Epitope Spreading in Autoimmune Diseases

CHAPTER 4

Epitope Spreading in Autoimmune Diseases Shivaprasad H. Venkatesha, Malarvizhi Durai, Kamal D. Moudgil1 Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA 1 Corresponding Author: [email protected]

1 INTRODUCTION The phenomenon of “epitope spreading” (or “determinant spreading”) is characterized by broadening or diversification of the initial immune response induced by immunization with a single peptide antigen or a multideterminant antigen.1–3 The new T cell and/or antibody responses are directed to different epitopes either within the same antigen (intramolecular spreading) or another antigen (intermolecular spreading). The spreading of initial immune reactivity has been shown to occur during the course of a variety of experimentally induced and spontaneously arising autoimmune diseases in animal models (Tables 1 and 2).2,3 Studies of patients with certain autoimmune diseases (Table 1) have further validated the significance of epitope spreading in disease pathogenesis. Depending on the disease process, epitope spreading can contribute to either the progression or the control of an autoimmune disease (Figure 1).1,3,10 The timing of epitope spreading during the course of an autoimmune disease and its functional attributes are of significance in designing appropriate immunotherapeutic approaches.

2 EXAMPLES OF EPITOPE SPREADING IN AUTOIMMUNE DISEASES 2.1 Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis Multiple sclerosis (MS) is a human autoimmune disease characterized by mononuclear cell infiltration and discrete areas of demyelination (plaques) within the central nervous system (CNS) and neurological dysfunction. Experimental autoimmune encephalomyelitis (EAE) is an experimental Infection and Autoimmunity http://dx.doi.org/10.1016/B978-0-444-63269-2.00003-9

© 2015 Elsevier B.V. All rights reserved.

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Table 1 Examples of Epitope Spreading in Animal Models and Human Autoimmune Diseases Diseases References (a) Animal models of autoimmune diseases

Experimental autoimmune encephalomyelitis (EAE) Diabetes in the non-obese diabetic (NOD) mouse Adjuvant-induced arthritis (AA) Lupus or systemic lupus erythematosus (SLE) Experimental autoimmune myasthenia gravis (EAMG) Experimental autoimmune neuritis (EAN) Equine recurrent uveitis (ERU) Experimental autoimmune gastritis (EAG) Autoimmune oophoritis Experimental autoimmune thyroiditis (EAT)

1,4–7 8,9 10–15 16–20 21 22 23 24 25 26

(b) Human autoimmune diseases

Multiple sclerosis (MS) Insulin-dependent diabetes mellitus (IDDM) or type I diabetes Rheumatoid arthritis (RA) Systemic lupus erythematosus (SLE) or lupus Myasthenia gravis (MG)

27–29 30–33 34–37 38–41 21

model of MS, and it can be induced in different mouse/rat strains by immunization (in adjuvant) with myelin antigens such as myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG) (Table 2).3,43,44 Epitope spreading was first demonstrated by Lehmann et al. in an EAE model using (SJL
B10.PL) F1 mice.1 It was shown that the initial T cell response of mice with acute EAE was directed to MBP Ac1-11, but spreading of the T cell response to new determinants of MBP, namely, 35– 47, 81–100, and 121–140, subsequently, occurred during the chronic stage of EAE.1,45 This broadening of the T cell response was attributed to the priming of new T cells by determinants within endogenous MBP following initial CNS damage. Miller’s group established the role of epitope spreading in the pathogenesis of relapsing EAE (R-EAE) and defined the mechanisms underlying epitope spreading. R-EAE can be induced in SJL mice by immunization with PLP 139–151.4,46 Using this model, it was observed that the T cell response to the disease-initiating epitope, PLP 139–151, was maintained in SJL mice throughout the course of EAE. However, spreading of the T cell response to non-cross-reactive PLP 178–191 and MBP 84–104 epitopes occurred after the first and second relapses, respectively. Furthermore, the T cells against

Table 2 The Antigen Specificity of Epitope Spreading in Experimental Models of Autoimmune Diseases Disease-Inducing Antigen/Epitopes Targeted During Disease Model Animals Tested Antigen/Agent Epitope Spreadinga

Experimental autoimmune encephalomyelitis (EAE)

Adjuvant-induced arthritis (AA)

Lupus or systemic lupus erythematosus (SLE)

(SJL
B10.PL)F1 mice

MBP Ac1–11

MBP 35–47, MBP 81–100, and MBP 121–140

1

SJL/J mice (SWR
SJL)F1 mice Lewis rats Callithrix jacchus (the common marmoset) NOD mice

PLP 139–151 PLP 139–151

PLP 178–191 and MBP 84–104 PLP 249–273, MBP 87–99, and PLP 137–198 Multiple T cell epitopes within MBP Anti-MOG antibodies

4 5

MBP MP4 fusion protein (PLP–MBP) Spontaneous

Spontaneous

Lewis rats

Mtb (H37Ra)

Lewis rats

Mtb (H37Ra)

NZW rabbits

Sm B/B0 peptide

Mice

La (or Ro) antigen

8

9

10 12,13 16

17 (Continued)

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NOD mice

T cell response to GAD65, carboxypeptidase-H, insulin, and HSP65 T cell and antibody response to GAD65/ 67, peripherin, carboxypeptidase-H, and HSP60 417–431, 441–455, 465–479, 513–527, 521–535 of Bhsp65 Multiple B cell epitopes within Bhsp65 after recovery from acute AA Antibody response to other epitopes of Sm B/B0 antigen and other spliceosomal proteins Antibody response to both La and Ro proteins

6 7

Spreading of immune responses in autoimmunity

Diabetes in the nonobese diabetic (NOD) mouse

References

Lewis rats

Horse Mice

Spontaneous Spontaneous Human AChR asubunit peptides

Peptides 56–71 and 180–199 of P0 protein IRBP H/K ATPase b-subunit

References

Antibody response to nucleosomal components Response to epitopes in VH region of anti-DNA antibody Antibodies to rabbit AChR

18

T cell response to other epitopes of P0 protein

22

Multiple T cell epitopes within IRBP and S-Ag T cell and antibody response to a-subunit of H/K ATPase

23

19 42

24

MBP, myelin basic protein; PLP, proteolipid protein; TMEV, Theiler’s murine encephalomyelitis virus; MOG, myelin oligodendrocyte glycoprotein; GAD65/67, glutamic acid decarboxylase 65/67; HSP65, heat shock protein 65; Mtb, heat-killed Mycobacterium tuberculosis H37Ra; Bhsp65, mycobacterial hsp65; AA, adjuvantinduced arthritis; Sm B/B´, Smith Ag B/B´; La & Ro, antigens within ribonucleoprotein complex; AChR, acetylcholine receptor; P0, peripheral nervous system myelin glycoprotein; IRBP, interphotoreceptor retinoid binding protein; S-Ag, retinal S-antigen. a Unless specified, all epitopes mentioned in the table refer to T cell responses.

Infection and autoimmunity

Experimental autoimmune myasthenia gravis (EAMG) Experimental autoimmune neuritis (EAN) Equine recurrent uveitis (ERU) Experimental autoimmune gastritis (EAG)

(SWR
NZB)F1 mice (NZB/NZW)F1 mice NZW rabbits

48

Table 2 The Antigen Specificity of Epitope Spreading in Experimental Models of Autoimmune Diseases—cont'd Disease-Inducing Antigen/Epitopes Targeted During Disease Model Animals Tested Antigen/Agent Epitope Spreading

Figure 1 Epitope spreading: the underlying mechanisms and role in the disease process. Initiation of an autoimmune disease, either spontaneously or following an antigenic challenge, creates a local inflammatory milieu that is conducive to the upregulation of antigen processing and presentation. In addition, the tissue damage associated with inflammation and infection may lead to the release of self antigens. Under these circumstances, self antigens are processed efficiently by the antigen-presenting cells, revealing previously cryptic/subdominant epitopes to potentially self-reactive T cells available in the mature T cell repertoire. In addition, the post-translational modification of antigens following inflammation and other stimuli generates neo-epitopes. The outcome of the priming of self-reactive T cells depends on multiple factors, including the balance between Th1/Th17 versus Th2/Treg cells. In parallel, the activated T cells may provide help to autoreactive B cells, leading to the spread of antibody responses. Antibodies and B cells in turn may influence T cell responses as well as disease severity. Accordingly, epitope spreading could either perpetuate (pathogenic epitope spreading) or attenuate (protective epitope spreading) the ongoing disease process.

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the spreading epitope (PLP 178–191) could transfer disease to naı¨ve syngeneic recipients.4 Interestingly, inducing tolerance against relapse-associated epitopes after the acute episode in SJL mice blocked disease progression and decreased the frequency of subsequent relapses.4 In addition, short-term blockade of either CD28–CD80 (B7.1) interaction by anti-CD80 F(ab) fragment47 or CD40–CD154 (CD40L) interaction using monoclonal anti-CD154 antibody48 during remission from acute disease significantly reduced both the incidence of disease relapse and the T cell response to relapse-associated epitopes. Epitope spreading also has been implicated in the induction of autoimmunity in Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease in SJL/J mice.49 Tuohy and colleagues studied the specificity of determinants and the functional significance of epitope spreading in R-EAE inducible in (SWR
SJL) F1 mice by injection with PLP 139–151.5 Interestingly, the T cells specific for the spreading determinant could passively transfer EAE to naı¨ve syngeneic recipients, whereas induction of peptide-specific tolerance to spreading epitopes after the onset of EAE could prevent the progression of EAE.5 Furthermore, interferon-b treatment of mice not only reduced the frequency/severity of disease relapses but also suppressed epitope spreading.50 The diversification of response to MBP epitopes also has been observed during the course of EAE in Lewis rats.6 The dominant encephalitogenic T cells in the induction phase of the disease were directed to epitope 71–90, whereas T cell responses to new epitopes within MBP appeared during the recovery phase of the disease.6 Another study revealed that Wistar Kyoto (WKY) rats having the same MHC haplotype as the Lewis rat were resistant to EAE despite raising potent T cell responses to the dominant encephalitogenic T cell epitope within MBP.51 However, the antigenspecific T cell response in WKY rats was skewed towards a predominantly T helper (Th) 2 type compared to a predominantly Th1 type in Lewis rats. Epitope spreading to MBP and additional MOG epitopes has been reported in the course of MOG peptide-induced EAE in humanized mice expressing DR4, which represents one of the disease susceptibility MHC alleles for patients with MS.52 In another study, autoantibody responses of mice with EAE were measured using a large set of autoantigens in a protein microarray.53 Chronic EAE was characterized by both intra- and intermolecular epitope spreading, and attenuation of EAE by a tolerizing DNA vaccination was associated with reduced epitope spreading of autoantibody responses. Similarly, the treatment of mice with EAE using a variety of other modalities (e.g., tolerance induction using antigen-decorated

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micro-particles,54 multi-peptide-coupled splenocyte-induced tolerance,55 multivalent bifunctional peptide inhibitor,56 poly(ADP-ribose) polymerase1 inhibitor,57 anti-IL-23 antibody therapy58 and suppressive oligodeoxynucleotide therapy)59 resulted in the inhibition of epitope spreading and protection against disease, including relapses. As in rodent EAE, epitope spreading also has been observed during the course of EAE in the common marmoset, Callithrix jacchus, and in patients with MS. The C. jacchus marmoset develops a chronic relapsing-remitting form of EAE following challenge with myelin antigens, and both the T cells and antibodies serve as immune effector mechanisms in the disease process.7,60 Interestingly, the treatment of these non-human primates with anti-CD40 antibody prevented intramolecular spreading and afforded protection against EAE.61,62 In a study of patients with isolated monosymptomatic demyelinating syndrome (IMDS), the T cell reactivity to PLP epitopes was found to decrease over time. However, spreading of T cell responses to other PLP epitopes was observed in those patients with IMDS who progressed to clinically definite MS.27–29

2.2 Insulin-Dependent Diabetes Mellitus or Type I Diabetes Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease involving mononuclear cell infiltration of the pancreatic islets (insulitis), destruction of b-islet cells, and insulin deficiency. Spontaneously developing diabetes in the non-obese diabetic (NOD) mouse serves as a model for human IDDM. Glutamic acid decarboxylase (GAD65) has been invoked as one of the early target antigens in the pathogenesis of autoimmune diabetes in the NOD mouse.8,9 With the progression of disease, the T cell responses spread to additional epitopes within GAD65 and to other b-cell antigens (e.g., to carboxypeptidase-H, insulin, and heat shock protein 65 (Hsp65) in one study8 and to GAD67, carboxypeptidase-H, peripherin, and Hsp60 in another study9) (Table 2). Furthermore, tolerization of GAD65-reactive T cells suppressed the development of insulitis, disease progression, and the spreading of T cell responses.8,9 Further, Th1 cell spreading leads to disease progression, whereas Th2 cell spreading is associated with protection from disease in NOD mice. In another study, new potential target epitopes within GAD65 and GAD67 were described in NOD mice,63 and mice given a disease-protective regimen (e.g. adjuvant challenge) revealed a different pattern of response to GAD65/67 compared to control mice. Studies of epitope spreading in human IDDM have revealed a pattern of autoantibody responses to b-cell antigens in children of diabetic patients.30

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The anti-islet autoantibody response in these subjects was characterized by the appearance of an early immunoglobulin G1 response to one or more islet antigens, particularly insulin. Thereafter, coupled with a decline in the titer of these antibodies, antibodies against other b-cell antigens sequentially appeared over a period of several years.30 In other studies of pre-clinical childhood type I diabetes, the initial antibody response to GAD of offspring of diabetic patients was directed primarily to epitopes within the middle portion of GAD65 but later spread to epitopes in other regions of GAD65 and GAD67.31,32 Similarly, intermolecular spreading of the T cell reactivity and antibody responses to islet antigens occurred during the pre-clinical phase of type I diabetes in subjects at risk (as defined by positivity for autoantibodies to b-islet antigens) of developing clinical diabetes.33

2.3 Arthritis Rheumatoid arthritis (RA) is a human autoimmune disease characterized by persistent inflammatory synovitis. Adjuvant-induced arthritis (AA) is an experimental model of human RA, and it can be induced in Lewis rats by immunization with heat-killed Mycobacterium tuberculosis H37Ra (Mtb) in mineral oil. The T cell response to the 65-kDa mycobacterial heat shock protein (Bhsp65) has been implicated in the pathogenesis of AA as well as RA.64–67 We showed that there is a shift in the epitope specificity of the T cell response to Bhsp65 during the course of AA in Lewis rats. In the acute phase of AA, the T cell response of arthritic Lewis rats was focused on peptide 177–191 (which contains the arthritogenic determinant 180–188) and other epitopes in the middle and N-terminal regions of Bhsp65. During the recovery phase of AA, however, new T cell responses directed to the five C-terminal epitopes of Bhsp65 (namely, 417–431, 441–455, 465–479, 513–527, and 521–535) appeared (Table 2). Interestingly, pre-treatment of naı¨ve Lewis rats with the synthetic peptides representing these five Bhsp65 C-terminal determinants (BCTDs) significantly reduced the severity of subsequently induced AA.10,68 Furthermore, T cell responses to BCTDs were observed early following Mtb challenge in WKY rats that possess the same MHC haplotype as the AA-susceptible Lewis rat but are resistant to the induction of AA. The simultaneous emergence of T cell responses to the pathogenic (180–188/177–191 determinant) and regulatory (BCTD) epitopes could explain, in part, the AA resistance of WKY rats. The results of one of our other studies showed that the C-terminal epitopes of self hsp65 also are disease-regulating in nature.69,70 The above-mentioned results

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suggest that spreading of the T cell responses to BCTDs during the course of AA might be involved in natural recovery from acute AA in the Lewis rat. Furthermore, these findings demonstrate that epitope spreading in the course of an autoimmune disease is not always pathogenic; instead, it can regulate disease in another situation. This is the first study10 reporting the disease-regulating aspect of epitope spreading in the course of an autoimmune disease. Another aspect of spontaneous emergence and spreading of T cell responses was revealed in a study of the Fischer F344 (F344) rat.11 We observed that F344 rats kept in a barrier facility (BF-F344) were susceptible to AA, whereas those maintained in a conventional facility (CV-F344) spontaneously acquired protection (or resistance) against AA. CV-F344 but not BF-F344 rats showed an increased T cell response to multiple epitopes of Bhsp65, including BCTD, and the level of these spontaneously arising T cell responses gradually increased with the duration and extent of exposure of F344 rats to the conventional environment. Adoptive transfer of BCTD-restimulated (in vitro) splenic cells of naı¨ve CV-F344 rats to naı¨ve BF-F344 recipients offered protection against AA. The role of a conventional environment in facilitating the induction of an autoimmune disease has been observed in various models of autoimmunity. By contrast, our study described above11 along with others of diabetes71 reflect on the protective effect of environment on autoimmunity. As for the T cell-mediated epitope spreading in AA, a couple studies have highlighted the role of spreading of antibody response to Bhsp65 in the regulation of AA. Lewis rats develop antibodies against Bhsp65 during the course of AA, and the number of epitopes within Bhsp65 recognized by these antibodies gradually increases during the recovery phase of the disease.12,13 Similarly, passive immunization with the antibodies directed against one of these epitopes (peptide 31–46), or the adoptive transfer of serum from late-phase arthritic rats, suppressed subsequent AA.12,13 Furthermore, the resistance of Brown Norway or WKY rats to AA correlates with natural antibody response to the same B cell epitopes as those involved in epitope spreading in the susceptible Lewis rats. Spreading of the tolerogenic effect of the disease-related epitope of Bhsp65, p180–188, and that of the suppressive effect of antigen-specific anergic T cells have been invoked in the downmodulation of the course of avridine-induced arthritis and/or AA.14,15 It was observed that induction of nasal tolerance against p180–188 provided protection against subsequent AA as well as avridine-induced arthritis.14 It was proposed that tolerization

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of T cells recognizing p180–188 or its mimic spread to T cells of other specificities that are involved in arthritis induction. Similarly, it was suggested that a subset of anergic T cells, in the presence of the specific antigen recognized by these cells, exerted a suppressive activity on the spreading of T cells of other antigen specificities.15 Furthermore, this amplification of suppressive effect was attributed to modulation of the activity of antigenpresenting cells (APCs) by anergic T cells. A study of the T cell repertoire in patients with RA showed that several dominant T cell clones were found in the synovial membrane but not in the peripheral blood.34 Analysis of the complementarity-determining region 3, following sequencing of the T cell receptor (TCR) Vb V-D-J junctional regions, showed evidence for antigen-driven selection of the TCR, which was attributed to determinant spreading during the course of RA. Additional similar studies of RA would help define the fine characteristics of the pathogenic T cell repertoire in this disease. Further, epitope spreading involving antibodies to post-translationally modified antigens has been reported in the pre-clinical phase of the disease in patients with RA.35–37

2.4 Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a multi-system human autoimmune disease characterized by the development of autoantibodies against a variety of autoantigens.72–74 Both intermolecular and intramolecular epitope spreading involving the above-mentioned autoantigens have been observed in SLE and an animal model of lupus (Table 2). For example, James et al.16 demonstrated that New Zealand white rabbits immunized with an Sm B/B0 peptide (representing a C-terminal epitope) developed antibodies directed against the immunogen and other epitopes within the middle and aminoterminal regions of the Sm B/B0 antigen, along with antibodies against other spliceosomal proteins (e.g., D, 70K, A, and C). In another study, mice immunized with La protein developed autoantibodies not only to the immunogen but also to 60-kDa Ro, whereas mice immunized with 60kDa Ro produced anti-Ro antibodies as well as anti-La antibodies.17 The results of another study75 validated the development of antibodies to multiple components of the La/Ro ribonucleoprotein complex after a challenge with a single component of the antigenic complex. The spreading of the Th and antibody responses to components of the nucleosome18 and intramolecular spreading of the T cell response to Th epitopes within the VH region of a pathogenic anti-DNA antibody19 represent cases of epitope spreading

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during spontaneously arising disease. Antibodies to post-translationally modified antigens in lupus also are reported.76 Interestingly, tolerization of lupus-prone mice against either autoantibody-derived peptides or the protein/peptides (e.g., nucleosomal peptides) representing antigenic determinants involved in epitope spreading can successfully halt the progression of epitope spreading as well as the disease process.20,77 Patients with SLE also develop autoantibodies to the variety of autoantigens described above. Studies of the antigen reactivity of the sera of patients with lupus have demonstrated temporal shifts in both the recognition of another antigen (e.g., intermolecular spreading from Sm antigen to RNP reactivity) as well as in the reactivity to different epitopes within the same antigen (e.g., intramolecular spreading within a given antigen depending on the model system: Sm B/B0 , Sm D, ribosomal protein L7, caspase-8, etc.).38–41

2.5 Other Autoimmune Diseases Myasthenia gravis (MG) is an autoimmune disease resulting from antibodymediated autoimmune attack against the nicotinic acetylcholine receptor (AChR). Epitope spreading has been reported in experimental autoimmune MG,21 and there is some evidence suggesting epitope spreading in patients with MG as well.21 Epitope spreading also has been observed in animal models of thyroiditis,26 neuritis,22 uveitis,23 gastritis,24 and oophoritis25 (Tables 1 and 2). Progression of myocarditis to dilated cardiomyopathy also has been linked with epitope spreading.78

3 MECHANISMS UNDERLYING EPITOPE SPREADING DURING THE COURSE OF AN AUTOIMMUNE DISEASE Considering the diverse experimental models of autoimmune diseases involving different target organs and predominantly either T cells (CD4+/ CD8 +) or antibodies as the pathogenic effector mediators (Table 2), various mechanisms have been proposed to explain the phenomenon of epitope spreading (Figure 1 and Table 3). These are described below.

3.1 Upregulation of the Display of Cryptic/Subdominant Epitopes Within a Self Antigen Under Inflammatory Conditions Native (whole) self and foreign antigens possess potential T cell epitopes that are processed and presented either efficiently (dominant determinants) or poorly (cryptic/subdominant determinants) by APCs.79 However, both sets of determinants are immunogenic in the peptide form. In the case of a self

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Table 3 Proposed Mechanisms Underlying the Phenomenon of Epitope Spreading

1. Upregulation of the display of cryptic/subdominant epitopes within a self antigen 2. Release of self antigens and their processing and presentation following tissue damage in the course of a microbial infection or an autoimmune disease 3. Post-translational modification of antigens generates neo-epitopes 4. The frequency and avidity of epitope-specific precursor T cells within the mature T cell repertoire favoring responsiveness to certain antigenic determinants over others 5. Presentation of neo-epitopes within a particular self antigen by the B cells specific for that antigen 6. The influence of antigen-bound antibodies on the processing and presentation of T cell epitopes within that antigen 7. Antigen cross-presentation and epitope spreading 8. Site of initiation of epitope spreading: target organ versus periphery

antigen, tolerance is readily induced to its dominant but not cryptic/ subdominant epitopes.80–83 For this reason, unlike a foreign dominant epitope that is generally immunogenic, a self-dominant determinant often fails to induce a response because of self-tolerance. However, the T cells against cryptic/subdominant self epitopes escape the induction of tolerance in the thymus and therefore are available in the mature T cell repertoire. These T cells can be activated provided the otherwise poorly processed cryptic/subdominant epitopes within the native self antigen are efficiently presented to the T cells by professional APCs. This could happen under conditions of upregulated antigen processing and presentation events, as in the case of inflammation and/or infection.3,84–87 The T cells specific for cryptic/ subdominant epitopes of an endogenous self antigen thus activated (constituting epitope spreading) can participate in further propagation of the ongoing disease process. This also applies to self antigens released following tissue damage (described below), which can contribute to epitope spreading. Similarly, quantitatively enhanced display of foreign antigenic epitopes that are cross-reactive with self epitopes can further expand the pool of self-reactive T cells via molecular mimicry (see below).

3.2 Release of Self Antigens and Their Processing and Presentation Following Tissue Damage in the Course of a Microbial Infection or an Autoimmune Disease The etiology of most human autoimmune diseases is not known. However, one trigger or precipitating factor for the induction of autoimmunity is microbial infection. Some of the mechanisms proposed to explain this association

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include (a) molecular mimicry: a microbial antigen/epitope structurally mimics a self antigen/epitope such that the T cells primed following microbial infection can be re-stimulated by the endogenous self antigen and can thereby target cells/tissue expressing that self antigen, leading to tissue damage;42,88–90 (b) bystander activation: inadvertent stimulation of potentially self-reactive T cells under the immune environment where priming of microbial antigen-specific T cells is taking place; the autoreactive T cells can then cause tissue damage3; and (c) tissue injury leading to induction of autoimmune response: the tissue damage caused by microbial infection results in the release of endogenous self antigens that can then be processed and presented by local as well as distant APCs, leading to the priming of self-reactive T cells.3,91,92 The role of virus-mediated tissue damage in the induction of autoimmunity has been demonstrated by Miller and colleagues in the TMEV-induced EAE model49 and by Rose and colleagues in the model of autoimmune myocarditis.93,94 In TMEV-induced EAE, the induction of autoimmunity also has been linked to epitope spreading resulting from the release of self antigens.49 Autoimmune myocarditis induced by coxsackievirus B3 has been shown to be a biphasic disease: an early “infection” phase and a subsequent “autoimmune” phase characterized by T cell and antibody response to cardiac myosin.94 (d) Apoptotic cells as the source of released antigen has been proposed by Rosen and colleagues95,96 as another mechanism for the release of intracellular self antigens; in this process, apoptotic cells serve as an important source of self antigens, and the novel antigenic fragments produced in apoptotic surface blebs are implicated in the reversal of self-tolerance, leading to the induction of autoimmunity.

3.3 Post-Translational Modification of Antigens Post-translational modification of naturally occurring proteins may lead to the generation of neo-epitopes, which might induce anti-self immune responses. In the face of a susceptible combination of genetic and environmental factors, such an immune response can initiate autoimmunity. In addition, the generation of neo-epitopes and subsequent immune response to them may perpetuate (via epitope spreading) the diversification of ongoing autoimmune response. The conversion of arginine to citrulline, the conversion of aspartate to isoaspartic acid, and the oxidation of amino acids by reactive oxygen species and reactive nitrogen species represent examples of modifications of proteins leading to the generation of neoepitopes and their relationship with autoimmunity.97–99 RA and SLE are

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two of the major autoimmune diseases whose pathogenesis involves the generation of the above-mentioned neo-epitopes, leading to initiation of autoimmunity and epitope spreading.35,100

3.4 The Frequency and Avidity of Epitope-Specific Precursor T Cells Within the Mature T Cell Repertoire Favoring Responsiveness to Certain Antigenic Determinants over Others The T cell responses to various epitopes within a native antigen, or to individual antigens within a mixture of antigens, are hierarchical and are influenced by multiple factors operating at the level of the APC (described above) as well as those relating to the size (frequency) and the composition (e.g. the relative levels of high avidity vs. low avidity T cells) of the mature T cell repertoire.44,101 These characteristics have been invoked, in part, to explain the hierarchy as well as the ordered sequential appearance of response to different antigens/epitopes involved in inter- or intramolecular epitope spreading.3–5,46

3.5 Presentation of Neo-Epitopes Within a Particular Self Antigen by the B Cells Specific for That Antigen Activated B cells serving as potent APCs also can participate in the induction and propagation of epitope spreading. Mamula and Janeway proposed an interesting model based on the role of B cells as APCs in the diversification of the T cell and antibody response.102 The initial T cell priming to self epitopes is done by APC-like dendritic cells (DCs); these activated T cells then provide help to the appropriate B cells. The activated B cells in turn can take up, process, and then present that antigen to the T cells. The new subsets of activated T cells then can provide help to a new population of B cells. These T–B interactions thus lead to the diversification of both T cell and antibody responses. These processes in the setting of epitope spreading have been demonstrated in experimental models of lupus.3,44 However, there also is evidence from studies of PLP-induced EAE in BALB/c mice that B cells can limit epitope spreading.103 Further, IL-10-producing regulatory B (B10) cells may play an important role in controlling autoreactive responses104 and thereby contribute to regulating epitope spreading as well.

3.6 The Influence of Antigen-Bound Antibodies on the Processing and Presentation of T Cell Epitopes Within That Antigen Studies have demonstrated that antigen-bound antibodies can significantly influence the processing and presentation of T cell epitopes within that antigen.84,105 Depending on the nature and the site (in the context of antigenic

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structure) of the interaction between the antigenic determinant and the antibody, antibodies bound to specific epitopes of an antigen can either enhance or suppress the T cell response to the epitope involved. This in turn can lead to a shift in the epitope specificity of the T cell response (as observed in epitope spreading) during the course of an immune response directed towards a microbial or self antigen.

3.7 Antigen Cross-Presentation and Epitope Spreading It has recently been reported that during the course of disease induced by CD4 + T cells, naive, MBP-reactive CD8+ T cells in the CNS were activated.106 These CD8 + T cells could directly recognize oligodendrocytes, which presented MHC class I-restricted epitopes of MBP. Interestingly, the cross-presentation of MBP leading to the activation of naive CD8+ T cells occurred by a subset of DCs, namely, tumor necrosis factor-a/inducible nitric oxide synthase-producing DCs.106 Thus, this example illustrates determinant spreading to antigen-specific CD8 + T cells during the course of CD4+ T cell-induced EAE.

3.8 Site of Initiation of Epitope Spreading: Target Organ Versus the Periphery The CNS has traditionally been viewed as being immune privileged. However, studies of PLP-induced R-EAE and TMEV-induced demyelination revealed that epitope spreading is initiated within the CNS.107 During the course of disease, naı¨ve T cells enter the inflamed CNS and are activated there by local APCs to initiate epitope spreading. A recent study showing determinant spreading to CD8+ T cell epitopes in CD4+ T cell-induced EAE also emphasized the CNS as the site of epitope spreading.106 However, there also is evidence to suggest an alternative viewpoint emphasizing that the CNS-draining lymph nodes are important for the induction of immune response during relapses in chronic R-EAE.108 Surgical removal of these lymph nodes reduced the severity of relapses of EAE. This proposition is supported by the observation that myelin antigens are expressed in the lymph node, spleen, and thymus of SJL mice.109

4 PHYSIOLOGICAL SIGNIFICANCE OF EPITOPE SPREADING: INVOLVEMENT OF EPITOPE SPREADING IN THE PATHOGENESIS OF AUTOIMMUNE DISEASE Experimental evidence from studies of different models of autoimmune diseases supports the role of epitope spreading in the pathogenesis of the disease process. The results of these studies can be categorized into three

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functional outcomes: (1) pathogenic epitope spreading: most of the studies summarized earlier (Table 2) describe that the new T cell responses emerging via epitope spreading are involved in the perpetuation of the initial autoimmune process and thereby the progression and chronicity of the disease process; (2) protective epitope spreading: other studies provide evidence favoring a regulatory or protective role for T cell/antibody responses comprising diversification of the initial immune response;10,12,13 and (3) epitope spreading unrelated to the disease process or no spreading at all: in a couple studies of EAE, epitope spreading either was evident but had no functional relationship with the disease process110 or did not occur at all.111 In another study, clinically relapsing disease was observed in transgenic mice with a single TCR that lack all T cell specificities except the one required for initiation of the disease process,112 suggesting that relapses were not dependent on other T cell specificities. Thus, there is no single functional outcome that can a priori be assigned to epitope spreading; therefore, each disease and the antigenic response associated with it needs to be examined objectively and without any pre-formed notion or bias. In this regard, any prediction regarding the contribution of epitope spreading to the disease process in a vastly heterogeneous human population poses an important challenge for both clinical prognosis and the custom designing of therapeutic regimens.

5 IMPLICATIONS OF EPITOPE SPREADING IN IMMUNOTHERAPY OF AUTOIMMUNE DISEASES: HINDERING VS. FACILITATING THE CONTROL OF THE AUTOIMMUNE PROCESS A great deal of the effort invested in developing immunotherapeutic approaches for autoimmune diseases has centered on the inactivation/tolerization of potentially pathogenic T cells. It is evident from extensive studies of animal models that it is relatively easier to modulate the antigen-specific immune response for preventing the development of autoimmunity than for controlling the ongoing disease process. Epitope spreading that is diseasepropagating in nature (Figure 1) may pose a major hurdle in the treatment of ongoing disease. For successful treatment, the patient would have to be treated very early in the course of disease before the occurrence of epitope spreading. However, it is not an easy task to correctly predict the timing of epitope spreading during the natural course of disease in individual members of a patient population. On the other hand, epitope spreading that is diseaseregulating in nature (Figure 1) can readily be exploited for therapeutic

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purposes by developing therapeutic regimens aimed at priming and expanding the regulatory T cells specific for the new epitopes arising during the course of disease. Here, the precise timing of the onset of epitope spreading might not be much of a concern. However, in either situation, carefully planned clinical trials are warranted to insure that the programmed modulation of the immune response delivers the expected outcome. Otherwise, strategies aimed at suppressing the disease might unexpectedly exacerbate the disease or have no effect at all. In this regard, identification of the “window” of therapeutic opportunity, in terms of selecting the right target antigen and the timing of intervention in animal models offers hope for developing better approaches for the treatment of human autoimmune diseases.3,113

6 CONCLUDING REMARKS Epitope spreading represents a dynamic quantitative/qualitative change in the T cell and/or antibody specificities during the course of an immune response that is generally initiated by a dominant antigen/epitope associated with a pathological condition. The primary event may either be triggered experimentally or arise spontaneously. The subsequently developing new T cell and/or antibody responses then participate in perpetuation of the initial pathological changes, leading to chronic disease. Depending on the disease process, however, the spreading of response to potentially diseaseregulating antigens/epitopes can be protective in nature; therefore, epitope spreading also represents a mechanism by which initial pathological immune responses can be controlled to effect natural recovery from the acute phase of the disease. We suggest that epitope spreading, like many other physiological processes in the body, represents a snapshot of the dynamic events attempting to strike a balance between the pathogenic and regulatory components of antigen-specific T cell responses and that the “picture” obtained would vary depending on the time when the responses are sampled and tested during the disease process. Further studies facilitated by the application of new tools such as MHC-peptide tetramers, MHC-Ig dimers, and autoantibody profiling using protein microarrays53 would help advance our understanding of the role of epitope spreading of antigen-specific T cell/antibody responses in the pathogenesis of autoimmune diseases. In addition, advances in the areas of immune regulation, modulation of adaptive immunity by components of the innate immune response, and interplay between the host and environment

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are expected to unravel additional mechanisms underlying epitope spreading. At this time there is far more information regarding pathogenic immune responses in epitope spreading than there is for the regulatory aspects of the process. Further integration of the mechanisms involving Foxp3-expressing CD4+CD25+ T cells and other regulatory T cells in the control of disease-propagating epitope spreading would advance our understanding of the pathogenesis of autoimmune diseases. In addition, the regulatory aspects of epitope spreading could be exploited for therapeutic advantage.

ACKNOWLEDGMENT The authors gratefully acknowledge grant support from the National Institutes of Health (Bethesda, MD).

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