triggers of autoimmunity

7/25/2019 Triggers of Autoimmunity

1/13

The immune system walks a fine line to distinguish selffrom harmful non-self to preserve the integrity of thehost. 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 thatinfluence the sensitivity of the immune system are associ-ated with autoimmune diseases, but this inherited sensi-tivity might only result in autoimmunity after exposure tocertain environmental factors, including viral infections.This also implies that the overreactive immune systemof individuals who are susceptible to autoimmune dis-ease might be triggered by more than one pathogen oreven by common pathogens that establish a more severeprimary infection in these susceptible individuals. Eitherpossibility makes it difficult to assign a role for distinct

pathogens to the development of particular autoimmunediseases. In this Review, we discuss the mechanisms bywhich pathogens could trigger autoimmune diseases andthe mechanisms by which autoimmune disease couldalter 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 ofautoimmune inflammation in the central nervous system(CNS) of mice following infection with Theilers murineencephalomyelitis virus (TMEV) and the dysregulationof immune responses against EpsteinBarr virus (EBV)in humans with the autoimmune disease multiple scle-rosis. A clearer understanding of the mechanisms and

correlations between altered immune responses to thesepathogens and autoimmune diseases could help guide thedevelopment of new therapeutic approaches or surrogatemarkers for disease activity in the future.

Antiviral responses can trigger immunity

Several mechanisms have been described to explainhow viruses might trigger autoimmune diseases, including

virus-induced general activation of the immune systemand the provision of viral antigens that specifically stimu-late immune responses that crossreact with self antigensand therefore cause autoreactive immunopathologies.

Adjuvant effect of pathogens in priming autoreactiveimmune responses.The ability of the host to defendagainst invading pathogens is largely mediated by a

group of germline-encoded receptors known as pattern-recognition receptors(PRRs). These molecules includeToll-like receptors (TLRs), nucleotide-binding andoligomerization domain (NOD)-like receptors, retinoic-acid-inducible gene I (RIG-I)-like helicases and a subsetof C-type lectin receptors, which together recognize alarge number of molecular patterns in bacteria, virusesand fungi (reviewed in REF. 1). The signalling path-ways that are triggered by receptor recognition of thesemolecules lead to cellular activation, which increasesthe antigen-presenting capacity and the expression ofco-stimulatory molecules by antigen-presenting cells(APCs), as well as their production of type I interferons,

*Viral Immunobiology,

Institute of Experimental

Immunology, University

Hospital Zrich,

Winterthurerstrasse 190,CH-8057 Zrich, Switzerland.Laboratory of Viral

Immunobiology, The

Rockefeller University, New

York, 10065 New York, USA.Department of

MicrobiologyImmunology

and Interdepartmental

Immunobiology Center,

Northwestern University,

Feinberg School of Medicine,

Chicago, 60611 Illinois, USA.

Correspondence to C.M.

e-mail: [email protected]

doi:10.1038/nri2527

Pattern-recognition

receptor

A 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-B) that lead to an

innate immune response.

Antiviral immune responses: triggers ofor triggered by autoimmunity?Christian Mnz*, Jan D. Lnemann, Meghann Teague Gettsand

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 lowconcordance 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.

R E V I E W S

246 |APRIL 2009 |VOLUME 9 www.nature.com/reviews/immunol

2009 Macmillan Publishers Limited. All rights reserved
mailto:[email protected]:[email protected]


2/13

|

Antibodies Type Iinterferons

Autoimmune tissue damage

Pro-inflammatorycytokines

Co-stimulatorymolecules andcell maturation

T-cellactivation

NF-B

Nucleus

p50 p65

Mitochondrion

Endosome

IRF7IRF3

Microbialantigen

CLRTLR

NLR

PAMP

MHCclass 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 culminatein the activation of interferon-regulatory factors (IRFs) and nuclear factor- B (NF-B),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.

Adjuvant

A 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 theinvading pathogen. Microbial antigens, as well as PRR-triggered inflammatory molecules, drive the clonalexpansion of pathogen-specific T and B cells. By trigger-ing PRRs, stimulating early responses by innate immunecells and increasing the function of APCs, pathogensact as adjuvantsfor the immune response, while at thesame time providing an antigen source to drive T-celland B-cell activation and effector function (FIG. 1). Inthis inflammatory environment, it is easy to imaginehow an aberrant destructive immune response mightbe triggered and/or escalated if autoreactive cells werepresent. There are several postulated mechanisms by

which pathogenic infections might trigger autoimmunedisease, but most evidence in animal models has beengathered to support the idea that crossreactive immuneresponses cause autoimmunity because of similaritiesbetween viral and self antigens.

Molecular mimicry.The well-documented degeneracyof antigen recognition by the T-cell receptor (TCR),such that a T cell can be activated by different peptidesbound to one or even several MHC molecules2, impliesthat responses to microbial antigens could result in theactivation of T cells that are crossreactive with self anti-gens. Similarly, monoclonal antibodies have also beenfound to recognize both microbial and self antigens3.This idea, known as molecular mimicry (FIG. 2A), wasfirst put forward by Fujinami and Oldstone4,5. It is nowgenerally accepted that a single T cell can respond to

various different peptides and that the same TCR cancrossreact with different peptideMHC complexes aslong as the complexes have similar charge distributionand overall shape68. This flexibility of TCR recogni-

tion is thought to be central to many immunologicalprocesses, including thymic selection and the abilityof TCRs to recognize nearly all pathogen-derived pep-tides. An undesirable side effect of this flexibility isthe potential induction of autoimmunity by microbialantigens. Indeed, in vitrostudies have shown that viralpeptides with some homology with self peptides canstimulate autoreactive T cells6. The identification ofsuch crossreactivities has proven useful in uncoveringthe aetiological agents of autoimmune disease.

Molecular mimicry is involved in triggering diseasein many animal models of autoimmune disease. Thesemodels include TMEV-induced demyelinating disease(TMEV-IDD), a model of human multiple sclerosis inwhich intracerebral TMEV infection of mice leads to anautoimmune demyelinating disorder 3040 days afterinfection9; herpes simplex virus (HSV)-associated stro-mal keratitis, in which HSV infection leads to T-cell-mediated blindness in both humans and mice1012; somemodels of type I diabetes13; autoimmune demyelinat-ing disease associated with Semliki Forest virus14; andautoimmune myocarditis associated with coxsackie-

virus15or murine cytomegalovirus infections16(TABLE 1).Other microbial pathogens have also been implicatedin contributing to autoimmune disease by molecularmimicry (for example, streptococcus in rheumatoidmyocarditis)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 serveto reveal potential mechanisms through which immuneresponses to infections could lead to autoimmunitythrough molecular mimicry. Several of these studies haveused models of molecular identity, in which a transgenethat encodes a known microbial protein or epitope isexpressed in a particular tissue. Transgene expressionalone does not generally make the animals susceptibleto the development of spontaneous autoimmune disease.However, after infection with the microorganism thatcontains the expressed protein, autoimmune responses

R E V I E W S

NATURE REVIEWS |IMMUNOLOGY VOLUME 9 |APRIL 2009 |247



3/13

|

TCR

Virus-specificCD4+T cell


AutoreactiveCD4+T cell



Viral

antigen

MHCclass II

Self antigen

APC

APC

Virus

Viral antigenwith similarityto self antigen

A

Ba b

c d

Cytokines and otherinflammatory molecules

Tissuedamage

Tissue cell

APC

Inflammatorymediators

Tissuecell

TLR

Viral PAMP

Superantigen



APC APC

T cell specificfor newself antigen

Newself antigen

Tissue damage Epitope spreading

Bystander

activation

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 activatedT cells and inflammatory mediators causes

the release of more self antigen from tissues. Bd |The T-cellresponse 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 thetransgenic protein1821. These approaches, although clearlyartificial, indicate that T cells specific for a self antigencan become activated by infection with a microorganismthat contains an identical antigen and provides the neces-sary innate immune signals to cause overt autoimmune

disease. Even when the transgene-expressed antigen isalso expressed in the thymus, so that normal mechanismsof negative selectionsignificantly reduce the number ofhigh-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 aself antigen and have escaped negative selection, as wouldbe the case for many self-antigen-specific responses,can be activated through molecular mimicry with amicrobial antigen and can cause disease.

This mechanism of molecular identity is involvedin the TMEV-IDD model of multiple sclerosis, a severerapid-onset demyelinating disease of the CNS that isinduced by intracerebral or peripheral infection withTMEV that has been engineered to express the immu-nodominant self epitope from myelin proteolipid protein(PLP) peptide 139151 (PLP

139151)22. Several bacterial and

viral peptides that mimic PLP139151

have been identified23,and these have been used in models that more directlyaddress the possibility that autoimmune disease could beinduced by molecular mimicry. TMEV can be engineered

to express peptides derived from Haemophilus influen-zae(which shares 6 of 13 amino acids with PLP

139151) or

murine hepatitis virus (which shares only 3 of 13 aminoacids with PLP

139151) that mimic PLP

139151. Infection with

such engineered TMEV induces a rapid-onset, severedemyelinating disease that is similar to that induced byinfection with TMEV that expresses PLP

139151itself22,24.

The H. influenzaepeptide mimic of PLP139151

can alsobe generated and presented when the recombinantTMEV contains larger portions of the bacterial proteinthat include the native flanking sequences of the peptide,which further supports the potential role for molecularmimicry in a natural infection25.

Importantly to human disease, bacterial peptidemimics of the myelin basic protein (MBP) epitope8599 (MBP

8599) derived from different pathogens,

such asMycobacterium tuberculosis, Bacillus subtilisandStaphylococcus aureus, induce demyelinating disease inmice that transgenically express a human MBP

8599-specific

TCR and an HLA class II molecule that can present thepeptide26. Molecular mimicry was also shown to beinvolved in a model of diabetes in which lymphocyticchoriomeningitis virus (LCMV) nucleoprotein (NP) wasexpressed under the control of the rat insulin promoter(RIP). Infection with Pichinde virus, which contains anepitope that is similar to a subdominant epitope in LCMVNP, accelerated autoimmune disease that had already been

established by previous infection with LCMV13. HSV-induced stromal keratitis has been shown to be mediatedby corneal-antigen-specific T-cell responses induced fol-lowing corneal infection with HSV10, and, in this naturallyoccurring autoimmune disease model, molecular mim-icry occurred in the absence of genetic manipulation10.However, a subsequent study questioned the involvementof T-cell-mediated molecular mimicry in HSV-inducedstromal keratitis, as the disease could be induced in micein the absence of T-cell responses against HSV11. In thissetting, it is possible that a failure to control the viruscaused keratitis through pathogen-induced immuno-pathology. Therefore, given that different model systems,

R E V I E W S


http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5354&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4155&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4155&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5354&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


4/13

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

Mouse model or infectious agent Proposed mechanism (ormechanisms) of autoimmunity

Comment References

Multiple sclerosis

TMEV-IDD Bystander activation and epitopespreading

Natural virus-induced autoimmune disease ofmice

9

TMEV expressing PLP139151 Molecular identity None 22TMEV expressing PLP

139151mimics Molecular mimicry None 22,24,25

Coxsackievirus B4 expressing PLP139151

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

None

LCMV infection of mice expressingLCMV 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 expressingLCMV protein in the pancreas

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

1820

Pichinde virus infection of miceexpressing LCMV protein in the pancreas

Molecular mimicry Autoimmunity can only be accelerated, andnot initiated, de novoby this approach

13

Myocarditis

Mouse cytomegalovirus infection Bystander activation or molecularmimicry

Possible role for molecular mimicry, but doesnot 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 bystanderactivation

Some controversy over which mechanism isresponsible

1012

CNS, central nervous system; HSV, herpes simplex virus; LCMV, lymphocytic choriomeningitis virus; PLP, proteolipid protein; TCR, T-cell receptor; TMEV-IDD,Theilers murine encephalomyelitis virus-induced demyelinating disease.

Molecular mimicry

A 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 selection

The intrathymic elimination

of double-positive orsingle-positive thymocytes that

express T-cell receptors with

high affinity for self antigens.

Polyfunctional T cell

A 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 theinitial study cannot be ruled out12.

In keeping with the idea that antigen-specific T cellsthat have been primed by pathogens and crossreactwith self antigens can cause autoimmunity in animalmodels, patients with autoimmune diseases such assystemic lupus erythematosus (SLE), rheumatoidarthritis and multiple sclerosis have been found tohave higher frequencies and activation states and/orreduced co-stimulatory requirements of self-reactivelymphocytes2730. In multiple sclerosis, receptor analysisof T and B cells in CNS tissue and in the cerebrospinalfluid showed evidence of clonal expansions in both

T- and B-cell populations, indicating that certain lym-phocyte clones are responding to a restricted number ofdisease-relevant antigens3133. In addition, longitudinalstudies provided evidence for the long-term persistenceof individual myelin-specific T-cell clones over severalyears in the blood of patients with multiple sclerosis3436,indicating that there is a strong, persistent memoryT-cell response and/or ongoing exposure of at least asubset 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 antigenswhich have been found to be associated with human

autoimmune diseases (TABLE 2). For example, the highviral loads that occur during symptomatic primaryinfection of EBV, and result in infectious mononucle-osis, are associated with an increased risk of developingmultiple sclerosis3739, and could prime these polyspe-cific T-cell responses. Accordingly, patients with mul-tiple sclerosis have predominant clonal expansionsof T cells that are specific for EBV nuclear antigen 1(EBNA1), the EBV antigen that is most commonlytargeted by CD4+T cells in healthy virus carriers, andEBNA1-specific T cells recognize myelin antigensmore frequently than other autoantigens that are notassociated with multiple sclerosis40. Notably, myelinand EBNA1 crossreactive T cells produce interferon-(IFN) and differ from EBNA1-monospecific cells in

their capacity to produce additional cytokines, suchas interleukin-2, which is indicative of polyfunctionalT cells. Because T cells successively produce more thanone cytokine during differentiation, polyfunctionalT cells are thought to be particularly important underconditions of antigen persistence and high antigen loadbecause they are less susceptible to clonal exhaustionoractivation-induced cell death41. However, viral titres incirculating 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 differfrom healthy EBV carriers in the rate of EBV-inducedB-cell transformation or in their ability to control

R E V I E W S




5/13

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

Virus Autoimmune disease Evidence Selectedreferences

RNA viruses

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

115,118120

Rubella virus Type 1 diabetes Tropism for pancreatic-cellsMolecular mimicry

121,122

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

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

124126

DNA viruses

HSV-1 (also knownas HHV-1)

Autoimmune stromal keratitis Molecular mimicry 10

EBV (also knownas HHV-4)

Multiple sclerosis Increased risk of developing multiple sclerosis after primary symptomaticinfection

Increased antibody responses in healthy individuals who will developmultiple sclerosis

Increased seroprevalenceAltered virus-specific T-cell and humoral immune responsesMolecular mimicry Localization of virus and virus-specific lymphocytes in diseased tissues

37,38,40,42,63,127130

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

92,93,109,131133

SLE Increased seroprevalenceAltered virus-specific immune responses Increased viral loadMolecular 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 tissuesClonally expanded CSF-infiltrating T cells recognize viral antigen

137

Parvovirus B19 Rheumatoid arthritis Phenotype of acute infection can mimic early rheumatoid arthritisDetection 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, EpsteinBarr virus; HHV, human herpesvirus; H SV-1, herpes simplex virus 1; H TLV-1; human T cell leukaemia virus type 1; SLE, systemiclupus erythematosus.

Clonal exhaustion

A state of non-reactivity in

which all precursor

lymphocytes are induced by apersistent antigen (or antigens)

to become effector cells,

purging the immune-response

repertoire of this specificity (or

specificities).

Activation-induced cell death

A 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. Thissuggests that increased viral replication or impairedimmune control of chronic EBV infection does notdrive EBV-specific T-cell expansion in patients withmultiple sclerosis. Instead, a more extensive primingof polyfunctional crossreactive T cells during symp-

tomatic primary EBV infection with high levels ofvira l load, and continuous restimulation caused byautoimmune tissue inflammation, could establish andmaintain a distinct repertoire of myelin-reactive virus-specific T cells, which could predispose individuals tomultiple sclerosis.

Bystander activation of autoreactive cells and epitopespreading.APCs that have become activated in the inflam-matory milieu of a pathogenic infection can stimulate theactivation and proliferation of autoreactive T or B cellsin 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, toautoreactive cells43,44(FIG. 2B). In addition, autoantigen-specific T or B cells can be primed through epitopespreading45, a mechanism by which an immune responsethat is initiated by various stimuli, including microbialinfection, trauma, transplanted tissue or autoimmunity,

spreads to include responses directed against a differentportion 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 antitumourimmune response, because the pathogen or tumourcannot easily escape immune control with a singlemutation in an immunogenic epitope. However, dis-ease potentially arises when the response spreads to andwithin self proteins subsequent to the destruction of selftissue. Epitope spreading in animal models proceeds inan orderly, directed and hierarchical manner, such thatresponses to more immunodominant epitopesare elicited

R E V I E W S




6/13

Bystander activation

Activation and/or expansion of

an immune response at a site

of direct inflammation-induced

tissue damage.

Epitope spreading

A 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 epitope

A portion of an antigen that is

targeted preferentially or to a

greater level during an immune

response.

Superantigen

A microbial protein that

activates all T cells which

express a particular set of T-cell

receptor (TCR) Vchains 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 inTMEV-IDD9,4850and in the non-obese diabetic mousemodel of type 1 diabetes51(S.D.M., unpublished obser-

vations). Although these examples document epitopespreading within autoantigens and to additional autoan-tigens, the inflammatory environment of viral infectionscould also support these immune response cascades byincreasing the presentation of self antigens through theprovision of ligands for PRR signalling.

An even broader form of bystander activation isachieved by microbial superantigens, which cross-linkMHC class II molecules with TCRs that comprise a cer-tain V domain, leading to T-cell activation independ-ently of specific antigen recognition. T-cell populationsthat are stimulated in this manner could contain a subsetof T cells that are specific for a self antigen52. Many stud-ies suggest that superantigens are involved in diseasessuch as EAE, arthritis and inflammatory bowel disease,

which supports the idea that microbial superantigensare involved in another mechanism by which bystanderactivation can initiate, or at least exacerbate, autoim-munity in mouse models5355. In these studies, staphy-lococcal, mycoplasmal and enteric microbiota-derivedsuperantigens were shown to amplify, but not initiate,autoimmune T-cell responses (TABLE 1). Furthermore,certain genotypes of the superantigen-encoding humanendogenous retrovirus K18 (HERV-K18), which is trans-activated by EBV56, have been reported to be associatedwith multiple sclerosis57. However, V7+and V13+T-cell populations, which are stimulated by HERV-K18superantigen, do not seem to be selectively expandedin patients with multiple sclerosis. Nevertheless, viral-antigen-specific and/or superantigen-expanded T cellsmight participate in the development or maintenanceof autoimmune disease.Therefore, although molecularmimicry might initially prime autoreactive T cells, theseresponses could be amplified by superantigen-mediatedexpansion of autoantigen-specific T cells.

Emerging mechanisms.Infections can affect the immuneresponse in many ways, and mechanisms such as molecu-lar mimicry and bystander activation are certainly not theonly ways in which pathogens might trigger or acceler-ate autoimmune disease. A recent study showed that in aspontaneous animal model of SLE, lipid raft aggregation

on T cells, which was induced by cholera toxin B fromVibrio choleraein this particular study but can be inducedby several microorganisms or toxins, enhanced T-cell sig-nalling and exacerbated SLE58. Furthermore, viral infec-tions could also directly maintain autoreactive effectorT cells or autoantigen-presenting cells59. For example,persistent infection of microglial cells with TMEV hasbeen shown to upregulate expression of MHC and co-stimulatory molecules and enhance the ability of thesecells 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 ininfected memory B cells, which usually do not express the

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

Although several causal relationships between patho-gen infection and autoimmunity have been identifiedin animal models and correlations have been drawn inhuman autoimmune diseases, pathogen-derived triggersof autoimmunity have been difficult to identify. This isbecause evidence of autoimmunity is likely to becomeclinically apparent only after a considerable periodof subclinical autoimmune responses, at which timethe pathogen might have already been cleared and/or theantiviral immune responses might have subsided; this iscalled 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 autoimmunityshould be viewed as a process that involves many path-ways occurring simultaneously and/or sequentially andnot as a defined event that involves a single mechanism(FIG. 2). For example, epitope spreading can be initiatedthrough molecular mimicry. This was revealed by astudy that detected the activation of PLP

178191-specific

T cells in SJL mice in which autoimmunity was inducedfollowing bystander damage or by infection with TMEVthat expressed either PLP

139151or a PLP

139151mimic

peptide22. Molecular mimicry can initially activateautoreactive T cells, which then expand and becomepathogenic through bystander activation, or vice versa.As a result, it can be difficult to distinguish betweenthe postulated mechanisms, even in seemingly simpleanimal models5,11,12,64.

Overt autoimmune disease by these mechanisms

Studies of animal models have made it clear that, inprinciple, infections can trigger autoimmune responses.However, this must be distinguished from the elicitationof overt autoimmune disease as a direct result of microbialinfection, which might be more difficult to establish.

Autoreactive T cells are unavoidably present in theperiphery in humans and animals. These cells can existbecause their cognate self antigen was not expressed inthe thymus and the antigen will therefore only become

available to the immune system after tissue destructionas a result of infection or trauma. Alternatively, whereasmany autoreactive T cells are deleted in the thymusduring development, some T cells that make their wayto 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 theperiphery does not necessarily predispose individuals toclinical autoimmune disease.

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

R E V I E W S




7/13

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 PLP139151

in complete Freunds adju-vant (CFA) or by infecting with TMEV that expresseda PLP

139151mimic23,24. However, priming with PLP

139151

mimics in CFA did not induce overt disease, eventhough T cells from mice primed with mimic peptidesresponded strongly to PLP

139151. It is probable that TLR

engagement and other innate immune stimuli that arepresent following infection with TMEV allow APCs toprovide the necessary signals for full activation and opti-mal migration of autoreactive T cells60. The nature ofthe pathogen that directs the type of immune responseelicited can therefore profoundly influence the potentialfor development of autoimmune disease, and could infact increase or decrease the likelihood of autoimmu-nity in the presence of autoreactive cells. In this regard,T helper 1 (T

H1)- and T

H17-polarized T-cell responses

have been proposed to accelerate autoimmunity, whereasT

H2-polarized responses might confer protection65.

Furthermore, in the case of molecular mimicry, thevirus-encoded mimic itself has an important role, as apeptide that partially mimics a self antigen (known as

an altered peptide ligand) could have a tolerizing ratherthan an activating effect, depending on the context ofthe infection60.

Even the presence of autoreactive T cells togetherwith an appropriate infection might not lead to autoim-mune disease. For example, in Pichinde virus infectionof RIPLCMVNP mice, the mimic-encoding Pichinde

virus was not sufficient to initiate overt autoimmunity,but was able to accelerate autoimmune disease that hadalready been established by infection with LCMV13.Viral adjuvant and self peptide mimics might there-fore only trigger autoimmune disease when autoreactivecells are already primed to some level, such that theautoreactive T cells have been previously activated andexist at a higher precursor frequency66. The affinity ofTCRs for various self peptideMHC complexes mightalso have a key role in the development of autoimmunedisease. Indeed, a threshold level of TCR affinity hasbeen shown to be important for the establishment ofautoimmunity67. In the RIPLCMVNP mouse model,whether or not the antigen (NP) was expressed inthe thymus during development (which affects T-cellaffinity) has a significant impact on the rate at whichautoimmune disease develops20. TLR engagement aloneis sufficient to induce the appropriate environment forthe development of autoimmune disease if autoreactiveT cells are of high enough affinity for self antigen 20,68.

However, as most T cells have low affinity for self underphysiological conditions, studies in which TCR affin-ity for self antigen is low may have greater relevance tohuman 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 actuallyoccurs can depend on various other coincident events,including the number of autoreactive T cells present,the avidity and affinity of these cells (determined byco-receptor expression and binding to peptideMHCcomplexes, respectively) and the presence of innateinflammatory signals required for these T cells to gain

a pathogenic phenotype. Despite the requirement forall of these elements, it is clear that they do not need tohappen at the same time or in the same place to elicitautoimmune disease.

Autoimmunity can occur at a site distal to the initiatinginfection.In many animal models, autoimmune responsesare triggered during the initial or acute response to aninfection, and autoimmune disease occurs exclusively inthe infected organ, such as during corneal HSV infection,which leads to stromal keratitis1012. Furthermore, sub-meningeal reservoirs of EBV-infected B cells have beenreported in the brains of patients with multiple sclero-sis63, although it remains unclear if these reservoirs focuspathogenic immune responses to the diseased tissue.Models in which infection directs autoreactive responsesto distinct tissues provide simple systems in which tostudy the pathological mechanisms of infection-inducedautoimmunity. However, in most cases, a robust immuneresponse to a pathogenic infection in the target organ isusually not associated with the development of autoim-

munity in humans. None of the proposed mechanismsfor the development of infection-induced autoimmunityexcludes 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 haveallowed investigators to study this aspect of infection-induced autoimmune disease, such studies might provideimportant insights that are relevant to human disease.

Autoimmune demyelinating disease of the CNS canbe triggered by molecular mimicry when the pathogencontaining the mimic epitope does not infect the CNSitself. When mice that express an LCMV protein in theCNS were peripherally infected with LCMV, autoim-mune responses occurred in the CNS despite the factthat LCMV was not detectable in that organ21. In wild-type mice, recombinant pancreatropic coxsackievirusthat expresses PLP

139151also induces CNS demyelinating

disease and was associated with PLP139151

-specific T-cellresponses in the absence of any apparent infection in theCNS itself (S.D.M., unpublished observations).

The fact that the various mechanisms for infection-induced autoimmunity discussed here are not mutuallyexclusive makes them both more complicated and moreplausible as potential causes for human autoimmune dis-ease. For example, molecular mimicry and adjuvant effectsof pathogens might be involved early during the devel-opment of autoimmune responses, whereas bystander

activation owing to the inflammatory environment ofinfections and/or superantigens might exacerbate autoim-mune responses later during development of the disease.However, as we consider the potentially multi-mechanisticand multistep nature of autoimmunity, it is important toremember that an established autoimmune response canalso have effects on pathogen-directed immune responsesoccurring in the same organ or elsewhere in the body.

Autoimmunity might trigger antiviral responses

The flip side of the idea that autoimmunity is driven byviral infections is that autoreactive immune responses, oreven only a predisposition to the development of these

R E V I E W S




8/13

|

TCR

Virus-specific T cell

Virus

Autoreactive T cell

Viral antigen

Crossreactive antigen

MHCclass 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

MHCclass 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 factor

An 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 antiviralimmune responses. This might alter the composition ofthese immune responses, the viral set point during chronicinfections and the anatomical distribution of virus-specificlymphocytes. These alterations could be used as surrogate

markers for autoimmune disease activity, but might notregulate the autoimmune disease itself.

Bystander activation.The activation of innate immunecells can be initiated by both pathogen-associatedstranger signals69and damage-associated, altered-selfdanger signals70. These apparently disparate signalstrigger inflammation through common means, as bothstranger and danger signals ligate PRRs. TLRs have aparticularly instructive role in innate immune responsesagainst microbial pathogens, as well as a role in the sub-sequent induction of adaptive immune responses. Bothexperimental infections in mice that lack individual

TLRs or key molecules of the TLR signalling pathways71and natural infections in humans with primary immuno-deficiencies that selectively impair TLR responses72clearlyshow the crucial role of TLRs in shaping protectiveantiviral immunity.

A role for TLR signalling in the induction and main-tenance of autoimmune diseases was first highlighted byLeadbetter et al.73, who showed that immunoglobulinin the blood provokes autoimmune responses whenimmune cells recognize it as a complex with self DNA.In B-cell receptor-transgenic mice, in which most B cellsexpress surface antibodies with low affinity for selfIgG2a, immunoglobulin neither activates the B cells normakes them tolerant unless these mice are crossed ontoan autoimmune-prone lprbackground74. Self IgG2a isimmunogenic in the offspring of this cross, resulting inhigh titres of circulating rheumatoid factorautoantibodies,a diagnostic marker of autoimmune disease. This studyfound that immune complexes consisting of self IgG2aand self DNA, which trigger surface B-cell receptors andendosomal TLRs, were necessary and sufficient for the

loss of self tolerance in this model. Similar models havebeen reported for RNA-containing immune complexesand activation of TLR7or TLR8(REFS 75,76). EndogenousTLR ligands, such as self DNA or self RNA, or nucleic-acid-associated proteins, could therefore act as adjuvantsin autoimmune diseases that are characterized by promi-nent tissue damage or impaired removal of apoptotic-cellor necrotic-cell debris77, and could assist in the primingof antiviral immune responses.

Furthermore, the induction and maintenance ofautoimmune tissue inflammation crucially dependson the cytokine profile of pathogenic T

Hcells in animal

models of T-cell-mediated autoimmune diseases65,78,79.Both T

H

1 and TH

17 cells are thought to coordinateautoimmune inflammation in these diseases, presum-ably through distinct pathways80. Although the T

H1-cell

cytokine IFN can inhibit the generation of TH17 cells,

it also reinforces TH

1-cell differentiation78, which isinstrumental in establishing protective antiviral immuneresponses. Therefore, the T

H1-polarizing milieu of

autoimmune diseases might support superior antiviralimmune 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, wesuggest that such signals probably affect host immuneresponses to microbial pathogens at sites of autoimmune

inflammation and enhance pathogen-specific innate andadaptive immune responses.

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

R E V I E W S




9/13

|

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-containingimmunecomplex

Cross-linking

Adjuvant activity

Reactivation of

latent proteinexpression

Reactivation ofviral replication

EBV latentmembrane protein

EBV latentnuclear 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 EpsteinBarr 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 replicationof EBV can only be observed in plasma cells86, and canbe induced by cross-linking surface immunoglobulin oninfected B cells87. Therefore, autoimmunity could trig-ger reactivation of these pathogens (FIG. 4), as has beendocumented in the case of EBV reactivation by malariaantigens88. Indeed, patients with SLE have abnormallyhigh frequencies of EBV-infected cells that have aberrantexpression of the immediate early lytic antigen BZLF1 inperipheral blood89. Interestingly, increased cell-associated

viral loads correlated with autoimmune disease activity.Moreover, in patients with SLE, increased EBV loadscorrelated with EBV-specific CD8+T-cell responses90,which had decreased cytotoxicity as a sign of exhaus-tion91, possibly owing to persistent restimulation by thehigh antigenic load. CD4+T-cell responses to EBV werealso upregulated in patients with SLE, but these responsesnegatively correlated with viral loads, suggesting thatthese cells provided increased immune protection90.

Whereas EBV viral loads are up to 40-fold increasedin patients with SLE, they are 10-fold increased in

patients with rheumatoid arthritis92,93. Similarly, CD8+T-cell responses to EBV antigens positively correlatewith these increased viral loads in patients with rheu-matoid arthrtis93. The increased antigen load in patientswith rheumatoid arthritis seems to cause further differ-entiation of EBV-specific CD8+T cells, resulting in thepresence of a subpopulation of terminally differentiated,and presumably co-stimulation-insensitive, CD27CD28T cells that are rarely observed in healthy EBV carriers94.In addition to EBV-specific T-cell responses, subdomi-nant antibody responses and broadened antibodyresponses to dominant EBV antigens are also observedin patients with rheumatoid arthritis93, again suggesting

that the increased EBV antigen load in these patientshyperstimulates EBV-specific humoral and cell-mediated immune responses. Although in most casesthese increased immune responses maintain EBV-specificimmune control, increased autoantigen-mediated stimu-lation of the B-cell compartment can result in lymphomadevelopment by driving B cells to hypermutation and ger-minal centre reactions, which increases the risk of acquir-ing transforming mutations. In the case of rheumatoidarthritis, Hodgkins lymphomas, including EBV+tumours,are more highly associated with the autoimmune diseasethan non-Hodgkins lymphomas95.

Together, these studies suggest that lymphotropicpathogens, such as EBV, can be affected by autoim-mune stimulation of host immune cells, leading toincreased viral t itres, increased immune responsesagainst the pathogen and even pathogen-associatedmalignancies. Collectively, the evidence indicates thatdysregulation of EBV-specific immune responses is afeature of rheumatoid arthritis and SLE, and is prob-ably driven by autoantigen-mediated activation of

EBV-infected B cells.

Genetic factors.Family-based genetic epidemiologicalstudies provide unequivocal evidence that the suscepti-bility for autoimmune diseases is inherited, and genome-wide microsatellite screens and large-scale associationstudies of single nucleotide polymorphisms have identi-fied chromosomal loci that are associated with specificdisorders, such as SLE, rheumatoid arthritis, type 1 diabe-tes and multiple sclerosis. HLA-DR and HLA-DQ allelesof the HLA class II region on chromosome 6p21 are thehighest-risk-conferring genes for all of these disorders9699.Although the MHC region has proven difficult to dissect

R E V I E W S




10/13

because of its strong and variable patterns of linkage dis-equilibrium, there is evidence that additional loci in theHLA class III and HLA class I genomic regions and locithat are telomeric to genes encoding the classical MHCmolecules might have independent associations withautoimmune disease96. Furthermore, less-robust suscep-tibility effects have been identified in non-MHC regions.For example, the ITGAMITGAX region on chromosome6p11 encodes the -chain of M2 integrin(also knownas 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 IL7RAregion on chromosome5p13 and IL2RAon chromosome 10p15 were identifiedas loci that are associated with multiple sclerosis102104.Epistatic interactions between these risk-conferring andprotective allelic variants are thought to define the overallgenetic threshold for susceptibility to disease8.

We propose that immune functions of autoimmunesusceptibility genes and their products probably affect

hostpathogen interactions in patients with autoimmunediseases72. In line with this idea, a study revealed that CD8+T cells that recognize an immunodominant EBV epitoperestricted by HLA-B8 crossreacted with HLA-B*4402,presumably presenting a self peptide105. This crossreac-tivity was strong enough to mediate alloreactivity againstHLA-B*4402+cells and to result in deletion of this EBVspecificity in HLA-B*4402+HLA-B8+individuals by nega-tive selection, which ablates T cells of this specificity fromthe repertoire of EBV-specific immune responses in theseindividuals. However, incomplete deletion of these allore-active T cells in genetically susceptible individuals couldresult in autoreactive and EBV-specific T cells. Similarlyto this finding that genetic variation of the host can favourthe presentation and recognition of a particular viralpeptide, genetic variation of viruses might also favourthe presentation of peptide that can stimulate crossreac-tive T cells. For example, EBV strain B95-8 has a pointmutation in the HLA-B8-restricted CD8+T-cell epitopediscussed above, which affects T-cell recognition of the

virus owing to inefficient binding of the variant peptideto HLA-B8 (REF. 106). Conversely, autoreactive T cellscould be preferentially triggered by certain virus strainsencoding peptide epitopes that stimulate crossreactiveT cells. The increased sequence variation that has recentlybeen characterized in EBNA1 (REF. 107)implies that anassociation between multiple sclerosis and a particular

EBV strain remains possible, and sequence variation inthe viral strain might enhance particular EBV-specificT- and B-cell responses that could participate in autoim-munity. Therefore, the particular HLA background of anindividual and the distinct viral strains carried by the indi-

vidual could select for T-cell specificities with autoreactivecapacity during antiviral immune responses.

To consider this potential mechanism, investiga-tions of the disease-promoting or disease-protectiveeffects of geneenvironment interactions shouldinvolve 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 shouldat least be matched for expression of alleles that con-fer high disease risk, such as HLA-DR and HLA-DQallelic variants, as this strategy minimizes the possibil-ity that any differences in pathogen-specific immuneresponses are a consequence rather than a cause ofdisease susceptibility.

Redistribution of antiviral immune responses to sites ofautoimmune inflammation.As discussed above, genetic

variation of both the pathogen and the host might favourdistinct virus-specific immune responses. However,the preferential homing of primed antiviral T cells toaffected organs might also falsely implicate pathogensin the immunopathology of autoimmune diseases. Forexample, lytic EBV infection was suspected to contributeto 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 immediateearly and early lytic EBV antigens were first cloned fromthe synovial fluid of patients with rheumatoid arthri-

tis109. These specificities, which are now recognized tobe among the most frequent T-cell responses, developduring persistent infection with EBV110. Similarly, CD4+T cells specific for lytic EBV antigens were also initiallycloned from patients with rheumatoid arthritis111.

Interestingly, it was subsequently found that theselytic-antigen-specific T cells home to various autoim-mune inflamed tissues112, including knee joints affectedby rheumatoid arthritis and the eyes of patients withuveitis. These data were thought to reflect the migra-tion of EBV-specific T cells in response to inflam-matory chemokines, such as the CXCR3 ligandCXC-chemokine ligand 10 (CXCL10), rather than adirect involvement of EBV-directed immunity in theimmunopathology of autoimmune diseases. Similarly,pathogen-infected lymphocytes can preferentiallymigrate to inflamed tissues, and this localization couldbe wrongly assumed to indicate that the pathogen con-tributes to autoimmune pathology rather than that thelocalization is consistent with the normal migratorybehaviour of infected host cells. The finding that EBV-infected B cells are enriched in the tertiary lymphoidtissues of post-mortem CNS tissue from patients withmultiple 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 alongthese lines113.

Therefore, the enrichment of both pathogen-specificand 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 associatedpathogens in the immunopathology of autoimmunediseases. Nevertheless, a better understanding of thesemechanisms could explain how certain pathogens targetthe autoimmune reactivity of a sensitized immune sys-tem to certain organs and indicate whether monitoringantiviral immune responses could be a useful surrogatemarker for autoimmune disease.

R E V I E W S


http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3684&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3627&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10563&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10563&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3627&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3684&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


11/13

Concluding remarks

Both genetic and environmental factors are known tobe involved in the initiation and promotion of autoim-mune diseases. Viral infections are the main candidateenvironmental factors owing to their capacity to elicitstrong immune activation and induce autoimmunediseases in animal models, as well as their correlationwith autoimmune diseases in humans. The studieshighlighted in this Review suggest that viruses can trig-ger autoimmunity through molecular mimicry and itsadjuvant effects during the initiation of disease, and canpromote autoimmune responses through bystanderactivation or epitope spreading by inflammation and/orsuperantigens.

The finding that dysregulated antiviral immuneresponses are associated with autoimmune disease must beinterpreted with caution, however, because these responsescan be primed differently in individuals with ongoingautoimmune disease or with a genetic predispositionto autoimmune disease. Furthermore, the autoimmunedisease can alter virus infection by affecting its host cellsand might lead to redistribution of antiviral lymphocytesto sites of autoreactive tissue inflammation. These changesmight prove to be useful as surrogate markers for autoim-mune disease reactivity and could be harnessed therapeuti-cally. However, any therapeutic approach that targets theseresponses should be used with caution so that immunecontrol against the pathogen is not compromised.

1. Ishii, K. J., Koyama, S., Nakagawa, A., Coban, C. &

Akira, S. Host innate immune receptors and beyond:

making sense of microbial infections. Cell Host

Microbe3, 352363 (2008).

2. Marrack, P., Scott-Browne, J. P., Dai, S., Gapin, L. &

Kappler, J. W. Evolutionarily conserved amino acids

that control TCRMHC interaction.Annu. Rev.

Immunol.26, 171203 (2008).

3. Fujinami, R. S., Oldstone, M. B., Wroblewska, Z.,

Frankel, M. E. & Koprowski, H. Molecular mimicry

in virus infection: crossreaction of measles virus

phosphoprotein or of herpes simplex virus protein

with human intermediate filaments. Proc. Natl Acad.

Sci. USA80, 23462350 (1983).

4. Oldstone, M. B. Molecular mimicry and immune-

mediated diseases. FASEB J.12, 12551265

(1998).

5. Fujinami, R. S. & Oldstone, M. B. Amino acid

homology between the encephalitogenic site of myelin

basic protein and virus: mechanism for autoimmunity.

Science230, 10431045 (1985).

This publication introduced the concept of

molecular mimicry.

6. Wucherpfennig, K. W. & Strominger, J. L. Molecular

mimicry in T cell-mediated autoimmunity: viral

peptides activate human T cell clones specific for

myelin basic protein. Cell 80, 695705 (1995).

7. Lang, H. L. et al.A functional and structural basis forTCR cross-reactivity in multiple sclerosis. Nature

Immunol.3, 940943 (2002).

8. Gregersen, J. W. et al.Functional epistasis on a

common MHC haplotype associated with multiple

sclerosis. Nature443, 574577 (2006).

9. Miller, S. D. et al.Persistent infection with Theilers

virus leads to CNS autoimmunity via epitope

spreading. Nature Med.3, 11331136 (1997).

The first description of a persistent virus infection

that can lead to autoimmunity through epitope

spreading.

10. Zhao, Z. S., Granucci, F., Yeh, L., Schaffer, P. A. &

Cantor, H. Molecular mimicry by herpes simplex virus-

type 1: autoimmune disease after viral infection.

Science279, 13441347 (1998).

11. Deshpande, S. P. et al.Herpes simplex virus-induced

keratitis: evaluation of the role of molecular mimicry

in lesion pathogenesis.J. Virol.75, 30773088

(2001).

12. Benoist, C. & Mathis, D. Autoimmunity provoked byinfection: how good is the case for T cell epitope

mimicry? Nature Immunol.2, 797801 (2001).

13. Christen, U. et al.A viral epitope that mimics a self

antigen can accelerate but not initiate autoimmune

diabetes.J. Clin. Invest.114, 12901298 (2004).

14. Mokhtarian, F., Zhang, Z., Shi, Y., Gonzales, E. &

Sobel, R. A. Molecular mimicry between a viral

peptide and a myelin oligodendrocyte glycoprotein

peptide induces autoimmune demyelinating disease

in mice.J. Neuroimmunol.95, 4354 (1999).

15. Gauntt, C. J. et al.Molecular mimicry, anti-

coxsackievirus B3 neutralizing monoclonal antibodies,

and myocarditis.J. Immunol.154, 29832995

(1995).

16. Lawson, C. M. Evidence for mimicry by viral antigens

in animal models of autoimmune disease including

myocarditis. Cell. Mol. Life Sci.57, 552560

(2000).

17. Cunningham, M. W. et al.Cytotoxic and viral

neutralizing antibodies crossreact with streptococcal

M protein, enteroviruses, and human cardiac myosin.

Proc. Natl Acad. Sci. USA89, 13201324 (1992).

18. Oldstone, M. B., Nerenberg, M., Southern, P., Price, J.

& Lewicki, H. Virus infection triggers insulin-

dependent diabetes mellitus in a transgenic model:

role of anti-self (virus) immune response. Cell65,

319331 (1991).

19. Ohashi, P. S. et al.Ablation of tolerance and

induction of diabetes by virus infection in viral antigen

transgenic mice. Cell65, 305317 (1991).

References 18 and 19 provide the first evidence

for the initiation of autoimmune disease following

viral infection of a transgenic mouse expressing

a viral protein.

20. von Herrath, M. G., Dockter, J. & Oldstone, M. B.

How virus induces a rapid or slow onset insulin-

dependent diabetes mellitus in a transgenic model.

Immunity1, 231242 (1994).

21. Evans, C. F., Horwitz, M. S., Hobbs, M. V. &

Oldstone, M. B. Viral infection of transgenic mice

expressing a viral protein in oligodendrocytes leads to

chronic central nervous system autoimmune disease.

J. Exp. Med.184, 23712384 (1996).

22. Olson, J. K., Croxford, J. L., Calenoff, M. A.,

Dal Canto, M. C. & Miller, S. D. A virus-induced

molecular mimicry model of multiple sclerosis.J. Clin. Invest.108, 311318 (2001).

This study provided the first description of initiation

of autoimmune disease following infection with a

non-pathological virus variant that was engineered

to express a peptide mimic of a myelin self antigen.

23. Carrizosa, A. M. et al.Expansion by self antigen is

necessary for the induction of experimental

autoimmune encephalomyelitis by T cells primed with

a cross-reactive environmental antigen.J. Immunol.

161, 33073314 (1998).

24. Croxford, J. L., Ercolini, A. M., Degutes, M. &

Miller, S. D. Structural requirements for initiation

of cross-reactivity and CNS autoimmunity with a

PLP139151 mimic peptide derived from murine

hepatitis virus. Eur. J. Immunol.36, 26712680

(2006).

25. Croxford, J. L., Olson, J. K., Anger, H. A. & Miller, S. D.

Initiation and exacerbation of autoimmune

demyelination of the central nervous system via

virus-induced molecular mimicry: implications forthe pathogenesis of multiple sclerosis.J. Virol.79,

85818590 (2005).

26. Greene, M. T., Ercolini, A. M., Degutes, M. &

Miller, S. D. Differential induction of experimental

autoimmune encephalomyelitis by myelin basic

protein molecular mimics in mice humanized for

HLA-DR2 and an MBP(8599)-specific T cell receptor.

J. Autoimmun.31, 399407 (2008).

27. Yurasov, S. et al.Defective B cell tolerance checkpoints

in systemic lupus erythematosus.J. Exp. Med.201,

703711 (2005).

28. Samuels, J., Ng, Y. S., Coupillaud, C., Paget, D. &

Meffre, E. Impaired early B cell tolerance in patients

with rheumatoid arthritis.J. Exp. Med.201,

16591667 (2005).

29. Lovett-Racke, A. E. et al.Decreased dependence of

myelin basic protein-reactive T cells on CD28-

mediated costimulation in multiple sclerosis patients.

A marker of activated/memory T cells.J. Clin. Invest.

101, 725730 (1998).

30. Markovic-Plese, S., Cortese, I., Wandinger, K. P.,

McFarland, H. F. & Martin, R. CD4+CD28

costimulation-independent T cells in multiple sclerosis.

J. Clin. Invest.108, 11851194 (2001).

31. Baranzini, S. E. et al.B cell repertoire diversity and

clonal expansion in multiple sclerosis brain lesions.

J. Immunol.163, 51335144 (1999).

32. Babbe, H. et al.Clonal expansions of CD8+T cells

dominate the T cell infiltrate in active multiple

sclerosis lesions as shown by micromanipulation and

single cell polymerase chain reaction.J. Exp. Med.

192, 393404 (2000).

33. Skulina, C. et al.Multiple sclerosis: brain-infiltrating

CD8+T cells persist as clonal expansions in the

cerebrospinal fluid and blood. Proc. Natl Acad. Sci.

USA101, 24282433 (2004).

34. Meinl, E. et al.Myelin basic protein-specific

T lymphocyte repertoire in multiple sclerosis.

Complexity of the response and dominance of nested

epitopes due to recruitment of multiple T cell clones.

J. Clin. Invest.92, 26332643 (1993).

35. Goebels, N. et al.Repertoire dynamics of

autoreactive T cells in multiple sclerosis patients

and healthy subjects: epitope spreading versus

clonal persistence. Brain123, 508518 (2000).

36. Muraro, P. A. et al.Molecular tracking of antigen-specific T cell clones in neurological immune-mediated

disorders. Brain126, 2031 (2003).

37. Thacker, E. L., Mirzaei, F. & Ascherio, A. Infectious

mononucleosis and risk for multiple sclerosis: a

meta-analysis.Ann. Neurol.59, 499503 (2006).

A meta-analysis of studies investigating the risk

for the development of multiple sclerosis after

symptomatic primary infect ion with EBV.

38. Nielsen, T. R. et al.Multiple sclerosis after infectious

mononucleosis.Arch. Neurol.64, 7275 (2007).

39. Nielsen, T. et al.Effects of infectious mononucleosis

and HLA-DRB1*15 in multiple sclerosis. Mult. Scler.

19 Jan 2009 (doi:10.1177/1352458508100037).

40. Lnemann, J. D. et al.EBNA1-specific T cells from

patients with multiple sclerosis cross react with myelin

antigens and co-produce IFN-and IL-2.J. Exp. Med.

205, 17631773 (2008).

A description of the selective expansion of

EBNA1-specific CD4+T cells in patients with

multiple sclerosis.41. Harari, A. et al.Skewed association of polyfunctional

antigen-specific CD8 T cell populations with HLA-B

genotype. Proc. Natl Acad. Sci. USA104,

1623316238 (2007).

42. Lnemann, J. D. et al.Increased frequency and

broadened specificity of latent EBV nuclear

antigen-1-specific T cells in multiple sclerosis.

Brain129, 14931506 (2006).

43. Zipris, D. et al.TLR activation synergizes with Kilham

rat virus infection to induce diabetes in BBDR rats.

J. Immunol.174, 131142 (2005).

44. Walker, L. S. & Abbas, A. K. The enemy within:

keeping self-reactive T cells at bay in the periphery.

Nature Rev. Immunol.2, 1119 (2002).

45. Lehmann, P. V., Forsthuber, T., Miller, A. & Sercarz, E. E.

Spreading of T-cell autoimmunity to cryptic determinants

of an autoantigen. Nature358, 155157 (1992).

The initial description of epitope spreading.

R E V I E W S




12/13

46. McRae, B. L., Vanderlugt, C. L., Dal Canto, M. C. &

Miller, S. D. Functional evidence for epitope spreading

in the relapsing pathology of experimental

autoimmune encephalomyelitis.J. Exp. Med.182,

7585 (1995).

The first study to show the functional and

pathological importance of epitope spreading to

disease progression in relapsing EAE.

47. Yu, M., Johnson, J. M. & Tuohy, V. K. A predictable

sequential determinant spreading cascade invariably

accompanies progression of experimental

autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease.J. Exp.

Med.183, 17771788 (1996).

48. Katz-Levy, Y. et al.Endogenous presentation of self

myelin epitopes by CNS-resident APCs in Theilers

virus-infected mice.J. Clin. Invest.104, 599610

(1999).

49. Katz-Levy, Y. et al.Temporal development of

autoreactive Th1 responses and endogenous

presentation of self myelin epitopes by central

nervous system-resident APCs in Theilers virus-

infected mice.J. Immunol.165, 53045314

(2000).

50. Borrow, P. et al.Investigation of the role of

delayed-type-hypersensitivity responses to myelin in

the pathogenesis of Theilers virus-induced

demyelinating disease. Immunology93, 478484

(1998).

51. Kaufman, D. L. et al.Spontaneous loss of T-cell

tolerance to glutamic acid decarboxylase in murine

insulin-dependent diabetes. Nature366, 6972

(1993).

52. Wucherpfennig, K. W. Mechanisms for the induction

of autoimmunity by infectious agents.J. Clin. Invest.

108, 10971104 (2001).

53. Brocke, S. et al.Induction of relapsing paralysis in

experimental autoimmune encephalomyelitis by

bacterial superantigen. Nature365, 642644

(1993).

54. Cole, B. C. & Griffiths, M. M. Triggering and

exacerbation of autoimmune arthritis by the

Mycoplasma arthritidissuperantigen MAM.Arthritis

Rheum. 36, 9941002 (1993).

55. Dalwadi, H., Wei, B., Kronenberg, M., Sutton, C. L. &

Braun, J. The Crohns disease-associated bacterial

protein I2 is a novel enteric T cell superantigen.

Immunity15, 149158 (2001).

56. Sutkowski, N., Conrad, B., Thorley-Lawson, D. A. &

Huber, B. T. EpsteinBarr virus transact ivates the

human endogenous retrovirus HERV-K18 that

encodes a superantigen. Immunity15, 579589

(2001).57. Tai, A. et al.Human endogenous retrovirus-K18 Env

as a risk factor in multiple sclerosis. Mult. Scler.14,

11751180 (2008).

58. Deng, G. M. & Tsokos, G. C. Cholera toxin B

accelerates disease progression in lupus-prone mice

by promoting lipid raft aggregation.J. Immunol.181,

40194026 (2008).

59. Pender, M. P. Infection of autoreactive B

lymphocytes with EBV, causing chronic

autoimmune diseases. Trends Immunol.24,

584588 (2003).

60. Olson, J. K., Ludovic Croxford, J. & Miller, S. D.

Innate and adaptive immune requirements for

induction of autoimmune demyelinating disease by

molecular mimicry. Mol. Immunol.40, 11031108

(2004).

61. Thorley-Lawson, D. A. & Gross, A. Persistence of the

EpsteinBarr virus and the origins of associated

lymphomas. N. Engl. J. Med.350, 13281337

(2004).62. Nanbo, A., Inoue, K., Adachi-Takasawa, K. & Takada, K.

EpsteinBarr virus RNA confers resistance to

interferon--induced apoptosis in Burkitts lymphoma.

EMBO J. 21, 954965 (2002).

63. Serafini, B. et al.Dysregulated EpsteinBarr virus

infection in the multiple sclerosis brain.J. Exp. Med.

204, 28992912 (2007).

This study characterized dysregulation of EBV

infection in the CNS of patients with multiple

sclerosis.

64. Fujinami, R. S., von Herrath, M. G., Christen, U. &

Whitton, J. L. Molecular mimicry, bystander

activation, or viral persistence: infections and

autoimmune disease. Clin. Microbiol. Rev. 19,

8094 (2006).

65. Gutcher, I. & Becher, B. APC-derived cytokines and

T cell polarization in autoimmune inflammation.

J. Clin. Invest.117, 11191127 (2007).

66. Hamilton-Williams, E. E. et al.Cutting edge: TLR

ligands are not sufficient to break cross-tolerance to

self-antigens.J. Immunol.174, 11591163 (2005).

67. Gronski, M. A. et al.TCR affinity and negative

regulation limit autoimmunity. Nature Med.10,

12341239 (2004).

68. Lang, K. S. et al.Toll-like receptor engagement

converts T-cell autoreactivity into overt autoimmune

disease. Nature Med. 11, 138145 (2005).

69. Medzhitov, R. & Janeway, C. A. Jr. Decoding the

patterns of self and nonself by the innate immune

system. Science296, 298300 (2002).70. Matzinger, P. An innate sense of danger.Ann. NY

Acad. Sci.961, 341342 (2002).

71. Qureshi, S. T. & Medzhitov, R. Toll-like receptors and

their role in experimental models of microbial

infection. Genes Immun.4, 8794 (2003).

72. Quintana-Murci, L., Alcais, A., Abel, L. & Casanova, J. L.

Immunology in natura: clinical, epidemiological and

evolutionary genetics of infectious diseases. Nature

Immunol.8, 11651171 (2007).

73. Leadbetter, E. A. et al.ChromatinIgG complexes

activate B cells by dual engagement of IgM and Toll-

like receptors. Nature416, 603607 (2002).

74. Leslie, D., Lipsky, P. & Notkins, A. L. Autoantibodies as

predictors of disease.J. Clin. Invest.108, 14171422

(2001).

75. Lau, C. M. et al.RNA-associated autoantigens activate

B cells by combined B cell antigen receptor/Toll-like

receptor 7 engagement.J. Exp. Med.202,

11711177 (2005).

76. Vollmer, J. et al.Immune stimulation mediated by

autoantigen binding sites within small nuclear RNAs

involves Toll-like receptors 7 and 8.J. Exp. Med.202,

15751585 (2005).

77. Bratton, D. L. & Henson, P. M. Autoimmunity and

apoptosis: refusing to go quietly. Nature Med.11,

2627 (2005).

78. Bettelli, E., Korn, T., Oukka, M. & Kuchroo, V. K.

Induction and effector functions of TH17 cells. Nature

453, 10511057 (2008).

79. McFarland, H. F. & Martin, R. Multiple sclerosis: a

complicated picture of autoimmunity. Nature

Immunol. 8, 913919 (2007).

80. Carlson, T., Kroenke, M., Rao, P., Lane, T. E. & Segal, B.

The Th17ELR+CXC chemokine pathway is essential

for the development of central nervous system

autoimmune disease.J. Exp. Med.205, 811823

(2008).

81. Maloy, K. J. et al.CD4+T cell subsets during virus

infection. Protective capacity depends on effector

cytokine secretion and on migratory capability.J. Exp.

Med.191, 21592170 (2000).82. Rentenaar, R. J. et al. Development of virus-specific

CD4+T cells during primary cytomegalovirus

infection.J. Clin. Invest. 105, 541548 (2000).

83. Matsuoka, M. & Jeang, K. T. Human T-cell leukaemia

virus type 1 (HTLV-1) infectivity and cellular

transformation.Nature Rev. Cancer7, 270280

(2007).

84. Babcock, G. J., Decker, L. L., Volk, M. &

Thorley-Lawson, D. A. EBV persistence in memory

B cells in vivo. Immunity9, 395404 (1998).

85. Dumais, N. et al. T-cell receptor/CD28 engagement

when combined with prostaglandin E2 treatment

leads to potent activation of human T-cell leukemia

virus type 1.J. Virol.77, 1117011179 (2003).

86. Laichalk, L. L. & Thorley-Lawson, D. A. Terminal

differentiation into plasma cells initiates the

replicative cycle of EpsteinBarr virus in vivo.J. Virol.

79, 12961307 (2005).

87. Daibata, M., Speck, S. H., Mulder, C. & Sairenji, T.

Regulation of the BZLF1 promoter of EpsteinBarrvirus by second messengers in anti-immunoglobulin-

treated B cells. Virology198, 446454 (1994).

88. Chene, A. et al. A molecular link between malaria and

EpsteinBarr virus reactivation. PLoS Pathog. 3, e80

(2007).

89. Gross, A. J., Hochberg, D., Rand, W. M. &

Thorley-Lawson, D. A. EBV and systemic lupus

erythematosus: a new perspective.J. Immunol.174,

65996607 (2005).

90. Kang, I. et al. Defective control of latent EpsteinBarr

virus infection in systemic lupus erythematosus.

J. Immunol. 172, 12871294 (2004).

91. Berner, B. R. et al.Phenotypic and functional analysis

of EBV-specific memory CD8 cells in SLE. Cell.

Immunol.235, 2938 (2005).

92. Balandraud, N. et al. EpsteinBarr virus load in the

peripheral blood of patients with rheumatoid arthritis:

accurate quantification using real-time polymerase

chain reaction.Arthritis Rheum. 48, 12231228

(2003).

93. Lnemann, J. D. et al.Increased frequency of EBV

specific effector memory CD8+T cells is associated

with higher viral load in rheumatoid arthritis.

J. Immunol.181, 9911000 (2008).

94. Appay, V. et al. Memory CD8+T cells vary in

differentiation phenotype in different persistent virus

infections. Nature Med. 8, 379385 (2002).

95. Smedby, K. E., Baecklund, E. & Askling, J. Malignant

lymphomas in autoimmunity and inflammation: a

review of risks, risk factors, and lymphomacharacteristics. Cancer Epidemiol. Biomarkers Prev.

15, 20692077 (2006).

96. Baranzini, S. E. et al.Genome-wide association analysis

of susceptibility and clinical phenotype in multiple

sclerosis. Hum. Mol. Genet.18, 767778 (2009).

97. Harley, J. B. et al.Genome-wide association scan in

women with systemic lupus erythematosus identifies

susceptibility variants in ITGAM, PXK, KIAA1542 and

other loci. Nature Genet.40, 204210 (2008).

98. Tamiya, G. et al.Whole genome association study of

rheumatoid arthritis using 27 039 microsatellites.

Hum. Mol. Genet.14, 23052321 (2005).

99. Concannon, P. et al.A second-generation screen of the

human genome for susceptibility to insulin-dependent

diabetes mellitus. Nature Genet. 19, 292296 (1998).

100. Hom, G. et al. Association of systemic lupus

erythematosus with C8orf13BLK and ITGAMITGAX.

N. Engl. J. Med. 358, 900909 (2008).

101. Nath, S. K. et al.A nonsynonymous functional variant

in integrin-M

(encoded by ITGAM) is associated with

systemic lupus erythematosus. Nature Genet. 40,

152154 (2008).

102. Hafler, D. A. et al. Risk alleles for multiple sclerosis

identified by a genomewide study. N. Engl. J. Med.

357, 851862 (2007).

103. Lundmark, F. et al.Variation in interleukin 7 receptor

chain (IL7R) influences risk of multiple sclerosis.

Nature Genet. 39, 11081113 (2007).

104. Gregory, S. G. et al. Interleukin 7 receptor chain

(IL7R) shows allelic and functional association with

multiple sclerosis. Nature Genet.39, 10831091

(2007).

105. Burrows, S. R., Khanna, R., Burrows, J. M. & Moss, D. J.

An alloresponse in humans is dominated by cytotoxic

T lymphocytes (CTL) cross-reactive with a single

EpsteinBarr virus CTL epitope: implications for

graft-versus-host disease.J. Exp. Med. 179,

11551161 (1994).

106.Apolloni, A. et al. Sequence variation of cytotoxic

T cell epitopes in different isolates of EpsteinBarr

virus. Eur. J. Immunol. 22, 183189 (1992).107. Bell, M. J. et al. Widespread sequence variation in

EpsteinBarr virus nuclear antigen 1 influences the

antiviral T cell response.J. Infect. Dis. 197,

15941597 (2008).

108. Redondo, M. J., Jeffrey, J., Fain, P. R., Eisenbarth, G. S.

& Orban, T. Concordance for islet autoimmunity

among monozygotic twins. N. Engl. J. Med. 359,

28492850 (2008).

109. Scotet, E. et al. T cell response to EpsteinBarr virus

transactivators in chronic rheumatoid arthritis.J. Exp.

Med. 184, 17911800 (1996).

110. Hislop, A. D. , Taylor, G. S., Sauce, D. & Rickinson, A. B.

Cellular responses to viral infection in humans: lessons

from EpsteinBarr virus.Annu. Rev. Immunol. 25

triggers of autoimmunity

Documents