antiviral immune responses: triggers of or triggered by autoimmunity?

The immune system walks a fine line to distinguish self from harmful non-self to preserve the integrity of the host. Deficits in this discrimination can result in suscep-tibility to infections or overreactivity to harmless anti-gens, leading to immunopathology and autoimmunity. Therefore, it is not surprising that genetic factors that influence the sensitivity of the immune system are associ-ated with autoimmune diseases, but this inherited sensi-tivity might only result in autoimmunity after exposure to certain environmental factors, including viral infections. This also implies that the overreactive immune system of individuals who are susceptible to autoimmune dis-ease might be triggered by more than one pathogen or even by common pathogens that establish a more severe primary infection in these susceptible individuals. Either possibility makes it difficult to assign a role for distinct pathogens to the development of particular autoimmune diseases. In this Review, we discuss the mechanisms by which pathogens could trigger autoimmune diseases and the mechanisms by which autoimmune disease could alter the ability of the host to control infections and reg-ulate the immune system. In discussing these aspects, we highlight recent studies that show the induction of autoimmune inflammation in the central nervous system (CNS) of mice following infection with Theiler’s murine encephalomyelitis virus (TMEV) and the dysregulation of immune responses against Epstein–Barr virus (EBV) in humans with the autoimmune disease multiple scle-rosis. A clearer understanding of the mechanisms and

correlations between altered immune responses to these pathogens and autoimmune diseases could help guide the development of new therapeutic approaches or surrogate markers for disease activity in the future.

Antiviral responses can trigger immunitySeveral mechanisms have been described to explain how viruses might trigger autoimmune diseases, including virus-induced general activation of the immune system and the provision of viral antigens that specifically stimu-late immune responses that crossreact with self antigens and therefore cause autoreactive immunopathologies.

Adjuvant effect of pathogens in priming autoreactive immune responses. The ability of the host to defend against invading pathogens is largely mediated by a group of germline-encoded receptors known as pattern-recognition receptors (PRRs). These molecules include Toll-like receptors (TLRs), nucleotide-binding and oligo merization domain (NOD)-like receptors, retinoic-acid-inducible gene I (RIG-I)-like helicases and a subset of C-type lectin receptors, which together recognize a large number of molecular patterns in bacteria, viruses and fungi (reviewed in REF. 1). The signalling path-ways that are triggered by receptor recognition of these molecules lead to cellular activation, which increases the antigen-presenting capacity and the expression of co-stimulatory molecules by antigen-presenting cells (APCs), as well as their production of type I interferons,

*Viral Immunobiology, Institute of Experimental Immunology, University Hospital Zürich, Winterthurerstrasse 190, CH‑8057 Zürich, Switzerland. ‡Laboratory of Viral Immunobiology, The Rockefeller University, New York, 10065 New York, USA. §Department of Microbiology–Immunology and Interdepartmental Immunobiology Center, Northwestern University, Feinberg School of Medicine, Chicago, 60611 Illinois, USA. Correspondence to C.M.e‑mail: [email protected]:10.1038/nri2527

Pattern-recognition receptorA host receptor (such as a Toll-like receptor) that can sense pathogen-associated molecular patterns and initiate signalling cascades (which involve activation of nuclear factor-κB) that lead to an innate immune response.

Antiviral immune responses: triggers of or triggered by autoimmunity?Christian Münz*‡, Jan D. Lünemann‡, Meghann Teague Getts§ and Stephen D. Miller§

Abstract | The predisposition of individuals to several common autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, is genetically linked to certain human MHC class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins, as well as the geographical distribution of disease risk, suggest the involvement of environmental factors in the development of these diseases. Among these environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. In this Review, we outline the mechanisms by which viral infection can trigger autoimmune disease and describe the pathways by which infection and immune control of infectious disease might be dysregulated during autoimmunity.

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Nature Reviews | Immunology

Antibodies Type I interferons

Autoimmune tissue damage

Pro-inflammatorycytokines

Co-stimulatorymolecules andcell maturation

T-cellactivation

NF-κB

Nucleus

p50 p65

Mitochondrion

Endosome

IRF7IRF3

Microbialantigen

CLRTLR

NLR

PAMP

MHC class II

RLH

IPS1

Figure 1 | Infectious agents function as adjuvants for the activation and promotion of immune responses and autoimmune diseases. Detection of pathogen-associated molecular patterns (PAMPs) occurs through pattern-recognition receptors (PRRs). These include Toll-like receptors (TLRs), which are expressed on the cell surface or in the endosomes or phagosomes of cells; NOD-like receptors (NLRs), which are found in the cytoplasm; retinoic-acid-inducible gene I (RIG-I)-like helicases (RLHs), which link to mitochondria using the adaptor protein IFNB-promoter stimulator 1 (IPS1) and detect viral RNA in the cytoplasm; and a subset of cell surface C-type lectin receptors (CLRs). Activation of these PRRs results in a cascade of events that culminate in the activation of interferon-regulatory factors (IRFs) and nuclear factor-κB (NF-κB), which trigger the production of type I interferons and pro-inflammatory cytokines, respectively. PRR ligation also results in cellular maturation and activation, which involve the upregulation of co-stimulatory molecules that promote efficient T-cell activation. Autoreactive T cells activated in this manner could then cause autoimmune tissue damage. In addition, PRR stimulation can result in antibody class switching and upregulation of antibody production in B cells114. For autoreactive B cells, PRR signalling can therefore directly augment autoimmune responses. Finally, a microbial infection provides antigen for activation of microorganism-specific T and B cells that potentiate the inflammatory response, or for the activation of T and B cells specific for antigens that are crossreactive with self antigens.

AdjuvantA non-infectious form of immune activation used to increase immune responses to antigen.

pro-inflammatory cytokines and chemokines, which initiate and direct the immune response against the invading pathogen. Microbial antigens, as well as PRR-triggered inflammatory molecules, drive the clonal expansion of pathogen-specific T and B cells. By trigger-ing PRRs, stimulating early responses by innate immune cells and increasing the function of APCs, pathogens act as adjuvants for the immune response, while at the same time providing an antigen source to drive T-cell and B-cell activation and effector function (FIG. 1). In this inflammatory environment, it is easy to imagine how an aberrant destructive immune response might be triggered and/or escalated if autoreactive cells were present. There are several postulated mechanisms by

which pathogenic infections might trigger autoimmune disease, but most evidence in animal models has been gathered to support the idea that crossreactive immune responses cause autoimmunity because of similarities between viral and self antigens.

Molecular mimicry. The well-documented degeneracy of antigen recognition by the T-cell receptor (TCR), such that a T cell can be activated by different peptides bound to one or even several MHC molecules2, implies that responses to microbial antigens could result in the activation of T cells that are crossreactive with self anti-gens. Similarly, monoclonal antibodies have also been found to recognize both microbial and self antigens3. This idea, known as molecular mimicry (FIG. 2A), was first put forward by Fujinami and Oldstone4,5. It is now generally accepted that a single T cell can respond to various different peptides and that the same TCR can crossreact with different peptide–MHC complexes as long as the complexes have similar charge distribution and overall shape6–8. This flexibility of TCR recogni-tion is thought to be central to many immunological processes, including thymic selection and the ability of TCRs to recognize nearly all pathogen-derived pep-tides. An undesirable side effect of this flexibility is the potential induction of autoimmunity by microbial antigens. Indeed, in vitro studies have shown that viral peptides with some homology with self peptides can stimulate autoreactive T cells6. The identification of such cross reactivities has proven useful in uncovering the aetiological agents of autoimmune disease.

Molecular mimicry is involved in triggering disease in many animal models of autoimmune disease. These models include TMEV-induced demyelinating disease (TMEV-IDD), a model of human multiple sclerosis in which intracerebral TMEV infection of mice leads to an autoimmune demyelinating disorder 30–40 days after infection9; herpes simplex virus (HSV)-associated stro-mal keratitis, in which HSV infection leads to T-cell-mediated blindness in both humans and mice10–12; some models of type I diabetes13; autoimmune demyelinat-ing disease associated with Semliki Forest virus14; and autoimmune myocarditis associated with coxsackie-virus15 or murine cytomegalovirus infections16 (TABLE 1). Other microbial pathogens have also been implicated in contributing to autoimmune disease by molecular mimicry (for example, streptococcus in rheumatoid myocarditis)17; however, we focus on the possible roles of viruses in autoimmune diseases.

Many less physiological scenarios that do not neces-sarily aim to closely model a particular disease also serve to reveal potential mechanisms through which immune responses to infections could lead to autoimmunity through molecular mimicry. Several of these studies have used models of molecular identity, in which a transgene that encodes a known microbial protein or epitope is expressed in a particular tissue. Transgene expression alone does not generally make the animals susceptible to the development of spontaneous autoimmune disease. However, after infection with the microorganism that contains the expressed protein, autoimmune responses

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TCR

Virus-specific CD4+ T cell


Autoreactive CD4+ T cell



Viralantigen

MHC class II

Self antigen

APC

APC

Virus

Viral antigenwith similarity to self antigen

A

Ba b

c d

Cytokines and other inflammatory molecules

Tissuedamage

Tissue cell

APC

Inflammatory mediators

Tissue cell

TLR

Viral PAMP

Superantigen



APC APCT cell specificfor ‘new’self antigen

‘New’self antigenTissue damage Epitope spreading

Bystanderactivation

Figure 2 | mechanisms of infection-induced autoimmunity. A | Autoreactive T cells can be activated through a mechanism of molecular mimicry that involves crossreactive recognition of a viral antigen that has similarity to self antigen. Ba | Microbial infection stimulates Toll-like receptors (TLRs) and other pattern-recognition receptors on antigen-presenting cells (APCs), leading to the production of pro-inflammatory mediators, which in turn can lead to tissue damage. Bb | Self antigen that is released from damaged tissue can be taken up by activated APCs, processed and presented to autoreactive T cells (concomitant with presentation of virus antigen to virus-specific T cells) in a process known as bystander activation. Alternatively, an infection can lead to microbial superantigen-induced activation of a subset of T cells, some of which could be specific for self antigen. Bc | Further tissue destruction by activated T cells and inflammatory mediators causes the release of more self antigen from tissues. Bd | The T-cell response can then spread to involve T cells specific for other self antigens in a process known as epitope spreading. PAMP, pathogen-associated molecular pattern; TCR, T-cell receptor.

ensue that are directed against the organ expressing the transgenic protein18–21. These approaches, although clearly artificial, indicate that T cells specific for a self antigen can become activated by infection with a microorganism that contains an identical antigen and provides the neces-sary innate immune signals to cause overt autoimmune

disease. Even when the transgene-expressed antigen is also expressed in the thymus, so that normal mechanisms of negative selection significantly reduce the number of high-affinity T cells that are specific for the antigen, infec-tion eventually results in autoimmunity20. These experi-ments indicate that even T cells that have low affinity for a self antigen and have escaped negative selection, as would be the case for many self-antigen-specific responses, can be activated through molecular mimicry with a microbial antigen and can cause disease.

This mechanism of molecular identity is involved in the TMEV-IDD model of multiple sclerosis, a severe rapid-onset demyelinating disease of the CNS that is induced by intracerebral or peripheral infection with TMEV that has been engineered to express the immu-nodominant self epitope from myelin proteolipid protein (PLP) peptide 139–151 (PLP139–151)

22. Several bacterial and viral peptides that mimic PLP139–151 have been identified23, and these have been used in models that more directly address the possibility that autoimmune disease could be induced by molecular mimicry. TMEV can be engineered to express peptides derived from Haemophilus influen-zae (which shares 6 of 13 amino acids with PLP139–151) or murine hepatitis virus (which shares only 3 of 13 amino acids with PLP139–151) that mimic PLP139–151. Infection with such engineered TMEV induces a rapid-onset, severe demyelinating disease that is similar to that induced by infection with TMEV that expresses PLP139–151 itself 22,24. The H. influenzae peptide mimic of PLP139–151 can also be generated and presented when the recombinant TMEV contains larger portions of the bacterial protein that include the native flanking sequences of the peptide, which further supports the potential role for molecular mimicry in a natural infection25.

Importantly to human disease, bacterial peptide mimics of the myelin basic protein (MBP) epitope 85–99 (MBP85–99) derived from different pathogens, such as Mycobacterium tuberculosis, Bacillus subtilis and Staphylococcus aureus, induce demyelinating disease in mice that transgenically express a human MBP85–99-specific TCR and an HLA class II molecule that can present the peptide26. Molecular mimicry was also shown to be involved in a model of diabetes in which lymphocytic choriomeningitis virus (LCMV) nucleoprotein (NP) was expressed under the control of the rat insulin promoter (RIP). Infection with Pichinde virus, which contains an epitope that is similar to a subdominant epitope in LCMV NP, accelerated autoimmune disease that had already been established by previous infection with LCMV13. HSV-induced stromal keratitis has been shown to be mediated by corneal-antigen-specific T-cell responses induced fol-lowing corneal infection with HSV10, and, in this naturally occurring autoimmune disease model, molecular mim-icry occurred in the absence of genetic manipulation10. However, a subsequent study questioned the involvement of T-cell-mediated molecular mimicry in HSV-induced stromal keratitis, as the disease could be induced in mice in the absence of T-cell responses against HSV11. In this setting, it is possible that a failure to control the virus caused keratitis through pathogen-induced immuno-pathology. Therefore, given that different model systems,

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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5354&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


Table 1 | Selected pathogen-induced mouse models of human autoimmune disease

mouse model or infectious agent Proposed mechanism (or mechanisms) of autoimmunity

Comment References

Multiple sclerosis

TMEV-IDD Bystander activation and epitope spreading

Natural virus-induced autoimmune disease of mice

9

TMEV expressing PLP139–151

Molecular identity None 22

TMEV expressing PLP139–151

mimics Molecular mimicry None 22,24,25

Coxsackievirus B4 expressing PLP139–151

Molecular identity Infection can be at a site distant from the site of autoimmune reaction

None

LCMV infection of mice expressing LCMV proteins in the CNS

Molecular identity None 21

Semliki Forest virus infection Molecular mimicry None 14

Type 1 diabetes

Coxsackievirus B4 infection Bystander activation None 115

LCMV infection of mice expressing LCMV protein in the pancreas

Molecular identity TCR affinity for the LCMV peptide determines rapidity and severity of autoimmune disease

18–20

Pichinde virus infection of mice expressing LCMV protein in the pancreas

Molecular mimicry Autoimmunity can only be accelerated, and not initiated, de novo by this approach

13

Myocarditis

Mouse cytomegalovirus infection Bystander activation or molecular mimicry

Possible role for molecular mimicry, but does not exclude bystander activation

16,116,117

Coxsackievirus B3 infection Molecular mimicry None 15,16,117

Stromal keratitis

Corneal HSV-induced stromal keratitis Molecular mimicry and/or bystander activation

Some controversy over which mechanism is responsible

10–12

CNS, central nervous system; HSV, herpes simplex virus; LCMV, lymphocytic choriomeningitis virus; PLP, proteolipid protein; TCR, T-cell receptor; TMEV-IDD, Theiler’s murine encephalomyelitis virus-induced demyelinating disease.

Molecular mimicryA term used to describe what happens when a T- or B-cell receptor recognizes a microbial peptide that is structurally similar to a self peptide. The immune response, which is initially directed at the microbial peptide, spreads to tissues that present the crossreactive self peptide, resulting in autoimmunity.

Negative selectionThe intrathymic elimination of double-positive or single-positive thymocytes that express T-cell receptors with high affinity for self antigens.

Polyfunctional T cellA T cell that has two or more functions, including, but not limited to, cytotoxicity and production of cytokines or chemokines. The development of multiparameter flow cytometry has facilitated the extensive analysis of T-cell effector functions at the single-cell level.

which might involve different disease mechanisms, were used to investigate HSV-induced stromal keratitis, the strong case for molecular mimicry put forward by the initial study cannot be ruled out12.

In keeping with the idea that antigen-specific T cells that have been primed by pathogens and crossreact with self antigens can cause autoimmunity in animal models, patients with autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis and multiple sclerosis have been found to have higher frequencies and activation states and/or reduced co-stimulatory requirements of self-reactive lymphocytes27–30. In multiple sclerosis, receptor analysis of T and B cells in CNS tissue and in the cerebro spinal fluid showed evidence of clonal expansions in both T- and B-cell populations, indicating that certain lym-phocyte clones are responding to a restricted number of disease-relevant antigens31–33. In addition, longitudinal studies provided evidence for the long-term persistence of individual myelin-specific T-cell clones over several years in the blood of patients with multiple sclerosis34–36, indicating that there is a strong, persistent memory T-cell response and/or ongoing exposure of at least a subset of myelin-reactive T cells to autoantigen.

we suggest that these memory T-cell responses reflect, at least in part, persisting clonal expansions of polyspe-cific T cells that recognize both self and virus antigens which have been found to be associated with human

autoimmune diseases (TABLE 2). For example, the high viral loads that occur during symptomatic primary infection of EBV, and result in infectious mononucle-osis, are associated with an increased risk of developing multiple sclerosis37–39, and could prime these polyspe-cific T-cell responses. Accordingly, patients with mul-tiple sclerosis have predominant clonal expansions of T cells that are specific for EBV nuclear antigen 1 (EBNA1), the EBV antigen that is most commonly targeted by CD4+ T cells in healthy virus carriers, and EBNA1-specific T cells recognize myelin antigens more frequently than other autoantigens that are not associated with multiple sclerosis40. Notably, myelin and EBNA1 crossreactive T cells produce interferon-γ (IFNγ) and differ from EBNA1-monospecific cells in their capacity to produce additional cytokines, such as interleukin-2, which is indicative of polyfunctional T cells. Because T cells successively produce more than one cytokine during differentiation, polyfunctional T cells are thought to be particularly important under conditions of antigen persistence and high antigen load because they are less susceptible to clonal exhaustion or activation-induced cell death41. However, viral titres in circulating blood cells from patients with multiple scle-rosis are similar to those detectable in healthy virus car-riers42, and patients with multiple sclerosis do not differ from healthy EBV carriers in the rate of EBV-induced B-cell transformation or in their ability to control

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Table 2 | Examples of viruses that have been implicated in human autoimmune diseases

Virus Autoimmune disease Evidence Selected references

RNA viruses

Coxsackievirus Type 1 diabetes • Altered virus-specific immune responses • Infected β-cells detected in pancreas from patients with type 1 diabetes• Experimental infection causes type 1 diabetes

115,118–120

Rubella virus Type 1 diabetes • Tropism for pancreatic β-cells• Molecular mimicry

121,122

HTLV-1 HTLV-1-associated myelopathy • Molecular mimicry 123

Measles virus Multiple sclerosis • Infection can result in demyelination• Higher titres of virus-specific IgG• Increased frequencies of virus-specific T cells in the CSF

124–126

DNA viruses

HSV-1 (also known as HHV-1)

Autoimmune stromal keratitis • Molecular mimicry 10

EBV (also known as HHV-4)

Multiple sclerosis • Increased risk of developing multiple sclerosis after primary symptomatic infection

• Increased antibody responses in healthy individuals who will develop multiple sclerosis

• Increased seroprevalence• Altered virus-specific T-cell and humoral immune responses• Molecular mimicry• Localization of virus and virus-specific lymphocytes in diseased tissues

37,38,40,42, 63,127–130

Rheumatoid arthritis • Altered virus-specific immune responses • Higher viral loads in circulating blood cells • Localization of virus in diseased tissues

92,93,109, 131–133

SLE • Increased seroprevalence• Altered virus-specific immune responses • Increased viral load• Molecular mimicry

89,90,134

HHV-6 Multiple sclerosis • Localization of virus in diseased tissue • Increased virus-specific immune responses

135,136

Torque teno virus Multiple sclerosis • Localization of virus in diseased tissues • Clonally expanded CSF-infiltrating T cells recognize viral antigen

137

Parvovirus B19 Rheumatoid arthritis • Phenotype of acute infection can mimic early rheumatoid arthritis• Detection of viral DNA in synovial tissue

138,139

SLE • Phenotype of acute infection can mimic early SLE• Increased frequency of virus carriers among patients with SLE

140

CSF, cerebrospinal fluid; EBV, Epstein–Barr virus; HHV, human herpesvirus; HSV-1, herpes simplex virus 1; HTLV-1; human T cell leukaemia virus type 1; SLE, systemic lupus erythematosus.

Clonal exhaustionA state of non-reactivity in which all precursor lymphocytes are induced by a persistent antigen (or antigens) to become effector cells, purging the immune-response repertoire of this specificity (or specificities).

Activation-induced cell deathA process by which fully activated T cells undergo programmed cell death through engagement of cell-surface-expressed death receptors, such as CD95 (also known as FAS) or the tumour-necrosis-factor receptor.

the outgrowth of EBV-infected B cells in vitro40. This suggests that increased viral replication or impaired immune control of chronic EBV infection does not drive EBV-specific T-cell expansion in patients with multiple sclerosis. Instead, a more extensive priming of polyfunctional crossreactive T cells during symp-tomatic primary EBV infection with high levels of viral load, and continuous restimulation caused by autoimmune tissue inflammation, could establish and maintain a distinct repertoire of myelin-reactive virus-specific T cells, which could predispose individuals to multiple sclerosis.

Bystander activation of autoreactive cells and epitope spreading. APCs that have become activated in the inflam-matory milieu of a pathogenic infection can stimulate the activation and proliferation of autoreactive T or B cells in a process known as bystander activation. In this proc-ess, APCs present self antigen, obtained following tissue

destruction and/or by the uptake of local dying cells, to autoreactive cells43,44 (FIG. 2B). In addition, auto antigen-specific T or B cells can be primed through epitope spreading45, a mechanism by which an immune response that is initiated by various stimuli, including microbial infection, trauma, transplanted tissue or autoimmunity, ‘spreads’ to include responses directed against a different portion of the same protein (intramolecular spreading) or a different protein (intermolecular spreading) (FIG. 2B). Activating a broader set of T cells through epitope spread-ing is beneficial during an antipathogen or antitumour immune response, because the pathogen or tumour cannot easily escape immune control with a single mutation in an immunogenic epitope. However, dis-ease potentially arises when the response spreads to and within self proteins subsequent to the destruction of self tissue. Epitope spreading in animal models proceeds in an orderly, directed and hierarchical manner, such that responses to more immunodominant epitopes are elicited

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Bystander activationActivation and/or expansion of an immune response at a site of direct inflammation-induced tissue damage.

Epitope spreadingA process by which autoreactive T-cell or B-cell responses induced by a single peptide (or epitope) can spread to include other peptides (or epitopes) in the same autoantigen (intramolecular spreading) or in other self antigens (intermolecular spreading) that are released after T- or B-cell-mediated bystander tissue damage.

Immunodominant epitopeA portion of an antigen that is targeted preferentially or to a greater level during an immune response.

SuperantigenA microbial protein that activates all T cells which express a particular set of T-cell receptor (TCR) Vβ chains by cross-linking the TCR to a particular MHC molecule regardless of the peptide presented.

first, followed by responses to less dominant epitopes. This type of epitope spreading has been shown in experi-mental autoimmune encephalomyelitis (EAE), a non-infectious model of multiple sclerosis46,47, as well as in TMEV-IDD9,48–50 and in the non-obese diabetic mouse model of type 1 diabetes51 (S.D.M., unpublished obser-vations). Although these examples document epitope spreading within autoantigens and to additional autoan-tigens, the inflammatory environment of viral infections could also support these immune response cascades by increasing the presentation of self antigens through the provision of ligands for PRR signalling.

An even broader form of bystander activation is achieved by microbial superantigens, which cross-link MHC class II molecules with TCRs that comprise a cer-tain Vβ domain, leading to T-cell activation independ-ently of specific antigen recognition. T-cell populations that are stimulated in this manner could contain a subset of T cells that are specific for a self antigen52. Many stud-ies suggest that superantigens are involved in diseases such as EAE, arthritis and inflammatory bowel disease, which supports the idea that microbial superantigens are involved in another mechanism by which bystander activation can initiate, or at least exacerbate, autoim-munity in mouse models53–55. In these studies, staphy-lococcal, mycoplasmal and enteric microbiota-derived superantigens were shown to amplify, but not initiate, autoimmune T-cell responses (TABLE 1). Furthermore, certain genotypes of the superantigen-encoding human endogenous retrovirus K18 (HERV-K18), which is trans-activated by EBV56, have been reported to be associated with multiple sclerosis57. However, Vβ7+ and Vβ13+ T-cell populations, which are stimulated by HERV-K18 superantigen, do not seem to be selectively expanded in patients with multiple sclerosis. Nevertheless, viral-antigen-specific and/or superantigen-expanded T cells might participate in the development or maintenance of autoimmune disease. Therefore, although molecular mimicry might initially prime autoreactive T cells, these responses could be amplified by superantigen-mediated expansion of autoantigen-specific T cells.

Emerging mechanisms. Infections can affect the immune response in many ways, and mechanisms such as molecu-lar mimicry and bystander activation are certainly not the only ways in which pathogens might trigger or acceler-ate autoimmune disease. A recent study showed that in a spontaneous animal model of SLE, lipid raft aggregation on T cells, which was induced by cholera toxin B from Vibrio cholerae in this particular study but can be induced by several microorganisms or toxins, enhanced T-cell sig-nalling and exacerbated SLE58. Furthermore, viral infec-tions could also directly maintain autoreactive effector T cells or autoantigen-presenting cells59. For example, persistent infection of microglial cells with TMEV has been shown to upregulate expression of MHC and co-stimulatory molecules and enhance the ability of these cells to function as effective APCs60. In another example, EBV immortalizes B cells and assists in their differentia-tion into long-lived memory B cells61. In addition, even in infected memory B cells, which usually do not express the

latent EBV proteins that are associated with immortaliza-tion, non-translated viral RNAs contribute to resistance of the cells to death62. These mechanisms could support the survival of autoreactive B cells or a reservoir of APCs that can present autoantigens to promote autoimmunity. Indeed, a reservoir of EBV-infected B cells was recently found in submeningeal aggregates of brains from patients with multiple sclerosis63.

Although several causal relationships between patho-gen infection and autoimmunity have been identified in animal models and correlations have been drawn in human autoimmune diseases, pathogen-derived triggers of autoimmunity have been difficult to identify. This is because evidence of autoimmunity is likely to become clinically apparent only after a considerable period of subclinical autoimmune responses, at which time the pathogen might have already been cleared and/or the antiviral immune responses might have subsided; this is called the ‘hit-and-run’ hypothesis.

All of the mechanisms discussed so far are dynamic, interrelated and not mutually exclusive, and therefore the contribution of microbial infection to autoimmunity should be viewed as a process that involves many path-ways occurring simultaneously and/or sequentially and not as a defined event that involves a single mechanism (FIG. 2). For example, epitope spreading can be initiated through molecular mimicry. This was revealed by a study that detected the activation of PLP178–191-specific T cells in SJL mice in which autoimmunity was induced following bystander damage or by infection with TMEV that expressed either PLP139–151 or a PLP139–151 mimic peptide22. Molecular mimicry can initially activate autoreactive T cells, which then expand and become pathogenic through bystander activation, or vice versa. As a result, it can be difficult to distinguish between the postulated mechanisms, even in seemingly simple animal models5,11,12,64.

Overt autoimmune disease by these mechanismsStudies of animal models have made it clear that, in principle, infections can trigger autoimmune responses. However, this must be distinguished from the elicitation of overt autoimmune disease as a direct result of microbial infection, which might be more difficult to establish.

Autoreactive T cells are unavoidably present in the periphery in humans and animals. These cells can exist because their cognate self antigen was not expressed in the thymus and the antigen will therefore only become available to the immune system after tissue destruction as a result of infection or trauma. Alternatively, whereas many autoreactive T cells are deleted in the thymus during development, some T cells that make their way to the periphery might have high affinity for a micro-bial antigen, but also have lesser affinity for a self anti-gen. However, the presence of autoreactive cells in the periphery does not necessarily predispose individuals to clinical autoimmune disease.

In many cases, an infection is necessary for the development of overt disease, even when abundant autoreactive T cells are present44. In a cogent example, demyelinating disease was readily induced in mice either

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Altered peptide ligand(APL). A peptide analogue of the original antigenic peptide. APLs commonly have amino acid substitutions at T-cell receptor (TCR) contact residues. TCR engagement by these APLs usually leads to partial or incomplete T-cell activation. Antagonistic APLs can specifically antagonize and inhibit T-cell activation induced by the wild-type antigenic peptide.

by priming with PLP139–151 in complete Freund’s adju-vant (CFA) or by infecting with TMEV that expressed a PLP139–151 mimic23,24. However, priming with PLP139–151 mimics in CFA did not induce overt disease, even though T cells from mice primed with mimic peptides responded strongly to PLP139–151. It is probable that TLR engagement and other innate immune stimuli that are present following infection with TMEV allow APCs to provide the necessary signals for full activation and opti-mal migration of autoreactive T cells60. The nature of the pathogen that directs the type of immune response elicited can therefore profoundly influence the potential for development of autoimmune disease, and could in fact increase or decrease the likelihood of autoimmu-nity in the presence of autoreactive cells. In this regard, T helper 1 (TH1)- and TH17-polarized T-cell responses have been proposed to accelerate autoimmunity, whereas TH2-polarized responses might confer protection65. Furthermore, in the case of molecular mimicry, the virus-encoded mimic itself has an important role, as a peptide that partially mimics a self antigen (known as an altered peptide ligand) could have a tolerizing rather than an activating effect, depending on the context of the infection60.

Even the presence of autoreactive T cells together with an appropriate infection might not lead to autoim-mune disease. For example, in Pichinde virus infection of RIP–LCMV–NP mice, the mimic-encoding Pichinde virus was not sufficient to initiate overt autoimmunity, but was able to accelerate autoimmune disease that had already been established by infection with LCMV13. Viral ‘adjuvant’ and self peptide mimics might there-fore only trigger autoimmune disease when autoreactive cells are already ‘primed’ to some level, such that the autoreactive T cells have been previously activated and exist at a higher precursor frequency66. The affinity of TCRs for various self peptide–MHC complexes might also have a key role in the development of autoimmune disease. Indeed, a threshold level of TCR affinity has been shown to be important for the establishment of autoimmunity67. In the RIP–LCMV–NP mouse model, whether or not the antigen (NP) was expressed in the thymus during development (which affects T-cell affinity) has a significant impact on the rate at which autoimmune disease develops20. TLR engagement alone is sufficient to induce the appropriate environment for the development of autoimmune disease if autoreactive T cells are of high enough affinity for self antigen20,68. However, as most T cells have low affinity for self under physiological conditions, studies in which TCR affin-ity for self antigen is low may have greater relevance to human autoimmune disease.

The potential for the development of overt dis-ease therefore depends on the presence of autoreac-tive T cells. However, whether overt disease actually occurs can depend on various other coincident events, including the number of autoreactive T cells present, the avidity and affinity of these cells (determined by co-receptor expression and binding to peptide–MHC complexes, respectively) and the presence of innate inflammatory signals required for these T cells to gain

a pathogenic phenotype. Despite the requirement for all of these elements, it is clear that they do not need to happen at the same time or in the same place to elicit autoimmune disease.

Autoimmunity can occur at a site distal to the initiating infection. In many animal models, autoimmune responses are triggered during the initial or acute response to an infection, and autoimmune disease occurs exclusively in the infected organ, such as during corneal HSV infection, which leads to stromal keratitis10–12. Furthermore, sub-meningeal reservoirs of EBV-infected B cells have been reported in the brains of patients with multiple sclero-sis63, although it remains unclear if these reservoirs focus pathogenic immune responses to the diseased tissue. Models in which infection directs autoreactive responses to distinct tissues provide simple systems in which to study the pathological mechanisms of infection-induced autoimmunity. However, in most cases, a robust immune response to a pathogenic infection in the target organ is usually not associated with the development of autoim-munity in humans. None of the proposed mechanisms for the development of infection-induced autoimmunity excludes the possibility that disease can occur tempo-rally and/or spatially distal from the site of the initiat-ing infection (FIG. 3). Although few animal models have allowed investigators to study this aspect of infection-induced autoimmune disease, such studies might provide important insights that are relevant to human disease.

Autoimmune demyelinating disease of the CNS can be triggered by molecular mimicry when the pathogen containing the mimic epitope does not infect the CNS itself. when mice that express an LCMV protein in the CNS were peripherally infected with LCMV, autoim-mune responses occurred in the CNS despite the fact that LCMV was not detectable in that organ21. In wild-type mice, recombinant pancreatropic coxsackievirus that expresses PLP139–151 also induces CNS demyelinating disease and was associated with PLP139–151-specific T-cell responses in the absence of any apparent infection in the CNS itself (S.D.M., unpublished observations).

The fact that the various mechanisms for infection-induced autoimmunity discussed here are not mutually exclusive makes them both more complicated and more plausible as potential causes for human autoimmune dis-ease. For example, molecular mimicry and adjuvant effects of pathogens might be involved early during the devel-opment of autoimmune responses, whereas bystander activation owing to the inflammatory environment of infections and/or superantigens might exacerbate autoim-mune responses later during development of the disease. However, as we consider the potentially multi-mechanistic and multistep nature of autoimmunity, it is important to remember that an established autoimmune response can also have effects on pathogen-directed immune responses occurring in the same organ or elsewhere in the body.

Autoimmunity might trigger antiviral responsesThe flip side of the idea that autoimmunity is driven by viral infections is that autoreactive immune responses, or even only a predisposition to the development of these

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TCR

Virus-specific T cellVirus

Autoreactive T cell

Viral antigen

Crossreactive antigen

MHC class II

a

APC

Primary infection in tissue X Tissue Y

Migration

With or without secondaryinfection or trauma

TCR

Virus-specific T cell

Autoreactive T cell

Viral antigen

Crossreactive antigen

MHC class II

b

APC

Primary infection in tissue X Tissue X or Y

Time

With or without secondaryinfection or trauma

Self antigen

Self antigen

Figure 3 | Autoimmunity can occur at a site distal to the initiating infection and/or following pathogen clearance. a | Autoreactive T cells can be activated through molecular mimicry or bystander activation in an infected tissue (tissue X) without eliciting overt autoimmune disease before the infection is resolved. After the activated autoreactive T cells migrate to a distant site (tissue Y), they can trigger autoimmune disease, if sufficient antigen is available at this site. If sufficient self antigen is not present, the induction of overt autoimmune disease may require a secondary infection or trauma event. b | T cells that are activated during infection in tissue X can later become reactivated by a secondary infection with the same or a different microorganism, or following trauma. It is probable that autoimmune disease following microbial clearance can occur in the initial tissue or in a secondary site, if enough self antigen is available to reactivate autoreactive T cells. TCR, T-cell receptor.

Rheumatoid factorAn antibody (usually IgM) that binds to the Fc region of IgG, thereby forming immune complexes. Rheumatoid factors are sometimes found in patients with rheumatoid arthritis or other autoimmune diseases, such as systemic lupus erythematosus.

responses, might affect the development of antiviral immune responses. This might alter the composition of these immune responses, the viral set point during chronic infections and the anatomical distribution of virus-specific lymphocytes. These alterations could be used as surrogate markers for autoimmune disease activity, but might not regulate the autoimmune disease itself.

Bystander activation. The activation of innate immune cells can be initiated by both pathogen-associated ‘stranger’ signals69 and damage-associated, altered-self ‘danger’ signals70. These apparently disparate signals trigger inflammation through common means, as both stranger and danger signals ligate PRRs. TLRs have a particularly instructive role in innate immune responses against microbial pathogens, as well as a role in the sub-sequent induction of adaptive immune responses. Both experimental infections in mice that lack individual

TLRs or key molecules of the TLR signalling pathways71 and natural infections in humans with primary immuno-deficiencies that selectively impair TLR responses72 clearly show the crucial role of TLRs in shaping protective antiviral immunity.

A role for TLR signalling in the induction and main-tenance of autoimmune diseases was first highlighted by Leadbetter et al.73, who showed that immunoglobulin in the blood provokes autoimmune responses when immune cells recognize it as a complex with self DNA. In B-cell receptor-transgenic mice, in which most B cells express surface antibodies with low affinity for self IgG2a, immunoglobulin neither activates the B cells nor makes them tolerant unless these mice are crossed onto an autoimmune-prone lpr background74. Self IgG2a is immunogenic in the offspring of this cross, resulting in high titres of circulating rheumatoid factor autoantibodies, a diagnostic marker of autoimmune disease. This study found that immune complexes consisting of self IgG2a and self DNA, which trigger surface B-cell receptors and endosomal TLRs, were necessary and sufficient for the loss of self tolerance in this model. Similar models have been reported for RNA-containing immune complexes and activation of TLR7 or TLR8 (REFS 75,76). Endogenous TLR ligands, such as self DNA or self RNA, or nucleic-acid-associated proteins, could therefore act as adjuvants in autoimmune diseases that are characterized by promi-nent tissue damage or impaired removal of apoptotic-cell or necrotic-cell debris77, and could assist in the priming of antiviral immune responses.

Furthermore, the induction and maintenance of autoimmune tissue inflammation crucially depends on the cytokine profile of pathogenic TH cells in animal models of T-cell-mediated autoimmune diseases65,78,79. Both TH1 and TH17 cells are thought to coordinate autoimmune inflammation in these diseases, presum-ably through distinct pathways80. Although the TH1-cell cytokine IFNγ can inhibit the generation of TH17 cells, it also reinforces TH1-cell differentiation78, which is instrumental in establishing protective antiviral immune responses. Therefore, the TH1-polarizing milieu of autoimmune diseases might support superior antiviral immune responses81,82.

Although the increased availability of intrinsic dan-ger signals released through autoimmune tissue dam-age has not yet been shown in experimental models, we suggest that such signals probably affect host immune responses to microbial pathogens at sites of autoimmune inflammation and enhance pathogen-specific innate and adaptive immune responses.

Increased pathogen replication. In addition to the adju-vant activity of autoimmunity, which might enhance pathogen-specific immune responses, autoimmunity can also affect pathogens that persist in lymphocytes, such as human T-cell leukaemia virus type 1 (HTLV-1) and EBV, which establish persistent infections in memory T cells and memory B cells, respectively. Both viruses seem to establish latent infection without detectable antigenic protein expression in these cells83,84. Reactivation of HTLV-1 occurs following engagement of the TCR and

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TCR

MHC class II

TCR

MHC class II

Latently infected B cell

T cell specific forEBV lytic protein

T cell specific forEBV latent protein

Autoantigenor autoantigen-containingimmune complex

Cross-linking

Adjuvant activity

Reactivation of latent protein expression

Reactivation of viral replication

EBV latent membrane proteinEBV latent nuclear protein

EBV lyticprotein antigen

EBV latentprotein antigen

BCR

EBV

Endosome TLR

Figure 4 | Adjuvant activity and specific recognition of autoantigen-containing immune complexes can lead to the reactivation of lymphotropic viruses. Cross-linking of the B-cell receptor (BCR) by autoantigen-containing immune complexes can activate B cells that are latently infected with Epstein–Barr virus (EBV) and trigger the virus to enter the lytic cycle. This results in increased production of new virus particles and expression of EBV lytic protein antigens, which can be presented to specific T cells. This might lead to improved EBV-specific immune control in patients with autoimmune disease. Triggering of endosomal Toll-like receptors (TLRs) by autoantigens or autoantigen-containing immune complexes provides adjuvant activity that might sustain or reactivate EBV latent protein expression in the activated B cells. Latent protein antigens could then be presented to specific T cells, protein in the expansion of virus-specific T-cell populations, as observed in some patients with autoimmune diseases. TCR, T-cell receptor.

co-stimulatory molecules85. Similarly, lytic replication of EBV can only be observed in plasma cells86, and can be induced by cross-linking surface immunoglobulin on infected B cells87. Therefore, autoimmunity could trig-ger reactivation of these pathogens (FIG. 4), as has been documented in the case of EBV reactivation by malaria antigens88. Indeed, patients with SLE have abnormally high frequencies of EBV-infected cells that have aberrant expression of the immediate early lytic antigen BZLF1 in peripheral blood89. Interestingly, increased cell-associated viral loads correlated with autoimmune disease activity. Moreover, in patients with SLE, increased EBV loads correlated with EBV-specific CD8+ T-cell responses90, which had decreased cytotoxicity as a sign of exhaus-tion91, possibly owing to persistent restimulation by the high antigenic load. CD4+ T-cell responses to EBV were also upregulated in patients with SLE, but these responses negatively correlated with viral loads, suggesting that these cells provided increased immune protection90.

whereas EBV viral loads are up to 40-fold increased in patients with SLE, they are 10-fold increased in patients with rheumatoid arthritis92,93. Similarly, CD8+ T-cell responses to EBV antigens positively correlate with these increased viral loads in patients with rheu-matoid arthrtis93. The increased antigen load in patients with rheumatoid arthritis seems to cause further differ-entiation of EBV-specific CD8+ T cells, resulting in the presence of a subpopulation of terminally differentiated, and presumably co-stimulation-insensitive, CD27–CD28– T cells that are rarely observed in healthy EBV carriers94. In addition to EBV-specific T-cell responses, subdomi-nant antibody responses and broadened antibody responses to dominant EBV antigens are also observed in patients with rheumatoid arthritis93, again suggesting

that the increased EBV antigen load in these patients hyperstimulates EBV-specific humoral and cell- mediated immune responses. Although in most cases these increased immune responses maintain EBV-specific immune control, increased autoantigen-mediated stimu-lation of the B-cell compartment can result in lymphoma development by driving B cells to hypermutation and ger-minal centre reactions, which increases the risk of acquir-ing transforming mutations. In the case of rheumatoid arthritis, Hodgkin’s lymphomas, including EBV+ tumours, are more highly associated with the autoimmune disease than non-Hodgkin’s lymphomas95.

Together, these studies suggest that lymphotropic pathogens, such as EBV, can be affected by autoim-mune stimulation of host immune cells, leading to increased viral titres, increased immune responses against the pathogen and even pathogen-associated malignancies. Collectively, the evidence indicates that dysregulation of EBV-specific immune responses is a feature of rheumatoid arthritis and SLE, and is prob-ably driven by autoantigen-mediated activation of EBV-infected B cells.

Genetic factors. Family-based genetic epidemiological studies provide unequivocal evidence that the suscepti-bility for autoimmune diseases is inherited, and genome-wide microsatellite screens and large-scale association studies of single nucleotide polymorphisms have identi-fied chromosomal loci that are associated with specific disorders, such as SLE, rheumatoid arthritis, type 1 diabe-tes and multiple sclerosis. HLA-DR and HLA-DQ alleles of the HLA class II region on chromosome 6p21 are the highest-risk-conferring genes for all of these disorders96–99. Although the MHC region has proven difficult to dissect

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because of its strong and variable patterns of linkage dis-equilibrium, there is evidence that additional loci in the HLA class III and HLA class I genomic regions and loci that are telomeric to genes encoding the classical MHC molecules might have independent associations with autoimmune disease96. Furthermore, less-robust suscep-tibility effects have been identified in non-MHC regions. For example, the ITGAM–ITGAX region on chromosome 6p11 encodes the α-chain of αMβ2 integrin (also known as MAC1, CR3 and CD11b), which is important for neu-trophil and monocyte adherence to stimulated endothe-lium as well as for the clearance of immune complexes, and was found to be associated with SLE in multiple stud-ies97,100,101. In addition, the IL7RA region on chromosome 5p13 and IL2RA on chromosome 10p15 were identified as loci that are associated with multiple sclerosis102–104. Epistatic interactions between these risk-conferring and protective allelic variants are thought to define the overall genetic threshold for susceptibility to disease8.

we propose that immune functions of autoimmune susceptibility genes and their products probably affect host–pathogen interactions in patients with autoimmune diseases72. In line with this idea, a study revealed that CD8+ T cells that recognize an immunodominant EBV epitope restricted by HLA-B8 crossreacted with HLA-B*4402, presumably presenting a self peptide105. This crossreac-tivity was strong enough to mediate alloreactivity against HLA-B*4402+ cells and to result in deletion of this EBV specificity in HLA-B*4402+HLA-B8+ individuals by nega-tive selection, which ablates T cells of this specificity from the repertoire of EBV-specific immune responses in these individuals. However, incomplete deletion of these allore-active T cells in genetically susceptible individuals could result in autoreactive and EBV-specific T cells. Similarly to this finding that genetic variation of the host can favour the presentation and recognition of a particular viral peptide, genetic variation of viruses might also favour the presentation of peptide that can stimulate crossreac-tive T cells. For example, EBV strain B95-8 has a point mutation in the HLA-B8-restricted CD8+ T-cell epitope discussed above, which affects T-cell recognition of the virus owing to inefficient binding of the variant peptide to HLA-B8 (REF. 106). Conversely, autoreactive T cells could be preferentially triggered by certain virus strains encoding peptide epitopes that stimulate crossreactive T cells. The increased sequence variation that has recently been characterized in EBNA1 (REF. 107) implies that an association between multiple sclerosis and a particular EBV strain remains possible, and sequence variation in the viral strain might enhance particular EBV-specific T- and B-cell responses that could participate in autoim-munity. Therefore, the particular HLA background of an individual and the distinct viral strains carried by the indi-vidual could select for T-cell specificities with autoreactive capacity during antiviral immune responses.

To consider this potential mechanism, investiga-tions of the disease-promoting or disease-protective effects of gene–environment interactions should involve a comparison between patients with autoim-mune diseases and syngeneic controls, such as non-affected monozygotic twins108. As this is not always

feasible, we suggest that patients and controls should at least be matched for expression of alleles that con-fer high disease risk, such as HLA-DR and HLA-DQ allelic variants, as this strategy minimizes the possibil-ity that any differences in pathogen-specific immune responses are a consequence rather than a cause of disease susceptibility.

Redistribution of antiviral immune responses to sites of autoimmune inflammation. As discussed above, genetic variation of both the pathogen and the host might favour distinct virus-specific immune responses. However, the preferential homing of primed antiviral T cells to affected organs might also falsely implicate pathogens in the immunopathology of autoimmune diseases. For example, lytic EBV infection was suspected to contribute to rheumatoid arthritis after it was found that T cells spe-cific from lytic EBV antigens were enriched in inflamed joints109. Indeed, CD8+ T cells specific for immediate early and early lytic EBV antigens were first cloned from the synovial fluid of patients with rheumatoid arthri-tis109. These specificities, which are now recognized to be among the most frequent T-cell responses, develop during persistent infection with EBV110. Similarly, CD4+ T cells specific for lytic EBV antigens were also initially cloned from patients with rheumatoid arthritis111.

Interestingly, it was subsequently found that these lytic-antigen-specific T cells home to various autoim-mune inflamed tissues112, including knee joints affected by rheumatoid arthritis and the eyes of patients with uveitis. These data were thought to reflect the migra-tion of EBV-specific T cells in response to inflam-matory chemokines, such as the CXCR3 ligand CXC-chemokine ligand 10 (CXCL10), rather than a direct involvement of EBV-directed immunity in the immunopathology of autoimmune diseases. Similarly, pathogen-infected lymphocytes can preferentially migrate to inflamed tissues, and this localization could be wrongly assumed to indicate that the pathogen con-tributes to autoimmune pathology rather than that the localization is consistent with the normal migratory behaviour of infected host cells. The finding that EBV-infected B cells are enriched in the tertiary lymphoid tissues of post-mortem CNS tissue from patients with multiple sclerosis might reflect changes in the migra-tory behaviour of the infected B cells63, a possibil-ity that requires further investigation. In particular, CXCL13-mediated recruitment of CXCR5+ B cells to multiple sclerosis lesions should be investigated along these lines113.

Therefore, the enrichment of both pathogen-specific and pathogen-infected lymphocytes at sites of autoim-munity might tell us more about the migratory behav-iour of these cells than the involvement of the associated pathogens in the immunopathology of autoimmune diseases. Nevertheless, a better understanding of these mechanisms could explain how certain pathogens target the autoimmune reactivity of a sensitized immune sys-tem to certain organs and indicate whether monitoring antiviral immune responses could be a useful surrogate marker for autoimmune disease.

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Concluding remarksBoth genetic and environmental factors are known to be involved in the initiation and promotion of autoim-mune diseases. Viral infections are the main candidate environmental factors owing to their capacity to elicit strong immune activation and induce autoimmune diseases in animal models, as well as their correlation with autoimmune diseases in humans. The studies highlighted in this Review suggest that viruses can trig-ger autoimmunity through molecular mimicry and its adjuvant effects during the initiation of disease, and can promote autoimmune responses through bystander activation or epitope spreading by inflammation and/or superantigens.

The finding that dysregulated antiviral immune responses are associated with autoimmune disease must be interpreted with caution, however, because these responses can be primed differently in individuals with ongoing autoimmune disease or with a genetic predisposition to autoimmune disease. Furthermore, the autoimmune disease can alter virus infection by affecting its host cells and might lead to redistribution of antiviral lymphocytes to sites of autoreactive tissue inflammation. These changes might prove to be useful as surrogate markers for autoim-mune disease reactivity and could be harnessed therapeuti-cally. However, any therapeutic approach that targets these responses should be used with caution so that immune control against the pathogen is not compromised.

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AcknowledgementsThe laboratory of C.M. is supported by the Dana Foundation’s Neuroimmunology programme, the Arnold and Mabel Beckman Foundation, the Alexandrine and Alexander Sinsheimer Foundation, the Burroughs Wellcome Fund, the Starr Foundation, the National Cancer Inst itute (R01CA108609 and R01CA101741), the National Institute of Allergy and Infectious Diseases (RFP-NIH-NIAID-DAIDS-BAA-06-19), the Foundation for the National Institutes of Health (Grand Challenges in Global Health) and an Institutional Clinical and Translational Science Award (to the Rockefeller University Hospital). J.D.L. is supported by a Dana Foundation and Irvington Institute’s Human Immunology Fellowship, a Pilot Grant from the National Multiple Sclerosis Society (PP1145) and an Institutional Clinical and Translational Science Pilot and Collaborative Project Grant (to the Rockefeller University Hospital). The laboratory of S.D.M. and M.T.G. is supported by the National Institute for Neurological Diseases and Stroke (R01 NS-023349, R01 NS-040460 and R01 NS-030871), the National Multiple Sclerosis Society (RG 3793-A-7) and the Myelin Repair Foundation.

DATABASESEntrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geneαMβ2 integrin | CXCL10 | CXCL13 | EBNA1 | IFNγ | MBP | PLP | TLR7 | TLR8

FURTHER INFORMATIONChristian Münz’s homepage: http://www.exp-immunologie.usz.ch

All lInkS ARE ACtIVE In thE onlInE Pdf

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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

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antiviral immune responses: triggers of or triggered by autoimmunity?

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