poorer survival outcomes (Grytten Torkildsen et al.,
2008). In T1D, relative mortality was found to be higher for Finnish
women than for men (Asao et al., 2003). Increased mortality in a
large multicentre international cohort of SLE patients have been
reported to be associated with female gender (Bernatsky et al.,
2006). Similar observations were documented in a Spanish popula-
tion (Ruiz et al., 2014). For PBC, a higher number of deaths have
been observed in English/Welsh women (Hamlyn and Sherlock,
1974). While data suggests that gender can influence the mortality
of autoimmune disease, it is important to note that co-morbidities
may significantly alter the course of disease. Moreover, survival
can be influenced by factors other than severity of disease, such
as quality of care, age of onset, and time to diagnosis.
3. Factors underlying sexual dimorphism in autoimmune
diseases
Above we have described the observable effects of gender on
the incidence and severity of autoimmune disease. Now we will
consider the possible underlying mechanisms that could lead to
these clinical effects. We limit our considerations to human obser-
vations and refer to mouse data when human data is restricted. We
have previously provided an extensive review of data pertaining to
mouse models of autoimmune disease (McCombe et al., 2009). The
underlying basis for sexual dimorphism in autoimmune disease is
yet to be determined. However, significant research has investi-
gated the impact of differences between males and females in
the immune response, organ vulnerability, reproductive function,
microchimerism, sex hormones, and the environment on the
Fig. 2. Factors underlying sexual dimorphism in autoimmune disease. While the
underlying basis for sexual dimorphism in autoimmune disease is yet to be
determined, a number of factors may contribute to gender differences in autoim-
mune disease. Females show increased immune reactivity, differences in the
number or responsiveness of cells that constitute the immune response, and
differential resistance to target organ damage, and this may influence propensity to
autoimmune disease. Hormonal changes during pubertal maturation, pregnancy,
and menopause may alter susceptibility to autoimmunity, and it is generally
accepted that pregnancy is associated with improved symptoms in autoimmune
disease. The protective effects that are exerted by female (estrogen, progesterone,
and prolactin) and male (androgens) hormones may also explain gender differences
in specific autoimmune diseases. Differential exposure to environmental factors
(including sunlight) can influence the prevalence and risk of developing an
autoimmune disease or the severity of disease. Genetic factors that might influence
the gender specific development of autoimmune disease may be related to
susceptibility genes, chromosomal differences, or epigenetics. When genetic factors
are combined with environmental factors, this can influence parental inheritance of
autoimmune disease. Epigenetic changes that arise in autoimmune disease can be
related to the sex of the parent, or can result from external factors. Genetic
imprinting, and in particular, miRNA imprinting, could also contribute to the sexual
dimorphism seen in autoimmune disease.
prevalence, susceptibility and severity of autoimmune disease
(Fig. 2). These factors are discussed below.
3.1. Differences between female and male immune systems
The gender differences in autoimmunity could be due to differ-
ences between male and female immune systems (McCombe and
Greer, 2013a). Such differences are found in most animal species;
males have immune suppression when compared to females and
this is linked to male sexual activity (McKean and Nunney,
2005). Females show increased immune reactivity (Hewagama
et al., 2009), and this greater immunocompetence may translate
to greater resilience to infectious and some non-infectious dis-
eases. However, it is possible that this greater immune reactivity
makes women more prone to developing autoimmune disease
(Zandman-Goddard et al., 2007).
3.1.1. T lymphocytes, B lymphocytes and natural killer cells
T lymphocytes, B lymphocytes and natural killer (NK) cells com-
prise the lymphocytes of the immune system. T lymphocyte
secreted cytokines including IL-2, IL-4, IL-10, IFNc and TNFa
underlie cell-mediated adaptive immunity. B lymphocytes produce
IgG and IgM antibodies against foreign antigens to mount antibody
driven adaptive immune responses. NK cells are effectors of cell-
mediated, innate immunity.
While there are age-associated changes in human lymphocyte
subtype numbers (Yan et al., 2010), the overall number of lympho-
cytes in males and females is the same. However, males have a
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
lower number of T lymphocytes (Bouman et al., 2004), and post-
menopausal women have decreased numbers of B lymphocytes
and helper T cells (Th cells) (Giglio et al., 1994; Yang et al.,
2000). B lymphocyte counts do not differ between genders, how-
ever, women produce higher levels of circulating antibodies than
men (Rowley and Mackay, 1969), which could underlie their pro-
pensity to produce higher levels of autoantibodies in autoimmune
diseases (Whitacre et al., 1999). Indeed, females have increased
levels of IgM when compared to their male counterparts
(Butterworth et al., 1967; Lichtman et al., 1967). While data on
NK cells is limited, when compared to men, fertile females have
decreased NK cell cytotoxic activity, but women with premature
menopause have higher numbers of NK cells (Giglio et al., 1994).
Females produce stronger humoral and cellular immune
responses to antigen than males (Ansar Ahmed et al., 1985). Stud-
ies in humans suggest that females produce higher levels of
CD4 + T cells in response to immunization (Ho et al., 1995). More-
over, the antibody response of females surpasses that of males
after vaccination for influenza, hepatitis B, rubella and tetanus
(Cook, 2008). In some instances, adverse effects in response to
immunization can be observed in females in the absence of a sig-
nificant humoral response (Shohat et al., 2000).
Gender differences are also seen in the outcome of immunity to
bacterial, parasitic, and viral infections. With bacterial infections,
decreased production of anti-lipoarabinomannan IgM is observed
in males with Mycobacterium tuberculosis infections (Demkow
et al., 2007). In secondary syphilis, females are more resistant as
CD4 + and CD8 + T lymphocytes are both elevated (Ho et al.,
1995). The prevalence, severity or susceptibility of parasitic infec-
tions, Schistosoma mansoni, Schistosoma haematobiainfections (Degu
et al., 2002), and Leishmania donovani (Goble and Konopka, 1973) is
greater in males than females. The decreased prevalence and
severity of Schistosoma infections in females may be attributed to
their ability to secrete greater amounts of anti-inflammatory cyto-
kines and differing antibody isotypes (Demkow et al., 2007), and
the decreased susceptibility in females to Leishmania may be due
to increased secretion of granulocyte macrophage colony-stimulat-
ing factor (Lezama-Davila et al., 2007). In the case of viruses, stud-
ies illustrate higher prevalence of herpes simplex virus type 2 in
females (Glynn et al., 2008; Howard et al., 2003; Rabenau et al.,
2002), and this may be due to higher levels of progesterone in
females since progesterone contraceptives hastens herpes simplex
virus type 1 (Stringer et al., 2007) (the role of progesterone in auto-
immunity will be discussed below). Increased levels of lympho-
cytes and neutrophils in young females (Pembrey et al., 2008)
may underlie their increased susceptibility to hepatitis C virus
(European Paediatric Hepatitis, 2005; Zanetti et al., 1998), although
chronic adult hepatitis C virus infection results in increased fibrosis
in males (Poynard et al., 1997).
3.1.2. Microglia, astrocytes, mast cells, and dendritic cells
The immune cells of that are resident in tissues could poten-
tially show gender differences that could influence autoimmune
disease. Little is known about gender differences in these cells.
To illustrate this issue we will use examples from the CNS. Microg-
lia and astrocytes account for the majority of the brain cell popula-
tion, and there is no indication of any gender difference with
respect to the spatial distribution of these cell types in the male
and female brain (Stark et al., 2007). While microglia represent
the primary immune cell of the central nervous system, astrocytes
are also considered to be immunocompetent, as they possess the
ability to synthesize immune molecules in response to insult/
injury (Farina et al., 2007; Gimsa et al., 2013; Jensen et al., 2013;
Kaur et al., 2010; Pivneva, 2008; Wirenfeldt et al., 2011). In the
context of immunity, mast cells and dendritic cells are also of par-
ticular importance. Mast cells are resident in a multitude of tissues
351
including the brain (Silverman et al., 2000; St John and Abraham,
2013) and take part in the host innate immune defence by releas-
ing chemoattractants that recruit eosinophils (Wardlaw et al.,
1986) and monocytes (Perry et al., 1993). Dendritic cells, which
are the antigen-presenting cells of the immune system, are gener-
ally present on tissues that are exposed to the environment
(Banchereau and Steinman, 1998; Silverman et al., 2000), but they
have also recently been suggested to be resident in brain (albeit
mouse brain) (Bulloch et al., 2008).
A number of in vivo studies provide insight into the roles of
microglia, astrocytes, mast cells, and dendritic cells in the neuro-
immune response in general. Interestingly, such studies have also
generated observations that might be of relevance when consider-
ing gender differences in autoimmune disease. For example: estro-
gen inhibits microglia and astrocyte activation in the striatum of a
mouse model of Parkinson’s Disease (Tripanichkul et al., 2006);
astrocytes in female mice may be more resistant to oxidative
stress-induced toxicity (Giordano et al., 2013), estrogen increases
the number and activation of mast cells in the brain (Boes and
Levy, 2012), and female mice have increased recruitment of den-
dritic cells to the brain after stroke (Manwani et al., 2013).
In the context of autoimmunity, studies in mice suggest that
estrogen may play a key role in the activation of microglia and
astrocytes, and the generation of tolerogenic dendritic cells. Myelin
basic protein-primed T cells from female mice and castrated male
mice induce microglial expression of proinflammatory cytokines
(Dasgupta et al., 2005), expression of the RNA binding protein
HuR in spinal cord astrocytes provides greater attenuation of dis-
ease in female experimental autoimmune encephalomyelitis
(EAE) mice (and this is reversed following ovariectomy) (Wheeler
et al., 2012), an estrogen receptor alpha ligand reduces inflamma-
tion and protects against axonal loss and reactive astrogliosis in
EAE mice (Spence et al., 2011), and estriol leads to the generation
of splenic dendritic cells that when transferred to mice prior to
active induction of EAE leads to protection from the development
of EAE (Papenfuss et al., 2011).
Data pertaining to human autoimmune disease is currently
limited to astrocytes and dendritic cells. Astrocytes in the rim
and center of MS lesions in male and female patients have recently
been found to upregulate different gender steroid-specific
enzymes, suggesting that these responses might underlie gender-
specific differences in steroid synthesis and signaling in the brains
of MS patients, and thus, the gender bias in MS prevalence and sus-
ceptibility (Luchetti et al., 2014). While dendritic cell numbers are
reported to be lower in MS (de Andres et al., 2009), primary SS
(Vogelsang et al., 2010), and SLE (Henriques et al., 2012), whether
there are gender differences in the expression or function of den-
dritic cells in these diseases remains unknown. Thus, future
research that aims to determine whether gender differences in
autoimmune disease can be attributed to differential expression
and function of microglia, astrocytes, mast cells, and dendritic cells
will generate significant interest.
3.2. Sexual dimorphism in target organ vulnerability to damage
Autoimmune disease results when an autoimmune attack on
target organs leads to dysfunction. Autoimmunity can occur with-
out clinical disease being evident. This means that there are two
issues involved in the development of autoimmune disease: the
presence of autoimmunity and the ability of the target organ to
resist the autoimmune attack. For example, in SLE, the presence
of autoantibodies does not always lead to end organ damage
(Lewis et al., 2013). The role of the target organ in autoimmunity
has been reviewed elsewhere (Hill et al., 2007). To consider gender
differences in the target organ that could lead to gender differences
in the incidence and severity of autoimmune disease, we need to
352 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
examine gender differences in the ability of different target organs
to tolerate damage. The processes that lead to an ability to with-
stand damage is sometimes referred to as cytoprotection; or neu-
roprotection or cardioprotection when referring to the ability of
the nervous system or the heart, respectively, to withstand dam-
age. A full discussion of this topic is beyond the scope of this
review, but the processes involved are fundamental and include
susceptibility to apoptosis, autophagy (Lista et al., 2011), mito-
chondrial function (Martel et al., 2012), and biochemical pathways
that promote survival such as the nrf2 pathway (Chen and Kunsch,
2004; Lee et al., 2005).
There are some studies that indicate that there are gender dif-
ferences in the ability to protect cells from damage. In general it
is thought that females have greater resistance, because of the
cytoprotective properties of estrogen (see below). Much of the
work in this area has been done in the nervous system, although
estrogen also has protective properties on endothelium (Si et al.,
2001). It is generally accepted that females tend to have improved
outcome after traumatic brain injury (Groswasser et al., 1998), and
although this has been debated (Bayir et al., 2004; Farace and
Alves, 2000; Wagner et al., 2000), this is thought to occur in
response to the effects of estrogen (Roof and Hall, 2000). While less
is known about gender differences in the processes and pathways
involved in neuroprotection, there is a study suggesting that there
are gender differences in autophagy (Lista et al., 2011). Additional
research is needed to determine in more detail whether gender
differences that target organ resistance are responsible for gender
differences in autoimmune disease.
3.3. Autoimmune disease and reproductive function
Reproductive load may significantly alter susceptibility to auto-
immunity, particularly in females. Careful consideration relative to
pubertal maturation (thus the onset of mature reproductive age),
and life events that alter reproductive function (including
pregnancy and menopause) should be made. For pregnancy, these
considerations extend to that of the fetus. We now survey the data
relating to reproductive issues and autoimmune disease.
3.3.1. Puberty
The incidence of autoimmune disease varies relative to the
onset of reproductive function, although with the exception of epi-
demiological studies, few studies differentiate between pre-puber-
tal and post-pubertal incidence, specifically in relation to gender
bias. This is surprising, given the impact of puberty on gender bias
in autoimmune diseases. For example, while pre-pubertal onset of
MS is rare, with only 3–5% of cases reported in individuals under
18 years of age (Chitnis et al., 2009; Duquette et al., 1987; Ghezzi
et al., 1997), gender bias within these cases of MS is absent
(reviewed in (Chitnis, 2013)). Following the onset of puberty, how-
ever, incidence changes rapidly and pubertal girls are found to be
at greater risk of developing MS than pre-pubertal girls
(Ramagopalan et al., 2010). Moreover, earlier onset of puberty in
girls is also associated with increased risk of developing MS
(Ramagopalan et al., 2009b). However, in SLE, the male to female
ratio of 1:9 may be as low as 1:2 prior to puberty (reviewed in
(Tedeschi et al., 2013)). By contrast, the incidence of UC in adoles-
cents is equivalent in males and females, but by early-adulthood
the ratio of male to female patients is 4:1 (Bove, 2013). These
reports could suggest that exposure to hormonal changes during
pubertal development could underlie the gender bias in autoim-
mune diseases. However, environmental effects may also play a
role. For example, relocation from a low-risk geographic to high-
risk geographic area during puberty significantly increased MS risk
(Dean and Elian, 1997). Although this was not gender specific, it is
an example of how factors other than hormones could influence
the effect of puberty on disease.
3.3.2. Pregnancy
Pregnancy involves physiological changes in the mother,
including elevation of cardiac output, increased basal metabolic
rate, increased lipid levels, and weight gain (Forsum and Lof,
2007; Granger, 2002; Lain and Catalano, 2007; Tan and Tan,
2013). In pregnancy there are changes in the levels of hormones
such as estriol, progesterone, prolactin, early pregnancy factor
(EPF), alpha-fetoprotein (Brunton and Russell, 2010) and leptin
(Molvarec et al., 2011), and elevated levels of growth factors such
as insulin-like growth factor (IGF) (Lauszus et al., 2003). After
delivery, there is a rapid decline in the levels of pregnancy hor-
mones and maternal physiology rapidly returns to normal,
although during lactation the levels of prolactin and oxytocin are
elevated (Uvnas-Moberg et al., 1990). It is generally thought that
the changes in maternal physiology are mediated through the
effects of the pregnancy hormones. In pregnancy, the mother plays
host to the fetus, which contains foreign antigens. Immune
changes in pregnancy tend to suppress the maternal immune
system, which is thought to be important in preventing rejection
of the fetus (Munoz-Suano et al., 2011; Veenstra van
Nieuwenhoven et al., 2003; Yip et al., 2006).
3.3.2.1. Immune responses in pregnancy. Regulatory T cells (Tregs)
mediate active immune tolerance to prevent any maternal lym-
phocyte-mediated damage to the fetus (Aluvihare et al., 2004;
Saito et al., 2005). A shift in Th1/Th2 activity in pregnancy favors
increased Th2-related and reduced Th1-related activities. This
results in an improvement in Th1-mediated diseases and an exac-
erbation of Th2-mediated diseases (Doria et al., 2002, 2004;
Ostensen et al., 2005). Indeed, the remission of the Th1 diseases
RA and AS during pregnancy is coupled with an inhibition of
Th1-related activities via an upregulation in cytokine inhibitors
(Ostensen et al., 2005). These findings are further corroborated
by a Th1 phenotype in abortion, and a Th2 phenotype during nor-
mal pregnancy (Raghupathy, 2001). While it is accepted that the
Th1/Th2 paradigm is a marker for pregnancy success, it has been
superseded by the Treg/Th17 paradigm. In 2004, Tregs were found
to be elevated during normal pregnancy (Somerset et al., 2004).
Elevated levels of Tregs correlate well with decreased activity of
Th1-related autoimmune diseases (Forger et al., 2008). The ratio
of Treg and IL-17 appears to be of pivotal importance during preg-
nancy as an imbalance in the Treg/IL-17 proportion is linked to
complications during pregnancy, including recurrent pregnancy
loss and pre-eclampsia (Darmochwal-Kolarz et al., 2012; Saito
et al., 2011). It is likely that steroid hormones drive these immuno-
logical changes in pregnancy; improvements in psoriasis (Th1-
dependent disease) is correlated with higher levels of estrogen
(Murase et al., 2005), and the increase in Tregs may be driven by
estradiol since low levels of Tregs are positively correlated with
low levels of estradiol in patients with missed abortion (Cao
et al., 2014). The steroid-associated immunological changes seen
in pregnancy may very well contribute to sex differences in auto-
immune disease, as discussed below.
Another pregnancy-associated change that may underlie gender
differences in autoimmune disease is a small protein of the heat
shock family, chaperonin 10 (cpn 10) (heat shock protein 10, hsp
10). Cpn 10 is released into blood during early pregnancy
(Morton et al., 1977). In line with its immunomodulatory capacity,
a 12 week course of cpn 10 treatment improves disease measures
in patients with RA (Vanags et al., 2006). Moreover, decreased T
lymphocyte-associated secretion of TNFa and interleukin 1b
occurs after 12 weeks of cpn 10 in psoriasis (Vanags et al., 2006).
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369 353

Thus, elevated levels of cpn 10 may contribute to the beneficial As detailed above, current data indicates that the differential
effects of pregnancy on autoimmune disease. effects imparted by pregnancy in autoimmune diseases are very
specific to autoimmune disease type. While it has been suggested
3.3.2.2. Autoimmune disease and pregnancy. The effects of preg- that some autoimmune diseases are not improved by pregnancy
nancy on autoimmune disease differ for inflammatory autoimmune (Adams Waldorf and Nelson, 2008), this is generally only the case
diseases, which tend to remit, and antibody mediated autoimmune for SLE, which is an antibody mediated disease. We note that preg-
diseases, where the effects are more variable. For instance, the nancy is documented to exert protective effects in AS, CD, MS, and
symptoms of MG vary considerably from woman to woman and RA, which are inflammatory diseases. In particular, there is over-
from pregnancy to pregnancy in the same woman (Hantai et al., whelming evidence to demonstrate that pregnancy is associated
2004), and pregnancy has been reported to worsen, improve, or with improved symptoms in MS and RA.
provide no change in MG symptoms (Batocchi et al., 1999). Like-
wise, pregnancy with psoriasis can lead to similar variations in dis-
3.3.2.3. Pregnancy, microchimerism and autoimmunity. Microchim-
ease response (Murase et al., 2005). In AS, pregnancy may not
erism, the trafficking of cells from the fetus to the mother and vice
aggravate disease (Lui et al., 2011), but it has been reported to cause
versa, occurs during pregnancy (Lo et al., 1996). It is well known
remission (Ostensen and Ostensen, 1998). For CD, the activity of
that, as a normal phenomenon, fetal cells persist in the maternal
disease was significantly lower during pregnancy as determined
circulation years after pregnancy (fetal microchimerism) (Bianchi
by the Harvey-Bradshaw index (Agret et al., 2005). In MS
et al., 1996), and that maternal cells persist in immunodeficient
(Borchers et al., 2010; Confavreux et al., 1998; McCombe and
and immunocompetent offspring into adult life (maternal
Greer, 2013b), and RA (Hench, 1983; Nelson and Ostensen, 1997;
microchimerism) (Evans et al., 1999; Maloney et al., 1999). Micro-
Ostensen and Villiger, 2007) however, it is widely accepted that
chimerism has been considered to be a possible trigger for autoim-
pregnancy is associated with the remission of symptoms, although
munity and has also been put forward as a protective mechanism
there can be a flare of disease post-partum. In contrast to MS and
(Fig. 3).
RA, SLE an antibody mediated disease, is reported to worsen during
If microchimerism were indeed linked to the development of
pregnancy (Ruiz-Irastorza et al., 1996; Stojan and Baer, 2012), and
autoimmune disease, then chimeric cells may persist as inactive
this can vary in the degree of severity (Lateef and Petri, 2012).
dendritic cells and lymphocytes (McNallan et al., 2007) until an
Pregnancy can also trigger the onset of autoimmune disease.
environmental factor, a shift in cytokine proportion, an infection,
Fulminant autoimmune diabetes can present during pregnancy
or a hormonal trigger activates these cells, thereby causing an allo-
or in the post-partum period (Inagaki et al., 2002), and other dor-
graft reaction, and subsequently, autoimmune disease in either the
mant autoimmune diseases, like thyroiditis, can become clinically
mother or the offspring (Nelson, 1999, 2002). The evidence for a
evident post-partum (Muller et al., 2001; Premawardhana et al.,
role for fetal microchimerism in the development of autoimmune
2004; Thompson and Farid, 1985). With evidence indicating a role
disease is conflicting. Fetal microchimeric cells have been found
of pregnancy in autoimmune disease, it must be noted however
in the blood and thyroid of women with autoimmune thyroid dis-
that heterogeneous study designs, variable presentation of disease,
ease (Lepez et al., 2012; Renne et al., 2004). Lepez and colleagues
and patient ethnicity can render the interpretation of pregnancy-
have also demonstrated that these fetal cells in women with thy-
associated data difficult.
roid disease were cytotoxic T lymphocytes, and hence, may have
Autoimmune disease during pregnancy can also result in fetal
been capable of initiating a graft-vs-host reaction to elicit autoim-
manifestations of disease. This is seen in diseases including MG
mune thyroid disease (Lepez et al., 2011). In line with a role for
(Eymard et al., 1991; Gveric-Ahmetasevic et al., 2008), SLE (Lee,
fetal micochimerism, women with increased odds of developing
2009; Yildirim et al., 2013), thyrotoxicosis (Batra, 2013; Radetti
autoimmune thyroid disease were noted to have had a previous
et al., 2002), autoimmune thrombocytopenic purpura (Sukenik-
pregnancy (Friedrich et al., 2008), but Bulow-Pederson and col-
Halevy et al., 2008; van der Lugt et al., 2013) and cutaneous lupus
leagues found no association between pregnancy and autoimmune
(Johnson, 2013). When placental transmission of autoantibodies
occurs, a temporary autoimmune disease can occur in the neonate.
In more severe cases, passively acquired autoimmunity can result
in congenital heart block due to transplacental transfer of anti-Ro
and anti-La from mothers with SLE (Brucato et al., 2001;
Wahren-Herlenius and Sonesson, 2006), or, from transfer of acetyl-
choline receptors antibodies, in arthrogryposis multiplex congenita
(Donaldson et al., 1981) or pulmonary hypoplasia (Newsom-Davis,
2007). Thus, given fetal complications associated with pregnant
mothers with autoimmune disease, due care is required for the
management of disease during the gestational period.
Autoimmune disease can also appear under conditions of
assisted pregnancy and ovarian hyperstimulation. Increased MS
activity and relapses of MS can occur after assisted reproductive
technology (ART) (Correale et al., 2012; Hellwig et al., 2008;
Laplaud et al., 2006), and this may be due to stress, immunological
changes in response to hormone therapy, or termination of
immune therapy upon the instigation of ART. ART pregnancies
have also been associated with exacerbation of SLE (Ben-Chetrit Fig. 3. Microchimerism and autoimmunity. Microchimerism is the trafficking of
and Ben-Chetrit, 1994; Casoli et al., 1997). Furthermore, complica- cells from the fetus to the mother and vice versa. Fetal microchimerism has been
tions can arise in autoimmune patients undergoing ART. Women proposed to have a beneficial role in helping a parous woman to recover from injury
with thyroid antibodies before the first cycle of ART have increased through the provision of additional mutipotential stem cells that could be used in
repair of damage. By contrast, maternal microchimerism may be harmful since
risk of miscarriage (Poppe et al., 2003), and a trend toward worse maternal cells are a possible source of graft versus host response, as is seen in
pregnancy and live-birth rate is becoming evident in SLE mothers systemic sclerosis. Since microchimerism occurs during pregnancy, microchimer-
undergoing ART (Costa and Colia, 2008). ism may contribute to gender differences in autoimmune disease.
354 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
thyroid disease, and thus argue that there is no association
between fetal microchimerism and autoimmune disease (Bulow
Pedersen et al., 2006).
The disease that has been most studied with respect to a caus-
ative role for fetal microchimerism is systemic sclerosis (sclero-
derma) given that chronic graft-vs-host disease after bone
marrow transplantation results in clinical presentations that are
similar to systemic sclerosis (Artlett et al., 1998; Gratwohl et al.,
1977). Much like the studies for thyroid disease however, those
that have investigated microchimerism as an underlying cause
for systemic sclerosis have presented variable results (Ichikawa
et al., 2001; Murata et al., 1999). Maternal microchimerism may
present as tissue-specific maternal microchimerism in neonates,
as has been suggested to be the case in neonatal lupus congenital
heart block (Stevens et al., 2003). The rate of maternal microchim-
erism is also higher in twins with MS (Willer et al., 2006). By con-
trast, maternal microchimerism appears to play no role in PBC
(Nomura et al., 2004).
Fetal microchimerism has also been proposed to have a
beneficial role in helping a parous woman to recover from injury.
Microchimeric cells have been demonstrated at sites of tissue
inflammation during pregnancy, forming blood vessels. After deliv-
ery, microchimeric cells have been found in the maternal liver after
liver injury, and many years after pregnancy, microchimeric fetal
cells have been found at sites of injury where these cells adopt a
variety of phenotypes (indicating their multipotent capacity). This
transfer of fetal stem cells could be helpful and provide additional
mutipotential stem cells that could be used in repair of damage
(Guillot et al., 2007; Johnson and Bianchi, 2004; Khosrotehrani
and Bianchi, 2005; Khosrotehrani et al., 2004; Lo et al., 1996). This
is speculative, but further investigation could be rewarding.
3.3.2.4. Long-term effects of pregnancy on autoimmunity. Another
consideration in autoimmune disease is the long-term effect of
pregnancy. There is little information in this area, except in the
case of MS. Overall, women with MS who have been pregnant have
a better long-term outcome than those who have not been preg-
nant (D’Hooghe et al., 2010). It seems that the effects are cumula-
tive since multiparous women seem to have a better outcome than
women with fewer, or who have no pregnancies (Runmarker and
Andersen, 1995; Verdru et al., 1994). Having been pregnant does
not increase the risk of secondary progression of disease (Koch
et al., 2009). Women who have children with different partners
do not have greater risk of disability as might be expected to occur
if the immune response to paternal genes was harmful (Basso et al.,
2004). Of interest, recent findings suggested that pregnancy fre-
quency lowers mortality in T1D (Sjöberg et al., 2013). This awaits
further validation, as it is a difficult topic to evaluate. There may
be reverse causation at work, such that women with less severe
disease could be more likely to decide to have children. However
there are some plausible biological mechanisms for long-term ben-
eficial effects of pregnancy, including fetal microchimerism which
could provide a reservoir of stem cells that could aid in repair (as
discussed above), and epigenetic changes (as discussed below).
3.3.3. Menopause
Menopause is a natural occurrence that marks the end of cycli-
cal changes associated with reproductive function in women. It is
characterized by lower levels of estrogens and progesterone, peak-
ing of FSH levels, follicular depletion, and irreversible cessation of
menses. There are conflicting reports about the effects of meno-
pause on MS that has developed earlier in life (Holmqvist et al.,
2006) (Smith and Studd, 1992; Wundes et al., 2011). In SLE,
however, menopausal transition has been reported to decrease
the frequency of flares, but to cause more damage in the organs
in which individual postmenopausal flares occur (Fernandez
et al., 2005; Sanchez-Guerrero et al., 2001; Urowitz et al., 2006).
In RA, postmenopausal women report higher physical disability
scores than premenopausal women (Kuiper et al., 2001). Meno-
pause has also been associated with the onset of autoimmune dis-
ease. For example, autoimmune hepatitis occurs most frequently in
the late teenage years in males, but occurs in women in the late
teens and after menopause (Werner et al., 2008). By contrast, men-
opause is not associated with high occurrence of SLE (Mok, 2008),
and SLE after menopause is generally less severe (Boddaert et al.,
2004). Early menopause however has shown to be associated with
an increased risk of developing SLE and RA (Costenbader et al.,
2007; Pikwer et al., 2012a,b). There are a number of immunological
changes associated with menopause including increased produc-
tion and response to pro-inflammatory cytokines, decreased secre-
tion of anti-inflammatory cytokines, decreased lymphocyte levels,
and decreased activity of NK cells (Gameiro and Romao, 2010;
Gameiro et al., 2010). These changes, coupled with altered endo-
crine function, may underlie the incidence and risk of autoimmune
disease that is associated with menopausal transition.
3.4. Role of hormones in the sexual dimorphism in autoimmunity
The strong gender bias in autoimmune disease susceptibility
could be due to the differential effects of gender-specific
hormones. Indeed, a considerable amount of evidence now demon-
strates not only the role of gender-specific hormones in contribut-
ing to disease, but also the differential roles of these hormones
relative to altered reproductive states (Fig. 4). For example, disease
flares for SLE are influenced by the age of onset of menarche, the
use of oral contraceptives, the age of onset of menopause, and
hormonal treatments in response to menopause (Costenbader
et al., 2007). These changes in reproductive function are all charac-
terized by significant changes in the hormonal milieu. The effects
of various sex hormones including estrogens, progesterone, andro-
gens, and prolactin are considered below. When possible, we will
discuss evidence of contribution to immunity, contribution to
autoimmune disease, and outcomes following treatments targeting
these hormones.
3.4.1. Estrogens
Acting through estrogen receptor subtypes (ERs) alpha (ERa)
and beta (ERb), estrogen mediates transcription activity of intracel-
lular machinery to produce genomic effects, whereas the rapid,
non-genomic actions of estrogen are triggered through activation
of membrane-associated ERs (mER). This results in changes in
intracellular activity that occur independent of transcription
pathways and protein synthesis. Endogenous estrogens include
estrogen (E1), estradiol (E2) and estriol (E3, produced only in preg-
nancy). These compounds differentially act on intracellular ERs
that are present in all cells of the immune system (Deroo and
Korach, 2006), including T and B lymphocyte subsets, and periph-
eral NK cells (Pernis, 2007; Pierdominici et al., 2010).
It has become clear that estrogens impact immunity by modu-
lating lymphocyte development and function (Grimaldi et al.,
2002; Smithson et al., 1998). Indeed, estrogens may facilitate
critical protective effects that negate detrimental changes follow-
ing inflammatory responses. For example, a decrease in CD4+/
CD8 + T-cell-subset ratios in cultures of human lymphocytes is
seen following estrogen treatment (Athreya et al., 1993). Similarly,
estrogen enhances immunoglobulin secretion from these cells
(Kanda and Tamaki, 1999). Estrogen may also directly affect B
lymphocyte subsets. In animal studies, estrogens increase bone
marrow progenitor B cells by protecting them from apoptosis
(Grimaldi et al., 2002; Medina et al., 2000), and by increasing the
survival of B cells (Grimaldi et al., 2002). In humans, estrogens
induce polyclonal activation of B cells. Specifically, estrogen
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369 355

Fig. 4. The role of hormones in the sexual dimorphism in autoimmunity. The strong gender bias in autoimmune disease susceptibility could be due to the differential effects
of gender-specific hormones in contributing to disease, and the differential roles of these hormones relative to altered reproductive states. Estrogen, which is seen in high
levels during pregnancy, impacts immunity by modulating lymphocyte development and function, and promoting cytoprotection. These actions of estrogen could lead to
improved cell-mediated disease or worsened antibody-mediated disease. Progesterones and androgens exert anti-inflammatory and immunosuppressive effects respectively,
and this is generally beneficial in autoimmune disease. Prolactin, which is high during pregnancy, induces pro-inflammatory effects, and this tends to worsen autoimmune
disease.

increases IgG and IgM production of peripheral blood mononuclear
cells. This occurs regardless of gender (Kanda and Tamaki, 1999;
Weetman et al., 1981). The role of estrogen in immunity has been
extensively reviewed (Bouman et al., 2005).
The potential cytoprotective role of estrogens may explain these
effects. Takao and colleagues showed that estrogen treatment
dose-dependently reversed the cytotoxic effects of TNFa in T cells.
In this study, the ER antagonist ICI-172.780 abolished the cytopro-
tective effects of 17b-estradiol on T cells (Takao et al., 2005).
Numerous reports demonstrate protective actions of estrogens on
the EAE mouse model of MS (Bebo et al., 2001; Ito et al., 2001;
Jansson et al., 1994). In this model of MS, inflammation is mediated
by T lymphocytes that react to CNS and brain-derived autoanti-
gens. To delineate the mechanisms through which estrogen may
be cytoprotective, Lélu and colleagues demonstrate that endoge-
nous estrogens limit the recruitment of blood-derived inflamma-
tory cells (CD4 + T cells) into the CNS (Lelu et al., 2010). Thus,
estrogen may protect the brain from damage following inflamma-
tory insults. This may underlie the potential cytoprotective effects
of estrogen during pregnancy.
In females, circulating levels of estrogens change dramatically
relative to reproductive function. This is important, as varying
levels of exposure to estrogens greatly affects immunity. At high
concentrations (such as in pregnancy), estrogen inhibits the Th-1
pro-inflammatory pathways (including TNFa, IL-1b and IL-6) and
stimulates Th-2 anti-inflammatory pathways (including IL-4, IL-
10 and TGFb). Conversely, at low levels (as seen after menopause),
estrogen stimulates pro-inflammatory pathways (including TNFa
and IL1-b) (Straub, 2007).
Relative to autoimmunity, estrogens may differentially impact
incidence across age and reproductive capacity. Second to this,
the actions of estrogens on inflammatory and immune responses
may change relative to the presence of autoimmune diseases. For
example, T lymphocytes from patients with SLE, but not from
healthy controls, are activated via ERa and ERb-specific agonists
(Rider et al., 2006). While evidence confirms the role of estrogens
in immunity, suggesting that they may play an important role in
autoimmunity, the mechanisms through which estrogens may
directly or indirectly mediate autoimmune responses remain
unknown. Elucidation of this will require more substantive
evidence demonstrating a direct involvement of estrogen in the
incidence of autoimmune disease.
The high female to male incidence rate for SLE (Fig. 1), coupled
with a dramatic reduction in gender ratios prior to puberty or fol-
lowing menopause (both conditions are associated with a reduc-
tion in circulating estrogen levels) has contributed to anecdotal
evidence suggesting that estrogen mediate immunity specific to
autoimmune diseases. This has been substantiated by studies
assessing the effects of estrogens on tissue collected from patients
suffering from autoimmune diseases. For example, lymphocytes
collected from SLE patients are more sensitive to the actions of
physiological levels of E2, whereas E2 may differentially modify
signaling pathways coupled to disease onset and severity in T cells
from SLE patients (reviewed in (Pierdominici and Ortona, 2013)).
Moreover, documented associations between autoimmune dis-
eases and various facets of estrogen signaling provide reason for
further assessment of potential causes. For example, in MS, ER
expression in the thymus changes dramatically (Zoller and Kersh,
2006), whereas estrogen concentrations in synovial fluid is mark-
edly increased in RA patients (Cutolo et al., 2004). However, this
does not necessarily mean that altered levels of endogenous estro-
gens will increase the risk for developing SLE. For example, the
incidence of SLE does not change relative to pregnancy and birth
rate (Cooper et al., 2002). Moreover, while the incidence of lupus
flares in patients with existing SLE increase during pregnancy
(Walker, 2007), this is not necessarily associated with alterations
in circulating levels of estrogens. For example, Doria et al. (2006)
demonstrated that estrogen levels in SLE patients may not rise dur-
ing the second and third trimesters of pregnancy, and thus disease
flares that occur at this time cannot be directly associated with
altered circulating levels of estrogens (Doria et al., 2006).
Accordingly, alterations in physiology not coupled to endogenous
estrogen may underlie autoimmune disease associations. To this
extent, the potential role of estrogen in the development of
autoimmune disease may be better identified when considering
exogenous estrogens, estrogen-like compounds, or modifiers of
estrogen action.
Immune responses may be compromised by naturally occurring
exogenous estrogens (phyto/myco-estrogens), or by synthetic
estrogen-like compounds (xenoestrogens) (reviewed in
356 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
(Chighizola and Meroni, 2012; Pierdominici and Ortona, 2013;
Vandenberg et al., 2012)). These compounds are widely found in
products used in the production of food and around the home,
including detergents, plastics, pesticides, and industrial chemicals.
While less potent than endogenous estrogens, these compounds
can accumulate in adipose tissue, where they may exert potent
effects on immunity (Chighizola and Meroni, 2012). Existing evi-
dence showing an involvement in phyto-, myco- or xenoestrogens
in autoimmune disease rely predominantly on epidemiological evi-
dence, or exposure studies conducted on animal models. Thus, it
remains unknown to what extent these compounds contribute to
autoimmune disease in the real world. Moreover, epidemiological
studies, and resulting assessment of the effects of exogenous estro-
gens on immune function may not necessarily accurately predict
direct estrogenic effects on autoimmune disease incidence.
Perhaps one of the most revealing cases of associations between
autoimmune disease and estrogen replacement therapy comes
from the use of Diethylstilbestrol (DES).
DES is a synthetic estrogen, historically used to reduce risk of
complications to pregnancy, to assist with postpartum lactation,
and for the treatment of other postmenopausal symptoms. Not
only did DES not improve pregnancy outcomes (Bamigboye and
Morris, 2003), it contributed to a number of complications. For
example, as a transplacental carcinogen, the exposure to DES con-
tributed to a significant rise in the development of rare vaginal
tumors (Herbst et al., 1971). Animal studies showed that DES has
a profound effect on immune responses (Luster et al., 1978),
confirming fears that DES exposure may have contribute to auto-
immune diseases in humans. However, while confirming that
females exposed to DES developed a number of autoimmune disor-
ders, the incidence was relatively low (Noller et al., 1988). This was
verified in more recent observations (Strohsnitter et al., 2010),
where the relative rise in incidence in RA in DES exposed females
below 45 years of age was offset by a much lower incidence in
older females. Thus, while animal studies demonstrate a significant
risk for autoimmunity following DES exposure, data from humans
provide little support for an association between the development
of an autoimmune disease and exposure to DES. This important
case highlights the need for rigorous assessment and careful
validation of autoimmune incidence following exogenous estrogen
exposure. This is of considerable importance, as estrogen-mediated
therapies may effectively alleviate complications with autoim-
mune diseases. In this instance, unsubstantiated concerns regard-
ing the use of estrogen-containing oral contraceptives may in
fact be to the detriment of women suffering from autoimmune
conditions, and in particular SLE.
While the potential benefits of estrogen therapy in some auto-
immune diseases are recognized, it should be noted that conflicting
observations make the interpretation of the extent of potential
benefits difficult. Moreover, identification of potential beneficial
effects of estrogen on autoimmune disease requires careful consid-
eration of the type and severity of the condition. For example,
while estrogen therapy in MS (Sicotte et al., 2002) and RA
(Bijlsma et al., 1987) may be beneficial, estrogen appears to
enhance disease severity in SLE. Thus, blockade of ER in SLE is
beneficial (Abdou et al., 2008). Similarly, while the use of contra-
ceptives may protect against RA (Vandenbroucke et al., 1982),
some evidence suggest that the beneficial effects are limited to
females under 35 years of age (Spector et al., 1990), or to females
that used contraceptives earlier in life (Hazes et al., 1990). In this
latter study, it was concluded that current use in older females
has no benefits. Accordingly, estrogen-containing contraceptives
for the prevention of RA may only be of some benefit to females
at childbearing age. Studies that directly assess this are however
scarce, and current observations are not promising. For example,
estrogen treatment (using lynestrenol plus ethinyl estradiol) of
women with RA for 6 months did not significantly improve symp-
toms (Hazes et al., 1989).
As with the use of oral contraceptives, conflicting reports exist
regarding the value and risk of hormone replacement therapy
(HRT) in women to treat autoimmune diseases. For example, HRT
does not appear to impact the ongoing course of disease in MS
(Holmqvist et al., 2006), or the risk of developing RA (Walitt
et al., 2008). HRT is thought to benefit postmenopausal women
with inflammatory bowel disease (Kane and Reddy, 2008), increase
bone mineral density in women with PBC (Ormarsdottir et al.,
2004), and improve incidence of isolated pulmonary hypertension
in post-menopausal women with systemic sclerosis (Beretta et al.,
2006). Conversely, in SLE, HRT may increase the risk of thrombosis
(Fernandez et al., 2007; Sanchez-Guerrero et al., 2007). Current
clinical trials assessing the potential roles of estrogens in prevent-
ing or minimizing disease impact for other autoimmune diseases
(for example ongoing efforts to assess the impact of estriol in
Relapsing Remitting Multiple Sclerosis, ClinicalTrials.gov Identi-
fier: NCT00451204) will shed light on the value of estogen-medi-
ated effects on autoimmunity.
3.4.2. Progesterone
Progesterone belongs to the class of steroid hormones known as
progestogens, named for their function in gestation (pro-gesta-
tion). Progesterone is produced predominantly in the gonads and
adrenal gland, and in pregnancy in the placenta. While critically
involved in pregnancy, detectable levels of progesterone are in cir-
culation in females throughout the menstrual cycle and in males in
levels similar to that seen in females during the follicular phase of
the menstrual cycle. The actions of progesterone in reproduction
are varied. In addition to directly regulating reproductive function
(including oocyte maturation, endometrial differentiation, embry-
onic implantation, placental growth etc.), progesterone may also
alter the actions of other steroid hormones at this time (Steyn
et al., 2008). Accordingly, interaction of progesterone with target
tissues may occur via indirect mechanisms.
Progesterone acts via its cytosolic receptor, the progesterone
receptor (PR). This receptor belongs to the nuclear hormone recep-
tor superfamily of transcription factors. Ligand binding of PR
induces changes in gene expression through direct binding to pro-
moter elements or through protein–protein interactions with other
transcription factors. Of interest, recent observations highlight that
actions of progestins (including progesterone) may occur indepen-
dent of the PR, therefore arguing for non-genomic interactions (Li
et al., 2004). As summarized by Hughes (2012), the actions of pro-
gesterone on immunity are best described by the wide distribution
of PRs on immune cells, including granulocytes, NK cells, dendritic
cells, T-cells and B cells (Hughes, 2012), although non-genomic
interactions may occur.
In general, the effects of progesterone in immunity are anti-
inflammatory. Of these, known effects include the promotion of
apoptosis and inhibition of IFNc production from NK cells
(Arruvito et al., 2008), the inhibition of macrophage activity
(Pisetsky and Spencer, 2011), the modulation of myeloid dendritic
cell activity (reviewed in (Hughes and Clark, 2007)), the inhibition
of glucocorticoid-mediated thymocyte apoptosis (McMurray et al.,
2000), the reduction of nitric oxide production (Miller et al., 1996)
and the expression of toll-like receptors (TLR) by macrophages
(Jones et al., 2008), the differentiation of Th2 cells in vitro
(Piccinni et al., 1995), and the expression of the co-stimulatory
molecules CD80, CD86 and CD40, as well as MHC II (Ivanova
et al., 2005; Liang et al., 2006). The role of progesterone in immu-
nity was recently reviewed (Hughes, 2012).
As with estrogens the potential actions of progesterone on
autoimmunity are more commonly defined in context of fluctua-
tions in endogenous progesterone levels, dictated by changes in
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
reproductive function. The rise in progesterone in pregnancy is
associated with remarkable changes in maternal immunity, and
may contribute to changes in immune responses. In general, the
effects of progesterone in immunity are anti-inflammatory. As with
estrogens, the potential effects of progesterone may also vary rel-
ative to disease severity and type. For example, progesterone pro-
tects against disease onset in gonadectomised lupus-prone NZB/W
mice (a model wherein mice spontaneously develop an autoim-
mune disorder similar to SLE) (Roubinian et al., 1978), whereas
in CIA rats (a common rat model for arthritis), progesterone alone
had no effect while reducing the beneficial effects of estrogen
(Ganesan et al., 2008). Similarly, continuous progesterone adminis-
tration to pre-autoimmune NZB/W mice delayed the development
of pathogenic serum anti-DNA antibodies and spontaneous auto-
immune disease and death (Hughes and Clark, 2007). In humans,
combined estrogen and progesterone hormone replacement
therapy may cause lupus flares in post-menopausal women
(Buyon et al., 2005), whereas a current clinical trial is assessing
the potential benefits of progestin treatment to prevent post-
partum flares in women with MS (Vukusic et al., 2009) (Results
from this trial are pending (ClinicalTrials.gov Identifier:
NCT00127075)). Given this variable response, substantive research
is needed before we can define the contribution of or treatment of
autoimmune diseases using therapies targeting progesterone.
3.4.3. Androgens
Androgens are steroid hormones commonly associated with the
development of masculine characteristics; implicated in testes for-
mation, spermatogenesis, and the deposition of lean muscle mass
at the expense of adipose. In males and females, androgens main-
tain bone mass while impacting behavior (including aggression).
Importantly, androgens are the precursors of all estrogens. While
generally present in high levels in males, androgens decline with
increasing age (Mitchell et al., 1995), whereas low circulating lev-
els of androgens persist throughout life in females (Davison et al.,
2005). As with estrogen and progesterone, androgens may act via
genomic (acting through the androgen receptor) and non-genomic
mechanisms (Lutz et al., 2003).
The actions of androgens on immune function may vary
depending on the type of androgen used, the dosage administered,
and the timing of administration. For example, some studies report
immunosuppressive effects (Fujii et al., 1975; Olsen and Kovacs,
1996; Paavonen, 1994), whereas endogenous androgens are also
thought to be immunostimulatory (Calabrese et al., 1989). Testos-
terone reduces the proliferation and differentiation of lymphocytes
(Sakiani et al., 2013; Sthoeger et al., 1988; Wyle and Kent, 1977),
and the use of androgens may suppress immunoglobulins, and in
particular IgA (Calabrese et al., 1989; Hirota et al., 1976). Andro-
gens, including supraphysiological doses of testosterone may inhi-
bit the cytotoxic activity of NK cells (Callewaert et al., 1991;
Marshall-Gradisnik et al., 2008; Sulke et al., 1985). Given that the
effects of androgens may vary considerably relative to the level
of exposure, and that multiple factors may contribute to the
immune profile in females, the potential role of endogenous andro-
gens in gender specific immune function remains unknown.
Androgen levels are higher in males, and autoimmune incidence
is generally lower. Thus, it is thought that androgens may to some
extent protect against autoimmunity. Indeed, gonadectomy of
male NZB/W mice result in overt autoimmunity and earlier death,
whereas treatment with androgens in ovariectomised female NZB/
W mice reduced mortality (Roubinian et al., 1977). In humans,
transdermal treatment with testosterone for 1 year was of some
benefit to men with MS, slowing cognitive decline and brain atro-
phy. Treatment, however, did not affect the number or volume of
enhancing lesions (Sicotte et al., 2007). In females with SLE,
testosterone administration via skin patches for 12 weeks did not
357
significantly improve disease severity (Gordon et al., 2008),
whereas the impact of dehydroepiandrosterone (DHEA) treatment
in SLE was inconsistent. For example, while initial reports showed
that oral DHEA treatment (200 mg/day for 6 months) improved SLE
Disease Activity Index (SLEDAI) scores and overall assessment
scores in patients (van Vollenhoven et al., 1994), subsequent dou-
ble-blinded studies from the same group were unable to corrobo-
rate these results (van Vollenhoven et al., 1995, 1999). Of
interest, a larger multicenter randomized, double-blind placebo
controlled trial showed significant improvements in assessment
scores from DHEA treated female patients (200 mg/day for
6 months), corresponding with a significant reduction in disease
flares (Chang et al., 2002). Importantly, DHEA is a precursor of both
androgens and estrogens, and thus these modest effects may not
necessarily involve direct androgenic roles. In light of potential
negative effects on HDL cholesterol (Casson et al., 1998), coupled
with the increased risk of developing atherosclerotic heart disease
in SLE patients (van Leuven et al., 2006), it is critical that the long-
term ramification on cardiovascular health be considered before
recommending DHEA as a treatment option for SLE.
3.4.4. Prolactin
While predominantly secreted from the anterior pituitary gland,
immune cells including lymphocytes secrete prolactin (Chavez-
Rueda et al., 2005; Vera-Lastra et al., 2002). The prolactin receptor,
a member of the cytokine receptor superfamily, is found on mono-
cytes and T lymphocytes, and other cells of the immune system
(Jara et al., 1991). Thus, while prolactin predominantly acts on the
brain and within the mammary gland to ensure physiological adap-
tation essential for sustained maternal behavior and lactation
(Grattan et al., 2008), it may play an important role in immunity,
and thus pregnancy associated changes in autoimmunity.
Functionally, the paracrine actions of prolactin produced within
lymphocytes may mediate important immunological effects. For
example, prolactin is able to induce the proliferation of lympho-
cytes, whereas inactivation of prolactin action through adminstra-
tion of neutralizing antibodies significantly decreases the
activation and proliferation of T lymphocytes (Chavez-Rueda
et al., 2005). Within the T lymphocytes, prolactin mediates T-bet,
an essential transcription factor involved in the production of
Th1-type cytokines, including IFN (Tomio et al., 2008). Thus, prolac-
tin may stimulate T-cell mediated inflammatory reactions (Tomio
et al., 2008). However, at high concentrations, prolactin may inhibit
the proinflammatory activation of T helper cells (Tomio et al., 2008).
Prolactin may enhance autoimmune disease, whereas serum
levels of prolactin may increase as a consequences of autoimmune
disease (Orbach and Shoenfeld, 2007). For example, hyperprolacti-
nemia is seen in autoimmune rheumatic diseases (ARD) including
SLE, RA, systemic sclerosis, SS, T1D, GD, HT, celiac disease, and MS
(Orbach et al., 2012). Elevated levels of prolactin was found in the
CSF in SLE patients with neuropsychiatric lupus (Jara et al., 1998),
while hyperprolactinemia is associated with activity of SLE in preg-
nancy (Jara et al., 2001). Of interest, hyperprolactinemia in patients
with pituitary tumors or following therapy with antipsychotic
drugs is associated with raised levels of thyroid autoantibodies
(Poyraz et al., 2008). Associations between prolactin and autoim-
munity are somewhat corroborated by animal studies, wherein
prolactin treatment often worsens disease severity. For example,
disease severity in NZB/W mice increases following prolactin treat-
ment, and improves following treatment with bromocriptine (an
ergoline derivative used to suppress endogenous prolactin produc-
tion) (McMurray et al., 1991).
Attempts to treat human autoimmune disease with bromocrip-
tine have produced some positive results. Notably, in some SLE
patients bromocriptine treatment reduces disease flares (Alvarez-
Nemegyei et al., 1998; McMurray et al., 1995). More recently, it
358 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
was found that bromocriptine treatment in postpartum lupus
patients reduce disease flares (Yang et al., 2003), whereas this pilot
clinical data suggest that bromocriptine treatment may prevent
complications in pregnancy including preterm birth and active dis-
ease (Jara et al., 2007). Given the potential value of bromocriptine
and other prolactin antagonists in the treatment of autoimmunity,
further studies to delineate the mechanisms by which PRL affects
autoimmune disease activity are of critical importance.
3.5. The environment
Environmental exposure can interact with the genotype of
(Selmi et al., 2012), and can influence the prevalence and influence
the risk of developing an autoimmune disease or the severity of
disease. Environmental candidates that have been proposed to play
a role in autoimmune diseases include infectious agents and chem-
icals (Chandran and Raychaudhuri, 2010; Costenbader et al., 2012;
Hemminki et al., 2010). Infectious agents are important in the
mosaic of autoimmunity (Shoenfeld et al., 2008), and a number
of autoimmune diseases have been linked to infection; rheumatic
fever presents after Streptococcus pyogenes infection (Fae et al.,
2006), primary anti-phospholipid syndrome patients have high
levels of IgM antibodies to rubella and Toxoplasma (Zinger et al.,
2009), diabetes is associated with Enterovirus (Richardson et al.,
2009), and active infections with Helicobacter pylori have been
observed in autoimmune gastritis (Annibale et al., 2001). Chemi-
cal/drug exposure, and immunotoxicity of such compounds are
linked to autoimmune disease. Chemicals that are commonly
found in cosmetics are associated with PBC (Rieger et al., 2006),
and acetaminophen may underlie the development of PBC by pro-
moting antimitochondrial autoantibodies (Leung et al., 2013).
Exposure to pesticides has been suggested to underlie the develop-
ment of autoantibodies (McConnachie and Zahalsky, 1991, 1992;
Thrasher et al., 1993), and lifetime exposure to insecticides is asso-
ciated with the presence of anti-nuclear antibodies (Rosenberg
et al., 1999). More recently, it has been found that exposure to
organic solvents is associated with an increased risk of developing
an autoimmune trait (Barragan-Martinez et al., 2012). Since these
exposures underlie the development of autoimmunity, gender dif-
ferences could occur if males and females have different types of
exposure or different biological response to these agents (Fig. 5).
We now discuss several examples.
Fig. 5. The role of the environment in the sexual dimorphism in autoimmunity.
Men and women are exposed to environmental factors to varying degrees (e.g. men
tend to get more sunlight than women), and they have different physiological
responses to such factors. This differential exposure and response might influence
the prevalence and the risk of developing an autoimmune disease, or the severity of
disease between men and women.
Vitamin D is an environmental factor that may underlie the
development of autoimmunity. Vitamin D has immunomodulatory
effects on T lymphocytes, B lymphocytes, and dendritic cells
(Arnson et al., 2007; Deluca and Cantorna, 2001). By signaling
through the vitamin D receptor, vitamin D reduces the effector T
cell response (Adorini, 2005; Gascon-Barre et al., 2003; Godfrey
et al., 2000; Lemire, 1992). Vitamin D also interacts with human
leukocyte antigen molecules, which predispose to MS
(Ramagopalan et al., 2009a). Evidence to support the a role for
sun exposure in autoimmunity is seen in SS (Erten et al., 2014),
RA (Gatenby et al., 2013), SLE (Kamen et al., 2006), and anti-
phospholipid syndrome (Andreoli et al., 2012; Piantoni et al.,
2012) where vitamin D deficiency is associated with disease or
increased risk of developing disease. Indeed, greater vitamin D3
synthetic rate resulting from higher intensity ultraviolet light at
high altitudes, may account for lower MS rates at higher altitudes
(Hayes et al., 1997). It must be noted however, that within any geo-
graphical location, exposure to sunlight between men and women
could vary, and this may be dependent on lifestyle factors, or occu-
pational choices. Given that men tend to have more unprotected
sun exposure (Hall et al., 1997), gender-specific responses to sun-
light may play a role in autoimmune disease. Another example of
differences in exposure to environmental triggers is the role of cos-
metics in PBC, where the exposure to cosmetics is much greater in
women than men. Other environmental agents that are implicated
in autoimmunity and that may have differential exposures in
males and females are mercury, pesticides and solvents (Pollard,
2012).
4. Genetic aspects of the sexual dimorphism in autoimmunity
Genetic factors may contribute to the sexual dimorphism that is
seen in autoimmune disease. Such factors that might influence the
development of autoimmune disease may be related to susceptibil-
ity genes, chromosomal differences, or epigenetics. The presenta-
tion of multiple autoimmune diseases in a given individual or
family suggests that common genetic factors may prejudice an
individual to developing autoimmunity. The clustering of suscepti-
bility genes in conditions like MS and CD suggests that in some
cases, autoimmune diseases may be controlled by a set of suscep-
tibility genes (Becker et al., 1998).
4.1. Interaction of genes and gender
The HLA genes are located in a region that includes a large
number of genes that are involved in the immune response. Asso-
ciations exist between HLA genes and a number of autoimmune
diseases including GD (Li and Chen, 2013), MG (Avidan et al.,
2013), MS (Cree, 2014), RA (Jin et al., 2014), and SLE (Deng et al.,
2013) amongst many others (Horton et al., 2004). The majority of
these associations are with HLA-DR and HLA-DQ genes (Gough
and Simmonds, 2007), which encode for proteins that play a cen-
tral role in presenting antigens to CD4 + T cells (Schendel and
Johnson, 1985). The association between HLA genes and autoim-
mune disease generally shows a gender bias toward females. In
MG, single nucleotide polymorphisms in the HLA-locus support
the premise that there is a female gender bias for increased risk
for MG (Avidan et al., 2013). Similarly, being female may further
the risk associated with HLA DR4 alleles in type 1 autoimmune
hepatitis, since females have a higher frequency of HLA DR4 than
men (Czaja and Donaldson, 2002). In MS, there is a strong associa-
tion between HLA-DR2, DQ6 in females (Celius et al., 2000), and in
chronic inflammatory demyelinating polyneuropathy the associa-
tion with HLA-DR2 is greater for females (Czaja and Donaldson,
2002). In RA, there is an association between disease and females
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
with a HLA DRB1 *0401/*0401 genotype (Meyer et al., 1996). In SLE
however, there is a reversal in gender bias, with a higher HLA asso-
ciated genetic risk in men (Hughes et al., 2012).
Non-HLA genes are also associated with susceptibility to auto-
immune disease. Polymorphisms in cytotoxic T-lymphocyte anti-
gen-4 (CTLA-4), acid phosphatase locus 1 (ACP1), Discs large
homolog 5 (DLG5), interleukin-10 (IL-10), and apolipoprotein E
(APOE) are commonly observed. Genetic A/G polymorphisms in
CTLA-4 have been identified in AS (Huang et al., 2014), GD (Du
et al., 2013), and T/C polymorphisms may be associated with SLE
risk (Zhu et al., 2013). By contrast, there is no evidence to suggest
that CTLA-4 polymorphisms confer susceptibility to MS (Gyu Song
and Ho Lee, 2013). While the majority of studies that investigate
CTLA-4 polymorphisms in autoimmune disease do not necessarily
consider results relative to gender, CTLA-4 A/G polymorphisms
can modify maternal inheritance of the HLA-DR3 (Fajardy et al.,
2002).
Polymorphisms in ACP1 and DLG5 are associated with CD
(Browning et al., 2008; Stoll et al., 2004), and there is evidence of
a reduced susceptibility to CD in females who possess ACP1*A
alleles (Gloria-Bottini et al., 2007), and modest evidence of reduced
risk of CD in females with the DLG5 R30Q variant (Browning et al.,
2008). Polymorphisms in IL-10 are linked to severity of HT (Inoue
et al., 2013), RA (Hee et al., 2007), and primary SS (Qin et al.,
2013). While these studies do not stratify risk according to gender,
an AA -1087 IL-10 genotype appears to be more common in women
with RA (Padyukov et al., 2004). Polymorphisms in APOE are asso-
ciated with primary SS (Pertovaara et al., 2004) and MS (Cocco
et al., 2005; Rafiei et al., 2012). Again, while not considered relative
to gender, female carriers of the apolipoprotein E epsilon4 allele
had a tendency for earlier onset of primary SS when compared to
female non-carriers (Pertovaara et al., 2004). In the case of MS
however, presence of the APOE alleles seems to favor females;
women carriers of the epsilon2 allele had reduced severity of dis-
ease (Kantarci et al., 2004), and cognitive decline is more promi-
nent in males who carry the epsilon4 allele (Savettieri et al., 2004).
The observations from these studies provide strong evidence to
support the notion that genetic risks underlie susceptibility to
some autoimmune diseases. While a large number of studies focus
on the involvement of HLA genes, it is becoming strikingly clear
that polymorphisms in non-HLA genes should also be taken into
account when considering the relationship between genetic factors
that predispose to autoimmune disease. Given the strong associa-
tions between HLA genes and non-HLA genes and autoimmune dis-
ease, future studies that investigate the genetic underpinning of
such diseases should be considered relative to gender.
4.2. The X chromosome in autoimmune disease
The X chromosome contains a large number of genes that are
involved in immunity (reviewed in (Fish, 2008; Libert et al.,
2010)). While females carry two X chromosomes, one X chromo-
some is inactivated early in embryogenesis. This allows for equal
gene expression dosage between males and females, but also
results in cellular mosaicism (Migeon, 2006). Consequently,
females may avoid any effects that arise from harmful gene-muta-
tions, and cellular mosaicism (arising from natural variations in
one gene that might result in two different alleles) may result in
added advantages in response to immune challenges (Migeon,
2006; Spolarics, 2007).
Autoimmune phenomena are observed in X-linked primary
immunodeficiencies. Thus it is likely that genes on the X chromo-
some may also play a role in autoimmunity (Bussone and
Mouthon, 2009; Carneiro-Sampaio and Coutinho, 2007; Mackay
and Rose, 2001). It has been suggested that X chromosome inacti-
vation, loss of X chromosomes or X monosomy may underlie the
359
development of autoimmune disease. Skewed X chromosome inac-
tivation is observed in HT, GD (Brix et al., 2005; Chabchoub et al.,
2009; Ozcelik et al., 2006), sclerodoma (Ozbalkan et al., 2005; Uz
et al., 2008), RA (Chabchoub et al., 2009), and SS (Ozcelik, 2008),
but not in SLE (Huang et al., 1997) and MS (Knudsen, 2009;
Knudsen et al., 2007). Data from a number of studies suggest that
X chromosome monosomy rates may also underlie the female pre-
dominance in autoimmune diseases. In disease such as PBC, HT,
and GD, enhanced X monosomy rates have been observed in
peripheral blood cells (Invernizzi et al., 2004, 2005), but this is
not the case for SLE (Invernizzi et al., 2007). Skewed X chromosome
inactivation and monosomy appear to be more common in autoim-
mune thyroid diseases (Brix et al., 2005; Chabchoub et al., 2009;
Invernizzi et al., 2005; Ozcelik et al., 2006).
Males with two X chromosomes (Chagnon et al., 2006), or males
with two X chromosomes and a Y chromosome have also been
known to present with SLE (Lahita, 1999). Interestingly, SLE males
that are XXY, are similar to female SLE patients in that they have
increased oxidation of testosterone (Lahita, 1999). These observa-
tions support a role for the X chromosome in SLE.
4.3. The Y chromosome in autoimmune disease
Compared to the X chromosome, the Y chromosome has
received little attention in human autoimmunity. The Y chromo-
some accounts for a small portion of the human genome, and is
associated with male fertility and testis formation (Quintana-
Murci et al., 2001). While the Y chromosome is linked to the inher-
itance of human coronary heart disease (Charchar et al., 2012), the
majority of studies that have assessed the contribution of the Y
chromosome to autoimmunity has been conducted in mouse mod-
els of SLE (Lin et al., 2010; Murphy and Roths, 1979; Santiago-
Raber et al., 2008; Subramanian et al., 2006) and MS (Palaszynski
et al., 2005; Spach et al., 2009; Teuscher et al., 2006) (reviewed
in (McCombe et al., 2009)). Recent studies have found an age-
dependent loss of the Y chromosome in PBC (Lleo et al., 2013),
and in HT and GD (Persani et al., 2012). These observations further
support the role of the X chromosome in autoimmune disease.
5. Parental inheritance/transmission in autoimmunity
Maternal and paternal inheritance occurs in autoimmune dis-
ease. While one study in Canada has found that there is equal
inheritance of MS from affected fathers and mothers (Herrera
et al., 2007), and paternal inheritance in MS has been reported
(Marrosu et al., 2004), the majority of studies assessing parent-
of-origin effects in MS are more indicative of a strong maternal
effect for risk of inheritance (Ebers et al., 2004), and predominant
maternal inheritance (Chao et al., 2010; Ebers et al., 2004;
Herrera et al., 2008; Hoppenbrouwers et al., 2008). Inheritance of
autoimmune disease in T1D however, takes on a paternal domi-
nance (MacDonald et al., 1986). Islet autoimmune antibodies are
more frequently transmitted via diabetic fathers (Yu et al., 1995),
paternal inheritance of the insulin gene B allele confers protection
from T1D (Pugliese et al., 1994), while paternal inheritance of the
11p15.5 region of the insulin gene (IDDM2) confers susceptibility
to T1D (Bui et al., 1996).
5.1. Causative factors for parental inheritance of autoimmunity
The interaction of genetic and environmental factors may
underlie parental inheritance of autoimmunity. In the case of
maternal inheritance, mitochondrial DNA could play a role. While
studies addressing mitochondrial DNA variants with autoimmune
disease are limited, MS has been associated with the mitochondrial
360 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
haplotype K (Vyshkina et al., 2008) and haplotype U (Ban et al.,
2008). Interestingly, variants in mitochondrial ND2 and ATP6
genes have also been found to be associated with MS and SLE, sug-
gesting that these two diseases may share a common mitochon-
drial genetic background.
In addition to genetic factors, environmental factors may also
contribute to parental inheritance of autoimmunity
(Hoppenbrouwers et al., 2008). Some of the best examples of envi-
ronmental influence in parental transmission in autoimmunity
have come from studies in MS cohorts. The development of MS
in affected offspring may arise from in utero exposure to epigenetic
changes that might result from environmental influences on the
mother (e.g. timing of birth is associated with risk of MS) (Willer
et al., 2005). This is discussed further below.
6. Epigenetics in autoimmunity
Epigenetics relates to the stable and heritable patterns of gene
expression that are not due to changes in the original DNA
sequence. Altered gene expression may be persistent, but not
permanent, and the epigenome of the cell can be defined by meth-
ylation, histone modification and micro RNA (miRNA) profile
(Goldberg et al., 2007; Jiang et al., 2004; Lu, 2013). Epigenetic
changes that arise in autoimmune disease can be related to the
sex of the parent, or can result from external factors. With respect
to parental gender, epigenetic changes occur via genetic imprinting,
whereby genes inherited either from the father or mother are
imprinted and inactivated, or when transcripts from either the
maternal or paternal chromosome are expressed in a monoallelic
fashion (Camprubi and Monk, 2011). Extrinsic influences in autoim-
mune disease include tobacco smoke, exposure to sunlight, and diet
(Ellis et al., 2014). Below, we discuss evidence that indicates a role
for genomic imprinting and epigenetics in driving sexual dimor-
phism in autoimmune disease.
6.1. Genomic imprinting as a cause for autoimmunity
Genomic imprinting is the allele-specific expression of genes in
a parent-of-origin fashion. It has been suggested that the genetics
underlying HLA susceptibility in T1D may exhibit parental inheri-
tance; Pani and colleagues suggest that the maternal HLA-DQ2 or
DQ8 alleles are risk factors for T1D (Pani et al., 2002). For psoriatic
arthritis, genetic linkage analysis suggests that there is imprinted
transmission at chromosome 16q that is of paternal origin
(Karason et al., 2003).
Imprinting of miRNAs may also underlie autoimmunity. Micro
RNAs play important roles in the post-transcriptional regulation
of gene expression. In this regard, a loss of miRNAs or the deregu-
lation of miRNAs could contribute to altered autoimmune gene
expression that would result in the development of autoimmune
disease. Indeed, imprinted miRNAs that may regulate autoimmune
disease associated genes have been identified for MS, RA, SLE, and
T1D (Camprubi and Monk, 2011). Given that there is differential
hormonal and chromosomal regulation of miRNAs between males
and females (Sharma and Eghbali, 2014), it is highly likely that
miRNA imprinting could contribute to the sexual dimorphism seen
in autoimmune disease.
6.2. Extrinsically driven epigenetic gene modifications in
autoimmunity
External stimuli including tobacco smoke, sunlight, and diet
that lead to DNA modification could explain gender differences in
autoimmune disease. Smoking is associated with an increased risk
for RA in both men and women when compared to non-smokers
(Sugiyama et al., 2010), and increased risk of MS (in women stud-
ied) (Hernan et al., 2001). Moreover, smoking has been found to be
a risk factor for relapsing–remitting MS (Hernan et al., 2005). Expo-
sure to lower levels of sunlight (Hammond et al., 1988; Kurtzke
et al., 1979; Taylor et al., 2010; van der Mei et al., 2003; Vukusic
et al., 2007), season of birth (Dobson et al., 2013; Willer et al.,
2005), low maternal exposure to sunlight (Staples et al., 2010),
and low levels of vitamin D (van der Mei et al., 2007) have been
well established to be associated with increased risk for MS. Recent
studies assessing dietary intake of vitamin D in women with MS
report that higher levels of vitamin D are associated with reduced
risk (Munger et al., 2004), and assessment of micronutrient intake
has provided insight into the geographical blueprint of autoim-
mune disease in China (Qin et al., 2009). While it is easy to specu-
late that varying exposure to extrinsic triggers would occur
between males and females, earlier adoption of smoking in men
(Zang and Wynder, 1996), increased unprotected exposure to sun-
light in men (Hall et al., 1997), and different dietary habits
between men and women (Dynesen et al., 2003; Ferraro and
Vieira, 2010; Friel et al., 2005) would support the notion that dif-
ferential exposure to extrinsic factors may play a role in gender
bias in autoimmune disease.
7. Conclusion
The gender differences that exist in autoimmunity tend to fol-
low a female bias. A number of factors may underlie this striking
gender difference. The clear differences between the female and
male immune systems would suggest that the increased immune
reactivity in females might predispose them to developing autoim-
mune disease. This may be explained in part by the effects of sex
hormones since estrogen suppresses Th1-dependent disease, but
potentiates Th2-dependent diseases. Accordingly, differences in
reproductive function, and pregnancy in women, may also explain
gender differences in autoimmunity. While the impact of micro-
chimerism during pregnancy in autoimmune disease remains to
be understood, parental inheritance, mitochondrial inheritance,
genomic imprinting and chromosomal inactivation could also play
a role. Finally, extrinsic epigenetic influences and more specifically,
the level of exposure to external factors and the subsequent
response to such factors might influence susceptibility to autoim-
mune disease. In conclusion, the striking evidence of gender differ-
ences in autoimmune disease should dictate that future studies
considering incidence, prevalence, severity, mortality, disease
mechanisms and potential therapies in autoimmunity be stratified
according to gender.
Acknowledgment
Dr. S. Ngo acknowledges the support of the Motor Neurone
Disease Research Institute of Australia.
References
Abdou, N.I., Rider, V., Greenwell, C., Li, X., Kimler, B.F., 2008. Fulvestrant (Faslodex),
an estrogen selective receptor downregulator, in therapy of women with
systemic lupus erythematosus. clinical, serologic, bone density, and T cell
activation marker studies: a double-blind placebo-controlled trial. J. Rheumatol.
35, 797.
Adams Waldorf, K.M., Nelson, J.L., 2008. Autoimmune disease during pregnancy and
the microchimerism legacy of pregnancy. Immunol. Invest. 37, 631–644.
Adorini, L., 2005. Intervention in autoimmunity: the potential of vitamin D receptor
agonists. Cell. Immunol. 233, 115–124.
Aggarwal, R., Malaviya, A.N., 2009. Clinical characteristics of patients with
ankylosing spondylitis in India. Clin. Rheumatol. 28, 1199–1205.
Agret, F., Cosnes, J., Hassani, Z., Gornet, J.M., Gendre, J.P., Lemann, M., Beaugerie, L.,
2005. Impact of pregnancy on the clinical activity of Crohn’s disease. Aliment.
Pharmacol. Ther. 21, 509–513.
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
Al-Chalabi, T., Underhill, J.A., Portmann, B.C., McFarlane, I.G., Heneghan, M.A., 2008.
Impact of gender on the long-term outcome and survival of patients with
autoimmune hepatitis. J. Hepatol. 48, 140–147.
Alshekhlee, A., Hussain, Z., Sultan, B., Katirji, B., 2008. Guillain–Barre syndrome:
incidence and mortality rates in US hospitals. Neurology 70, 1608–1613.
Aluvihare, V.R., Kallikourdis, M., Betz, A.G., 2004. Regulatory T cells mediate
maternal tolerance to the fetus. Nat. Immunol. 5, 266–271.
Alvarez-Nemegyei, J., Cobarrubias-Cobos, A., Escalante-Triay, F., Sosa-Munoz, J.,
Miranda, J.M., Jara, L.J., 1998. Bromocriptine in systemic lupus erythematosus: a
double-blind, randomized, placebo-controlled study. Lupus 7, 414–419.
Amarapurkar, D.N., Patel, N.D., 2007. Spectrum of autoimmune liver diseases in
western India. J. Gastroenterol. Hepatol. 22, 2112–2117.
Anderson, S.G., Narayanan, R.P., Amlesh, J., Qureshi, M.Z., Heald, A.H., 2012. Type 1
diabetes in Cheshire: cardiometabolic risk factor trends (2004–2009). Primary
Diabet. 6, 123–126.
Andreoli, L., Piantoni, S., Dall’Ara, F., Allegri, F., Meroni, P.L., Tincani, A., 2012.
Vitamin D and antiphospholipid syndrome. Lupus 21, 736–740.
Annibale, B., Negrini, R., Caruana, P., Lahner, E., Grossi, C., Bordi, C., Delle Fave, G.,
2001. Two-thirds of atrophic body gastritis patients have evidence of
Helicobacter pylori infection. Helicobacter 6, 225–233.
Ansar Ahmed, S., Penhale, W.J., Talal, N., 1985. Sex hormones, immune responses,
and autoimmune diseases. Mechanisms of sex hormone action. Am. J. Pathol.
121, 531–551.
Arnson, Y., Amital, H., Shoenfeld, Y., 2007. Vitamin D and autoimmunity: new
aetiological and therapeutic considerations. Ann. Rheum. Dis. 66, 1137–1142.
Arruvito, L., Giulianelli, S., Flores, A.C., Paladino, N., Barboza, M., Lanari, C., Fainboim,
L., 2008. NK cells expressing a progesterone receptor are susceptible to
progesterone-induced apoptosis. J. Immunol. 180, 5746–5753.
Artlett, C.M., Smith, J.B., Jimenez, S.A., 1998. Identification of fetal DNA and cells in
skin lesions from women with systemic sclerosis. New Engl. J. Med. 338, 1186–
1191.
Asakura, K., Nishiwaki, Y., Inoue, N., Hibi, T., Watanabe, M., Takebayashi, T., 2009.
Prevalence of ulcerative colitis and Crohn’s disease in Japan. J. Gastroenterol. 44,
659–665.
Asao, K., Sarti, C., Forsen, T., Hyttinen, V., Nishimura, R., Matsushima, M., Reunanen,
A., Tuomilehto, J., Tajima, N.Diabetes Epidemiology Research International
Mortality Study, G., 2003. Long-term mortality in nationwide cohorts of
childhood-onset type 1 diabetes in Japan and Finland. Diabetes Care 26,
2037–2042.
Athreya, B.H., Pletcher, J., Zulian, F., Weiner, D.B., Williams, W.V., 1993. Subset-
specific effects of sex hormones and pituitary gonadotropins on human
lymphocyte proliferation in vitro. Clin. Immunol. Immunopathol. 66, 201–211.
Australia and New Zealand Multiple Sclerosis Genetics, C., 2009. Genome-wide
association study identifies new multiple sclerosis susceptibility loci on
chromosomes 12 and 20. Nat. Genet. 41, 824–828.
Avidan, N., Le Panse, R., Berrih-Aknin, S., Miller, A., 2013. Genetic basis of
myasthenia gravis – a comprehensive review. J. Autoimmun., 11.
Bamigboye, A.A., Morris, J., 2003. Oestrogen Supplementation, Mainly
Diethylstilbestrol, for Preventing Miscarriages and Other Adverse Pregnancy
Outcomes. The Cochrane Database of Systematic Reviews. CD004353.
Ban, M., Elson, J., Walton, A., Turnbull, D., Compston, A., Chinnery, P., Sawcer, S.,
2008. Investigation of the role of mitochondrial DNA in multiple sclerosis
susceptibility. PLoS One 3, e2891.
Banchereau, J., Steinman, R.M., 1998. Dendritic cells and the control of immunity.
Nature 392, 245–252.
Barragan-Martinez, C., Speck-Hernandez, C.A., Montoya-Ortiz, G., Mantilla, R.D.,
Anaya, J.M., Rojas-Villarraga, A., 2012. Organic solvents as risk factor for
autoimmune diseases: a systematic review and meta-analysis. PLoS One 7,
e51506.
Barrett, J.C., Clayton, D.G., Concannon, P., Akolkar, B., Cooper, J.D., Erlich, H.A., Julier,
C., Morahan, G., Nerup, J., Nierras, C., Plagnol, V., Pociot, F., Schuilenburg, H.,
Smyth, D.J., Stevens, H., Todd, J.A., Walker, N.M., Rich, S.S.Type 1 Diabetes
Genetics, C., 2009. Genome-wide association study and meta-analysis find that
over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703–707.
Basso, O., Campi, R., Frydenberg, M., Koch-Henriksen, N., Bronnum-Hansen,
H., Olsen, J., 2004. Multiple sclerosis in women having children by
multiple partners. A population-based study in Denmark. Multip. Scl. 10,
621–625.
Batocchi, A.P., Majolini, L., Evoli, A., Lino, M.M., Minisci, C., Tonali, P., 1999. Course
and treatment of myasthenia gravis during pregnancy. Neurology 52, 447–452.
Batra, C.M., 2013. Fetal and neonatal thyrotoxicosis. Ind. J. Endocrinol. Metabol. 17,
S50–S54.
Bayir, H., Marion, D.W., Puccio, A.M., Wisniewski, S.R., Janesko, K.L., Clark, R.S.,
Kochanek, P.M., 2004. Marked gender effect on lipid peroxidation after severe
traumatic brain injury in adult patients. J. Neurotrauma 21, 1–8.
Bebo Jr., B.F., Fyfe-Johnson, A., Adlard, K., Beam, A.G., Vandenbark, A.A., Offner, H.,
2001. Low-dose estrogen therapy ameliorates experimental autoimmune
encephalomyelitis in two different inbred mouse strains. J. Immunol. 166,
2080–2089.
Becker, K.G., Simon, R.M., Bailey-Wilson, J.E., Freidlin, B., Biddison, W.E., McFarland,
H.F., Trent, J.M., 1998. Clustering of non-major histocompatibility complex
susceptibility candidate loci in human autoimmune diseases. Proc. Nat. Acad.
Sci. U.S.A. 95, 9979–9984.
Ben-Chetrit, A., Ben-Chetrit, E., 1994. Systemic lupus erythematosus induced by
ovulation induction treatment. Arthritis Rheum. 37, 1614–1617.
361
Bentzen, J., Flachs, E.M., Stenager, E., Bronnum-Hansen, H., Koch-Henriksen, N.,
2010. Prevalence of multiple sclerosis in Denmark 1950–2005. Multip. Scl. 16,
520–525.
Beretta, L., Caronni, M., Origgi, L., Ponti, A., Santaniello, A., Scorza, R., 2006. Hormone
replacement therapy may prevent the development of isolated pulmonary
hypertension in patients with systemic sclerosis and limited cutaneous
involvement. Scand. J. Rheumatol. 35, 468–471.
Bernatsky, S., Boivin, J.F., Joseph, L., Manzi, S., Ginzler, E., Gladman, D.D., Urowitz, M.,
Fortin, P.R., Petri, M., Barr, S., Gordon, C., Bae, S.C., Isenberg, D., Zoma, A.,
Aranow, C., Dooley, M.A., Nived, O., Sturfelt, G., Steinsson, K., Alarcon, G.,
Senecal, J.L., Zummer, M., Hanly, J., Ensworth, S., Pope, J., Edworthy, S., Rahman,
A., Sibley, J., El-Gabalawy, H., McCarthy, T., St Pierre, Y., Clarke, A., Ramsey-
Goldman, R., 2006. Mortality in systemic lupus erythematosus. Arthritis Rheum.
54, 2550–2557.
Bhadada, S.K., Kochhar, R., Bhansali, A., Dutta, U., Kumar, P.R., Poornachandra, K.S.,
Vaiphei, K., Nain, C.K., Singh, K., 2011. Prevalence and clinical profile of celiac
disease in type 1 diabetes mellitus in north India. J. Gastroenterol. Hepatol. 26,
378–381.
Bhattacharya, M., Kapoor, S., Dubey, A.P., 2013. Celiac disease presentation in a
tertiary referral centre in India: current scenario. Ind. J. Gastroenterol.: Off. J.
Ind. Soc. Gastroenterol. 32, 98–102.
Bianchi, D.W., Zickwolf, G.K., Weil, G.J., Sylvester, S., DeMaria, M.A., 1996. Male fetal
progenitor cells persist in maternal blood for as long as 27 years postpartum.
Proc. Nat. Acad. Sci. U.S.A. 93, 705–708.
Bias, W.B., Reveille, J.D., Beaty, T.H., Meyers, D.A., Arnett, F.C., 1986. Evidence that
autoimmunity in man is a Mendelian dominant trait. Am. J. Hum. Genet. 39,
584–602.
Bijlsma, J.W., Huber-Bruning, O., Thijssen, J.H., 1987. Effect of oestrogen treatment
on clinical and laboratory manifestations of rheumatoid arthritis. Ann. Rheum.
Dis. 46, 777–779.
Biver, E., Beague, V., Verloop, D., Mollet, D., Lajugie, D., Baudens, G., Neirinck, P.,
Flipo, R.M., 2009. Low and stable prevalence of rheumatoid arthritis in northern
France. Joint, Bone, Spine : Revue du Rhumatisme 76, 497–500.
Blum, S., Reddel, S., Spies, J., McCombe, P., 2013. Clinical features of patients with
Guillain–Barre syndrome at seven hospitals on the East Coast of Australia. J.
Peripher. Nerv. Syst.: JPNS 18, 316–320.
Boddaert, J., Huong, D.L., Amoura, Z., Wechsler, B., Godeau, P., Piette, J.C., 2004. Late-
onset systemic lupus erythematosus: a personal series of 47 patients and
pooled analysis of 714 cases in the literature. Medicine 83, 348–359.
Boes, T., Levy, D., 2012. Influence of sex, estrous cycle, and estrogen on intracranial
dural mast cells. Cephalalgia: Int. J. Headache 32, 924–931.
Borchers, A.T., Naguwa, S.M., Keen, C.L., Gershwin, M.E., 2010. The implications of
autoimmunity and pregnancy. J. Autoimmun. 34, J287-99.
Bouman, A., Schipper, M., Heineman, M.J., Faas, M.M., 2004. Gender difference in the
non-specific and specific immune response in humans. Am. J. Reprod. Immunol.
52, 19–26.
Bouman, A., Heineman, M.J., Faas, M.M., 2005. Sex hormones and the immune
response in humans. Hum. Reprod. Update 11, 411–423.
Bove, R., 2013. Autoimmune diseases and reproductive aging. Clin. Immunol. 149,
251–264.
Brix, T.H., Knudsen, G.P., Kristiansen, M., Kyvik, K.O., Orstavik, K.H., Hegedus, L.,
2005. High frequency of skewed X-chromosome inactivation in females with
autoimmune thyroid disease: a possible explanation for the female
predisposition to thyroid autoimmunity. J. Clin. Endocrinol. Metab. 90, 5949–
5953.
Browning, B.L., Annese, V., Barclay, M.L., Bingham, S.A., Brand, S., Buning, C., Castro,
M., Cucchiara, S., Dallapiccola, B., Drummond, H., Ferguson, L.R., Ferraris, A.,
Fisher, S.A., Gearry, R.B., Glas, J., Henckaerts, L., Huebner, C., Knafelz, D., Lakatos,
L., Lakatos, P.L., Latiano, A., Liu, X., Mathew, C., Muller-Myhsok, B., Newman,
W.G., Nimmo, E.R., Noble, C.L., Palmieri, O., Parkes, M., Petermann, I., Rutgeerts,
P., Satsangi, J., Shelling, A.N., Siminovitch, K.A., Torok, H.P., Tremelling, M.,
Vermeire, S., Valvano, M.R., Witt, H., 2008. Gender-stratified analysis of DLG5
R30Q in 4707 patients with Crohn disease and 4973 controls from 12 Caucasian
cohorts. J. Med. Genet. 45, 36–42.
Brucato, A., Frassi, M., Franceschini, F., Cimaz, R., Faden, D., Pisoni, M.P., Muscara, M.,
Vignati, G., Stramba-Badiale, M., Catelli, L., Lojacono, A., Cavazzana, I.,
Ghirardello, A., Vescovi, F., Gambari, P.F., Doria, A., Meroni, P.L., Tincani, A.,
2001. Risk of congenital complete heart block in newborns of mothers with
anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a
prospective study of 100 women. Arthritis Rheum. 44, 1832–1835.
Brunton, P.J., Russell, J.A., 2010. Endocrine induced changes in brain function during
pregnancy. Brain Res. 1364, 198–215.
Buckley, O.E., 1954. Introduction. In: Miner, R.W. (Ed.), The Status of Multiple
Sclerosis. Ann NY Acad Sci, pp. 541–720.
Bui, M.M., Luo, D.F., She, J.Y., Maclaren, N.K., Muir, A., Thomson, G., She, J.X., 1996.
Paternally transmitted IDDM2 influences diabetes susceptibility despite
biallelic expression of the insulin gene in human pancreas. J. Autoimmun. 9,
97–103.
Bulloch, K., Miller, M.M., Gal-Toth, J., Milner, T.A., Gottfried-Blackmore, A., Waters,
E.M., Kaunzner, U.W., Liu, K., Lindquist, R., Nussenzweig, M.C., Steinman, R.M.,
McEwen, B.S., 2008. CD11c/EYFP transgene illuminates a discrete network of
dendritic cells within the embryonic, neonatal, adult, and injured mouse brain.
J. Comp. Neurol. 508, 687–710.
Bulow Pedersen, I., Laurberg, P., Knudsen, N., Jorgensen, T., Perrild, H., Ovesen, L.,
Rasmussen, L.B., 2006. Lack of association between thyroid autoantibodies and
362 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
parity in a population study argues against microchimerism as a trigger of
thyroid autoimmunity. Eur. J. Endocrinol./Eur. Fed. Endocr. Soc. 154, 39–45.
Bussone, G., Mouthon, L., 2009. Autoimmune manifestations in primary immune
deficiencies. Autoimmun. Rev. 8, 332–336.
Butterworth, M., McClellan, B., Allansmith, M., 1967. Influence of sex in
immunoglobulin levels. Nature 214, 1224–1225.
Buyon, J.P., Petri, M.A., Kim, M.Y., Kalunian, K.C., Grossman, J., Hahn, B.H., Merrill,
J.T., Sammaritano, L., Lockshin, M., Alarcon, G.S., Manzi, S., Belmont, H.M.,
Askanase, A.D., Sigler, L., Dooley, M.A., Von Feldt, J., McCune, W.J., Friedman, A.,
Wachs, J., Cronin, M., Hearth-Holmes, M., Tan, M., Licciardi, F., 2005. The effect
of combined estrogen and progesterone hormone replacement therapy on
disease activity in systemic lupus erythematosus: a randomized trial. Ann.
Intern. Med. 142, 953–962.
Calabrese, L.H., Kleiner, S.M., Barna, B.P., Skibinski, C.I., Kirkendall, D.T., Lahita, R.G.,
Lombardo, J.A., 1989. The effects of anabolic steroids and strength training on
the human immune response. Med. Sci. Sports Exerc. 21, 386–392.
Callewaert, D.M., Moudgil, V.K., Radcliff, G., Waite, R., 1991. Hormone specific
regulation of natural killer cells by cortisol. Direct inactivation of the cytotoxic
function of cloned human NK cells without an effect on cellular proliferation.
FEBS Lett. 285, 108–110.
Camprubi, C., Monk, D., 2011. Does genomic imprinting play a role in
autoimmunity? In: Ballestar, E. (Ed.), Epigenetic Contributions in
Autoimmune Disease. Springer, New York, USA.
Cao, W., Xu, W., Chen, T., Wang, X., Wang, X., Qiu, J., Chen, N., Mao, Y., 2014.
CD4CD25FoxP3 regulatory T cells and cytokines interact with estradiol in cases
of missed abortion. Exp. Therap. Med. 7, 417–422.
Carle, A., Pedersen, I.B., Knudsen, N., Perrild, H., Ovesen, L., Rasmussen, L.B.,
Laurberg, P., 2011. Epidemiology of subtypes of hyperthyroidism in
Denmark: a population-based study. Eur. J. Endocrinol./Eur. Fed. Endocr.
Soc. 164, 801–809.
Carneiro-Sampaio, M., Coutinho, A., 2007. Tolerance and autoimmunity: lessons at
the bedside of primary immunodeficiencies. Adv. Immunol. 95, 51–82.
Casoli, P., Tumiati, B., La Sala, G., 1997. Fatal exacerbation of systemic lupus
erythematosus after induction of ovulation. J. Rheumatol. 24, 1639–1640.
Casson, P.R., Santoro, N., Elkind-Hirsch, K., Carson, S.A., Hornsby, P.J., Abraham, G.,
Buster, J.E., 1998. Postmenopausal dehydroepiandrosterone administration
increases free insulin-like growth factor-I and decreases high-density
lipoprotein: a six-month trial. Fertil. Steril. 70, 107–110.
Celius, E.G., Harbo, H.F., Egeland, T., Vartdal, F., Vandvik, B., Spurkiand, A., 2000. Sex
and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in
multiple sclerosis. J. Neurol. Sci. 178, 132–135.
Chabchoub, G., Uz, E., Maalej, A., Mustafa, C.A., Rebai, A., Mnif, M., Bahloul, Z., Farid,
N.R., Ozcelik, T., Ayadi, H., 2009. Analysis of skewed X-chromosome inactivation
in females with rheumatoid arthritis and autoimmune thyroid diseases. Arth.
Res. Ther. 11, R106.
Chagnon, P., Schneider, R., Hebert, J., Fortin, P.R., Provost, S., Belisle, C., Gingras, M.,
Bolduc, V., Perreault, C., Silverman, E., Busque, L., 2006. Identification and
characterization of an Xp22.33;Yp11.2 translocation causing a triplication of
several genes of the pseudoautosomal region 1 in an XX male patient with
severe systemic lupus erythematosus. Arth. Rheum. 54, 1270–1278.
Chandran, V., Raychaudhuri, S.P., 2010. Geoepidemiology and environmental factors
of psoriasis and psoriatic arthritis. J. Autoimmun. 34, J314-21.
Chang, D.M., Lan, J.L., Lin, H.Y., Luo, S.F., 2002. Dehydroepiandrosterone treatment of
women with mild-to-moderate systemic lupus erythematosus: a multicenter
randomized, double-blind, placebo-controlled trial. Arth. Rheum. 46, 2924–
2927.
Chao, M.J., Herrera, B.M., Ramagopalan, S.V., Deluca, G., Handunetthi, L., Orton, S.M.,
Lincoln, M.R., Sadovnick, A.D., Ebers, G.C., 2010. Parent-of-origin effects at the
major histocompatibility complex in multiple sclerosis. Hum. Mol. Genet. 19,
3679–3689.
Charchar, F.J., Bloomer, L.D., Barnes, T.A., Cowley, M.J., Nelson, C.P., Wang, Y.,
Denniff, M., Debiec, R., Christofidou, P., Nankervis, S., Dominiczak, A.F., Bani-
Mustafa, A., Balmforth, A.J., Hall, A.S., Erdmann, J., Cambien, F., Deloukas, P.,
Hengstenberg, C., Packard, C., Schunkert, H., Ouwehand, W.H., Ford, I., Goodall,
A.H., Jobling, M.A., Samani, N.J., Tomaszewski, M., 2012. Inheritance of coronary
artery disease in men: an analysis of the role of the Y chromosome. Lancet 379,
915–922.
Chavez-Rueda, K., Hernandez, J., Zenteno, E., Leanos-Miranda, A., Legorreta-Haquet,
M.V., Blanco-Favela, F., 2005. Identification of prolactin as a novel
immunomodulator on the expression of co-stimulatory molecules and
cytokine secretions on T and B human lymphocytes. Clin. Immunol. 116, 182–
191.
Chen, X.L., Kunsch, C., 2004. Induction of cytoprotective genes through Nrf2/
antioxidant response element pathway: a new therapeutic approach for the
treatment of inflammatory diseases. Curr. Pharm. Des. 10, 879–891.
Chen, Y., Ma, F., Zhang, J., Chu, X., Xu, Y., 2014. Population incidence of Guillain–
Barre syndrome in parts of China: three large populations in Jiangsu province,
2008–2010. Eur. J. Neurol.: Off. J. Eur. Fed. Neurol. Soc. 21, 124–129.
Cheng, Q., Cheng, X.J., Jiang, G.X., 2009. Multiple sclerosis in China–history and
future. Multip. Scl. 15, 655–660.
Chiche, L., Jourde, N., Ulmann, C., Mancini, J., Darque, A., Bardin, N., Dicostanzo, M.P.,
Thomas, G., Harle, J.R., Vienne, J., Loukos, H., Bornet, C., 2012. Seasonal
variations of systemic lupus erythematosus flares in southern France. Eur. J.
Internal Med. 23, 250–254.
Chighizola, C., Meroni, P.L., 2012. The role of environmental estrogens and
autoimmunity. Autoimmun. Rev. 11. A493-501.
Chitnis, T., 2013. Role of puberty in multiple sclerosis risk and course. Clin.
Immunol. 149, 192–200.
Chitnis, T., Glanz, B., Jaffin, S., Healy, B., 2009. Demographics of pediatric-onset
multiple sclerosis in an MS center population from the Northeastern United
States. Multip. Scl. 15, 627–631.
Clayton, D.G., 2009. Prediction and interaction in complex disease genetics:
experience in type 1 diabetes. PLoS Genet. 5, e1000540.
Cocco, E., Sotgiu, A., Costa, G., Murru, M.R., Mancosu, C., Murru, R., Lai, M., Contu, P.,
Marrosu, M.G., 2005. HLA-DR, DQ and APOE genotypes and gender influence in
Sardinian primary progressive MS. Neurology 64, 564–566.
Confavreux, C., Aimard, G., Devic, M., 1980. Course and prognosis of multiple
sclerosis assessed by the computerized data processing of 349 patients. Brain: J.
Neurol. 103, 281–300.
Confavreux, C., Hutchinson, M., Hours, M.M., Cortinovis-Tourniaire, P., Moreau, T.,
1998. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in
Multiple Sclerosis Group. New Engl. J. Med. 339, 285–291.
Cook, I.F., 2008. Sexual dimorphism of humoral immunity with human vaccines.
Vaccine 26, 3551–3555.
Cooper, G.S., Dooley, M.A., Treadwell, E.L., St Clair, E.W., Gilkeson, G.S., 2002.
Hormonal and reproductive risk factors for development of systemic lupus
erythematosus: results of a population-based, case-control study. Arth. Rheum.
46, 1830–1839.
Correale, J., Farez, M.F., Ysrraelit, M.C., 2012. Increase in multiple sclerosis activity
after assisted reproduction technology. Ann. Neurol. 72, 682–694.
Costa, M., Colia, D., 2008. Treating infertility in autoimmune patients.
Rheumatology 47 (Suppl. 3), iii38-41.
Costenbader, K.H., Feskanich, D., Stampfer, M.J., Karlson, E.W., 2007. Reproductive
and menopausal factors and risk of systemic lupus erythematosus in women.
Arth. Rheum. 56, 1251–1262.
Costenbader, K.H., Gay, S., Alarcon-Riquelme, M.E., Iaccarino, L., Doria, A., 2012.
Genes, epigenetic regulation and environmental factors: which is the most
relevant in developing autoimmune diseases? Autoimmun. Rev. 11, 604–609.
Courvoisier, N., Dougados, M., Cantagrel, A., Goupille, P., Meyer, O., Sibilia, J., Daures,
J.P., Combe, B., 2008. Prognostic factors of 10-year radiographic outcome in
early rheumatoid arthritis: a prospective study. Arth. Res. Ther. 10, R106.
Cree, B.A., 2014. Multiple sclerosis genetics. Handbook Clin. Neurol. 122, 193–209.
Crosslin, K.L., Wiginton, K.L., 2011. Sex differences in disease severity among
patients with systemic lupus erythematosus. Gend. Med. 8, 365–371.
Cutolo, M., Villaggio, B., Seriolo, B., Montagna, P., Capellino, S., Straub, R.H., Sulli, A.,
2004. Synovial fluid estrogens in rheumatoid arthritis. Autoimmun. Rev. 3, 193–
198.
Czaja, A.J., Donaldson, P.T., 2002. Gender effects and synergisms with
histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am. J.
Gastroenterol. 97, 2051–2057.
Darmochwal-Kolarz, D., Kludka-Sternik, M., Tabarkiewicz, J., Kolarz, B., Rolinski, J.,
Leszczynska-Gorzelak, B., Oleszczuk, J., 2012. The predominance of Th17
lymphocytes and decreased number and function of Treg cells in
preeclampsia. J. Reprod. Immunol. 93, 75–81.
Dasgupta, S., Jana, M., Liu, X., Pahan, K., 2005. Myelin basic protein-primed T cells of
female but not male mice induce nitric-oxide synthase and proinflammatory
cytokines in microglia: implications for gender bias in multiple sclerosis. J. Biol.
Chem. 280, 32609–32617.
Davison, S.L., Bell, R., Donath, S., Montalto, J.G., Davis, S.R., 2005. Androgen levels in
adult females: changes with age, menopause, and oophorectomy. J. Clin.
Endocrinol. Metab. 90, 3847–3853.
de Andres, C., Aristimuno, C., Bartolome, M., de Las Heras, V., Martinez-Gines, M.L.,
Arroyo, R., Fernandez-Cruz, E., Sanchez-Ramon, S., 2009. Clinical response to
interferon-beta-1a may be linked to low baseline circulating BDCA1 myeloid
dendritic cells differential role of circulating dendritic cells and CD4+ regulatory
T-cells in relapsing-remitting multiple sclerosis: a 1-year longitudinal study. J.
Neuroimmunol. 212, 112–120.
Dean, G., Elian, M., 1997. Age at immigration to England of Asian and Caribbean
immigrants and the risk of developing multiple sclerosis. J. Neurol. Neurosurg.
Psychiat. 63, 565–568.
Degu, G., Mengistu, G., Jones, J., 2002. Some factors affecting prevalence of and
immune responses to Schistosoma mansoni in schoolchildren in Gorgora,
northwest Ethiopia. Ethiop. Med. J. 40, 345–352.
Deluca, H.F., Cantorna, M.T., 2001. Vitamin D: its role and uses in immunology.
FASEB J: Off. Publ. Fed. Am. Soc. Exp. Biol. 15, 2579–2585.
Demkow, U., Filewska, M., Michalowska-Mitczuk, D., Kus, J., Jagodzinski, J., Zielonka,
T., Zwolska, Z., Wasik, M., Rowinska-Zakrzewska, E., 2007. Heterogeneity of
antibody response to myobacterial antigens in different clinical manifestations
of pulmonary tuberculosis. J. Physiol. Pharmacol.: Off. J. Polish Physiol. Soc. 58
(Suppl 5), 117–127.
Deng, F.Y., Lei, S.F., Zhang, Y.H., Zhang, Z.L., Guo, Y.F., 2013. Functional relevance for
associations between genetic variants and systemic lupus erythematosus. PLoS
One 8, e53037.
Deroo, B.J., Korach, K.S., 2006. Estrogen receptors and human disease. J. Clin. Invest.
116, 561–570.
Dhadke, S.V., Dhadke, V.N., Bangar, S.S., Korade, M.B., 2013. Clinical profile of
Guillain Barre syndrome. J. Assoc. Phys. India 61, 168–172.
D’Hooghe, M.B., Nagels, G., Uitdehaag, B.M., 2010. Long-term effects of childbirth in
MS. J. Neurol. Neurosurg. Psychiatry 81, 38–41.
Dobson, R., Giovannoni, G., Ramagopalan, S., 2013. The month of birth effect in
multiple sclerosis: systematic review, meta-analysis and effect of latitude. J.
Neurol. Neurosurg. Psychiat. 84, 427–432.
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
Donaldson, J.O., Penn, A.S., Lisak, R.P., 1981. Antiaceytlcholine receptor antibody in
neonatal myasthenia gravis. Am. J. Dis. Child. 135, 222–226.
Doria, A., Cutolo, M., Ghirardello, A., Zampieri, S., Vescovi, F., Sulli, A., Giusti, M.,
Piccoli, A., Grella, P., Gambari, P.F., 2002. Steroid hormones and disease activity
during pregnancy in systemic lupus erythematosus. Arth. Rheum. 47, 202–209.
Doria, A., Ghirardello, A., Iaccarino, L., Zampieri, S., Punzi, L., Tarricone, E., Ruffatti,
A., Sulli, A., Sarzi-Puttini, P.C., Gambari, P.F., Cutolo, M., 2004. Pregnancy,
cytokines, and disease activity in systemic lupus erythematosus. Arth. Rheum.
51, 989–995.
Doria, A., Iaccarino, L., Sarzi-Puttini, P., Ghirardello, A., Zampieri, S., Arienti, S.,
Cutolo, M., Todesco, S., 2006. Estrogens in pregnancy and systemic lupus
erythematosus. Ann. N. Y. Acad. Sci. 1069, 247–256.
Du, L., Yang, J., Huang, J., Ma, Y., Wang, H., Xiong, T., Xiang, Z., Zhang, Y., Huang, J.,
2013. The associations between the polymorphisms in the CTLA-4 gene and the
risk of Graves’ disease in the Chinese population. BMC Med. Genet. 14, 46.
Duquette, P., Murray, T.J., Pleines, J., Ebers, G.C., Sadovnick, D., Weldon, P., Warren,
S., Paty, D.W., Upton, A., Hader, W., et al., 1987. Multiple sclerosis in childhood:
clinical profile in 125 patients. J. Pediat. 111, 359–363.
Dynesen, A.W., Haraldsdottir, J., Holm, L., Astrup, A., 2003. Sociodemographic
differences in dietary habits described by food frequency questions–results
from Denmark. Eur. J. Clin. Nutr. 57, 1586–1597.
Eaton, W.W., Rose, N.R., Kalaydjian, A., Pedersen, M.G., Mortensen, P.B., 2007.
Epidemiology of autoimmune diseases in Denmark. J. Autoimmun. 29, 1–9.
Ebers, G.C., Sadovnick, A.D., Dyment, D.A., Yee, I.M., Willer, C.J., Risch, N., 2004.
Parent-of-origin effect in multiple sclerosis: observations in half-siblings.
Lancet 363, 1773–1774.
El Adssi, H., Debouverie, M., Guillemin, F.Group, L., 2012. Estimating the prevalence
and incidence of multiple sclerosis in the Lorraine region, France, by the
capture-recapture method. Multip. Scl. 18, 1244–1250.
Ellis, J.A., Kemp, A.S., Ponsonby, A.L., 2014. Gene–environment interaction in
autoimmune disease. Expert Rev. Mol. Med. 16, e4.
Erten, S., Sahin, A., Altunoglu, A., Gemcioglu, E., Koca, C., 2014. Comparison of
plasma vitamin D levels in patients with Sjogren’s syndrome and healthy
subjects. Int. J.Rheum. Dis. http://dx.doi.org/10.1111/1756-185X.12298.
European Paediatric Hepatitis, C.V.N., 2005. A significant sex – but not elective
cesarean section – effect on mother-to-child transmission of hepatitis C virus
infection. J. Infect. Dis. 192, 1872–1879.
Evans, P.C., Lambert, N., Maloney, S., Furst, D.E., Moore, J.M., Nelson, J.L., 1999. Long-
term fetal microchimerism in peripheral blood mononuclear cell subsets in
healthy women and women with scleroderma. Blood 93, 2033–2037.
Eymard, B., Vernet-der Garabedian, B., Berrih-Aknin, S., Pannier, C., Bach, J.F., Morel,
E., 1991. Anti-acetylcholine receptor antibodies in neonatal myasthenia gravis:
heterogeneity and pathogenic significance. J. Autoimmun. 4, 185–195.
Fae, K.C., da Silva, D.D., Oshiro, S.E., Tanaka, A.C., Pomerantzeff, P.M., Douay, C.,
Charron, D., Toubert, A., Cunningham, M.W., Kalil, J., Guilherme, L., 2006.
Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell
clones from rheumatic heart disease. J. Immunol. 176, 5662–5670.
Fairweather, D., Frisancho-Kiss, S., Rose, N.R., 2008. Sex differences in autoimmune
disease from a pathological perspective. Am. J. Pathol. 173, 600–609.
Fajardy, I., Vambergue, A., Stuckens, C., Weill, J., Danze, P.M., Fontaine, P., 2002.
CTLA-4 49 A/G dimorphism and type 1 diabetes susceptibility: a French case-
control study and segregation analysis. Evidence of a maternal effect. Eur. J.
Immunogen.: Off. J. Brit. Soc. Histocompat. Immunogen. 29, 251–257.
Farace, E., Alves, W.M., 2000. Do women fare worse: a metaanalysis of gender
differences in traumatic brain injury outcome. J. Neurosurg. 93, 539–545.
Farina, C., Aloisi, F., Meinl, E., 2007. Astrocytes are active players in cerebral innate
immunity. Trends Immunol. 28, 138–145.
Feldman, C.H., Hiraki, L.T., Liu, J., Fischer, M.A., Solomon, D.H., Alarcon, G.S.,
Winkelmayer, W.C., Costenbader, K.H., 2013. Epidemiology and
sociodemographics of systemic lupus erythematosus and lupus nephritis
among US adults with Medicaid coverage, 2000–2004. Arth. Rheum. 65, 753–
763.
Fernandez, M., Calvo-Alen, J., Alarcon, G.S., Roseman, J.M., Bastian, H.M., Fessler, B.J.,
McGwin Jr., G., Vila, L.M., Sanchez, M.L., Reveille, J.D., 2005. Systemic lupus
erythematosus in a multiethnic US cohort (LUMINA): XXI. Disease activity,
damage accrual, and vascular events in pre- and postmenopausal women. Arth.
Rheum. 52, 1655–1664.
Fernandez, M., Calvo-Alen, J., Bertoli, A.M., Bastian, H.M., Fessler, B.J., McGwin Jr., G.,
Reveille, J.D., Vila, L.M., Alarcon, G.S., 2007. Systemic lupus erythematosus in a
multiethnic US cohort (LUMINA L II): relationship between vascular events and
the use of hormone replacement therapy in postmenopausal women. J. Clin.
Rheumatol.: Pract. Rep. Rheum. Musculoskel. Dis. 13, 261–265.
Ferraro, M., Vieira, A.R., 2010. Explaining gender differences in caries: a
multifactorial approach to a multifactorial disease. Int. J. Dentistry 2010,
649643.
Ferreira, R., Barreto, M., Santos, E., Pereira, C., Martins, B., Andreia, R., Crespo, F.,
Viana, J.F., Vasconcelos, C., Ferreira, C., Vicente, A.M., Fesel, C., 2005. Heritable
factors shape natural human IgM reactivity to Ro60/SS-A and may predispose
for SLE-associated IgG anti-Ro and anti-La autoantibody production. J.
Autoimmun. 25, 155–163.
Fish, E.N., 2008. The X-files in immunity: sex-based differences predispose immune
responses. Nat. Rev. Immunol. 8, 737–744.
Forger, F., Marcoli, N., Gadola, S., Moller, B., Villiger, P.M., Ostensen, M., 2008.
Pregnancy induces numerical and functional changes of CD4+CD25 high
regulatory T cells in patients with rheumatoid arthritis. Ann. Rheum. Dis. 67,
984–990.
363
Forsum, E., Lof, M., 2007. Energy metabolism during human pregnancy. Annu. Rev.
Nutr. 27, 277–292.
Fraser, P.A., Ding, W.Z., Mohseni, M., Treadwell, E.L., Dooley, M.A., St Clair, E.W.,
Gilkeson, G.S., Cooper, G.S., 2003. Glutathione S-transferase M null
homozygosity and risk of systemic lupus erythematosus associated with sun
exposure: a possible gene-environment interaction for autoimmunity. J.
Rheumatol. 30, 276–282.
Friedrich, N., Schwarz, S., Thonack, J., John, U., Wallaschofski, H., Volzke, H., 2008.
Association between parity and autoimmune thyroiditis in a general female
population. Autoimmunity 41, 174–180.
Friel, S., Newell, J., Kelleher, C., 2005. Who eats four or more servings of fruit and
vegetables per day? Multivariate classification tree analysis of data from the
1998 Survey of Lifestyle, Attitudes and Nutrition in the Republic of Ireland.
Public Health Nutrit. 8, 159–169.
Fujii, H., Nawa, Y., Tsuchiya, H., Matsuno, K., Fukumoto, T., Fukuda, S., Kotani, M.,
1975. Effect of a single administration of testosterone on the immune response
and lymphoid tissues in mice. Cell. Immunol. 20, 315–326.
Gameiro, C., Romao, F., 2010. Changes in the immune system during menopause
and aging. Front. Biosci. 2, 1299–1303.
Gameiro, C.M., Romao, F., Castelo-Branco, C., 2010. Menopause and aging: changes
in the immune system – a review. Maturitas 67, 316–320.
Ganesan, K., Balachandran, C., Manohar, B.M., Puvanakrishnan, R., 2008.
Comparative studies on the interplay of testosterone, estrogen and
progesterone in collagen induced arthritis in rats. Bone 43, 758–765.
Gascon-Barre, M., Demers, C., Mirshahi, A., Neron, S., Zalzal, S., Nanci, A., 2003. The
normal liver harbors the vitamin D nuclear receptor in nonparenchymal and
biliary epithelial cells. Hepatology 37, 1034–1042.
Gatenby, P., Lucas, R., Swaminathan, A., 2013. Vitamin D deficiency and risk for
rheumatic diseases: an update. Curr. Opin. Rheumatol. 25, 184–191.
Gathungu, G., Zhang, C.K., Zhang, W., Cho, J.H., 2012. A two-marker haplotype in the
IRF5 gene is associated with inflammatory bowel disease in a North American
cohort. Genes Immun. 13, 351–355.
Gaujoux, S., Leenhardt, L., Tresallet, C., Rouxel, A., Hoang, C., Jublanc, C., Chigot, J.P.,
Menegaux, F., 2006. Extensive thyroidectomy in Graves’ disease. J. Am. Coll.
Surg. 202, 868–873.
Ghezzi, A., Deplano, V., Faroni, J., Grasso, M.G., Liguori, M., Marrosu, G., Pozzilli, C.,
Simone, I.L., Zaffaroni, M., 1997. Multiple sclerosis in childhood: clinical
features of 149 cases. Multip. Scl. 3, 43–46.
Giglio, T., Imro, M.A., Filaci, G., Scudeletti, M., Puppo, F., De Cecco, L., Indiveri, F.,
Costantini, S., 1994. Immune cell circulating subsets are affected by gonadal
function. Life Sci. 54, 1305–1312.
Gimsa, U., Mitchison, N.A., Brunner-Weinzierl, M.C., 2013. Immune privilege as an
intrinsic CNS property: astrocytes protect the CNS against T-cell-mediated
neuroinflammation. Med. Inflamm. 2013, 320519.
Giordano, G., Tait, L., Furlong, C.E., Cole, T.B., Kavanagh, T.J., Costa, L.G., 2013. Gender
differences in brain susceptibility to oxidative stress are mediated by levels of
paraoxonase-2 expression. Free Rad. Biol. Med. 58, 98–108.
Gloria-Bottini, F., Bottini, N., Renzetti, G., Bottini, E., 2007. ACP1 and Th class of
immunological disease: evidence of interaction with gender. Int. Arch. Allergy
Immunol. 143, 170–176.
Glynn, J.R., Crampin, A.C., Ngwira, B.M., Ndhlovu, R., Mwanyongo, O., Fine, P.E., 2008.
Herpes simplex virus type 2 trends in relation to the HIV epidemic in northern
Malawi. Sex. Transmitt. Infect. 84, 356–360.
Goble, F.C., Konopka, E.A., 1973. Sex as a factor in infectious disease. Trans. N.Y.
Acad. Sci. 35, 325–346.
Godfrey, D.I., Hammond, K.J., Poulton, L.D., Smyth, M.J., Baxter, A.G., 2000. NKT cells:
facts, functions and fallacies. Immunol. Today 21, 573–583.
Goldberg, A.D., Allis, C.D., Bernstein, E., 2007. Epigenetics: a landscape takes shape.
Cell 128, 635–638.
Gordon, C., Wallace, D.J., Shinada, S., Kalunian, K.C., Forbess, L., Braunstein, G.D.,
Weisman, M.H., 2008. Testosterone patches in the management of patients with
mild/moderate systemic lupus erythematosus. Rheumatology 47, 334–338.
Gough, S.C., Simmonds, M.J., 2007. The HLA region and autoimmune disease:
associations and mechanisms of action. Curr. Genom. 8, 453–465.
Granger, J.P., 2002. Maternal and fetal adaptations during pregnancy: lessons in
regulatory and integrative physiology. Am. J. Physiol. Regul. Integ. Comp.
Physiol. 283, R1289-92.
Grattan, D.R., Steyn, F.J., Kokay, I.C., Anderson, G.M., Bunn, S.J., 2008. Pregnancy-
induced adaptation in the neuroendocrine control of prolactin secretion. J.
Neuroendocrinol. 20, 497–507.
Gratwohl, A.A., Moutsopoulos, H.M., Chused, T.M., Akizuki, M., Wolf, R.O., Sweet, J.B.,
Deisseroth, A.B., 1977. Sjogren-type syndrome after allogeneic bone-marrow
transplantation. Ann. Intern. Med. 87, 703–706.
Greer, J.M., Csurhes, P.A., Pender, M.P., McCombe, P.A., 2004. Effect of gender on T-
cell proliferative responses to myelin proteolipid protein antigens in patients
with multiple sclerosis and controls. J. Autoimmun. 22, 345–352.
Grimaldi, C.M., Cleary, J., Dagtas, A.S., Moussai, D., Diamond, B., 2002. Estrogen alters
thresholds for B cell apoptosis and activation. J. Clin. Invest. 109, 1625–1633.
Groswasser, Z., Cohen, M., Keren, O., 1998. Female TBI patients recover better than
males. Brain Injury: [BI] 12, 805–808.
Grytten Torkildsen, N., Lie, S.A., Aarseth, J.H., Nyland, H., Myhr, K.M., 2008. Survival
and cause of death in multiple sclerosis: results from a 50-year follow-up in
Western Norway. Multip. Scl. 14, 1191–1198.
Guillot, P.V., Gotherstrom, C., Chan, J., Kurata, H., Fisk, N.M., 2007. Human first-
trimester fetal MSC express pluripotency markers and grow faster and have
longer telomeres than adult MSC. Stem Cells 25, 646–654.
364 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
Guo, T., Huo, Y., Zhu, W., Xu, F., Liu, C., Liu, N., Cao, M., Cui, B., Ning, G., 2013. Genetic
association between IL-17F gene polymorphisms and the pathogenesis of
Graves’ Disease in the Han Chinese population. Gene 512, 300–304.
Gupta, N., Bostrom, A.G., Kirschner, B.S., Ferry, G.D., Winter, H.S., Baldassano, R.N.,
Gold, B.D., Abramson, O., Smith, T., Cohen, S.A., Heyman, M.B., 2007. Gender
differences in presentation and course of disease in pediatric patients with
Crohn disease. Pediatrics 120, e1418-25.
Guptill, J.T., Marano, A., Krueger, A., Sanders, D.B., 2011. Cost analysis of myasthenia
gravis from a large U.S. insurance database. Muscle Nerve 44, 907–911.
Guy-Coichard, C., Nguyen, D.T., Delorme, T., Boureau, F., 2008. Pain in hereditary
neuromuscular disorders and myasthenia gravis: a national survey of
frequency, characteristics, and impact. J. Pain Sympt. Manage. 35, 40–50.
Gveric-Ahmetasevic, S., Colic, A., Elvedji-Gasparovic, V., Gveric, T., Vukelic, V., 2008.
Can neonatal myasthenia gravis be predicted? J. Perinat. Med. 36, 503–506.
Gyu Song, G., Ho Lee, Y., 2013. CTLA-4 +49 A/G and -318 C/T polymorphisms and
susceptibility to multiple sclerosis: a meta-analysis. Immunol. Invest. 42, 409–
422.
Hadjimichael, O., Vollmer, T., Oleen-Burkey, M.North American Research
Committee on Multiple, S., 2008. Fatigue characteristics in multiple sclerosis:
the North American Research Committee on Multiple Sclerosis (NARCOMS)
survey. Health Qual. Life Outcomes 6, 100.
Hall, H.I., May, D.S., Lew, R.A., Koh, H.K., Nadel, M., 1997. Sun protection behaviors of
the U.S. white population. Prev. Med. 26, 401–407.
Hamlyn, A.N., Sherlock, S., 1974. The epidemiology of primary biliary cirrhosis: a
survey of mortality in England and Wales. Gut 15, 473–479.
Hammond, S.R., McLeod, J.G., Millingen, K.S., Stewart-Wynne, E.G., English, D.,
Holland, J.T., McCall, M.G., 1988. The epidemiology of multiple sclerosis in three
Australian cities: Perth, Newcastle and Hobart. Brain: J. Neurol. 111 (Pt 1), 1–25.
Hantai, D., Richard, P., Koenig, J., Eymard, B., 2004. Congenital myasthenic
syndromes. Curr. Opin. Neurol. 17, 539–551.
Harada, K., Hirohara, J., Ueno, Y., Nakano, T., Kakuda, Y., Tsubouchi, H., Ichida, T.,
Nakanuma, Y., 2013. Incidence of and risk factors for hepatocellular carcinoma
in primary biliary cirrhosis: national data from Japan. Hepatology 57, 1942–
1949.
Hayes, C.E., Cantorna, M.T., DeLuca, H.F., 1997. Vitamin D and multiple sclerosis.
Proc. Soc. Exp. Biol. Med. Soc. Exp. Biol. Med. 216, 21–27.
Hazes, J.M., Dijkmans, B.A., Vandenbroucke, J.P., Cats, A., 1989. Oral contraceptive
treatment for rheumatoid arthritis: an open study in 10 female patients. Br. J.
Rheumatol. 28 (Suppl. 1), 28–30.
Hazes, J.M., Dijkmans, B.C., Vandenbroucke, J.P., de Vries, R.R., Cats, A., 1990.
Reduction of the risk of rheumatoid arthritis among women who take oral
contraceptives. Arth. Rheum. 33, 173–179.
Hee, C.S., Gun, S.C., Naidu, R., Gupta, E., Somnath, S.D., Radhakrishnan, A.K., 2007.
Comparison of single nucleotide polymorphisms in the human interleukin-10
gene promoter between rheumatoid arthritis patients and normal subjects in
Malaysia. Mod. Rheumatol./Jpn. Rheumatism Assoc. 17, 429–435.
Hellwig, K., Beste, C., Brune, N., Haghikia, A., Muller, T., Schimrigk, S., Gold, R., 2008.
Increased MS relapse rate during assisted reproduction technique. J. Neurol.
255, 592–593.
Hemminki, K., Li, X., Sundquist, J., Sundquist, K., 2010. The epidemiology of Graves’
disease: evidence of a genetic and an environmental contribution. J.
Autoimmun. 34, J307-13.
Hench, P.S., 1983. The ameliorating effect of pregnancy on chronic atrophic
(infectious rheumatoid) arthritis, fibrositis, and intermittent hydrathrosis.
Proc. Staff Meet. Mayo Clin. 13, 161–167.
Henriques, A., Ines, L., Carvalheiro, T., Couto, M., Andrade, A., Pedreiro, S., Laranjeira,
P., Morgado, J.M., Pais, M.L., da Silva, J.A., Paiva, A., 2012. Functional
characterization of peripheral blood dendritic cells and monocytes in
systemic lupus erythematosus. Rheumatol. Int. 32, 863–869.
Herbst, A.L., Ulfelder, H., Poskanzer, D.C., 1971. Adenocarcinoma of the vagina.
Association of maternal stilbestrol therapy with tumor appearance in young
women. New Engl. J. Med. 284, 878–881.
Hernan, M.A., Olek, M.J., Ascherio, A., 2001. Cigarette smoking and incidence of
multiple sclerosis. Am. J. Epidemiol. 154, 69–74.
Hernan, M.A., Jick, S.S., Logroscino, G., Olek, M.J., Ascherio, A., Jick, H., 2005. Cigarette
smoking and the progression of multiple sclerosis. Brain: J. Neurol. 128, 1461–
1465.
Herrera, B.M., Ramagopalan, S.V., Orton, S., Chao, M.J., Yee, I.M., Sadovnick, A.D.,
Ebers, G.C., 2007. Parental transmission of MS in a population-based Canadian
cohort. Neurology 69, 1208–1212.
Herrera, B.M., Ramagopalan, S.V., Lincoln, M.R., Orton, S.M., Chao, M.J., Sadovnick,
A.D., Ebers, G.C., 2008. Parent-of-origin effects in MS: observations from
avuncular pairs. Neurology 71, 799–803.
Hewagama, A., Patel, D., Yarlagadda, S., Strickland, F.M., Richardson, B.C., 2009.
Stronger inflammatory/cytotoxic T-cell response in women identified by
microarray analysis. Genes Immun. 10, 509–516.
Hill, N.J., Hultcrantz, M., Sarvetnick, N., Flodstrom-Tullberg, M., 2007. The target
tissue in autoimmunity – an influential niche. Eur. J. Immunol. 37, 589–597.
Hirota, Y., Suzuki, T., Chazono, Y., Bito, Y., 1976. Humoral immune responses
characteristic of testosterone-propionate-treated chickens. Immunology 30,
341–348.
Ho, H.N., Wu, M.Y., Chen, H.F., Chao, K.H., Yang, Y.S., Huang, S.C., Lee, T.Y., Gill 3rd,
T.J., 1995. In vivo CD3+CD25+ lymphocyte subpopulation is down-regulated
without increased serum-soluble interleukin-2 receptor (sIL-2R) by
gonadotropin releasing hormone agonist (GnRH-a). Am. J. Reprod. Immunol.
33, 134–139.
Holmqvist, P., Wallberg, M., Hammar, M., Landtblom, A.M., Brynhildsen, J., 2006.
Symptoms of multiple sclerosis in women in relation to sex steroid exposure.
Maturitas 54, 149–153.
Hoppenbrouwers, I.A., Liu, F., Aulchenko, Y.S., Ebers, G.C., Oostra, B.A., van Duijn,
C.M., Hintzen, R.Q., 2008. Maternal transmission of multiple sclerosis in a dutch
population. Arch. Neurol. 65, 345–348.
Horton, R., Wilming, L., Rand, V., Lovering, R.C., Bruford, E.A., Khodiyar, V.K., Lush,
M.J., Povey, S., Talbot Jr., C.C., Wright, M.W., Wain, H.M., Trowsdale, J., Ziegler, A.,
Beck, S., 2004. Gene map of the extended human MHC. Nat. Rev. Genet. 5, 889–
899.
Howard, M., Sellors, J.W., Jang, D., Robinson, N.J., Fearon, M., Kaczorowski, J.,
Chernesky, M., 2003. Regional distribution of antibodies to herpes simplex virus
type 1 (HSV-1) and HSV-2 in men and women in Ontario, Canada. J. Clin.
Microbiol. 41, 84–89.
Huang, Q., Parfitt, A., Grennan, D.M., Manolios, N., 1997. X-chromosome inactivation
in monozygotic twins with systemic lupus erythematosus. Autoimmunity 26,
85–93.
Huang, C.H., Wei, J.C., Chen, C.C., Chuang, C.S., Chou, C.H., Lin, Y.J., Wang, M.F., Wong,
R.H., 2014. Associations of the PTPN22 and CTLA-4 genetic polymorphisms with
Taiwanese ankylosing spondylitis. Rheumatol. Int. 34, 683–691.
Huang, X., Liu, W.B., Men, L.N., Feng, H.Y., Li, Y., Luo, C.M., Qiu, L., 2013. Clinical
features of myasthenia gravis in southern China: a retrospective review of 2,154
cases over 22 years. Neurol. Sci.: Off. J. Italian Neurol. Soc. Ital. Soc. Clin.
Neurophysiol. 34, 911–917.
Hughes, G.C., 2012. Progesterone and autoimmune disease. Autoimmun. Rev. 11.
A502-14.
Hughes, G.C., Clark, E.A., 2007. Regulation of dendritic cells by female sex steroids:
relevance to immunity and autoimmunity. Autoimmunity 40, 470–481.
Hughes, T., Adler, A., Merrill, J.T., Kelly, J.A., Kaufman, K.M., Williams, A., Langefeld,
C.D., Gilkeson, G.S., Sanchez, E., Martin, J., Boackle, S.A., Stevens, A.M., Alarcon,
G.S., Niewold, T.B., Brown, E.E., Kimberly, R.P., Edberg, J.C., Ramsey-Goldman, R.,
Petri, M., Reveille, J.D., Criswell, L.A., Vila, L.M., Jacob, C.O., Gaffney, P.M., Moser,
K.L., Vyse, T.J., Alarcon-Riquelme, M.E., Network, B., James, J.A., Tsao, B.P.,
Scofield, R.H., Harley, J.B., Richardson, B.C., Sawalha, A.H., 2012. Analysis of
autosomal genes reveals gene–sex interactions and higher total genetic risk in
men with systemic lupus erythematosus. Ann. Rheum. Dis. 71, 694–699.
Ichikawa, N., Kotake, S., Hakoda, M., Kamatani, N., 2001. Microchimerism in
Japanese patients with systemic sclerosis. Arth. Rheum. 44, 1226–1228.
Inagaki, T., Nishii, Y., Suzuki, N., Suzuki, S., Koizumi, Y., Aizawa, T., Hashizume, K.,
2002. Fulminant diabetes mellitus associated with pregnancy: case reports and
literature review. Endocr. J. 49, 319–322.
Inoue, N., Watanabe, M., Wada, M., Morita, M., Hidaka, Y., Iwatani, Y., 2013. IL-10 -
592A/C polymorphism is associated with severity of Hashimoto’s disease.
Cytokine 64, 370–374.
Invernizzi, P., Miozzo, M., Battezzati, P.M., Bianchi, I., Grati, F.R., Simoni, G., Selmi, C.,
Watnik, M., Gershwin, M.E., Podda, M., 2004. Frequency of monosomy X in
women with primary biliary cirrhosis. Lancet 363, 533–535.
Invernizzi, P., Miozzo, M., Selmi, C., Persani, L., Battezzati, P.M., Zuin, M., Lucchi, S.,
Meroni, P.L., Marasini, B., Zeni, S., Watnik, M., Grati, F.R., Simoni, G., Gershwin,
M.E., Podda, M., 2005. X chromosome monosomy: a common mechanism for
autoimmune diseases. J. Immunol. 175, 575–578.
Invernizzi, P., Miozzo, M., Oertelt-Prigione, S., Meroni, P.L., Persani, L., Selmi, C.,
Battezzati, P.M., Zuin, M., Lucchi, S., Marasini, B., Zeni, S., Watnik, M., Tabano, S.,
Maitz, S., Pasini, S., Gershwin, M.E., Podda, M., 2007. X monosomy in female
systemic lupus erythematosus. Ann. N. Y. Acad. Sci. 1110, 84–91.
Ito, A., Bebo Jr., B.F., Matejuk, A., Zamora, A., Silverman, M., Fyfe-Johnson, A., Offner,
H., 2001. Estrogen treatment down-regulates TNF-alpha production and
reduces the severity of experimental autoimmune encephalomyelitis in
cytokine knockout mice. J. Immunol. 167, 542–552.
Ivanova, E., Kyurkchiev, D., Altankova, I., Dimitrov, J., Binakova, E., Kyurkchiev, S.,
2005. CD83 monocyte-derived dendritic cells are present in human decidua and
progesterone induces their differentiation in vitro. Am. J. Reprod. Immunol. 53,
199–205.
Jain, A.K., Sircar, S., Jain, M., Adkar, S., Waghmare, C., 2012. Inflammatory bowel
disease in central India: a single centre experience over five years. Trop. Doct.
42, 198–199.
Jansson, L., Olsson, T., Holmdahl, R., 1994. Estrogen induces a potent suppression of
experimental autoimmune encephalomyelitis and collagen-induced arthritis in
mice. J. Neuroimmunol. 53, 203–207.
Jara, L.J., Lavalle, C., Fraga, A., Gomez-Sanchez, C., Silveira, L.H., Martinez-Osuna, P.,
Germain, B.F., Espinoza, L.R., 1991. Prolactin, immunoregulation, and
autoimmune diseases. Semin. Arth. Rheum. 20, 273–284.
Jara, L.J., Irigoyen, L., Ortiz, M.J., Zazueta, B., Bravo, G., Espinoza, L.R., 1998. Prolactin
and interleukin-6 in neuropsychiatric lupus erythematosus. Clin. Rheumatol.
17, 110–114.
Jara, L.J., Vera-Lastra, O., Miranda, J.M., Alcala, M., Alvarez-Nemegyei, J., 2001.
Prolactin in human systemic lupus erythematosus. Lupus 10, 748–756.
Jara, L.J., Cruz-Cruz, P., Saavedra, M.A., Medina, G., Garcia-Flores, A., Angeles, U.,
Miranda-Limon, J.M., 2007. Bromocriptine during pregnancy in systemic lupus
erythematosus: a pilot clinical trial. Ann. N. Y. Acad. Sci. 1110, 297–304.
Jensen, C.J., Massie, A., De Keyser, J., 2013. Immune players in the CNS: the astrocyte.
J. Neuroimmun. Pharmacol.: Off. J. Soc. NeuroImmune Pharmacol. 8, 824–839.
Jess, T., Riis, L., Vind, I., Winther, K.V., Borg, S., Binder, V., Langholz, E., Thomsen, O.O.,
Munkholm, P., 2007. Changes in clinical characteristics, course, and prognosis of
inflammatory bowel disease during the last 5 decades: a population-based
study from Copenhagen, Denmark. Inflamm. Bowel Dis. 13, 481–489.
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
Jiang, Y.H., Bressler, J., Beaudet, A.L., 2004. Epigenetics and human disease. Annu.
Rev. Genom. Hum. Genet. 5, 479–510.
Jin, H., Arase, N., Hirayasu, K., Kohyama, M., Suenaga, T., Saito, F., Tanimura, K.,
Matsuoka, S., Ebina, K., Shi, K., Toyama-Sorimachi, N., Yasuda, S., Horita, T.,
Hiwa, R., Takasugi, K., Ohmura, K., Yoshikawa, H., Saito, T., Atsumi, T., Sasazuki,
T., Katayama, I., Lanier, L.L., Arase, H., 2014. Autoantibodies to IgG/HLA class II
complexes are associated with rheumatoid arthritis susceptibility. Proc. Natl.
Acad. Sci. U.S.A. 111, 3787–3792.
Johnson, B., 2013. Overview of neonatal lupus. J. Pediat. Health Care: Off., Publ. Natl.
Assoc. Pediat. Nurse Associat. Practition. http://dx.doi.org/10.1016/
j.pedhc.2013.07.015.
Johnson, K.L., Bianchi, D.W., 2004. Fetal cells in maternal tissue following
pregnancy: what are the consequences? Hum. Reprod. Update 10, 497–502.
Jones, L.A., Anthony, J.P., Henriquez, F.L., Lyons, R.E., Nickdel, M.B., Carter, K.C.,
Alexander, J., Roberts, C.W., 2008. Toll-like receptor-4-mediated macrophage
activation is differentially regulated by progesterone via the glucocorticoid and
progesterone receptors. Immunology 125, 59–69.
Kamen, D.L., Cooper, G.S., Bouali, H., Shaftman, S.R., Hollis, B.W., Gilkeson, G.S., 2006.
Vitamin D deficiency in systemic lupus erythematosus. Autoimmun. Rev. 5,
114–117.
Kanda, N., Tamaki, K., 1999. Estrogen enhances immunoglobulin production by
human PBMCs. J. Allergy Clin. Immunol. 103, 282–288.
Kane, S.V., Reddy, D., 2008. Hormonal replacement therapy after menopause is
protective of disease activity in women with inflammatory bowel disease. Am. J.
Gastroenterol. 103, 1193–1196.
Kantarci, O.H., Hebrink, D.D., Achenbach, S.J., Pittock, S.J., Altintas, A., Schaefer-Klein,
J.L., Atkinson, E.J., De Andrade, M., McMurray, C.T., Rodriguez, M., Weinshenker,
B.G., 2004. Association of APOE polymorphisms with disease severity in MS is
limited to women. Neurology 62, 811–814.
Karason, A., Gudjonsson, J.E., Upmanyu, R., Antonsdottir, A.A., Hauksson, V.B.,
Runasdottir, E.H., Jonsson, H.H., Gudbjartsson, D.F., Frigge, M.L., Kong, A.,
Stefansson, K., Valdimarsson, H., Gulcher, J.R., 2003. A susceptibility gene for
psoriatic arthritis maps to chromosome 16q: evidence for imprinting. Am. J.
Hum. Genet. 72, 125–131.
Kaur, G., Han, S.J., Yang, I., Crane, C., 2010. Microglia and central nervous system
immunity. Neurosurg. Clin. N. Am. 21, 43–51.
Kawasaki, E., Eguchi, K., 2004. Is Type 1 diabetes in the Japanese population the
same as among Caucasians? Ann. N. Y. Acad. Sci. 1037, 96–103.
Khor, B., Gardet, A., Xavier, R.J., 2011. Genetics and pathogenesis of inflammatory
bowel disease. Nature 474, 307–317.
Khosrotehrani, K., Bianchi, D.W., 2005. Multi-lineage potential of fetal cells in
maternal tissue: a legacy in reverse. J. Cell Sci. 118, 1559–1563.
Khosrotehrani, K., Johnson, K.L., Cha, D.H., Salomon, R.N., Bianchi, D.W., 2004.
Transfer of fetal cells with multilineage potential to maternal tissue. JAMA, J.
Am. Med. Assoc. 292, 75–80.
Knudsen, G.P., 2009. Gender bias in autoimmune diseases: X chromosome
inactivation in women with multiple sclerosis. J. Neurol. Sci. 286, 43–46.
Knudsen, G.P., Harbo, H.F., Smestad, C., Celius, E.G., Akesson, E., Oturai, A., Ryder,
L.P., Spurkland, A., Orstavik, K.H., 2007. X chromosome inactivation in females
with multiple sclerosis. Eur. J. Neurol.: Off. J. Eur. Fed. Neurol. Soc. 14, 1392–
1396.
Koch, M., Uyttenboogaart, M., Heersema, D., Steen, C., De Keyser, J., 2009. Parity and
secondary progression in multiple sclerosis. J. Neurol. Neurosurg. Psychiat. 80,
676–678.
Kuiper, S., van Gestel, A.M., Swinkels, H.L., de Boo, T.M., da Silva, J.A., van Riel, P.L.,
2001. Influence of sex, age, and menopausal state on the course of early
rheumatoid arthritis. J. Rheumatol. 28, 1809–1816.
Kurtzke, J.F., Beebe, G.W., Norman Jr., J.E., 1979. Epidemiology of multiple sclerosis
in U.S. veterans: 1. Race, sex, and geographic distribution. Neurology 29, 1228–
1235.
Kuusisto, H., Kaprio, J., Kinnunen, E., Luukkaala, T., Koskenvuo, M., Elovaara, I., 2008.
Concordance and heritability of multiple sclerosis in Finland: study on a
nationwide series of twins. Eur. J. Neurol.: Off. J. Eur. Fed. Neurol. Soc. 15, 1106–
1110.
Lahita, R.G., 1999. Emerging concepts for sexual predilection in the disease systemic
lupus erythematosus. Ann. N. Y. Acad. Sci. 876, 64–69, discussion 69-70.
Lain, K.Y., Catalano, P.M., 2007. Metabolic changes in pregnancy. Clin. Obstet.
Gynecol. 50, 938–948.
Lamb, M.M., Myers, M.A., Barriga, K., Zimmet, P.Z., Rewers, M., Norris, J.M., 2008.
Maternal diet during pregnancy and islet autoimmunity in offspring. Pediat.
Diabet. 9, 135–141.
Laplaud, D.A., Leray, E., Barriere, P., Wiertlewski, S., Moreau, T., 2006. Increase in
multiple sclerosis relapse rate following in vitro fertilization. Neurology 66,
1280–1281.
Lateef, A., Petri, M., 2012. Management of pregnancy in systemic lupus
erythematosus. Nat. Rev. Rheumatol. 8, 710–718.
Lauszus, F.F., Klebe, J.G., Bek, T., Flyvbjerg, A., 2003. Increased serum IGF-I during
pregnancy is associated with progression of diabetic retinopathy. Diabetes 52,
852–856.
Lee, L.A., 2009. The clinical spectrum of neonatal lupus. Arch. Dermatol. Res. 301,
107–110.
Lee, J.M., Li, J., Johnson, D.A., Stein, T.D., Kraft, A.D., Calkins, M.J., Jakel, R.J., Johnson,
J.A., 2005. Nrf2, a multi-organ protector? FASEB J.: Off. Publ. Fed. Am. Soc. Exp.
Biol. 19, 1061–1066.
Lelu, K., Delpy, L., Robert, V., Foulon, E., Laffont, S., Pelletier, L., Engelhardt, B., Guery,
J.C., 2010. Endogenous estrogens, through estrogen receptor alpha, constrain
365
autoimmune inflammation in female mice by limiting CD4+ T-cell homing into
the CNS. Eur. J. Immunol. 40, 3489–3498.
Lemire, J.M., 1992. Immunomodulatory role of 1,25-dihydroxyvitamin D3. J. Cell.
Biochem. 49, 26–31.
Lepez, T., Vandewoestyne, M., Hussain, S., Van Nieuwerburgh, F., Poppe, K.,
Velkeniers, B., Kaufman, J.M., Deforce, D., 2011. Fetal microchimeric cells in
blood of women with an autoimmune thyroid disease. PLoS One 6, e29646.
Lepez, T., Vandewoestyne, M., Deforce, D., 2012. Fetal microchimeric cells in blood
and thyroid glands of women with an autoimmune thyroid disease. Chimerism
3, 21–23.
Leung, P.S., Wang, J., Naiyanetr, P., Kenny, T.P., Lam, K.S., Kurth, M.J., Gershwin, M.E.,
2013. Environment and primary biliary cirrhosis: electrophilic drugs and the
induction of AMA. J. Autoimmun. 41, 79–86.
Lewis, J.E., Fu, S.M., Gaskin, F., 2013. Autoimmunity, end organ damage, and the
origin of autoantibodies and autoreactive T cells in systemic lupus
erythematosus. Discov. Med. 15, 85–92.
Lezama-Davila, C.M., Oghumu, S., Satoskar, A.R., Isaac-Marquez, A.P., 2007. Sex-
associated susceptibility in humans with chiclero’s ulcer: resistance in females
is associated with increased serum-levels of GM-CSF. Scand. J. Immunol. 65,
210–211.
Li, H., Chen, Q., 2013. Genetic susceptibility to Grave’s disease. Front. Biosci.
(Landmark Ed) 18, 1080–1087.
Li, X., Lonard, D.M., O’Malley, B.W., 2004. A contemporary understanding of
progesterone receptor function. Mech. Ageing Dev. 125, 669–678.
Li, R., Sun, J., Ren, L.M., Wang, H.Y., Liu, W.H., Zhang, X.W., Chen, S., Mu, R., He, J.,
Zhao, Y., Long, L., Liu, Y.Y., Liu, X., Lu, X.L., Li, Y.H., Wang, S.Y., Pan, S.S., Li, C.,
Wang, H.Y., Li, Z.G., 2012. Epidemiology of eight common rheumatic diseases in
China: a large-scale cross-sectional survey in Beijing. Rheumatology 51, 721–
729.
Liang, J., Sun, L., Wang, Q., Hou, Y., 2006. Progesterone regulates mouse dendritic
cells differentiation and maturation. Int. Immunopharmacol. 6, 830–838.
Libert, C., Dejager, L., Pinheiro, I., 2010. The X chromosome in immune functions:
when a chromosome makes the difference. Nat. Rev. Immunol. 10, 594–604.
Lichtman, M.A., Vaughan, J.H., Hames, C.G., 1967. The distribution of serum
immunoglobulins, anti-gamma-G globulins (‘‘rheumatoid factors’’) and
antinuclear antibodies in White and Negro subjects in Evans County, Georgia.
Arth. Rheumat. 10, 204–215.
Lin, Q., Hou, R., Sato, A., Ohtsuji, M., Ohtsuji, N., Nishikawa, K., Tsurui, H., Amano, H.,
Amano, E., Sudo, K., Nishimura, H., Shirai, T., Hirose, S., 2010. Inhibitory IgG Fc
receptor promoter region polymorphism is a key genetic element for murine
systemic lupus erythematosus. J. Autoimmun. 34, 356–363.
Lindholm, E., Hallengren, B., Agardh, C.D., 2004. Gender differences in GAD
antibody-positive diabetes mellitus in relation to age at onset, C-peptide and
other endocrine autoimmune diseases. Diabet./Metab. Res. Rev. 20, 158–164.
Lista, P., Straface, E., Brunelleschi, S., Franconi, F., Malorni, W., 2011. On the role of
autophagy in human diseases: a gender perspective. J. Cell Mol. Med. 15, 1443–
1457.
Lleo, A., Oertelt-Prigione, S., Bianchi, I., Caliari, L., Finelli, P., Miozzo, M., Lazzari, R.,
Floreani, A., Donato, F., Colombo, M., Gershwin, M.E., Podda, M., Invernizzi, P.,
2013. Y chromosome loss in male patients with primary biliary cirrhosis. J.
Autoimmun. 41, 87–91.
Lo, Y.M., Lo, E.S., Watson, N., Noakes, L., Sargent, I.L., Thilaganathan, B., Wainscoat,
J.S., 1996. Two-way cell traffic between mother and fetus: biologic and clinical
implications. Blood 88, 4390–4395.
Lu, Q., 2013. The critical importance of epigenetics in autoimmunity. J. Autoimmun.
41, 1–5.
Luchetti, S., van Eden, C.G., Schuurman, K., van Strien, M.E., Swaab, D.F., Huitinga, I.,
2014. Gender differences in multiple sclerosis: induction of estrogen signaling
in male and progesterone signaling in female lesions. J. Neuropathol. Exp.
Neurol. 73, 123–135.
Lui, N.L., Haroon, N., Carty, A., Shen, H., Cook, R.J., Shanmugarajah, S., Gladman, D.D.,
Inman, R.D., 2011. Effect of pregnancy on ankylosing spondylitis: a case-control
study. J. Rheumatol. 38, 2442–2444.
Luster, M.I., Faith, R.E., McLachlan, J.A., 1978. Alterations of the antibody response
following in utero exposure to diethylstilbestrol. Bull. Environ. Contam. Toxicol.
20, 433–437.
Lutz, L.B., Jamnongjit, M., Yang, W.H., Jahani, D., Gill, A., Hammes, S.R., 2003.
Selective modulation of genomic and nongenomic androgen responses by
androgen receptor ligands. Mol. Endocrinol. 17, 1106–1116.
MacDonald, M.J., Gottschall, J., Hunter, J.B., Winter, K.L., 1986. HLA-DR4 in insulin-
dependent diabetic parents and their diabetic offspring: a clue to dominant
inheritance. Proc. Natl. Acad. Sci. U.S.A. 83, 7049–7053.
Mackay, I.R., 2001. Tolerance and autoimmunity. West J. Med. 174, 118–123.
Mackay, I.R., Burnet, F.M., 1963. Autoimmune Diseases, Pathogenesis, Chemistry
and Therapy. Thomas, Springfield.
Mackay, I.R., Rose, N.R., 2001. Autoimmunity and lymphoma: tribulations of B cells.
Nat. Immunol. 2, 793–795.
Maloney, S., Smith, A., Furst, D.E., Myerson, D., Rupert, K., Evans, P.C., Nelson, J.L.,
1999. Microchimerism of maternal origin persists into adult life. J. Clin. Invest.
104, 41–47.
Manwani, B., Liu, F., Scranton, V., Hammond, M.D., Sansing, L.H., McCullough, L.D.,
2013. Differential effects of aging and sex on stroke induced inflammation
across the lifespan. Exp. Neurol. 249, 120–131.
Marrosu, M.G., Sardu, C., Cocco, E., Costa, G., Murru, M.R., Mancosu, C., Murru, R., Lai,
M., Contu, P., 2004. Bias in parental transmission of the HLA-DR3 allele in
Sardinian multiple sclerosis. Neurology 63, 1084–1086.
366 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
Marshall-Gradisnik, S., Weatherby, R.P., Deakin, G.B., Coutts, R.A., Meir, R.,
Connellan, P., Stevenson, L.M., Rogerson, S., Zhou, S., 2008. Natural killer cell
activity following 6 weeks of strength training in healthy young males with/
without testosterone enanthate adminstration. J. Exerc. Sci. Fit. 6, 106–114.
Martel, C., Huynh le, H., Garnier, A., Ventura-Clapier, R., Brenner, C., 2012. Inhibition
of the mitochondrial permeability transition for cytoprotection: direct versus
indirect mechanisms. Biochem. Res. Int. 2012, 213403.
McCombe, P.A., 2003. Gender issues in multiple sclerosis. Expert Rev. Neurother. 3,
649–660.
McCombe, P.A., Greer, J.M., 2013a. Sexual dimorphism in the immune system. In:
Rose, N.R., Mackay, I.R. (Eds.), The Autoimmune Diseases. Academic Press, pp.
319–328.
McCombe, P.A., Greer, J.M., 2013b. Female reproductive issues in multiple sclerosis.
Multip. Scler. 19, 392–402.
McCombe, P.A., Chalk, J.B., Pender, M.P., 1990. Familial occurrence of multiple
sclerosis with thyroid disease and systemic lupus erythematosus. J. Neurol. Sci.
97, 163–171.
McCombe, P.A., Greer, J.M., Mackay, I.R., 2009. Sexual dimorphism in autoimmune
disease. Curr. Mol. Med. 9, 1058–1079.
McConnachie, P.R., Zahalsky, A.C., 1991. Immunological consequences of exposure
to pentachlorophenol. Arch. Environ. Health 46, 249–253.
McConnachie, P.R., Zahalsky, A.C., 1992. Immune alterations in humans exposed to
the termiticide technical chlordane. Arch. Environ. Health 47, 295–301.
McKean, K.A., Nunney, L., 2005. Bateman’s principle and immunity: phenotypically
plastic reproductive strategies predict changes in immunological sex
differences. Evol. Int. J. Org. Evol. 59, 1510–1517.
McMurray, R., Keisler, D., Kanuckel, K., Izui, S., Walker, S.E., 1991. Prolactin
influences autoimmune disease activity in the female B/W mouse. J. Immunol.
147, 3780–3787.
McMurray, R.W., Weidensaul, D., Allen, S.H., Walker, S.E., 1995. Efficacy of
bromocriptine in an open label therapeutic trial for systemic lupus
erythematosus. J. Rheumatol. 22, 2084–2091.
McMurray, R.W., Wilson, J.G., Bigler, L., Xiang, L., Lagoo, A., 2000. Progesterone
inhibits glucocorticoid-induced murine thymocyte apoptosis. Int. J.
Immunopharmacol. 22, 955–965.
McNallan, K.T., Aponte, C., el-Azhary, R., Mason, T., Nelson, A.M., Paat, J.J., Crowson,
C.S., Reed, A.M., 2007. Immunophenotyping of chimeric cells in localized
scleroderma. Rheumatology 46, 398–402.
McNally, R.J., James, P.W., Ducker, S., James, O.F., 2011. Seasonal variation in the
patient diagnosis of primary biliary cirrhosis: further evidence for an
environmental component to etiology. Hepatology 54, 2099–2103.
Medina, K.L., Strasser, A., Kincade, P.W., 2000. Estrogen influences the
differentiation, proliferation, and survival of early B-lineage precursors. Blood
95, 2059–2067.
Menke, A., Orchard, T.J., Imperatore, G., Bullard, K.M., Mayer-Davis, E., Cowie, C.C.,
2013. The prevalence of type 1 diabetes in the United States. Epidemiology 24,
773–774.
Meyer, J.M., Han, J., Singh, R., Moxley, G., 1996. Sex influences on the penetrance of
HLA shared-epitope genotypes for rheumatoid arthritis. Am. J. Hum. Genet. 58,
371–383.
Migeon, B.R., 2006. The role of X inactivation and cellular mosaicism in women’s
health and sex-specific diseases. JAMA, J. Am. Med. Assoc. 295, 1428–1433.
Miller, L., Alley, E.W., Murphy, W.J., Russell, S.W., Hunt, J.S., 1996. Progesterone
inhibits inducible nitric oxide synthase gene expression and nitric oxide
production in murine macrophages. J. Leukoc. Biol. 59, 442–450.
Misra, R., Hissaria, P., Tandon, V., Aggarwal, A., Krishnani, N., Dabadghao, S., 2003.
Primary Sjogren’s syndrome: rarity in India. J. Assoc. Phys. Ind. 51, 859–862.
Mitchell, R., Hollis, S., Rothwell, C., Robertson, W.R., 1995. Age related changes in the
pituitary-testicular axis in normal men; lower serum testosterone results from
decreased bioactive LH drive. Clin. Endocrinol. 42, 501–507.
Mitsui, Y., Kusunoki, S., Arimura, K., Kaji, R., Kanda, T., Kuwabara, S., Sonoo, M.,
Takada, K., the Japanese, G.B.S.S.G., 2013. A multicentre prospective study of
Guillain–Barre Syndrome in Japan: a focus on the incidence of subtypes. J.
Neurol. Neurosurg. Psychiat.
Mok, C.C., 2008. Hormone replacement therapy in systemic lupus erythematosus.
Nat. Clin. Pract. Rheumatol. 4, 60–61.
Molvarec, A., Szarka, A., Walentin, S., Beko, G., Karadi, I., Prohaszka, Z., Rigo Jr., J.,
2011. Serum leptin levels in relation to circulating cytokines, chemokines,
adhesion molecules and angiogenic factors in normal pregnancy and
preeclampsia. Reprod. Biol. Endocrinol.: RB&E 9, 124.
Morton, H., Rolfe, B., Clunie, G.J., 1977. An early pregnancy factor detected in human
serum by the rosette inhibition test. Lancet 1, 394–397.
Muller, A.F., Drexhage, H.A., Berghout, A., 2001. Postpartum thyroiditis and
autoimmune thyroiditis in women of childbearing age: recent insights and
consequences for antenatal and postnatal care. Endocr. Rev. 22, 605–630.
Munger, K.L., Zhang, S.M., O’Reilly, E., Hernan, M.A., Olek, M.J., Willett, W.C.,
Ascherio, A., 2004. Vitamin D intake and incidence of multiple sclerosis.
Neurolog. 62, 60–65.
Munoz-Suano, A., Hamilton, A.B., Betz, A.G., 2011. Gimme shelter: the immune
system during pregnancy. Immunol. Rev. 241, 20–38.
Murase, J.E., Chan, K.K., Garite, T.J., Cooper, D.M., Weinstein, G.D., 2005. Hormonal
effect on psoriasis in pregnancy and post partum. Arch. Dermatol. 141, 601–
606.
Murata, H., Nakauchi, H., Sumida, T., 1999. Microchimerism in Japanese women
patients with systemic sclerosis. Lancet 354, 220.
Murphy, E.D., Roths, J.B., 1979. A Y chromosome associated factor in strain BXSB
producing accelerated autoimmunity and lymphoproliferation. Arth. Rheum.
22, 1188–1194.
Myasoedova, E., Crowson, C.S., Turesson, C., Gabriel, S.E., Matteson, E.L., 2011.
Incidence of extraarticular rheumatoid arthritis in Olmsted County, Minnesota,
in 1995–2007 versus 1985–1994: a population-based study. J. Rheumatol. 38,
983–989.
Nannini, C., Jebakumar, A.J., Crowson, C.S., Ryu, J.H., Matteson, E.L., 2013. Primary
Sjogren’s syndrome 1976–2005 and associated interstitial lung disease: a
population-based study of incidence and mortality. BMJ Open. 3, e003569.
Nelson, J.L., 1999. Microchimerism: implications for autoimmune disease. Lupus 8,
370–374.
Nelson, J.L., 2002. Microchimerism and human autoimmune diseases. Lupus 11,
651–654.
Nelson, J.L., Ostensen, M., 1997. Pregnancy and rheumatoid arthritis. Rheum. Dis.
Clin. North Am. 23, 195–212.
Nerich, V., Monnet, E., Etienne, A., Louafi, S., Ramee, C., Rican, S., Weill, A., Vallier, N.,
Vanbockstael, V., Auleley, G.R., Allemand, H., Carbonnel, F., 2006. Geographical
variations of inflammatory bowel disease in France: a study based on national
health insurance data. Inflamm. Bowel Dis. 12, 218–226.
Newsom-Davis, J., 2007. The emerging diversity of neuromuscular junction
disorders. Acta Myol.: Myopathies Cardiomyopathies: Off. J. Mediterran. Soc.
Myol./edited by the Gaetano Conte Academy for the Study of Striated Muscle
Diseases 26, 5–10.
Ng, S.C., Tang, W., Ching, J.Y., Wong, M., Chow, C.M., Hui, A.J., Wong, T.C., Leung, V.K.,
Tsang, S.W., Yu, H.H., Li, M.F., Ng, K.K., Kamm, M.A., Studd, C., Bell, S., Leong, R.,
de Silva, H.J., Kasturiratne, A., Mufeena, M.N., Ling, K.L., Ooi, C.J., Tan, P.S., Ong,
D., Goh, K.L., Hilmi, I., Pisespongsa, P., Manatsathit, S., Rerknimitr, R., Aniwan, S.,
Wang, Y.F., Ouyang, Q., Zeng, Z., Zhu, Z., Chen, M.H., Hu, P.J., Wu, K., Wang, X.,
Simadibrata, M., Abdullah, M., Wu, J.C., Sung, J.J., Chan, F.K., Asia-Pacific,
C.S.Colitis Epidemiologic Study Study, G., 2013. Incidence and phenotype of
inflammatory bowel disease based on results from the Asia–Pacific Crohn’s and
colitis epidemiology study. Gastroenterology 145, 158-165 e2.
Nijhawan, S., Katiyar, P., Nagaich, N., Saradava, V., Nijhawan, M., Gupta, G., Mathur,
A., Sharma, R., Nepalia, S., 2013. Prevalence of associated disorders in Indian
patients with celiac disease. Ind. J. Gastroenterol.: Off. J. Ind. Soc. Gastroenterol.
32, 330–334.
Noller, K.L., Blair, P.B., O’Brien, P.C., Melton 3rd, L.J., Offord, J.R., Kaufman, R.H.,
Colton, T., 1988. Increased occurrence of autoimmune disease among women
exposed in utero to diethylstilbestrol. Fertil. Steril. 49, 1080–1082.
Nomura, K., Sumida, Y., Yoh, T., Morita, A., Matsumoto, Y., Taji, S., Yoshida, N.,
Minami, M., Itoh, Y., Horiike, S., Kataoka, K., Taniwaki, M., Okanoue, T., 2004.
Lack of evidence for leukocyte maternal microchimerism in primary biliary
cirrhosis. World J. Gastroenterol.: WJG 10, 2415–2416.
Oldroyd, J., Schachna, L., Buchbinder, R., Staples, M., Murphy, B., Bond, M., Briggs, A.,
Lassere, M., March, L., 2009. Ankylosing spondylitis patients commencing
biologic therapy have high baseline levels of comorbidity: a report from the
Australian rheumatology association database. Int. J. Rheumatol. 2009, 268569.
Olsen, N.J., Kovacs, W.J., 1996. Gonadal steroids and immunity. Endocr. Rev. 17,
369–384.
Orbach, H., Shoenfeld, Y., 2007. Hyperprolactinemia and autoimmune diseases.
Autoimmun. Rev. 6, 537–542.
Orbach, H., Zandman-Goddard, G., Boaz, M., Agmon-Levin, N., Amital, H., Szekanecz,
Z., Szucs, G., Rovensky, J., Kiss, E., Doria, A., Ghirardello, A., Gomez-Arbesu, J.,
Stojanovich, L., Ingegnoli, F., Meroni, P.L., Rozman, B., Blank, M., Shoenfeld, Y.,
2012. Prolactin and autoimmunity: hyperprolactinemia correlates with
serositis and anemia in SLE patients. Clin. Rev. Allergy Immunol. 42, 189–198.
Ormarsdottir, S., Mallmin, H., Naessen, T., Petren-Mallmin, M., Broome, U.,
Hultcrantz, R., Loof, L., 2004. An open, randomized, controlled study of
transdermal hormone replacement therapy on the rate of bone loss in
primary biliary cirrhosis. J. Intern. Med. 256, 63–69.
Osoegawa, M., Kira, J., Fukazawa, T., Fujihara, K., Kikuchi, S., Matsui, M., Kohriyama,
T., Sobue, G., Yamamura, T., Itoyama, Y., Saida, T., Sakata, K., Ochi, H., Matsuoka,
T.Research Committee of Neuroimmunological, D., 2009. Temporal changes and
geographical differences in multiple sclerosis phenotypes in Japanese:
nationwide survey results over 30 years. Multip. Scl. 15, 159–173.
Ostensen, M., Ostensen, H., 1998. Ankylosing spondylitis – the female aspect. J.
Rheumatol. 25, 120–124.
Ostensen, M., Villiger, P.M., 2007. The remission of rheumatoid arthritis during
pregnancy. Semin. Immunopathol. 29, 185–191.
Ostensen, M., Forger, F., Nelson, J.L., Schuhmacher, A., Hebisch, G., Villiger, P.M.,
2005. Pregnancy in patients with rheumatic disease: anti-inflammatory
cytokines increase in pregnancy and decrease post partum. Ann. Rheum. Dis.
64, 839–844.
Ozbalkan, Z., Bagislar, S., Kiraz, S., Akyerli, C.B., Ozer, H.T., Yavuz, S., Birlik, A.M.,
Calguneri, M., Ozcelik, T., 2005. Skewed X chromosome inactivation in blood
cells of women with scleroderma. Arth. Rheum. 52, 1564–1570.
Ozcelik, T., 2008. X chromosome inactivation and female predisposition to
autoimmunity. Clin. Rev. Allergy Immunol. 34, 348–351.
Ozcelik, T., Uz, E., Akyerli, C.B., Bagislar, S., Mustafa, C.A., Gursoy, A., Akarsu, N.,
Toruner, G., Kamel, N., Gullu, S., 2006. Evidence from autoimmune thyroiditis of
skewed X-chromosome inactivation in female predisposition to autoimmunity.
Eur. J. Hum. Gen.: EJHG 14, 791–797.
Paavonen, T., 1994. Hormonal regulation of immune responses. Ann. Med. 26, 255–
258.
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
Padyukov, L., Hytonen, A.M., Smolnikova, M., Hahn-Zoric, M., Nilsson, N., Hanson,
L.A., Tarkowski, A., Klareskog, L., 2004. Polymorphism in promoter region of
IL10 gene is associated with rheumatoid arthritis in women. J. Rheumatol. 31,
422–425.
Palaszynski, K.M., Smith, D.L., Kamrava, S., Burgoyne, P.S., Arnold, A.P., Voskuhl, R.R.,
2005. A yin-yang effect between sex chromosome complement and sex
hormones on the immune response. Endocrinology 146, 3280–3285.
Pandit, L., Kundapur, R., 2014. Prevalence and patterns of demyelinating central
nervous system disorders in urban Mangalore, South India. Multip. Scler. http://
dx.doi.org/10.1177/1352458514521503.
Pani, M.A., Van Autreve, J., Van der Auwera, B.J., Gorus, F.K., Badenhoop, K., 2002.
Non-transmitted maternal HLA DQ2 or DQ8 alleles and risk of Type I diabetes in
offspring: the importance of foetal or post partum exposure to diabetogenic
molecules. Diabetologia 45, 1340–1343.
Papenfuss, T.L., Powell, N.D., McClain, M.A., Bedarf, A., Singh, A., Gienapp, I.E.,
Shawler, T., Whitacre, C.C., 2011. Estriol generates tolerogenic dendritic cells
in vivo that protect against autoimmunity. J. Immunol. 186, 3346–3355.
Pedersen, J.K., Svendsen, A.J., Horslev-Petersen, K., 2011. Prevalence of rheumatoid
arthritis in the southern part of denmark. Open Rheumatol. J. 5, 91–97.
Pedersen, E.G., Hallas, J., Hansen, K., Jensen, P.E., Gaist, D., 2013. Late-onset
myasthenia not on the increase: a nationwide register study in Denmark, 1996–
2009. Eur. J. Neurol.: Off. J. Eur. Fed. Neurol. Soc. 20, 309–314.
Pelfrey, C.M., Cotleur, A.C., Lee, J.C., Rudick, R.A., 2002. Sex differences in cytokine
responses to myelin peptides in multiple sclerosis. J. Neuroimmunol. 130, 211–
223.
Pembrey, L., Newell, M.L., Tovo, P.A.European Paediatric Hepatitis, C.V.N., 2008. Age-
related lymphocyte and neutrophil levels in children of hepatitis C-infected
women. Pediatr. Infect. Dis. J. 27, 800–807.
Pender, M.P., Greer, J.M., 2007. Immunology of multiple sclerosis. Curr. Aller.
Asthma Rep. 7, 285–292.
Pernis, A.B., 2007. Estrogen and CD4+ T cells. Curr. Opin. Rheumatol. 19, 414–420.
Perry, V.H., Andersson, P.B., Gordon, S., 1993. Macrophages and inflammation in the
central nervous system. Trends Neurosci. 16, 268–273.
Persani, L., Bonomi, M., Lleo, A., Pasini, S., Civardi, F., Bianchi, I., Campi, I., Finelli, P.,
Miozzo, M., Castronovo, C., Sirchia, S., Gershwin, M.E., Invernizzi, P., 2012.
Increased loss of the Y chromosome in peripheral blood cells in male patients
with autoimmune thyroiditis. J. Autoimmun. 38, J193-6.
Pertovaara, M., Lehtimaki, T., Rontu, R., Antonen, J., Pasternack, A., Hurme, M., 2004.
Presence of apolipoprotein E epsilon4 allele predisposes to early onset of
primary Sjogren’s syndrome. Rheumatology 43, 1484–1487.
Phitayakorn, R., Morales-Garcia, D., Wanderer, J., Lubitz, C.C., Gaz, R.D., Stephen,
A.E., Ehrenfeld, J.M., Daniels, G.H., Hodin, R.A., Parangi, S., 2013. Surgery for
Graves’ disease: a 25-year perspective. Am. J. Surg. 206, 669–673.
Piantoni, S., Andreoli, L., Allegri, F., Meroni, P.L., Tincani, A., 2012. Low levels of
vitamin D are common in primary antiphospholipid syndrome with thrombotic
disease. Reumatismo 64, 307–313.
Piccinni, M.P., Giudizi, M.G., Biagiotti, R., Beloni, L., Giannarini, L., Sampognaro, S.,
Parronchi, P., Manetti, R., Annunziato, F., Livi, C., et al., 1995. Progesterone favors
the development of human T helper cells producing Th2-type cytokines and
promotes both IL-4 production and membrane CD30 expression in established
Th1 cell clones. J. Immunol. 155, 128–133.
Pierdominici, M., Ortona, E., 2013. Estrogen impact on autoimmunity onset and
progression: the paradigm of systemic lupus erythematosus. Int. Trends
Immun. 1, 24–34.
Pierdominici, M., Maselli, A., Colasanti, T., Giammarioli, A.M., Delunardo, F., Vacirca,
D., Sanchez, M., Giovannetti, A., Malorni, W., Ortona, E., 2010. Estrogen receptor
profiles in human peripheral blood lymphocytes. Immunol. Lett. 132, 79–85.
Pikwer, M., Bergstrom, U., Nilsson, J.A., Jacobsson, L., Turesson, C., 2012a. Early
menopause is an independent predictor of rheumatoid arthritis. Ann. Rheum.
Dis. 71, 378–381.
Pikwer, M., Nilsson, J.A., Bergstrom, U., Jacobsson, L.T., Turesson, C., 2012b. Early
menopause and severity of rheumatoid arthritis in women older than 45 years.
Arth. Res. Ther. 14, R190.
Pisetsky, D.S., Spencer, D.M., 2011. Effects of progesterone and estradiol sex
hormones on the release of microparticles by RAW 264.7 macrophages
stimulated by Poly(I:C). Clin. Vaccine Immunol: CVI 18, 1420–1426.
Pivneva, T.A., 2008. Microglia in normal condition and pathology. Fiziolohichnyi
zhurnal 54, 81–89.
Pollard, K.M., 2012. Gender differences in autoimmunity associated with exposure
to environmental factors. J. Autoimmun. 38, J177-86.
Ponsonby, A.L., Lucas, R.M., van der Mei, I.A., 2005. UVR, vitamin D and three
autoimmune diseases–multiple sclerosis, type 1 diabetes, rheumatoid arthritis.
Photochem. Photobiol. 81, 1267–1275.
Poppe, K., Glinoer, D., Tournaye, H., Devroey, P., van Steirteghem, A., Kaufman, L.,
Velkeniers, B., 2003. Assisted reproduction and thyroid autoimmunity: an
unfortunate combination? J. Clin. Endocrinol. Metab. 88, 4149–4152.
Poynard, T., Bedossa, P., Opolon, P., 1997. Natural history of liver fibrosis
progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR,
CLINIVIR, and DOSVIRC groups. Lancet 349, 825–832.
Poyraz, B.C., Aksoy, C., Balcioglu, I., 2008. Increased incidence of autoimmune
thyroiditis in patients with antipsychotic-induced hyperprolactinemia. Eur.
Neuropsychopharmacol.: J. Eur. College Neuropsychopharmacol. 18, 667–672.
Premawardhana, L.D., Parkes, A.B., John, R., Harris, B., Lazarus, J.H., 2004. Thyroid
peroxidase antibodies in early pregnancy: utility for prediction of postpartum
thyroid dysfunction and implications for screening. Thyroid : Off. J. Am. Thyroid
Assoc. 14, 610–615.
367
Pugliese, A., Awdeh, Z.L., Alper, C.A., Jackson, R.A., Eisenbarth, G.S., 1994. The
paternally inherited insulin gene B allele (1,428 FokI site) confers protection
from insulin-dependent diabetes in families. J. Autoimmun. 7, 687–694.
Qin, Y., Melse-Boonstra, A., Shi, Z., Pan, X., Yuan, B., Dai, Y., Zhao, J., Zimmermann,
M.B., Kok, F.J., Zhou, M., 2009. Dietary intake of zinc in the population of Jiangsu
Province, China. Asia Pacif. J. Clin. Nutrit. 18, 193–199.
Qin, B., Wang, J., Liang, Y., Yang, Z., Zhong, R., 2013. The association between TNF-
alpha, IL-10 gene polymorphisms and primary Sjogren’s syndrome: a meta-
analysis and systemic review. PLoS One 8, e63401.
Quintana-Murci, L., Krausz, C., McElreavey, K., 2001. The human Y chromosome:
function, evolution and disease. Forensic Sci. Int. 118, 169–181.
Rabenau, H.F., Buxbaum, S., Preiser, W., Weber, B., Doerr, H.W., 2002.
Seroprevalence of herpes simplex virus types 1 and type 2 in the Frankfurt
am Main area, Germany. Med. Microbiol. Immunol. 190, 153–160.
Radetti, G., Zavallone, A., Gentili, L., Beck-Peccoz, P., Bona, G., 2002. Foetal and
neonatal thyroid disorders. Minerva Pediatr. 54, 383–400.
Rafiei, M., Zarif Yeganeh, M., Sheikholeslami, S., Gozalpour, E., Ghaffarpour, M.,
Hedayati, M., 2012. Apolipoprotein E polymorphisms status in Iranian patients
with multiple sclerosis. J. Neurol. Sci. 320, 22–25.
Raghupathy, R., 2001. Pregnancy: success and failure within the Th1/Th2/Th3
paradigm. Semin. Immunol. 13, 219–227.
Ramagopalan, S.V., Maugeri, N.J., Handunnetthi, L., Lincoln, M.R., Orton, S.M.,
Dyment, D.A., Deluca, G.C., Herrera, B.M., Chao, M.J., Sadovnick, A.D., Ebers,
G.C., Knight, J.C., 2009a. Expression of the multiple sclerosis-associated MHC
class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 5,
e1000369.
Ramagopalan, S.V., Valdar, W., Criscuoli, M., DeLuca, G.C., Dyment, D.A., Orton, S.M.,
Yee, I.M., Ebers, G.C., Sadovnick, A.D.Canadian Collaborative Study, G., 2009b.
Age of puberty and the risk of multiple sclerosis: a population based study. Eur.
J. Neurol.: Off. J. Eur. Fed. Neurol. Soc. 16, 342–347.
Ramagopalan, S.V., Byrnes, J.K., Orton, S.M., Dyment, D.A., Guimond, C., Yee, I.M.,
Ebers, G.C., Sadovnick, A.D., 2010. Sex ratio of multiple sclerosis and clinical
phenotype. Eur. J. Neurol.: Off. J. Eur. Fed. Neurol. Soc. 17, 634–637.
Ramagopalan, S.V., Goldacre, R., Skingsley, A., Conlon, C., Goldacre, M.J., 2013.
Associations between selected immune-mediated diseases and tuberculosis:
record-linkage studies. BMC Med. 11, 97.
Renne, C., Ramos Lopez, E., Steimle-Grauer, S.A., Ziolkowski, P., Pani, M.A., Luther, C.,
Holzer, K., Encke, A., Wahl, R.A., Bechstein, W.O., Usadel, K.H., Hansmann, M.L.,
Badenhoop, K., 2004. Thyroid fetal male microchimerisms in mothers with
thyroid disorders: presence of Y-chromosomal immunofluorescence in thyroid-
infiltrating lymphocytes is more prevalent in Hashimoto’s thyroiditis and
Graves’ disease than in follicular adenomas. J. Clin. Endocrinol. Metab. 89,
5810–5814.
Reveille, J.D., 2011. Epidemiology of spondyloarthritis in North America. Am. J. Med.
Sci. 341, 284–286.
Richardson, S.J., Willcox, A., Bone, A.J., Foulis, A.K., Morgan, N.G., 2009. The
prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic
islets in human type 1 diabetes. Diabetologia 52, 1143–1151.
Rider, V., Li, X., Peterson, G., Dawson, J., Kimler, B.F., Abdou, N.I., 2006. Differential
expression of estrogen receptors in women with systemic lupus erythematosus.
J. Rheumatol. 33, 1093–1101.
Rieger, R., Gershwin, M.E., 2007. The X and why of xenobiotics in primary biliary
cirrhosis. J. Autoimmun. 28, 76–84.
Rieger, R., Leung, P.S., Jeddeloh, M.R., Kurth, M.J., Nantz, M.H., Lam, K.S., Barsky, D.,
Ansari, A.A., Coppel, R.L., Mackay, I.R., Gershwin, M.E., 2006. Identification of 2-
nonynoic acid, a cosmetic component, as a potential trigger of primary biliary
cirrhosis. J. Autoimmun. 27, 7–16.
Roof, R.L., Hall, E.D., 2000. Gender differences in acute CNS trauma and stroke:
neuroprotective effects of estrogen and progesterone. J. Neurotrauma 17, 367–
388.
Rose, N.R., Bona, C., 1993. Defining criteria for autoimmune diseases (Witebsky’s
postulates revisited). Immunol. Today 14, 426–430.
Rosenberg, A.M., Semchuk, K.M., McDuffie, H.H., Ledingham, D.L., Cordeiro, D.M.,
Cessna, A.J., Irvine, D.G., Senthilselvan, A., Dosman, J.A., 1999. Prevalence of
antinuclear antibodies in a rural population. J. Toxicol. Environ. Health Part A
57, 225–236.
Roubinian, J.R., Papoian, R., Talal, N., 1977. Androgenic hormones modulate
autoantibody responses and improve survival in murine lupus. J. Clin. Invest.
59, 1066–1070.
Roubinian, J.R., Talal, N., Greenspan, J.S., Goodman, J.R., Siiteri, P.K., 1978. Effect
of castration and sex hormone treatment on survival, anti-nucleic acid
antibodies, and glomerulonephritis in NZB/NZW F1 mice. J. Exp. Med. 147,
1568–1583.
Rowley, M.J., Mackay, I.R., 1969. Measurement of antibody-producing capacity in
man. I. The normal response to flagellin from Salmonella adelaide. Clin. Exp.
Immunol. 5, 407–418.
Ruiz, E., Ramalle-Gomara, E., Elena, A., Quinones, C., Alonso, V., Posada, M., Spain,
R.D.R.W.g., 2014. Trends in systemic lupus erythematosus mortality in Spain
from 1981 to 2010. Lupus 23, 431–435.
Ruiz-Irastorza, G., Lima, F., Alves, J., Khamashta, M.A., Simpson, J., Hughes, G.R.,
Buchanan, N.M., 1996. Increased rate of lupus flare during pregnancy and the
puerperium: a prospective study of 78 pregnancies. Br. J. Rheumatol. 35, 133–
138.
Runmarker, B., Andersen, O., 1993. Prognostic factors in a multiple sclerosis
incidence cohort with twenty-five years of follow-up. Brain: J. Neurol. 116 (Pt
1), 117–134.
368 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
Runmarker, B., Andersen, O., 1995. Pregnancy is associated with a lower risk of
onset and a better prognosis in multiple sclerosis. Brain: J. Neurol. 118 (Pt 1),
253–261.
Saito, S., Sasaki, Y., Sakai, M., 2005. CD4(+)CD25high regulatory T cells in human
pregnancy. J. Reprod. Immunol. 65, 111–120.
Saito, S., Nakashima, A., Ito, M., Shima, T., 2011. Clinical implication of recent
advances in our understanding of IL-17 and reproductive immunology. Expert
Rev. Clin. Immunol. 7, 649–657.
Sakai, R., Matsui, S., Fukushima, M., Yasuda, H., Miyauchi, H., Miyachi, Y., 2005.
Prognostic factor analysis for plaque psoriasis. Dermatology 211, 103–106.
Sakiani, S., Olsen, N.J., Kovacs, W.J., 2013. Gonadal steroids and humoral immunity.
Nat. Rev. Endocrinol. 9, 56–62.
Sanchez-Guerrero, J., Villegas, A., Mendoza-Fuentes, A., Romero-Diaz, J., Moreno-
Coutino, G., Cravioto, M.C., 2001. Disease activity during the premenopausal and
postmenopausal periods in women with systemic lupus erythematosus. Am. J.
Med. 111, 464–468.
Sanchez-Guerrero, J., Gonzalez-Perez, M., Durand-Carbajal, M., Lara-Reyes, P.,
Jimenez-Santana, L., Romero-Diaz, J., Cravioto, M.D., 2007. Menopause
hormonal therapy in women with systemic lupus erythematosus. Arth.
Rheum. 56, 3070–3079.
Santiago-Raber, M.L., Kikuchi, S., Borel, P., Uematsu, S., Akira, S., Kotzin, B.L., Izui, S.,
2008. Evidence for genes in addition to Tlr7 in the Yaa translocation linked with
acceleration of systemic lupus erythematosus. J. Immunol. 181, 1556–1562.
Savettieri, G., Messina, D., Andreoli, V., Bonavita, S., Caltagirone, C., Cittadella, R.,
Farina, D., Fazio, M.C., Girlanda, P., Le Pira, F., Liguori, M., Lugaresi, A., Nocentini,
U., Reggio, A., Salemi, G., Tedeschi, G., Trojano, M., Valentino, P., Quattrone, A.,
2004. Gender-related effect of clinical and genetic variables on the cognitive
impairment in multiple sclerosis. J. Neurol. 251, 1208–1214.
Schendel, D.J., Johnson, J.P., 1985. T cells specific for different antigens express
different HLA-D region products. Eur. J. Immunol. 15, 1239–1243.
Selmi, C., Lu, Q., Humble, M.C., 2012. Heritability versus the role of the environment
in autoimmunity. J. Autoimmun. 39, 249–252.
Seror, R., Gottenberg, J.E., Devauchelle-Pensec, V., Dubost, J.J., Le Guern, V., Hayem,
G., Fauchais, A.L., Goeb, V., Hachulla, E., Hatron, P.Y., Larroche, C., Morel, J.,
Pedriger, A., Puechal, X., Rist, S., Saraux, A., Sene, D., Sibilia, J., Vittecoq, O.,
Zarnitsky, C., Labetoulle, M., Ravaud, P., Mariette, X., 2013. European league
against rheumatism Sjogren’s syndrome disease activity index and european
league against rheumatism Sjogren’s syndrome patient-reported index: a
complete picture of primary Sjogren’s syndrome patients. Arth. Care Res. 65,
1358–1364.
Sharma, S., Eghbali, M., 2014. Influence of sex differences on microRNA gene
regulation in disease. Biol. Sex diff. 5, 3.
Shen, M., Zhang, F., Zhang, X., 2009. Pulmonary hypertension in primary biliary
cirrhosis: a prospective study in 178 patients. Scand. J. Gastroenterol. 44, 219–
223.
Shoenfeld, Y., Blank, M., Abu-Shakra, M., Amital, H., Barzilai, O., Berkun, Y., Bizzaro,
N., Gilburd, B., Zandman-Goddard, G., Katz, U., Krause, I., Langevitz, P., Mackay,
I.R., Orbach, H., Ram, M., Sherer, Y., Toubi, E., Gershwin, M.E., 2008. The mosaic
of autoimmunity: prediction, autoantibodies, and therapy in autoimmune
diseases–2008. Israel Med. Assoc. J.: IMAJ 10, 13–19.
Shohat, T., Green, M.S., Nakar, O., Ballin, A., Duvdevani, P., Cohen, A., Shohat, M.,
2000. Gender differences in the reactogenicity of measles-mumps-rubella
vaccine. Israel Med. Assoc. J.: IMAJ 2, 192–195.
Si, M.L., Al-Sharafi, B., Lai, C.C., Khardori, R., Chang, C., Su, C.Y., 2001. Gender
difference in cytoprotection induced by estrogen on female and male bovine
aortic endothelial cells. Endocrine 15, 255–262.
Sicotte, N.L., Liva, S.M., Klutch, R., Pfeiffer, P., Bouvier, S., Odesa, S., Wu, T.C., Voskuhl,
R.R., 2002. Treatment of multiple sclerosis with the pregnancy hormone estriol.
Ann. Neurol. 52, 421–428.
Sicotte, N.L., Giesser, B.S., Tandon, V., Klutch, R., Steiner, B., Drain, A.E., Shattuck,
D.W., Hull, L., Wang, H.J., Elashoff, R.M., Swerdloff, R.S., Voskuhl, R.R., 2007.
Testosterone treatment in multiple sclerosis: a pilot study. Arch. Neurol. 64,
683–688.
Silverman, A.J., Sutherland, A.K., Wilhelm, M., Silver, R., 2000. Mast cells migrate
from blood to brain. J. Neurosci.: Off. J. Soc. Neurosci. 20, 401–408.
Singhal, B.S., Bhatia, N.S., Umesh, T., Menon, S., 2008. Myasthenia gravis: a study
from India. Neurol. Ind. 56, 352–355.
Sjöberg, L., He, L., Tuomilehto, J., Kaaja, R., Pitkäniemi, J., 2013. Mortality and Having
Offspring in Type 1 Diabetes, European Association for the Study of Diabetes,
Barcelona.
Smith, R., Studd, J.W., 1992. A pilot study of the effect upon multiple sclerosis of the
menopause, hormone replacement therapy and the menstrual cycle. J. R. Soc.
Med. 85, 612–613.
Smithson, G., Couse, J.F., Lubahn, D.B., Korach, K.S., Kincade, P.W., 1998. The role of
estrogen receptors and androgen receptors in sex steroid regulation of B
lymphopoiesis. J. Immunol. 161, 27–34.
Somerset, D.A., Zheng, Y., Kilby, M.D., Sansom, D.M., Drayson, M.T., 2004. Normal
human pregnancy is associated with an elevation in the immune suppressive
CD25+ CD4+ regulatory T-cell subset. Immunology 112, 38–43.
Sood, S., Gow, P.J., Christie, J.M., Angus, P.W., 2004. Epidemiology of primary biliary
cirrhosis in Victoria, Australia: high prevalence in migrant populations.
Gastroenterology 127, 470–475.
Spach, K.M., Blake, M., Bunn, J.Y., McElvany, B., Noubade, R., Blankenhorn, E.P.,
Teuscher, C., 2009. Cutting edge: the Y chromosome controls the age-dependent
experimental allergic encephalomyelitis sexual dimorphism in SJL/J mice. J.
Immunol. 182, 1789–1793.
Spector, T.D., Roman, E., Silman, A.J., 1990. The pill, parity, and rheumatoid arthritis.
Arth. Rheum. 33, 782–789.
Speight, J., Browne, J.L., Holmes-Truscott, E., Hendrieckx, C., Pouwer, F., 2012.
Diabetes MILES–Australia (management and impact for long-term
empowerment and success): methods and sample characteristics of a
national survey of the psychological aspects of living with type 1 or type 2
diabetes in Australian adults. BMC Publ. Health 12, 120.
Spence, R.D., Hamby, M.E., Umeda, E., Itoh, N., Du, S., Wisdom, A.J., Cao, Y., Bondar,
G., Lam, J., Ao, Y., Sandoval, F., Suriany, S., Sofroniew, M.V., Voskuhl, R.R., 2011.
Neuroprotection mediated through estrogen receptor-alpha in astrocytes. Proc.
Nat. Acad. Sci. U.S.A. 108, 8867–8872.
Spolarics, Z., 2007. The X-files of inflammation: cellular mosaicism of X-linked
polymorphic genes and the female advantage in the host response to injury and
infection. Shock 27, 597–604.
St John, A.L., Abraham, S.N., 2013. Innate immunity and its regulation by mast cells.
J. Immunol. 190, 4458–4463.
Staples, J., Ponsonby, A.L., Lim, L., 2010. Low maternal exposure to ultraviolet
radiation in pregnancy, month of birth, and risk of multiple sclerosis in
offspring: longitudinal analysis. BMJ 340, c1640.
Stark, A.K., Petersen, A.O., Gardi, J., Gundersen, H.J., Pakkenberg, B., 2007. Spatial
distribution of human neocortical neurons and glial cells according to sex and
age measured by the saucer method. J. Neurosci. Methods 164, 19–26.
Stevens, A.M., Hermes, H.M., Rutledge, J.C., Buyon, J.P., Nelson, J.L., 2003.
Myocardial-tissue-specific phenotype of maternal microchimerism in
neonatal lupus congenital heart block. Lancet 362, 1617–1623.
Steyn, F.J., Anderson, G.M., Grattan, D.R., 2008. Hormonal regulation of suppressors
of cytokine signaling (SOCS) messenger ribonucleic acid in the arcuate nucleus
during late pregnancy. Endocrinology 149, 3206–3214.
Sthoeger, Z.M., Chiorazzi, N., Lahita, R.G., 1988. Regulation of the immune response
by sex hormones. I. In vitro effects of estradiol and testosterone on pokeweed
mitogen-induced human B cell differentiation. J. Immunol. 141, 91–98.
Stojan, G., Baer, A.N., 2012. Flares of systemic lupus erythematosus during
pregnancy and the puerperium: prevention, diagnosis and management.
Expert Rev. Clin. Immunol. 8, 439–453.
Stoll, M., Corneliussen, B., Costello, C.M., Waetzig, G.H., Mellgard, B., Koch, W.A.,
Rosenstiel, P., Albrecht, M., Croucher, P.J., Seegert, D., Nikolaus, S., Hampe, J.,
Lengauer, T., Pierrou, S., Foelsch, U.R., Mathew, C.G., Lagerstrom-Fermer, M.,
Schreiber, S., 2004. Genetic variation in DLG5 is associated with inflammatory
bowel disease. Nat. Genet. 36, 476–480.
Straub, R.H., 2007. The complex role of estrogens in inflammation. Endocr. Rev. 28,
521–574.
Stringer, E.M., Kaseba, C., Levy, J., Sinkala, M., Goldenberg, R.L., Chi, B.H., Matongo, I.,
Vermund, S.H., Mwanahamuntu, M., Stringer, J.S., 2007. A randomized trial of
the intrauterine contraceptive device vs hormonal contraception in women
who are infected with the human immunodeficiency virus. Am. J. Obstet.
Gynecol. 197 (144), e1-8.
Strohsnitter, W.C., Noller, K.L., Troisi, R., Robboy, S.J., Hatch, E.E., Titus-Ernstoff, L.,
Kaufman, R.H., Palmer, J.R., Anderson, D., Hoover, R.N., 2010. Autoimmune
disease incidence among women prenatally exposed to diethylstilbestrol. J.
Rheumatol. 37, 2167–2173.
Subramanian, S., Tus, K., Li, Q.Z., Wang, A., Tian, X.H., Zhou, J., Liang, C., Bartov, G.,
McDaniel, L.D., Zhou, X.J., Schultz, R.A., Wakeland, E.K., 2006. A Tlr7
translocation accelerates systemic autoimmunity in murine lupus. Proc. Nat.
Acad. Sci. U.S.A. 103, 9970–9975.
Sugiyama, D., Nishimura, K., Tamaki, K., Tsuji, G., Nakazawa, T., Morinobu, A.,
Kumagai, S., 2010. Impact of smoking as a risk factor for developing
rheumatoid arthritis: a meta-analysis of observational studies. Ann. Rheum.
Dis. 69, 70–81.
Sukenik-Halevy, R., Ellis, M.H., Fejgin, M.D., 2008. Management of immune
thrombocytopenic purpura in pregnancy. Obstet. Gynecol. Surv. 63, 182–188.
Sulke, A.N., Jones, D.B., Wood, P.J., 1985. Hormonal modulation of human natural
killer cell activity in vitro. J. Reprod. Immunol. 7, 105–110.
Suzuki, Y., Utsugisawa, K., Suzuki, S., Nagane, Y., Masuda, M., Kabasawa, C., Shimizu,
Y., Utsumi, H., Uchiyama, S., Fujihara, K., Suzuki, N., 2011. Factors associated
with depressive state in patients with myasthenia gravis: a multicentre cross-
sectional study. BMJ Open 1, e000313.
Takao, T., Kumagai, C., Hisakawa, N., Matsumoto, R., Hashimoto, K., 2005. Effect of
17beta-estradiol on tumor necrosis factor-alpha-induced cytotoxicity in the
human peripheral T lymphocytes. J. Endocrinol. 184, 191–197.
Tan, E.K., Tan, E.L., 2013. Alterations in physiology and anatomy during pregnancy.
Best Pract. Res. Clin. Obstet. Gynaecol. 27, 791–802.
Taylor, B.V., Pearson, J.F., Clarke, G., Mason, D.F., Abernethy, D.A., Willoughby, E.,
Sabel, C., 2010. MS prevalence in New Zealand, an ethnically and latitudinally
diverse country. Multip. Scler. 16, 1422–1431.
Tedeschi, S.K., Bermas, B., Costenbader, K.H., 2013. Sexual disparities in the
incidence and course of SLE and RA. Clin. Immunol. 149, 211–218.
Teuscher, C., Noubade, R., Spach, K., McElvany, B., Bunn, J.Y., Fillmore, P.D., Zachary,
J.F., Blankenhorn, E.P., 2006. Evidence that the Y chromosome influences
autoimmune disease in male and female mice. Proc. Nat. Acad. Sci. U.S.A. 103,
8024–8029.
Thompson, C., Farid, N.R., 1985. Post-partum thyroiditis and goistrous
(Hashimoto’s) thyroiditis are associated with HLA-DR4. Immunol. Lett. 11,
301–303.
Thrasher, J.D., Madison, R., Broughton, A., 1993. Immunologic abnormalities in
humans exposed to chlorpyrifos: preliminary observations. Arch. Environ.
Health 48, 89–93.
 S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369
Tomio, A., Schust, D.J., Kawana, K., Yasugi, T., Kawana, Y., Mahalingaiah, S., Fujii, T.,
Taketani, Y., 2008. Prolactin can modulate CD4+ T-cell response through
receptor-mediated alterations in the expression of T-bet. Immunol. Cell Biol. 86,
616–621.
Tripanichkul, W., Sripanichkulchai, K., Finkelstein, D.I., 2006. Estrogen down-
regulates glial activation in male mice following 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine intoxication. Brain Res. 1084, 28–37.
Tsuboi, H., Asashima, H., Takai, C., Hagiwara, S., Hagiya, C., Yokosawa, M., Hirota, T.,
Umehara, H., Kawakami, A., Nakamura, H., Sano, H., Tsubota, K., Ogawa, Y.,
Takamura, E., Saito, I., Inoue, H., Nakamura, S., Moriyama, M., Takeuchi, T., Tanaka,
Y., Hirata, S., Mimori, T., Yoshifuji, H., Ohta, A., Matsumoto, I., Sumida, T., 2014.
Primary and secondary surveys on epidemiology of Sjogren’s syndrome in Japan.
Mod. Rheumatol./Jpn. Rheumat. Assoc 24, 464–470.
Urowitz, M.B., Ibanez, D., Jerome, D., Gladman, D.D., 2006. The effect of menopause on
disease activity in systemic lupus erythematosus. J. Rheumatol. 33, 2192–2198.
Uvnas-Moberg, K., Widstrom, A.M., Werner, S., Matthiesen, A.S., Winberg, J., 1990.
Oxytocin and prolactin levels in breast-feeding women. Correlation with milk
yield and duration of breast-feeding. Acta Obstet. Gynecol. Scand. 69, 301–306.
Uz, E., Loubiere, L.S., Gadi, V.K., Ozbalkan, Z., Stewart, J., Nelson, J.L., Ozcelik, T., 2008.
Skewed X-chromosome inactivation in scleroderma. Clin. Rev. Allergy Immunol.
34, 352–355.
van der Lugt, N.M., van Kampen, A., Walther, F.J., Brand, A., Lopriore, E., 2013.
Outcome and management in neonatal thrombocytopenia due to maternal
idiopathic thrombocytopenic purpura. Vox Sang. 105, 236–243.
van der Mei, I.A., Ponsonby, A.L., Dwyer, T., Blizzard, L., Simmons, R., Taylor, B.V.,
Butzkueven, H., Kilpatrick, T., 2003. Past exposure to sun, skin phenotype, and
risk of multiple sclerosis: case-control study. BMJ 327, 316.
van der Mei, I.A., Ponsonby, A.L., Dwyer, T., Blizzard, L., Taylor, B.V., Kilpatrick, T.,
Butzkueven, H., McMichael, A.J., 2007. Vitamin D levels in people with multiple
sclerosis and community controls in Tasmania, Australia. J. Neurol. 254, 581–590.
van Leuven, S.I., Kastelein, J.J., D’Cruz, D.P., Hughes, G.R., Stroes, E.S., 2006.
Atherogenesis in rheumatology. Lupus 15, 117–121.
van Vollenhoven, R.F., Engleman, E.G., McGuire, J.L., 1994. An open study of
dehydroepiandrosterone in systemic lupus erythematosus. Arth. Rheum. 37,
1305–1310.
van Vollenhoven, R.F., Engleman, E.G., McGuire, J.L., 1995. Dehydroepiandrosterone
in systemic lupus erythematosus. Results of a double-blind, placebo-controlled,
randomized clinical trial. Arth. Rheum. 38, 1826–1831.
van Vollenhoven, R.F., Park, J.L., Genovese, M.C., West, J.P., McGuire, J.L., 1999. A
double-blind, placebo-controlled, clinical trial of dehydroepiandrosterone in
severe systemic lupus erythematosus. Lupus 8, 181–187.
Vanags, D., Williams, B., Johnson, B., Hall, S., Nash, P., Taylor, A., Weiss, J., Feeney, D.,
2006. Therapeutic efficacy and safety of chaperonin 10 in patients with
rheumatoid arthritis: a double-blind randomised trial. Lancet 368, 855–863.
Vandenberg, L.N., Colborn, T., Hayes, T.B., Heindel, J.J., Jacobs Jr., D.R., Lee, D.H.,
Shioda, T., Soto, A.M., vom Saal, F.S., Welshons, W.V., Zoeller, R.T., Myers, J.P.,
2012. Hormones and endocrine-disrupting chemicals: low-dose effects and
nonmonotonic dose responses. Endocr. Rev. 33, 378–455.
Vandenbroucke, J.P., Valkenburg, H.A., Boersma, J.W., Cats, A., Festen, J.J., Huber-
Bruning, O., Rasker, J.J., 1982. Oral contraceptives and rheumatoid arthritis:
further evidence for a preventive effect. Lancet 2, 839–842.
Veenstra van Nieuwenhoven, A.L., Heineman, M.J., Faas, M.M., 2003. The
immunology of successful pregnancy. Hum. Reprod. Update 9, 347–357.
Vera-Lastra, O., Jara, L.J., Espinoza, L.R., 2002. Prolactin and autoimmunity.
Autoimmun. Rev. 1, 360–364.
Verdru, P., Theys, P., D’Hooghe, M.B., Carton, H., 1994. Pregnancy and multiple
sclerosis: the influence on long term disability. Clin. Neurol. Neurosurg. 96, 38–41.
Vogelsang, P., Brun, J.G., Oijordsbakken, G., Skarstein, K., Jonsson, R., Appel, S., 2010.
Levels of plasmacytoid dendritic cells and type-2 myeloid dendritic cells are
reduced in peripheral blood of patients with primary Sjogren’s syndrome. Ann.
Rheum. Dis. 69, 1235–1238.
Vukusic, S., Van Bockstael, V., Gosselin, S., Confavreux, C., 2007. Regional variations
in the prevalence of multiple sclerosis in French farmers. J. Neurol. Neurosurg.
Psychiat. 78, 707–709.
Vukusic, S., Ionescu, I., El-Etr, M., Schumacher, M., Baulieu, E.E., Cornu, C.,
Confavreux, C.Prevention of Post-Partum Relapses with, P., and Estradiol in
Multiple Sclerosis Study, G., 2009. The Prevention of Post-Partum Relapses with
Progestin and Estradiol in Multiple Sclerosis (POPART’MUS) trial: rationale,
objectives and state of advancement. J. Neurol. Sci. 286, 114–118.
Vyshkina, T., Sylvester, A., Sadiq, S., Bonilla, E., Canter, J.A., Perl, A., Kalman, B., 2008.
Association of common mitochondrial DNA variants with multiple sclerosis and
systemic lupus erythematosus. Clin. Immunol. 129, 31–35.
Wagner, A.K., Sasser, H.C., Hammond, F.M., Wiercisiewski, D., Alexander, J., 2000.
Intentional traumatic brain injury: epidemiology, risk factors, and associations
with injury severity and mortality. J. Trauma 49, 404–410.
Wahren-Herlenius, M., Sonesson, S.E., 2006. Specificity and effector mechanisms of
autoantibodies in congenital heart block. Curr. Opin. Immunol. 18, 690–696.
Walitt, B., Pettinger, M., Weinstein, A., Katz, J., Torner, J., Wasko, M.C., Howard,
B.V.Women’s Health Initiative, I., 2008. Effects of postmenopausal hormone
therapy on rheumatoid arthritis: the women’s health initiative randomized
controlled trials. Arthritis Rheum. 59, 302–310.
Walker, S.E., 2007. The importance of sex hormones in lupus. In: Wallace, D.J., Hahn,
G.H. (Eds.), Dubois Lupus Erythematosus Williams and Wilkins, Baltimore.
Wardlaw, A.J., Moqbel, R., Cromwell, O., Kay, A.B., 1986. Platelet-activating factor. A
potent chemotactic and chemokinetic factor for human eosinophils. J. Clin.
Invest. 78, 1701–1706.
369
Weetman, A.P., McGregor, A.M., Smith, B.R., Hall, R., 1981. Sex hormones enhance
immunoglobulin synthesis by human peripheral blood lymphocytes. Immunol.
Lett. 3, 343–346.
Weinshenker, B.G., Rice, G.P., Noseworthy, J.H., Carriere, W., Baskerville, J., Ebers,
G.C., 1991. The natural history of multiple sclerosis: a geographically based
study. 3. Multivariate analysis of predictive factors and models of outcome.
Brain: J. Neurol. 114 (Pt 2), 1045–1056.
Werner, M., Prytz, H., Ohlsson, B., Almer, S., Bjornsson, E., Bergquist, A., Wallerstedt,
S., Sandberg-Gertzen, H., Hultcrantz, R., Sangfelt, P., Weiland, O., Danielsson, A.,
2008. Epidemiology and the initial presentation of autoimmune hepatitis in
Sweden: a nationwide study. Scand. J. Gastroenterol. 43, 1232–1240.
Wheeler, C., Nabors, L.B., Barnum, S., Yang, X., Hu, X., Schoeb, T.R., Chen, D., Ardelt,
A.A., King, P.H., 2012. Sex hormone-dependent attenuation of EAE in a
transgenic mouse with astrocytic expression of the RNA regulator HuR. J.
Neuroimmunol. 246, 34–37.
Whitacre, C.C., Reingold, S.C., O’Looney, P.A., 1999. A gender gap in autoimmunity.
Science 283, 1277–1278.
Willer, C.J., Dyment, D.A., Risch, N.J., Sadovnick, A.D., Ebers, G.C.Canadian
Collaborative Study, G., 2003. Twin concordance and sibling recurrence rates
in multiple sclerosis. Proc. Nat. Acad. Sci. U.S.A. 100, 12877–12882.
Willer, C.J., Dyment, D.A., Sadovnick, A.D., Rothwell, P.M., Murray, T.J., Ebers,
G.C.Canadian Collaborative Study, G., 2005. Timing of birth and risk of multiple
sclerosis: population based study. BMJ 330, 120.
Willer, C.J., Herrera, B.M., Morrison, K.M., Sadovnick, A.D., Ebers, G.C.Canadian
Collaborative Study on Genetic Susceptibility to Multiple, S., 2006. Association
between microchimerism and multiple sclerosis in Canadian twins. J.
Neuroimmunol. 179., 145–151.
Wirenfeldt, M., Babcock, A.A., Vinters, H.V., 2011. Microglia – insights into immune
system structure, function, and reactivity in the central nervous system. Histol.
Histopathol. 26, 519–530.
Witebsky, E., Rose, N.R., Terplan, K., Paine, J.R., Egan, R.W., 1957. Chronic thyroiditis
and autoimmunization. J. Am. Med. Assoc. 164, 1439–1447.
Wundes, A., Amtmann, D., Brown, T., Christian, S., 2011. Menopause in women with
multiple sclerosis. Int. J. MS Care 12, 47.
Wyle, F.A., Kent, J.R., 1977. Immunosuppression by sex steroid hormones. The effect
upon PHA- and PPD-stimulated lymphocytes. Clin. Exp. Immunol. 27, 407–415.
Xiang, Y.J., Dai, S.M., 2009. Prevalence of rheumatic diseases and disability in China.
Rheumatol. Int. 29, 481–490.
Yamanaka, H., Sugiyama, N., Inoue, E., Taniguchi, A., Momohara, S., 2013. Estimates
of the prevalence of and current treatment practices for rheumatoid arthritis in
Japan using reimbursement data from health insurance societies and the IORRA
cohort (I). Mod. Rheumatol./Jpn. Rheumat. Assoc.
Yan, J., Greer, J.M., Hull, R., O’Sullivan, J.D., Henderson, R.D., Read, S.J., McCombe,
P.A., 2010. The effect of ageing on human lymphocyte subsets: comparison of
males and females. Immunity Ageing: I & A 7, 4.
Yang, J.H., Chen, C.D., Wu, M.Y., Chao, K.H., Yang, Y.S., Ho, H.N., 2000. Hormone
replacement therapy reverses the decrease in natural killer cytotoxicity but
does not reverse the decreases in the T-cell subpopulation or interferon-gamma
production in postmenopausal women. Fertil. Steril. 74, 261–267.
Yang, X.Y., Liang, L.Q., Xu, H.S., He, M., Yao, S.Z., Zhan, Z.P., Ye, Y.J., 2003. Efficacy of
oral bromocriptine in protecting the postpartum systemic lupus erythematosus
patients from disease relapse. Zhonghua nei ke za zhi. 42, 621–624.
Yildirim, A., Tunaoolu, F.S., Karaaoac, A.T., 2013. Neonatal congenital heart block.
Ind. Pediatr. 50, 483–488.
Yip, L., McCluskey, J., Sinclair, R., 2006. Immunological aspects of pregnancy. Clin.
Dermatol. 24, 84–87.
Yu, L., Chase, H.P., Falorni, A., Rewers, M., Lernmark, A., Eisenbarth, G.S., 1995.
Sexual dimorphism in transmission of expression of islet autoantibodies to
offspring. Diabetologia 38, 1353–1357.
Zandman-Goddard, G., Peeva, E., Shoenfeld, Y., 2007. Gender and autoimmunity.
Autoimmun. Rev. 6, 366–372.
Zanetti, A.R., Tanzi, E., Romano, L., Zuin, G., Minola, E., Vecchi, L., Principi, N., 1998. A
prospective study on mother-to-infant transmission of hepatitis C virus.
Intervirology 41, 208–212.
Zang, E.A., Wynder, E.L., 1996. Differences in lung cancer risk between men and
women: examination of the evidence. J. Natl. Cancer Inst. 88, 183–192.
Zhang, L., Li, H., Ji, Q.H., Zhu, Y.X., Wang, Z.Y., Wang, Y., Huang, C.P., Shen, Q., Li, D.S.,
Wu, Y., 2012. The clinical features of papillary thyroid cancer in Hashimoto’s
thyroiditis patients from an area with a high prevalence of Hashimoto’s disease.
BMC Cancer 12, 610.
Zhao, J., Ng, S.C., Lei, Y., Yi, F., Li, J., Yu, L., Zou, K., Dan, Z., Dai, M., Ding, Y., Song, M.,
Mei, Q., Fang, X., Liu, H., Shi, Z., Zhou, R., Xia, M., Wu, Q., Xiong, Z., Zhu, W., Deng,
L., Kamm, M.A., Xia, B., 2013. First prospective, population-based inflammatory
bowel disease incidence study in mainland of China: the emergence of
‘‘western’’ disease. Inflamm. Bowel Dis. 19, 1839–1845.
Zhu, J.M., Li, B.K., Chen, G.M., Feng, C.C., Cen, H., Fan, Y.G., Wang, B., Pan, H.F., Ye,
D.Q., 2013. CTLA-4 -1722T/C polymorphism and systemic lupus erythematosus
susceptibility: a meta-analysis involving ten separate studies. Immunol. Invest.
42, 91–105.
Zinger, H., Sherer, Y., Goddard, G., Berkun, Y., Barzilai, O., Agmon-Levin, N., Ram, M.,
Blank, M., Tincani, A., Rozman, B., Cervera, R., Shoenfeld, Y., 2009. Common
infectious agents prevalence in antiphospholipid syndrome. Lupus 18, 1149–
1153.
Zoller, A.L., Kersh, G.J., 2006. Estrogen induces thymic atrophy by eliminating early
thymic progenitors and inhibiting proliferation of beta-selected thymocytes. J.
Immunol. 176, 7371–7378.