Autoimmunity Reviews 8 (2009) 400–404

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Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev

The role of innate immune responses in autoimmune disease development☆

Hanspeter Waldner ⁎
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA

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

Article history: Autoimmune diseases are systemic or organ-specific disorders that are the result of an attack of
Received 2 December 2008 the immune system against the body's own tissue. Development of autoimmune disease is
Accepted 23 December 2008 generally avoided by distinct mechanisms that silence adaptive self-reactive T or B cells. The
Available online 20 January 2009
innate immune system is critically involved in the defense against pathogens and the induction
of primary adaptive immune responses. Toll-like receptors (TLRs) are key receptors that activate
Keywords: the innate immunity in response to pathogen recognition. Recent data show that activation of
Autoimmune disease
innate immune cells such as dendritic cells (DCs) can break this state of tolerance and induce
Innate immune system
autoimmunity by priming autoreactive T cells. Here we review recent examples of how innate
Dendritic cells
Toll-like receptors immune responses influence the adaptive immunity in the induction or regulation of
Susceptibility to autoimmunity autoimmune disease.
© 2009 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
2. Induction of innate immune responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
3. DC subsets and their functional specialization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
4. Innate responses in selected autoimmune diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
4.1. Systemic lupus erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
4.2. Type 1 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
4.3. Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

1. Introduction conditions are the result of multi-factorial processes involving

There are at least 80 different autoimmune diseases, which
affect approximately 20 million people in the USA, according to
the Autoimmune Diseases Coordinating Committee of the U. S.
National Institutes of Health. These systemic or organ-specific
☆ Supported by a grant from the National Multiple Sclerosis Society
(NMSS).
⁎ Tel.: +1 717 531 0003; fax: +1 717 51 6522.
E-mail address: hpwaldner@psu.edu.
disregulation of the innate and adaptive immune system that
lead the body to attack its own tissues [1].
The innate immune system is the host's immediate line of
defense against invading microorganisms while the adaptive
immune system responds to the infection in a time-delayed
but antigen-specific fashion. Specific cell populations of the
innate immune system such as the antigen-presenting
dendritic cells (DCs) are critical in promoting primary T and
B cell responses and thereby bridge the gap between innate
and adaptive immunity [2]. T cells that are reactive to self-

1568-9972/$ – see front matter © 2009 Published by Elsevier B.V.

doi:10.1016/j.autrev.2008.12.019
 H. Waldner / Autoimmunity Reviews 8 (2009) 400–404
antigens are largely deleted in the thymus in an active process
termed thymic or central tolerance induction [3]. Since this
process is not absolute, self-reactive T cells can be found in the
periphery of even healthy individuals. However, the devel-
opment of autoimmune disease is generally prevented in
most of us due to distinct safety mechanisms in the periphery
that render the host tolerant to these potentially pathogenic T
cells [4]. Infections or overt stimulation of antigen-presenting
cells (APCs) can break peripheral tolerance and induce the
priming of self-reactive T cells in draining lymph nodes,
which may lead to development of autoimmune disease in
predisposed hosts [5]. Furthermore, diverse microbial pro-
ducts that activate innate immunity via specific pattern-
recognition receptors (PPRs) can trigger autoimmune disease
in mice [6,7].
The purpose of this review is to discuss the contribution of
innate immune responses in the development and regulation
of selected autoimmune diseases based on recent experi-
mental data from animal models.
2. Induction of innate immune responses
While certain types of innate immune cells are specialized
to attack infected cells directly, the function of others is to
activate the adaptive immune system and to induce effector
functions to eliminate the pathogen. Here we will focus on the
innate immune cells that are known to be the most potent
activator and modulator of the adaptive immune system, the
dendritic cells (DCs) [2]. DCs reside in peripheral tissues and
are equipped with a variety of pattern-recognition receptors
(PRRs), including the evolutionary conserved family of Toll-
like receptors (TLRs) [8]. TLRs are expressed either at the cell
surface where they recognize products from bacterial and
fungal cell walls or flagella, or these receptors (TLR3, TLR7,
TLR8, TLR9) are found in endosomes of DCs and detect virus-
derived nucleic acids [9]. The binding of microbial products to
TLRs activates myeloid differentiation factor 88 (MyD88)-
dependent or MyD88-independent (via TLR3) signaling path-
ways that result in the activation and maturation of DCs [9].
Mature DCs display up-regulated expression of MHC II (signal
1) and costimulatory molecules such as CD80 and CD86
(signal 2). Importantly, TLR-mediated activation of DCs also
leads to the induction of various soluble and membrane-
bound proteins (signal 3) that are critical for inducing
different CD4+ and CD8+ T cell effector functions [10]. In
addition to pathogen-derived signals, the activation of DCs
can also be influenced by inflammation-associated tissue
factors from infected tissues or by natural IgG [11], [12].
3. DC subsets and their functional specialization
Depending on the response of the activated DC subset,
naïve CD4+ T cells can differentiate into different Th subsets,
which are characterized by distinct cytokine profiles and
effector functions as initially discovered by Mosmann and
Cofmann. Th1 and the recently identified Th17 cells produce
the pro-inflammatory cytokines IFN-γ and IL-17, respectively
[13]. Th1 cells are crucial for the induction of B cell and
cytotoxic T lymphocyte responses. Moreover, Th1 and Th17
have been demonstrated to act as critical mediators of a
number of T cell-mediated autoimmune diseases [14]. Th2
401
cells, which mainly secrete IL-4 are responsible for inducing
humoral responses and for clearing extracellular pathogens.
These cells can exert ameliorative or protective effects in
certain autoimmune diseases [15].
DCs represent a heterogeneous cell population that
consists of different subsets with distinct phenotypes and
functional properties. In the spleen of mice one can
distinguish at least three major DC subsets based on their
expression of CD11c and CD8α [16]. Mature CD8α− (myeloid)
and CD8α+ (lymphoid) DCs express CD11c hi and are potent
APCs, whereas plasmacytoid DCs (pDCs) (CD8a+/−B220+)
express CD11c at intermediate levels and are inefficient
APCs. In response to microbial stimulation CD8α+ DCs differ
from CD8α− DCs in their much higher production of IL-12p70,
which promotes Th1 differentiation. This partly explains why
CD8α+ and CD8α− DCs preferentially induce Th1 and Th2
responses, respectively [17]. However, importantly, this
functional specialization appears to be flexible since different
experimental conditions (e.g. low antigen dose) can alter the
function of DC subsets [10]. The detailed role of CD8α+ and
CD8α− DCs in the induction of Th17 responses is still unclear
and under investigation. pDCs are specialized to detect viral
nucleic acids via TLR7 or TLR9, resulting in the production of
high levels of IFN-α, which promotes CTL and Th1 responses
[18]. In the absence of DC-activating signals such as microbial
products, different DC subsets, including pDCs and CD8α+
DCs have been shown to induce peripheral T cell tolerance
[19]. However, it is not clear whether such DCs have received
signals that mediate exhaustion or alternative maturation to
exert their tolerogenic functions on T cells. DCs that were
exhaustively activated ceased to produce pro-inflammatory
cytokines and promoted the induction of Th2 cells. Various
factors including IL-10 were able to alternatively activate DCs,
which thereby promoted the induction of Tregs [10].
4. Innate responses in selected autoimmune diseases
4.1. Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a chronic multisystem
autoimmune disease, which is characterized by the production of
autoantibodies, in particular against double-stranded DNA and
nuclear proteins from dead cells [1]. In humans the disease
manifests itself by a wide range of clinical features and can affect
many organs, including most frequently the kidneys or the brain.
Patients with SLE show increased production of IFN-α that is
mainly produced by pDCs in response to continuous stimulation
by circulating immune complexes [20]. These complexes consist
of self-nucleic acid that is bound to DNA- or RNA-specific
autoantibodies. The findings of various in vitro studies have
implicated that the internalization of these immune complexes
via CD32 (FcgammaRIIA) and subsequent detection of DNA and
RNA by endosomal TLR9 and TLR7 in PDCs, respectively, is a
crucial event in the pathogenesis of SLE [21,22]. An in vivo role for
TLR7- and TLR9-mediated innate immune responses in SLE
development has been suggested by studies in mice. Male BXSP
mice show a twofold increase in the expression of TLR7 due to the
Y-chromosome-linked autoimmune accelerator (Yaa) mutation
and develop an SLE-like disease at much higher incidence than
their female counterparts with normal TLR7 expression [23].
Furthermore, TLR9-mediated activation of pDCs by stimulatory
402 H. Waldner / Autoimmunity Reviews 8 (2009) 400–404
oligodeoxynucleotides (ODNs) results in INF-a production, which
can be blocked by ODNs that contain inhibitory sequence motifs.
Importantly, administration of such inhibitory ODNs in mouse
models of SLE inhibits the development and severity of disease
[24]. While these findings support a critical role for TLR9- or
TLR7-mediated activation of PDCs in the pathogenesis of SLE,
myeloid DCs may also contribute to SLE pathogenesis [25]. We
also refer to a recent review that discusses the role of innate
immunity in the induction of SLE in more details [26].
4.2. Type 1 diabetes
Type 1 diabetes (T1D) is an organ-specific autoimmune
disease that results from T cell-mediated destruction of
insulin-producing pancreatic beta cells in genetically predis-
posed individuals (1). In non-obese diabetic (NOD) mice,
diabetes develops spontaneously at high incidence that can
be affected by the microbial environment of the housing
facility or reduced by the administration of microbial
adjuvants such as complete Freund's adjuvant (CFA) [27].
However, a number of studies demonstrated that TLR-
mediated innate immune responses could contribute to the
induction of diabetes in mice. For example, secondary
necrotic apoptotic beta-cells activated antigen-presenting
innate immune cells via TLR2, which primed islet-specific
CD4+ T cells that mediated T1D in NOD mice [28]. Interest-
ingly, findings of a recent study suggested that the attributed
critical role of innate immune activation in T1D development
might be an oversimplification. This study demonstrated that
MyD88-deficient NOD mice that were housed under germ-
free conditions were susceptible to T1D development,
whereas their counterparts that were housed in an SPF
facility did not develop T1D [29]. These findings indicated that
MyD88-mediated microbial activation of the innate immunity
was not required for the induction of T1D. Notably, the study
discovered that the intestinal microbiota in the SPF-housed
MyD88-deficient NOD mice protected them from develop-
ment of diabetes in a MyD88-independent manner. The
results of this study are in contrast with those of many
previous studies for reasons, which remain to be elucidated.
4.3. Multiple Sclerosis
Multiple Sclerosis (MS) is an autoimmune demyelinating
disease of the central nervous system (CNS) and represents the
leading cause of paralysis in young adults [1]. The animal
model of MS, experimental autoimmune encephalomyelitis
(EAE), is mediated by pro-inflammatory myelin-specific CD4+ T
cells following immunization of animals with myelin proteins
in the presence of Mycobacterium tuberculosis (MT) containing
CFA [30]. A number of studies have documented that activation
of innate immunity by various microbial TLR ligands is critical
for the priming of encephalitogenic CD4+ T cells and induction
of EAE [6,7,31]. Initiation of disease requires MyD88-dependent
signals because MyD88-deficient mice are resistant to MOG-
induced EAE [32,33]. The MyD88-dependent resistance to EAE
was associated with the lack of pro-inflammatory Th1 or Th17
induction due to impaired IL-6 and IL-23 responses by myeloid
DCs, respectively. [33]. The role of innate immune responses
induced by individual TLRs in EAE development is less clear.
The same authors using TLR9-deficient mice have produced
Fig. 1. Differential induction of pro-inflammatory PLP-specific T cells by SJL and
B10.S BMDCs. DCs were derived from SJL and B10.S bone marrow cells and
enriched for CD11c+ cells by magnetic bead isolation. CD11c+ DCs (2 × 105cells/
well) were used to stimulate naïve PLP TCR transgenic CD4+ T cells (1 ×106 cells/
well) with PLP139-151 (25 μg/ml) in the presence or absence of indicated TLR
ligands (0.1 μg/ml LPS, 10 μg/ml Pam3Cys, 1 μM CpG) for 72 h. T cells were
subsequently stimulated with PMA (10 ng/ml)/Ionomycin (500 ng/ml) in
presence of brefeldin A for 5 h before they were assayed for intracellular IFN-γ
by flow cytometry. A similar strain-specific bias in the induction of IL-17-
producing transgenic CD4+ T cells (Th17) was found, albeit at lower frequencies
than for INF-g-producing T cells (data not shown). Mean percentages+ SD of
IFN-γ+ CD4+ T cells are shown. ⁎ P b 0.05 (Student's t-test).
conflicting results and suggested that TLR9-induced innate
immune responses could have exacerbating or ameliorative
effects in EAE [32,33]. In addition to the critical role of TLR-
mediated signals, several studies have demonstrated that
specific DC subsets play an important role in inducing
immunogenic or tolerogenic T cell responses against myelin-
antigens in EAE. For example, myeloid DCs (CD11b+) that
infiltrated the CNS in mice with EAE promoted the induction
and expansion of IL-17-producing PLP-specific CD4+ T cells
[34,35]. During EAE, pDCs were also found to infiltrate the CNS
and suppress the myeloid DC-driven activation of pro-
inflammatory PLP-specific CD4+ T cell responses (IL-17, IFN-γ)
[36]. In the periphery, CD8α− (myeloid) DCs could also mediate
suppression of myelin-specific T cell functions and EAE severity
by inducing the production of the anti-inflammatory cytokine
IL-10 [37]. Taken together, the findings of such studies indicate
that TLR-induced innate immune responses can drive or
counter-regulate the development and progression of EAE in a
dynamic fashion. The net outcome of the interplay between
innate and adaptive immunity depends on multiple factors, in
particular the specific TLR ligand and the DC subset activated.
Given the critical role of the innate immunity in shaping
adaptive immune responses, it is reasonable to assume that
innate immune cells influence the susceptibility to EAE.
Indeed, studies from our laboratory have suggested that the
innate immunity is involved in conferring differential suscept-
ibility to spontaneous EAE. In mice that are transgenic for a
PLP139-151 T cell receptor (TCR) and congenic for H-2s, EAE
develops spontaneously at a high incidence in SJL but rarely in
B10.S mice [38,7]. The relative resistance to spontaneous EAE
in PLP TCR B10.S mice was not due to T cell specific defects or
the induction of Tregs cells but rather appeared to be
controlled by APCs [7]. Consistent with these findings, TLR-
activated bone marrow derived DCs (BMDCs) from B10.S mice
 H. Waldner / Autoimmunity Reviews 8 (2009) 400–404
were significantly less efficient in promoting activation and
differentiation of naive CD4+ T cells into pro-inflammatory
PLP-specific T cells compared to SJL BMDCs (Fig. 1). A similar
strain-specific bias was found for the induction of IL-17-
producing transgenic CD4+ T cells (Th17), albeit at lower
frequencies compared to Th1 cells (data not shown). These
data indicated that TLR-activated SJL and B10.S DCs differential
induction of pro-inflammatory effector T cells and thereby
may influence susceptibility to EAE in SJL and B10.S mice.
5. Conclusions
The immediate task of innate immune responses is to
clear the host from extracellular or intracellular pathogens
and to induce an antigen-specific adaptive immune response
against the invading organism. The type of adaptive immune
response that is induced in the host primarily depends on
the type of pathogen or various tissue-derived factors that
activate local DC subsets via PRRs. Overt or long-term
activation of innate immunity can break peripheral toler-
ance to self-antigens and result in the induction of auto-
immune disease even in resistant hosts [17]. A critical factor
that critically influences the host's susceptibility to devel-
opment of autoimmune disease is the intrinsic response of
its innate immunity to TLR-mediated activation. Depending
on this response, self-reactive T cells can differentiate into
effector cells and promote development of autoimmune
disease. It is crucial to elucidate the mechanisms by which
innate immune responses shape adaptive immunity because
they will help our understanding in the pathogenesis of
autoimmune diseases. Furthermore, the findings will allow
the development of therapeutic strategies to combat these
disorders in patients [39,40].
Take-home messages
• Innate immune cells use pattern recognition receptors (PPRs),
including Toll like receptors (TLRs) to detect a variety of
extracellular and intracellular pathogens.
• DCs are a heterogeneous population of antigen presenting
innate immune cells, which undergo significant functional
changes following TLR-mediated activation.
• Activated DCs induce different effector functions in T cells,
primarily depending on the type of TLR ligand and DC subset.
• Responses of specific DC subsets play a critical role in the
induction and regulation of various autoimmune diseases
in mice.
• TLR-activated BMDCs from EAE-susceptible SJL mice induce
higher frequencies of pro-inflammatory PLP-specific T cells
than those from B10.S mice.
• Strain-specific innate immune responses may control
differential development of spontaneous EAE in PLP TCR
transgenic SJL and B10.S mice.
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Increased expression of CD40 on bone marrow CD34+ hematopoietic progenitor cells in patients with systemic lupus
erythematosus: Contribution to Fas-mediated apoptosis

It has been shown that patients with systemic lupus erythematosus (SLE) display increased apoptosis of bone marrow (BM) CD34+
hematopoietic progenitor cells. However the role of CD 40/CD40L as one of the mediators of this phenomena had been not explored
before. In a recent study Pyrovolaki K, et al. (Arthritis Rheum. 2009; 60: 543-552), evaluated the expression of CD40 and CD40L in
the BM of SLE patients, and explored the possible involvement of these molecules in the apoptosis of CD34+ cells. Thus, the
proportion and survival characteristics of CD40+ cells within the BM CD34+ fraction from SLE patients and healthy controls were
evaluated by flow cytometry. The production of CD40L by BM stromal cells was assessed using long-term BM cultures, and the effect
of CD40L on the survival characteristics and clonogenic potential of CD34+ cells was evaluated ex vivo by flow cytometry and
clonogenic assays. As a result they found that SLE patients displayed an increased proportion of CD40+ cells within the CD34+
fraction as compared with controls. The CD34+CD40+ subpopulation contained an increased proportion of apoptotic cells
compared with the CD34+CD40- fraction in patients and controls, suggesting that CD40 is involved in the apoptosis of CD34+ cells.
Stimulation of patients' CD34+ cells with CD40L increased the proportion of apoptotic cells and decreased the proportion of colony-
forming cells as compared with untreated cultures. The CD40L-mediated effects were amplified following treatment with
recombinant Fas ligand, suggesting that the effects of these ligands are synergistic. CD40L levels were significantly increased in
long-term BM culture supernatants and adherent layers of BM cells from SLE patients as compared with controls. These data reveal
a novel role for the CD40/CD40L lygand in SLE by demonstrating that up-regulation and induction of CD40 on BM CD34+ cells from
patients with SLE contribute to the amplification of Fas-mediated apoptosis of progenitor cells.

Beta(2)-glycoprotein I is a cofactor for tissue plasminogen activator-mediated plasminogen activation

The regulation of the conversion of plasminogen to plasmin by tissue plasminogen activator (tPA) is critical in the control of
fibrin deposition. While several plasminogen activators have been described, soluble plasma cofactors that stimulate
fibrinolysis have not been characterized. In one study Bu C, et al. (Arthritis Rheum. 2009; 60:559-568), investigated the
effects of beta (2)-glycoprotein I (beta(2)GPI), an abundant plasma glycoprotein, on tPA-mediated plasminogen activation. The
effect of beta (2)GPI on tPA-mediated activation of plasminogen was assessed using amidolytic assays, a fibrin gel, and plasma
clots. Binding of beta (2)GPI to tPA and plasminogen was determined in parallel. The effects of IgG fractions and anti-beta (2)
GPI antibodies from patients with antiphospholipid syndrome (APS) on tPA-mediated plasminogen activation were also
measured. They found that Beta (2)-glycoprotein I stimulated tPA-dependent plasminogen activation in the fluid phase and
within a fibrin gel. The beta(2)GPI region responsible for stimulating tPA activity was shown to be at least partly contained
within beta(2)GPI domain V. In addition, beta (2)GPI bound tPA with high affinity (K(d) approximately 20 nM), stimulated tPA
amidolytic activity, and caused an overall 20-fold increase in the catalytic efficiency (K(cat)/K(m)) of tPA-mediated conversion
of Glu-plasminogen to plasmin. Moreover, depletion of beta(2)GPI from plasma led to diminished rates of clot lysis, with
restoration of normal lysis rates following beta(2)GPI repletion. Stimulation of tPA-mediated plasminogen activity by beta (2)
GPI was inhibited by monoclonal anti-beta (2)GPI antibodies as well as by anti-beta (2)GPI antibodies from patients with APS.
These findings suggest that beta (2)GPI may be an endogenous regulator of fibrinolysis. Impairment of beta (2)GPI-stimulated
fibrinolysis by anti-beta(2)GPI antibodies may contribute to the development of thrombosis in patients with APS.