TEM-986; No.
of Pages 9
Review
Hashimoto’s thyroiditis and papillary
thyroid cancer: are they
immunologically linked?
Margret Ehlers and Matthias Schott
Division for Specific Endocrinology, Medical Faculty, University of Duesseldorf, Duesseldorf, Germany
Hashimoto’s thyroiditis (HT) is the most common auto-
immune disease in humans frequently leading to hypo-
thyroidism. HT is characterized by a cellular immune
response with lymphatic infiltration of the thyroid gland
by T and B cells, as well as by a humoral immune
response leading to specific antibody production. The
synchronous appearance of HT and papillary thyroid
cancer (PTC) indicates an immunological link between
the two entities. Three different pathomechanisms may
be postulated, including preexisting autoimmunity lead-
ing to malignancy due to inflammation, immunity to-
wards preexisiting tumor cells leading to specific
autoimmunity, and immune tolerance leading to malig-
nancy despite (auto)immunity. In this article we review
data describing these potential mechanisms that might
lead to the synchronous appearance of HT and PTC.
Hashimoto’s thyroiditis and papillary thyroid cancer:
two immunological opposites?
The thyroid gland is affected by autoimmune attacks more
than any other organ, with Hashimoto’s thyroiditis (HT, see
Glossary) being the most common thyroidal autoimmune
disease [1]. The annual incidence of HT worldwide is estimat-
ed to be 0.3–1.5 cases per 1000 persons [1,2]. The key factor in
the pathogenesis of HT is the breakdown of immune tolerance
towards the thyroid gland. Following an initial stimulus, such
as environmental factors including iodine intake, among
others (reviewed in [3]), formerly thyroid-tolerant immune
cells become activated and lose their thyroid tolerance. As a
consequence, leukocytes infiltrate the tissue thus promoting
the development of an autoimmune response [4]. In fact, HT is
defined as a destructive tissue-specific autoimmune disease
with detectable anti-thyroglobulin (Tg) and anti-thyroid per-
oxidase (TPO) antibodies. As a result, HT frequently leads to
hypothyroidism, which is characterized by a deficit of thyroid
hormones [triiodothyronine (T3) and thyroxine (T4)] and
elevated thyroid-stimulating hormone (TSH) levels. The ele-
vated TSH might potentially increase the risk of thyroid
cancer owing to TSH-induced proliferation of thyroid cells
Corresponding authors: Ehlers, M. (Margret.Ehlers@uni-duesseldorf.de); Schott, M.
(Matthias.Schott@med.uni-duesseldorf.de).
Keywords: thyroid gland; Hashimoto’s thyroiditis; papillary thyroid carcinoma;
cellular immunity.
1043-2760/
ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2014.09.001
[5]. In fact, a relation between papillary thyroid cancer (PTC)
and serum TSH levels has been shown. Treatment with L-
thyroxine reduces TSH levels and decreases the occurrence of
clinically detectable PTC [5].
Glossary
Antigen-presenting cell (APC): displays antigens (peptide fragments) com-
plexed with MHC molecules on their surfaces for T cell activation.
Autoimmune thyroiditis (AIT): an autoimmune thyroid disease. It is usually
used as a synonym for Hashimoto’s thyroiditis. Graves’ disease, another
autoimmune thyroid disease leading to hyperthyroidism, is occasionally also
classified as AIT.
B7 homolog 1 (B7H1): also known as CD274, programmed cell death-1 (PD-1)
ligand. Binding to its receptor (PD-1, CD279), results in apoptosis of target cells
(e.g., immune cells).
Cytotoxic T lymphocyte (CTL): usually expresses CD8 and recognizes peptides
displayed by MHC molecules. Following, altered cells (infected host cells,
cancer cells) are killed by CTLs.
Dendritic cell (DC): an antigen-presenting cell that induces adaptive immune
responses by activating naı̈ve T lymphocytes.
Fas ligand (FasL): a member of the TNF family that upon binding to its receptor,
triggers apoptosis. It plays a role in the regulation of the immune system and
the progression of cancer.
Hashimoto’s thyroiditis (HT): one type of autoimmune thyroiditis. HT is
characterized by thyroidal lymphatic infiltration leading to tissue destruction
and frequently hypothyroidism.
High mobility group box 1 (HMGB1): a key chromatin protein. In the nucleus,
HMGB1 interacts with histones, nucleosomes, and transcription factors. In
necrotic cells it is released passively and behaves as a trigger of inflammation.
Histocompatibility antigen, class I, G (HLA-G): a non-classical HLA class I
molecule that exerts an overall negative immune function by inhibiting the
activity of NK cells, CTLs, and APCs.
Immunosubversion and immunoediting: immunosubversion is a mechanism
by which the tumor is not recognized as being immunologically conspicuous;
immunoediting is initiated by immunosurveillance, a mechanism by which
resistant tumor cells are selected potentially due to T cell tolerance.
Major histocompatibility complex (MHC) molecule: a membrane protein that
displays peptides for recognition by T lymphocytes. MHC class I molecules are
recognized by CD8+ T cells and MHC class II molecules by CD4+ T cells.
Papillary thyroid carcinoma (PTC): a common (75–85% of all thyroid cancer
cases) well-differentiated thyroid cancer. It originates from epithelial cells and
is mainly characterized by slow growth and lymphatic spread with rarely
occurring distant metastasis.
Papillary thyroid microcarcinomas (PTMC): a subset of PTC that is less than
10 mm in diameter.
Regulatory T cell (Treg): a subpopulation of T cells that modulate the immune
system. Tregs maintain tolerance to self-antigens and can help abolish
autoimmune disease.
T helper 1 (Th1): a type of T cell that plays an important role in the adaptive
immune system. Th1 cells release cytokines that activate other immune cells.
Thyroglobulin (Tg): the most-abundant protein of the thyroid gland. Tg is
composed of two polypeptide chains that give rise to triiodothyronine (T3) and
thyroxine (T4).
Thyroid peroxidase (TPO): the major enzyme involved in thyroid hormone
synthesis. It assists the chemical reaction that adds iodine to Tg for the
production of T4 or T3.
Thyroid-stimulating hormone (TSH): a hormone secreted by the pituitary
gland. TSH stimulates the thyroid gland to produce T4 and T3.
Trends in Endocrinology and Metabolism xx (2014) 1–9 1
TEM-986; No. of Pages 9
Review
In fact, the thyroid gland is affected by one of the most
common endocrine tumors such as differentiated thyroid
cancer, with PTC being the most common. Differentiated
thyroid cancer comprises 90% of all cases of thyroid carci-
noma, is generally indolent, and shows an excellent prog-
nosis (10 year survival of more than 90%) unless it is
metastasized and is not treatable with radioactive iodine
therapy or surgery [6]. The incidence of differentiated
thyroid cancer has been increasing over the past 30 years
from 3.6/100000 persons in 1973 to 12.2/100000 persons in
2010 [7]. The reason for this increase is likely multifacto-
rial and not entirely understood. One explanation is the
increase of coincidentally identified microcarcinomas ow-
ing to more sensitive diagnostic procedures.
An association between HT and PTC has been a topic of
discussion for a considerable time because contradictory
data have been obtained [8–12]. PTC commonly develops
in patients with autoimmune thyroiditis [5,13,14], raising
the question of how thyroid malignancies develop despite
immune responses. Or, does autoimmune thyroiditis de-
velop because of an antitumor immune response? In this
article we review the current research advances in our
understanding of cellular and humoral immune mecha-
nisms of HT, with a particular emphasis on the immuno-
logical correlation between autoimmune diseases and
thyroid cancer.
Hashimoto’s thyroiditis
Target antigens
The idea of specific thyroid molecules that are recognized
by autoimmune cells has been known for decades. In 1995,
Sugihara and colleagues described thyroid epithelial cell
reactive CD8 T cells in autoimmune thyroiditis (AIT)
patients, and delivered a proof of MHC-I restricted T cell
activation [15]. Regarding the specificity of these cells, TPO
and Tg have been described to represent the key autoanti-
gens.
TPO is the major enzyme involved in thyroid hormone
synthesis. Together with dual oxidase-1 (DUOX-1),
caveolin-1, and other proteins, it forms the thyroxisome,
a multiprotein complex that is required for thyroid hor-
mone synthesis on the apical surface of the thyrocyte
[16]. Anti-TPO antibodies are high-affinity IgG-class
antibodies with two immunodominant regions that are
recognized by sera from about 74% of HT patients
[17]. Immunity to TPO in humans does not appear to
develop in response to TPO released from damaged cells:
thyrocytes seem to present TPO epitopes, acting thereby
as antigen-presenting cells for the induction of anti-TPO
antibodies as well as TPO-specific autoimmune T cells
[18].
Tg is the most abundant protein of the thyroid gland
giving rise to the thyroid hormones T3 and T4. Tg is stored
in the thyroid follicules, leaks into the circulation, and is
exposed to the immune system. Existence of anti-Tg anti-
bodies is one of the clinical features for HT diagnosis that is
met in approximately 90% of HT patients. Anti-Tg anti-
bodies are believed to reflect a more initial type of immune
response because HT patients with different thyroid func-
tional status exhibit a different Tg epitope recognition
pattern [19].
2
Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x
Both TPO and Tg also seem to represent target antigens
for autoreactive T cells because T cells recognizing these
molecules have been found in sera and thyroid infiltrates of
HT patients [20]. Recent evidence indicates a balanced
TPO- and Tg-specific cellular immune response in HT
[20]. The cells were also able to lyse TPO- and Tg-epi-
tope-presenting target cells [20]. Furthermore, in thyroid-
itis mouse models, TPO and Tg represented the targets for
the immune reaction towards the thyroid, including direct
cellular toxicity by CD8+ T cells and a humoral immune
response by production of specific antibodies [21,22].
Cellular immune response
The etiology of HT is yet unknown. Certainly, intrathyr-
oidal accumulation of leukocytes and the secretion of cyto-
kines and chemokines that commonly belong to the T
helper 1 (Th1) immune response are consistently observed
[23,24] (Figure 1). This process is believed to start with the
infiltration of antigen-presenting cells (APC), for example
dendritic cells (DCs). Already in 1988 Kabel et al. described
a higher number of DCs in the thyroid of HT patients
versus healthy thyroid tissue [25]. In addition, these DCs
were often seen in contact with intrathyroidal lympho-
cytes, probably leading to their stimulation.
Th17 cells, a proinflammatory cell type that is charac-
terized by the secretion of interleukin 17 (IL-17), seem to
participate in the context of cell mediated cytotoxicity in
murine and human HT because a higher frequency of IL-
17-positive T cells was found in HT [26].
In addition, regulatory T (Treg) cells that are important
for the peripheral homeostatic immune suppression might
play a role in the pathology of HT. In fact, in autoimmune
thyroiditis mouse models, thyroiditis was induced after
overcoming the immunoregulatory effect of Treg cells
[27]. In humans, HT patients and healthy controls show
an equal frequency of Treg cells but, interestingly, HT-
derived Treg cells seem to be partly dysfunctional: they
were less capable of inhibiting the proliferation of effector
T cells compared to controls, possibly explaining their
contribution to autoimmunity [28].
A further imbalance in the amount of chemokines and
cytokines favoring the proinflammatory fraction [e.g., in-
terferon-g (IFN-g) in first line, IFN-a, tumor necrosis
factor-alpha (TNF-a)] was found in thyroid tissue samples
and the peripheral blood of HT patients, with some leading
to thyroid tissue damage, thus directly accelerating the
ongoing inflammatory condition [24,29–34]. In line, lower
amounts of the anti-inflammatory tumor growth factor-b1
(TGF-b1) are described to contribute to disease progres-
sion as a result of decreased immunosuppressive effect
[35].
Remarkably, thyrocytes themselves (HT-derived or
stimulated), as a source of cytokine and chemokines
[36,37], are directly involved in the immunological process
as both target and immune influencing cells (Figure 1).
Humoral immune response
Humoral immunity in HT mainly consists of antibodies
recognizing TPO and Tg as specific antigens, as men-
tioned above (Figure 1). An age-depended increase of
these antibodies has already been demonstrated in the
TEM-986; No. of Pages 9

Review Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x

Angen presentaon by leucocytes

(e.g., dendric cells) and
thyrocytes

Regulatory TGF-β
CD4 T cell Dendric
IL-10 cell
Thyroid angens
Thyrocyte
IL-10 IL-10 IL-12
IL-15
IL-4
Th17 IL-21
IL-23
Plasma Th1
cell immune response
CTL
CD4 Th2
CTL CTL helper T cell immune response
Th17 Th17
immune response
Thyrocytes CD4
Plasma
cell helper T cell CD4
Cytotoxic helper T cell
CD8 T cell
(CTL)
TFN-γ Plasma B cell
IL-2 TNF-α (PBC)
T helper 17 cell
Inial destrucon of (Th17)
thyrocytes by auto- IL-4
IL-10
reacve lymphocytes or
environmental factors
IL-17
IL-21
IL-22
TRENDS in Endocrinology & Metabolism

Figure 1. Autoimmune response in Hashimoto’s thyroiditis. The immune response in autoimmune thyroiditis involves the participation of Th1, Th2, and Th17 immune
responses. Antigen-presenting cells and CD4+ T helper cells play a significant role in that phenomenon, leading to the activation of effector T cells: in response to thyroid-
specific antigens (e.g., TPO; Tg) CD8 + T cells are activated leading to the generation of cytotoxic T lymphocytes (CTL) that directly destroy thyroid cells on the one hand; on
the other hand, B cells might develop into plasma cells generating thyroid-restricted antibodies, followed by antibody or complement-restricted thyroid cell death. Th17
cells are also postulated to participate in the destruction process. Destroyed thyrocytes might increase the release of thyroid-specific antigens leading to the acceleration of
the immune process. Inhibition of regulatory T cells (Treg) as well as secretion of inflammatory molecules (CXCL8, CXCL10, IFNg) by the thyroid itself could further enhance
the autoimmune process (the main cytokines secreted by specific cells or within a specific immune response are indicated. Abbreviations: IFN-g, interferon-g; IL, interleukin;
TGF-b, tumor growth factor b; Th, T helper; TNF-a, tumor necrosis factor-a).

past, indicating a high prevalence of HT in elderly
humans [38]. The National Health and Nutrition Exami-
nation Survey (NHANES) III revealed similar results and
indicated a significant correlation between overt hypo-
thyroidism and the presence of anti-TPO antibodies
[39]. This observation is in accordance with results from
the Whickham Survey which in a 20 year follow-up
showed a higher risk for developing overt hypothyroidism
in females with normal TSH level but with the presence of
anti-TPO antibodies [40].
Of note, in defining the clinical parameters for HT
diagnosis, one has to keep in mind that 20% of subjects
showing symptoms of HT (mild TSH elevation together
with histologically proven leukocytic infiltration) have no
thyroid antibodies detectable (so-called seronegative
patients), indicating the pivotal role for the cellular im-
mune response that seems to occur before the humoral
immune response, at least in some cases.
Animal models of AIT
Animal models of AIT have helped elucidate many of the
molecular mechanisms underlying thyroid autoimmunity.
These models can principally be divided into four groups:
(i) spontaneous development of AIT that is observed in, for
example, obese strain chickens and non-obese diabetic
[NOD] H-2h4 mice [41,42]; (ii) induced AIT through the
immunization with TPO and Tg or thyroid gland suspen-
sions [43,44]; (iii) xenograft transplantation of human
thyroid tissue or human peripheral blood mononuclear
cells (PBMCs) [45]; and (iv) transgenic models [21]. Inves-
tigating the immunologic mechanisms of thyroid autoim-
munity in these animals several significant findings have
been made. These include the important role of the genetic
background [46], the immunogenic effect of TPO and Tg
[21,43], the kinetic of thyroidal infiltration [47], the par-
ticipation of cytokines and chemokines (e.g., TGFb, IFNg,
IL-12) [42,47–49], the participation of thyroidal adhesion
molecules [50], and the interplay between immune cells
(e.g., T cells, Treg cells, B cells) [51]. Furthermore, these
animal models have offered additional basic insights, such
as the effect of T cells in autoimmunity and the important
role of Treg cells in the regulation of immune cells
[27,52,53].
Immunological link between autoimmunity and
malignancy
As mentioned above, PTC is mainly characterized by a
rather slow growth and lymphatic spread with rarely
3
TEM-986; No. of Pages 9
Review
occurring distant metastasis, leading to an overall excel-
lent prognosis (10 year survival of more than 90%) [6]. PTCs
show a low mortality of 1–2% at 20 years after diagnosis, in
contrast to follicular thyroid cancer (10–20% at 20 years)
[54]. These clinical features might be caused by the fre-
quent appearance of lymphatic infiltration into the tumor
site. Whether these leukocytes are attracted by an anti-
cancer immune response, or by a preexisting autoimmune
process (HT), or by both phenomena, remains unclear. At
least, an immunological association between these two
entities cannot be excluded because both disorders are
described to coexist [13,14] and show leukocytic infiltra-
tion. As mentioned above, the pathologic process in HT is
believed to start with infiltration of DCs followed by fur-
ther leucocytes, leading to the thyroid-specific immune
response. In fact, DCs were also reported to exist in
PTC, isolated in the background and/or in association with
tumor cells [55], potentially facilitating a further immune
cell infiltration. The impact of leukocytes on PTC tumor
defense and tumor progression is still unclear. Naturally,
the health of an individual is defended by a process named
cancer immunosurveillance in which cells of the immune
system detect and eliminate malignant cells. Several stud-
ies have been published describing cancer immunosurveil-
lance in the context of the thyroid gland: the presence of
leukocyte infiltration with T cells, B cells, macrophages, and
Th17 cells was related with a better prognosis in patients
with differentiated thyroid carcinoma [8]. In addition, the
absence of key cells for immunostimulation, for example,
CD83-positive mature and activated DCs, in cancer nodules
of PTC patients might contribute to the pathogenesis of PTC
and seems to correlate with poor prognosis [11].
By contrast, some publications discuss the opposite ef-
fect: a positive correlation between leukocyte infiltration
and tumor progression. Existence of tumor-associated T
cells and macrophages, plasmacytoid DCs, as well as Treg
cells in thyroid tumor sites and tumor-involved lymph nodes
has been described to be associated with tumor progression
and invasion, a higher risk for lymph node metastasis, and
decreased cancer-related survival [9,10,12].
These facts lead to the question of whether thyroid
malignancies develop despite, or due to, immune
responses. Or, does an autoimmune thyroid disease devel-
op because of an existing antitumor immune response?
Malignancy despite an (auto)immune response
The immune system is able to discriminate between self
and non-self antigens, preventing immune reaction to self,
and approving recognition of and reaction to foreign sig-
nals. Dysfunction of these mechanisms of central and
peripheral tolerance may result in autoimmunity or can-
cer, respectively. Malignancy despite an immune response
might occur because of immune tolerance or because of
tumor immune-escape mechanisms.
Several immune-escape mechanisms, correlating with
PTC aggressiveness, are known for PTCs, including secre-
tion of specific immune-regulatory cytokines, changed fre-
quency of immune cells, and the expression of specific
surface molecules (Figure 2).
Thyroid tumor cells are known to upregulate cytokines
such as IL-4 and IL-10 to edit the immune response by
4
Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x
manipulating the phenotype of immune cells [56,57]. IL-4
was shown to decrease the proliferation and impair the
function of cytotoxic CD8+ T cells by downregulating
CD127 expression [56].
Furthermore, the frequency of tumor-associated Treg
cells is described to increase with PTC aggressiveness
and lymph node metastasis [9,12,58]. This potential tu-
mor-escape mechanism might be favored by PTC-derived
plasmacytoid DCs that possibly induce the differentiation
of naı̈ve CD4+ T cells into Treg cells [12]. Double-negative T
cells might further contribute to tumor tolerance and
active avoidance of tumor immunity because they have
been described to exist within the leukocytic infiltration in
thyroid cancer where they might regulate the proliferation
and effector function of T cells [59].
In addition, the frequency of cytotoxic and regulatory
natural killer (NK) cells seems to inversely correlate with
PTC disease stage [58,60]. This observation might be a
result of the ability of Treg cell to suppress NK cell effector
functions (e.g., homeostatic proliferation, cytotoxicity) by
selectively expressing membrane-bound TGF-b, which
downregulates NKG2D expression on NK cells in vitro
and in vivo [61].
As mentioned above, specific surface molecules might
contribute to tumor development and growth despite the
immune response. Expression of histocompatibility anti-
gen, class I, G (HLA-G), Fas ligand (FasL), and B7 homolog
1 (B7H1) was described to be associated with the aggres-
siveness and unfavorable clinical presentation of PTC [62–
64], and is known to be increased by tumor-microenviron-
ment factors such as indoleamine 2,3-dioxygenase, IFN-g,
TNF-a, and IL-1 [65–67].
Furthermore, an antigen-specific humoral immune re-
sponse also seems to be of importance. Elevated anti-TPO
antibodies appear to protect against thyroid cancer in
patients with HT [68]. This tumor-protecting feature of
TPO might be explained by (i) complement-mediated cell
death, that is anti-TPO antibody-dependent because anti-
Tg antibodies do not fix complement [69], and (ii) anti-TPO
antibody-dependent cell toxicity due to the exclusive bind-
ing of anti-TPO antibodies to their effector cells via Fc-g
receptor I (CD64) that is known to be expressed on mono-
cytes [70]. By contrast, anti-Tg antibodies seem to repre-
sent a risk factor for PTC [71,72]. One reason for this effect
could be the fact that anti-Tg antibodies from PTC patients
recognize different Tg epitopes than do anti-Tg antibodies
from patients with autoimmune thyroid diseases (HT and
Graves’ disease) and from PTC patients with associated
thyroiditis [73].
Malignancy due to autoimmunity
The relationship between cancer and inflammation is well
known from other disease mechanisms, for example Heli-
cobacter pylori-induced gastritis and gastric cancer. Be-
cause HT and PTC commonly appear synchronously, the
concept of ‘inflammation-induced carcinoma’ has emerged
(Figure 3) [74]. Two interrelated pathways have been
described to link both diseases: the intrinsic pathway
(oncogenic events, e.g., RET oncogene); and the extrinsic
pathway (inflammatory condition: tumor-infiltrating in-
flammatory cells) [75]. Here environmental factors, such
TEM-986; No. of Pages 9

Review Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x

Papillary
HLA-G thyroid carcinoma
Tumor-derived Natural killer
plasmacytoid cell FasL
dendric cell
IL-4
B7H1
Cytotoxic
CD8 T cell
(CTL)

Naïve Regulatory
CD4 T cell CD4 T cell
Plasma B cell
(PBC)
Regulatory Thyroid (cancer)
CD4 T cell Regulatory angens
CD4 T cell
T helper 17 cell
(Th17)
IL-10 CD4 Dendric
helper T cell cell

Angen presentaon by
leucocytes (e.g., dendric cells)
TRENDS in Endocrinology & Metabolism

Figure 2. Malignancy despite an immune response. Papillary thyroid carcinoma (PTCs) are known to have the ability to escape the immune system. Enhanced levels of anti-
inflammatory cytokines (IL-4, IL-10) as well as the expression of several immune-regulatory molecules (HLA-G, B7H1, FasL) on tumor cells leads to the downregulation of
the immune process at several levels: antigen-presenting cells, CD4+ T helper cells, CD8+ T cells, and B cells have been described to be affected by immune-escape
mechanisms, resulting in a decreased immune response. In addition, inhibition of the cytolytic function of natural killer cells and increased presence of regulatory T cells
can amplify the escape mechanisms.

as hepatitis C virus (HCV) infection, seem to be associated
with thyroid autoimmunity and malignancy. As shown by
Antonelli et al., HCV-infected patients show a high preva-
lence of autoimmune thyroiditis (characterized by TSH
levels, anti-Tg and anti-TPO antibodies, and hypothyroid-
ism) as well as PTC (separate and synchronous appear-
ance) [76]. Further studies supported the impact of HCV
infection on thyroid inflammation: HCV RNA has been
found in thyroid tissue from patients with chronic HCV
[77], HCV can infect human thyroid cells in vitro [78], and
HCV induces the production of the proinflammatory cyto-
kine IL-8 by thyrocytes [79].
Investigating the extrinsic pathway, the localization of
infiltrated lymphocytes seems to be important: tumor-in-
filtrating lymphocytes need to be distinguished from ‘back-
ground’ thyroiditis. As recently shown, patients with
tumor-associated lymphocytes exhibited higher disease
stage and increased incidence of invasion and lymph node
metastasis compared to patients without lymphocytes, or
with background thyroiditis [9]. Higher frequencies of Treg
cells within the tumor and in tumor-involved lymph nodes
were associated with more aggressive disease [9]. In addi-
tion, tumor-associated macrophages seem also to be linked
to advanced thyroid cancer [10], with their density being
positively associated with lymph node metastasis [10].
Furthermore, molecular targets and signaling pathways
participating with apoptosis, increased proliferation rate,
and angiogenesis, as well as the duration of inflammation,
might represent important points [80]. Proinflammatory
cytokines with growth factor activity (e.g., IL-17, IFN-g,
and TNF-a [81,82]) have been described in higher amounts
in HT patients, as mentioned above. Angiogenesis, an im-
portant point in tumor development, is also described to be
enhanced by TNF-a, vascular endothelial growth factor
(VEGF), the macrophage attractants nitric oxide and high
mobility group box 1 protein (HMGB1), all of which are
found in thyroiditis and PTC patients [83–85]. In addition,
nitric oxide and HMGB1 are known to promote matrix
remodeling, suppress immune responses, and inhibit indi-
rectly cell cycle regulators, potentially increasing the risk of
PTC in the inflammatory scenario [86].
A further point is the participation of reactive oxygen
species (ROS) in tumor development, molecules that are
known to induce DNA damage and promote the epithelial
to mesenchymal transition [87]. One naturally existing
thyroidal ROS candidate is hydrogen peroxide (H2O2) that
is essential for thyroid hormone formation. An imbalance
in the relation of un- and neutralized H2O2 towards un-
neutralized H2O2 during inflammation, and the mem-
brane-permeable nature of H2O2, support a scenario of
5
TEM-986; No. of Pages 9

Review Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x

Immune response (Auto-)immune response

towards thyroid towards healthy
cancer thyroid

Thyroid Thyroid
angens angens

Angen Micro- Healthy Angen

presentaon carcinoma thyrocytes presentaon

Cross-
reacvity ?

CD4 CD4
helper T cell helper T cell

Plasma CTL
CTL Plasma
cell Treg
cell
Treg
Th17 Th17

TRENDS in Endocrinology & Metabolism

Figure 3. Cross-reactivity between thyroidal anticancer immunity and autoimmunity. Target-specific immunity taking place as an antitumor immune response to
inconspicuous papillary thyroid microcarcinoma (left side) might be misguided, potentially leading to immune cross-reactivity and to target-specific destruction of healthy
thyroid cells, resulting in the development of autoimmune thyroiditis (right side). Current data do not clarify whether autoimmune thyroiditis develops owing to a pure
autoimmune reaction or perhaps in consequence of lymphocyte infiltration in the course of an anticancer immune response. Furthermore, the development of thyroid
cancer may be facilitated by a preexisting autoimmune reaction (inflammation). This immune reaction potentially influences several crucial points that are known to play a
role in cancer: signaling pathways participating with apoptosis, increased proliferation rate of thyroid cells, and angiogenesis, as well as the duration of inflammation.
Abbreviations: CTL, cytotoxic CD8 T lymphocyte; Th17, T helper 17 cells.

ROS-dependent ‘inflammation-induced carcinoma’ in the
thyroid [88,89].
Of note, in line with the data presented here, the
pathology of HT (destructive, clinically evident hypothy-
roid form vs a less-destructive, nonclinically evident form)
might play a role in differentiated thyroid cancer risk.
Patients with less destructive HT (euthyroid, or not fully
hypothyroid) were described to show a higher risk for
differentiated thyroid cancer than were patients with a
clear destructive HT [68]. These observations provide fur-
ther support for the hypothesis that the duration of inflam-
mation could be the determining point. Patients with
prolonged exposure to inflammation (e.g., chronic inflam-
mation) might have a higher risk for cancer than patients
with recent onset of HT [68].
In addition, genetic predisposition could also be responsi-
ble for ‘inflammation-induced carcinoma’ (intrinsic pathway).
6
In PTC, oncogenes that are responsible for cell neoplastic
transformation, such as RET/PTC and BRAFV600E, may
potentially elicit an inflammatory protumorigenic microen-
vironment [90]. RET/PTC appears to be more represented in
PTCs associated with autoimmunity, and BRAFV600E in
patients with PTC alone [91]. PTC progression in RET/
PTC oncoprotein-expressing patients might be maintained
by the secretion of proinflammatory molecules (e.g., CXCL10,
MCP-1) that influence immune responses, or the delivery of
autocrine growth and survival factors for thyroid tumor cells
[74]. These observations point to a crucial role of the onco-
protein RET/PTC in the modulation of the autoimmune
response [74,91].
Autoimmunity due to antitumor immune response
Finally, a mechanism known as ‘tumor defense-induced
autoimmunity’ might play a role in the synchronous
TEM-986; No. of Pages 9
Review
existence of PTC and HT. Autoimmunity due to therapeu-
tic modulation has been described for several immune
interventions in the field of tumor therapy. Both arms of
immune response are involved: adoptive immunotherapy
as well as antibody therapy (reviewed in [92,93]). This
mechanism has been proposed in the therapy-independent
and synchronous appearance of vitiligo, a condition that
results in loss of skin pigmentation, in melanoma patients,
owing to the presence of target-specific cytotoxic T cells.
This has led to the conclusion that vitiligo may be a visible
effect of a spontaneous antitumoral immune response in
melanoma patients [94]. In fact, melanoma patients with
vitiligo often have a better outcome than melanoma
patients without vitiligo [95].
The mechanism of ‘tumor defense-induced autoimmu-
nity’ might also occur in the thyroid gland during autoim-
mune disease (Figure 3). Genetic predisposition to thyroid
autoimmune disease could enhance autoimmunity during
therapeutic induction of tumor immunity, as shown for
thyroiditis-susceptible mice [96]. Recently, a meta-analy-
sis by Lee et al. investigated the correlation between PTC
and histologically proven HT [97]. HT was found in 17% of
patients with PTC and was significantly associated with a
longer duration of recurrence-free survival. This observa-
tion is supported by a study in which immune cell infiltra-
tion was related to a better prognosis for patients with PTC
[8], demonstrating an ongoing antitumor immune re-
sponse.
Furthermore, in about 20% of thyroid cancer patients,
anti-Tg antibodies can be found in the peripheral blood,
with the incidence of both anti-Tg and anti-TPO antibodies
being approximately twofold higher in PTC patients com-
pared to the general population [98]. This clearly indicates
a humoral immune response in PTC to target antigens that
were initially described for HT. Taking into account that
anti-Tg antibodies from patients with autoimmune thyroid
diseases, and from PTC patients with associated thyroid-
itis, recognize similar Tg epitopes [73] (as mentioned
above), an immune response towards PTC cells might also
cross-react with healthy thyrocytes. However, whether
PTC-patient thyroid-specific cytotoxic T cells also recog-
nize these molecules (TPO and Tg) needs investigation.
The reason for the induced antitumor immune response
might be the existence of yet undiagnosed papillary thyroid
microcarcinomas (PTMC). Owing to similar gene expres-
sion profiles, PTMC should not be considered as a simple
occult indolent thyroid cancer but as the earlier stage of
disease which eventually evolves into PTC [99], potentially
triggered by growth factors produced by the thyroid
[100]. Possibly, these small malignancies that induce a
locally defined antitumor immune response, followed by a
locally defined inflammation that promotes cross-reactivi-
ty, induce an epitope-specific autoimmune response
(Figure 3). This hypothesis certainly needs investigation.
Concluding remarks and future perspectives
HT is a multifaceted autoimmune thyroid disease caused
by genetic predisposition as well as environmental influ-
ence (e.g., iodine intake, viral infection). Immunologic
tolerance towards the thyroid gland is lost, leading to a
thyroid-specific immune response characterized by an
Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x
Box 1. Outstanding questions
 Do thyroid malignancies develop despite immune responses?
 Does autoimmune thyroiditis develop because of an antitumor
immune response?
 Does autoimmune thyroid disease develop because of an existing
antitumor immune response?
 Thyroid peroxidase and thyroglobulin: do they represent target
antigens for the immune response (humoral and cell mediated) in
Hashimoto’s thyroiditis as well as in papillary thyroid cancer?
increased amount of proinflammatory cells and cytokines,
partly dysfunctional Treg cells, and a decreased level of
anti-inflammatory cytokines. Tg and TPO represent the
main target antigens for cellular cytotoxic as well as
humoral immune reactions, and are presented by APCs
and thyrocytes. The consequence of this immune dysfunc-
tion is target-specific thyroid destruction resulting in hy-
pothyroidism.
By analogy to HT, TPO and Tg also seem to represent
the specific target antigens for the immune response in
PTC (at least for the humoral part). This phenomenon
indicates an immunological link between these opportu-
nistic diseases. Whether PTC develop despite (auto)immu-
nity (tumor immune-escape mechanism), or due to a
target-specific immune response (inflammation, preexist-
ing autoimmunity), or whether HT develops because of
cross-reacting antitumor immunity, is a matter of debate.
Determination of specific target antigens (epitopes) in both
diseases might help to further identify the immunological
link between PTC and HT (outstanding questions are
listed in Box 1). The detailed understanding of the patho-
genetic link between the two entities might also help to
establish specific (immuno)therapies, such as immuniza-
tions/cell transfer therapies in PTC, as well as immune
tolerance-inducing therapies in HT.
References
1 Ahmed, R. et al. (2012) Hashimoto thyroiditis: a century later. Adv.
Anat. Pathol. 3, 181–186
2 Latina, A. et al. (2013) Hashimoto’s thyroiditis: similar and dissimilar
characteristics in neighboring areas. Possible implications for the
epidemiology of thyroid cancer. PLoS ONE 8, e55450
3 Duntas, L.H. (2011) Environmental factors and thyroid
autoimmunity. Ann. Endocrinol. (Paris) 2, 108–113
4 Amani, H.K. (2011) Histopathologic and immunohistochemical
features of Hashimoto thyroiditis. Indian J. Pathol. Microbiol. 3,
464–471
5 Fiore, E. et al. (2011) Hashimoto’s thyroiditis is associated with
papillary thyroid carcinoma: role of TSH and of treatment with L-
thyroxine. Endocr. Relat. Cancer 4, 429–437
6 Shoup, M. et al. (2003) Prognostic indicators of outcomes in patients
with distant metastases from differentiated thyroid carcinoma. J. Am.
Coll. Surg. 2, 191–197
7 Howlader, N. et al. (2013) SEER Cancer Statistics Review, 1975-2010,
National Cancer Institute
8 Cunha, L.L. et al. (2012) Infiltration of a mixture of immune cells may
be related to good prognosis in patients with differentiated thyroid
carcinoma. Clin. Endocrinol. (Oxf) 6, 918–925
9 French, J.D. et al. (2012) Programmed death-1+ T cells and regulatory
T cells are enriched in tumor-involved lymph nodes and associated
with aggressive features in papillary thyroid cancer. J. Clin.
Endocrinol. Metab. 6, E934–E943
10 Qing, W. et al. (2012) Density of tumor-associated macrophages
correlates with lymph node metastasis in papillary thyroid
carcinoma. Thyroid 9, 905–910
7
TEM-986; No. of Pages 9
Review
11 Xu, W.C. et al. (2011) Expression and distribution of S-100, CD83, and
costimulatory molecules (CD80 and CD86) in tissues of thyroid
papillary carcinoma. Cancer Invest. 4, 286–292
12 Yu, H. et al. (2013) Regulatory T cells and plasmacytoid dendritic cells
contribute to the immune escape of papillary thyroid cancer coexisting
with multinodular non-toxic goiter. Endocrine 1, 172–181
13 Caturegli, P. et al. (2013) Hashimoto’s thyroiditis: celebrating the
centennial through the lens of the Johns Hopkins hospital surgical
pathology records. Thyroid 2, 142–150
14 Chen, Y.K. et al. (2013) Cancer risk in patients with Hashimoto’s
thyroiditis: a nationwide cohort study. Br. J. Cancer 9, 2496–2501
15 Sugihara, S. et al. (1995) Self-thyroid epithelial cell (TEC)-reactive
CD8+ T cell lines/clones derived from autoimmune thyroiditis lesions.
They recognize self-thyroid antigens directly on TEC to exhibit T
helper cell 1-type lymphokine production and cytotoxicity against
TEC. J. Immunol. 3, 1619–1628
16 Senou, M. et al. (2009) Role of caveolin-1 in thyroid phenotype, cell
homeostasis, and hormone synthesis: in vivo study of caveolin-1
knockout mice. Am. J. Physiol. Endocrinol. Metab. 2, E438–E451
17 Nielsen, C.H. et al. (2008) Epitope recognition patterns of thyroid
peroxidase autoantibodies in healthy individuals and patients with
Hashimoto’s thyroiditis*. Clin. Endocrinol. (Oxf) 4, 664–668
18 McLachlan, S.M. and Rapoport, B. (2007) Thyroid peroxidase as an
autoantigen. Thyroid 10, 939–948
19 Liu, M. et al. (2012) Epitope recognition patterns of thyroglobulin
antibody in sera from patients with Hashimoto’s thyroiditis on
different thyroid functional status. Clin. Exp. Immunol. 3, 283–290
20 Ehlers, M. et al. (2012) Evidence of a combined cytotoxic thyroglobulin
and thyroperoxidase epitope-specific cellular immunity in
Hashimoto’s thyroiditis. J. Clin. Endocrinol. Metab. 4, 1347–1354
21 Quaratino, S. et al. (2004) Degenerate self-reactive human T-cell
receptor causes spontaneous autoimmune disease in mice. Nat.
Med. 9, 920–926
22 Watanabe, H. et al. (1999) Experimental autoimmune thyroiditis
induced by thyroglobulin-pulsed dendritic cells. Autoimmunity 4,
273–282
23 Drugarin, D. et al. (2000) The pattern of a T(H)1 cytokine in
autoimmune thyroiditis. Immunol. Lett. 2, 73–77
24 Kemp, E.H. et al. (2003) Detection and localization of chemokine gene
expression in autoimmune thyroid disease. Clin. Endocrinol. (Oxf) 2,
207–213
25 Kabel, P.J. et al. (1988) Intrathyroidal dendritic cells. J. Clin.
Endocrinol. Metab. 1, 199–207
26 Figueroa-Vega, N. et al. (2010) Increased circulating pro-
inflammatory cytokines and Th17 lymphocytes in Hashimoto’s
thyroiditis. J. Clin. Endocrinol. Metab. 2, 953–962
27 Morris, G.P. et al. (2009) Naturally-existing CD4+CD25+Foxp3+
regulatory T cells are required for tolerance to experimental
autoimmune thyroiditis induced by either exogenous or endogenous
autoantigen. J. Autoimmun. 1, 68–76
28 Glick, A.B. et al. (2013) Impairment of regulatory T-cell function in
autoimmune thyroid disease. Thyroid 7, 871–878
29 Domberg, J. et al. (2008) Circulating chemokines in patients with
autoimmune thyroid diseases. Horm. Metab. Res. 6, 416–421
30 Antonelli, A. et al. (2011) Circulating chemokine (CXC motif) ligand
(CXCL)9 is increased in aggressive chronic autoimmune thyroiditis,
in association with CXCL10. Cytokine 2, 288–293
31 del Prete, G.F. et al. (1989) High potential to tumor necrosis factor
alpha (TNF-alpha) production of thyroid infiltrating T lymphocytes in
Hashimoto’s thyroiditis: a peculiar feature of destructive thyroid
autoimmunity. Autoimmunity 4, 267–276
32 Akeno, N. et al. (2011) IFN-alpha mediates the development of
autoimmunity both by direct tissue toxicity and through immune
cell recruitment mechanisms. J. Immunol. 8, 4693–4706
33 Rebuffat, S.A. et al. (2013) IL-1beta and TSH disturb thyroid
epithelium integrity in autoimmune thyroid diseases.
Immunobiology 3, 285–291
34 Salzano, M. et al. (2012) Interferon-gamma inhibits integrin-mediated
adhesion to fibronectin and survival signaling in thyroid cells. J.
Endocrinol. 3, 439–444
35 Vural, P. et al. (2009) The relationship between transforming growth
factor-beta1, vascular endothelial growth factor, nitric oxide and
Hashimoto’s thyroiditis. Int. Immunopharmacol. 2, 212–215
8
Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x
36 Rotondi, M. et al. (2013) Interferon-gamma and tumor necrosis factor-
alpha sustain secretion of specific CXC chemokines in human
thyrocytes: a first step toward a differentiation between
autoimmune and tumor-related inflammation? J. Clin. Endocrinol.
Metab. 1, 308–313
37 Bossowski, A. et al. (2011) Cytometric evaluation of intracellular IFN-
gamma and IL-4 levels in thyroid follicular cells from patients with
autoimmune thyroid diseases. Thyroid Res. 4, 13
38 Mariotti, S. et al. (1992) Thyroid and other organ-specific
autoantibodies in healthy centenarians. Lancet 8808, 1506–1508
39 Hollowell, J.G. et al. (2002) Serum TSH, T(4), and thyroid antibodies
in the United States population (1988 to 1994): National Health and
Nutrition Examination Survey (NHANES III). J. Clin. Endocrinol.
Metab. 2, 489–499
40 Vanderpump, M.P. et al. (1995) The incidence of thyroid disorders in
the community: a twenty-year follow-up of the Whickham Survey.
Clin. Endocrinol. (Oxf) 1, 55–68
41 Wick, G. (1970) Spontaneous autoimmune thyroiditis in chickens.
Hautarzt 8, 383–385 in German
42 Braley-Mullen, H. et al. (1999) Spontaneous autoimmune thyroiditis
in NOD.H-2h4 mice. J. Autoimmun. 3, 157–165
43 Ng, H.P. et al. (2004) Development of a murine model of autoimmune
thyroiditis induced with homologous mouse thyroid peroxidase.
Endocrinology 2, 809–816
44 Velicky, J. et al. (1993) Experimental thyroiditis in guinea pigs and
rabbits. Immunization with thyroglobulin and bovine thyroid gland
suspension. Funct. Dev. Morphol. 4, 259–267
45 Volpe, R. et al. (1993) The use of the severe combined
immunodeficient mouse and the athymic ‘nude’ mouse as models
for the study of human autoimmune thyroid disease. Clin. Immunol.
Immunopathol. 2, 93–99
46 Vladutiu, A.O. and Rose, N.R. (1971) Autoimmune murine thyroiditis
relation to histocompatibility (H-2) type. Science 4014, 1137–1139
47 Bonita, R.E. et al. (2003) Kinetics of mononuclear cell infiltration and
cytokine expression in iodine-induced thyroiditis in the NOD-H2h4
mouse. Exp. Mol. Pathol. 1, 1–12
48 Yu, S. et al. (2002) Dual roles for IFN-gamma, but not for IL-4, in
spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J.
Immunol. 7, 3999–4007
49 Braley-Mullen, H. et al. (2001) Role of TGFbeta in development of
spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J.
Immunol. 12, 7111–7118
50 Bonita, R.E. et al. (2002) Adhesion molecules as susceptibility factors
in spontaneous autoimmune thyroiditis in the NOD-H2h4 mouse.
Exp. Mol. Pathol. 3, 155–163
51 Yu, S. et al. (2006) B cell-deficient NOD.H-2h4 mice have CD4+CD25+
T regulatory cells that inhibit the development of spontaneous
autoimmune thyroiditis. J. Exp. Med. 2, 349–358
52 Ellis, J.S. et al. (2013) Transient depletion of CD4+ CD25+ regulatory
T cells results in multiple autoimmune diseases in wild-type and B-
cell-deficient NOD mice. Immunology 2, 179–186
53 Wick, G. et al. (1978) No development of experimental autoimmune
thyroiditis in nude mice. Z. Immunitatsforsch. Immunobiol. 2, 162–
168
54 Cooper, D.S. et al. (2009) Revised American Thyroid Association
management guidelines for patients with thyroid nodules and
differentiated thyroid cancer. Thyroid 11, 1167–1214
55 Pusztaszeri, M.P. et al. (2013) Association of CD1a-positive dendritic
cells with papillary thyroid carcinoma in thyroid fine-needle
aspirations: a cytologic and immunocytochemical evaluation.
Cancer Cytopathol. 4, 206–213
56 Crawley, A.M. et al. (2010) Interleukin-4 downregulates CD127
expression and activity on human thymocytes and mature CD8+ T
cells. Eur. J. Immunol. 5, 1396–1407
57 Todaro, M. et al. (2006) Autocrine production of interleukin-4 and
interleukin-10 is required for survival and growth of thyroid cancer
cells. Cancer Res. 3, 1491–1499
58 Gogali, F. et al. (2012) Phenotypical analysis of lymphocytes with
suppressive and regulatory properties (Tregs) and NK cells in the
papillary carcinoma of thyroid. J. Clin. Endocrinol. Metab. 5, 1474–
1482
59 Imam, S. et al. (2014) Lymphocytic profiling in thyroid cancer provides
clues for failure of tumor immunity. Endocr. Relat. Cancer 3, 505–516
TEM-986; No. of Pages 9
Review
60 Gogali, F. et al. (2013) CD3 CD16 CD56bright immunoregulatory NK
cells are increased in the tumor microenvironment and inversely
correlate with advanced stages in patients with papillary thyroid
cancer. Thyroid 12, 1561–1568
61 Ghiringhelli, F. et al. (2006) The role of regulatory T cells in the control
of natural killer cells: relevance during tumor progression. Immunol.
Rev. 229–238
62 Cunha, L.L. et al. (2013) Differentiated thyroid carcinomas may elude
the immune system by B7H1 upregulation. Endocr. Relat. Cancer 1,
103–110
63 Mitsiades, N. et al. (1999) Fas ligand expression in thyroid
carcinomas: a potential mechanism of immune evasion. J. Clin.
Endocrinol. Metab. 8, 2924–2932
64 Nunes, L.M. et al. (2012) Association between the HLA-G molecule
and lymph node metastasis in papillary thyroid cancer. Hum.
Immunol. 4, 447–451
65 Dong, H. et al. (2002) Tumor-associated B7-H1 promotes T-cell
apoptosis: a potential mechanism of immune evasion. Nat. Med. 8,
793–800
66 Moretti, S. et al. (2014) Indoleamine 2,3-dioxygenase 1 (IDO1) is up-
regulated in thyroid carcinoma and drives the development of an
immunosuppressant tumor microenvironment. J. Clin. Endocrinol.
Metab. 5, E832–E840
67 Rouas-Freiss, N. et al. (2007) Expression of tolerogenic HLA-G
molecules in cancer prevents antitumor responses. Semin. Cancer
Biol. 6, 413–421
68 Paparodis, R. et al. (2014) Hashimoto’s thyroiditis pathology and risk
for thyroid cancer. Thyroid 7, 1107–1114
69 Weetman, A.P. (2004) Autoimmune thyroid disease. Autoimmunity 4,
337–340
70 Rebuffat, S.A. et al. (2008) Antithyroperoxidase antibody-dependent
cytotoxicity in autoimmune thyroid disease. J. Clin. Endocrinol.
Metab. 3, 929–934
71 Vasileiadis, I. et al. (2014) Thyroglobulin antibodies could be a
potential predictive marker for papillary thyroid carcinoma. Ann.
Surg. Oncol. 8, 2725–2732
72 Grani, G. et al. (2013) Thyroid autoimmunity and risk of malignancy
in thyroid nodules submitted to fine-needle aspiration cytology. Head
Neck http://dx.doi.org/10.1002/hed.23587
73 Latrofa, F. et al. (2008) Characterization of thyroglobulin epitopes in
patients with autoimmune and non-autoimmune thyroid diseases
using recombinant human monoclonal thyroglobulin
autoantibodies. J. Clin. Endocrinol. Metab. 2, 591–596
74 Liotti, F. et al. (2012) Inflammation in thyroid oncogenesis. Am. J.
Cancer Res. 3, 286–297
75 Colotta, F. et al. (2009) Cancer-related inflammation, the seventh
hallmark of cancer: links to genetic instability. Carcinogenesis 7,
1073–1081
76 Antonelli, A. et al. (2007) Thyroid cancer in HCV-related chronic
hepatitis patients: a case-control study. Thyroid 5, 447–451
77 Bartolome, J. et al. (2008) Detection of hepatitis C virus in thyroid
tissue from patients with chronic HCV infection. J. Med. Virol. 9,
1588–1594
78 Blackard, J.T. et al. (2013) Hepatitis C virus infection of a thyroid cell
line: implications for pathogenesis of hepatitis C virus and thyroiditis.
Thyroid 7, 863–870
Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x
79 Akeno, N. et al. (2008) HCV E2 protein binds directly to thyroid cells
and induces IL-8 production: a new mechanism for HCV induced
thyroid autoimmunity. J. Autoimmun. 4, 339–344
80 Landskron, G. et al. (2014) Chronic inflammation and cytokines in the
tumor microenvironment. J. Immunol. Res. 2014, 149185
81 He, D. et al. (2012) IL-17 mediated inflammation promotes tumor
growth and progression in the skin. PLoS ONE 7, e32126
82 Zhu, G. et al. (2014) TNF-alpha promotes gallbladder cancer cell
growth and invasion through autocrine mechanisms. Int. J. Mol.
Med. 6, 1431–1440
83 Fajardo, L.F. et al. (1992) Dual role of tumor necrosis factor-alpha in
angiogenesis. Am. J. Pathol. 3, 539–544
84 Ji, B. et al. (2012) COX-2 expression and tumor angiogenesis in
thyroid carcinoma patients among northeast Chinese population-
result of a single-center study. Int. J. Med. Sci. 3, 237–242
85 Mardente, S. et al. (2010) Cross-talk between NO and HMGB1 in
lymphocytic thyroiditis and papillary thyroid cancer. Oncol. Rep. 6,
1455–1461
86 Mardente, S. et al. (2012) HMGB1 induces the overexpression of miR-
222 and miR-221 and increases growth and motility in papillary
thyroid cancer cells. Oncol. Rep. 6, 2285–2289
87 Wang, Z. et al. (2010) Signaling mechanism(s) of reactive oxygen
species in Epithelial-Mesenchymal Transition reminiscent of cancer
stem cells in tumor progression. Curr. Stem Cell Res. Ther. 1, 74–80
88 Ohye, H. and Sugawara, M. (2010) Dual oxidase, hydrogen peroxide
and thyroid diseases. Exp. Biol. Med. (Maywood) 4, 424–433
89 Duntas, L.H. (2008) Environmental factors and autoimmune
thyroiditis. Nat. Clin. Pract. Endocrinol. Metab. 8, 454–460
90 Borrello, M.G. et al. (2008) Inflammation and cancer: the oncogene-
driven connection. Cancer Lett. 2, 262–270
91 Muzza, M. et al. (2010) The tight relationship between papillary
thyroid cancer, autoimmunity and inflammation: clinical and
molecular studies. Clin. Endocrinol. (Oxf) 5, 702–708
92 Amos, S.M. et al. (2011) Autoimmunity associated with
immunotherapy of cancer. Blood 3, 499–509
93 Kong, Y.C. et al. (2010) Opportunistic autoimmune disorders: from
immunotherapy to immune dysregulation. Ann. N. Y. Acad. Sci. 222–236
94 Le Gal, F.A. et al. (2001) Direct evidence to support the role of antigen-
specific CD8(+) T cells in melanoma-associated vitiligo. J. Invest.
Dermatol. 6, 1464–1470
95 Byrne, K.T. and Turk, M.J. (2011) New perspectives on the role of
vitiligo in immune responses to melanoma. Oncotarget 9, 684–694
96 Kari, S. et al. (2013) Enhanced autoimmunity associated with
induction of tumor immunity in thyroiditis-susceptible mice.
Thyroid 12, 1590–1599
97 Lee, J.H. et al. (2013) The association between papillary thyroid
carcinoma and histologically proven Hashimoto’s thyroiditis: a
meta-analysis. Eur. J. Endocrinol. 3, 343–349
98 Spencer, C.A. (2011) Clinical review: clinical utility of thyroglobulin
antibody (TgAb) measurements for patients with differentiated
thyroid cancers (DTC). J. Clin. Endocrinol. Metab. 12, 3615–3627
99 Kim, H.Y. et al. (2010) Comparative analysis of gene expression
profiles of papillary thyroid microcarcinoma and papillary thyroid
carcinoma. J. Cancer Res. Ther. 4, 452–457
100 Saranac, L. et al. (2011) Why is the thyroid so prone to autoimmune
disease? Horm. Res. Paediatr. 3, 157–165