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Epitope spreading: protection from pathogens, but propagation of autoimmunity?
http://www.blackwell-synergy.com/Journals/issuelist.asp?journal=ced

Clinical & Experimental Dermatology
Volume 26 Issue 5 Page 427 - July 2001
A. M. Powell and M. M. Black

An epitope is an antigenic determinant, or a site on the surface of an antigenic molecule, to which a single antibody binds. Epitope spreading (ES) refers to the development of an immune response to epitopes distinct from, and noncross-reactive with, the disease-causing epitope. Diversification, or the ability of the immune system to attack multiple targets on a pathogen has obvious advantages. Here we review some of the evidence regarding its role in autoimmunity, in humans and in animal disease models. We consider the implications of ES on the development of highly specific therapies for autoimmune disease. We stress that pathogenic ES probably occurs in the context of inherent abnormalities in control mechanisms for the prevention of autoimmunity or other genetic predisposing factors.

Introduction

An epitope is an antigenic determinant, or a site on the surface of an antigenic molecule, to which a single antibody binds. It is usually a short peptide sequence. Every antigen (Ag) generally has several epitopes, which react with antibodies (Abs) of different specificities and affinities. The dominant or primary epitopes are those to which an animal initially responds when primed with a protein or infectious agent (Table 1).

Some epitopes are hidden or cryptic, in that they are located within an unexposed region of the molecule and are prevented from interacting with Abs or lymphocytes unless exposed by a conformational change or stereochemical alteration of molecular structure (Table 2, Table 3). Because they are unable to interact with lymphocytes, they are therefore unable to induce either an immune response or tolerance. For example, tolerance does not normally develop to Ags sequestered from the immune system, such as sperm Ags or ocular lens crystallin, and auto-Abs against these structures can often be detected following tissue trauma, which allows contact between these Ags and the immune system.

The term epitope spreading (ES) means the development of immune responses to epitopes distinct from, and noncross-reactive with, the dominant epitope. In autoimmunity it refers to the development of immune responses against endogenous epitopes, secondary to the release of self-Ag during a chronic autoimmune or infectious response. Ag-specific autoimmune responses can spread to different epitopes on one protein, intramolecular ES, or to epitopes on other structural/functional proteins, intermolecular ES. The secondary epitopes, which are often cryptic epitopes on the same molecule or dominant epitopes on neighbouring molecules, are those to which responses arise later. In autoimmunity the process of ES may begin with molecular mimicry, a fortuitous antigenic similarity, or cross-reactivity, between a particular microbial epitope and a host epitope.

ES in the immune response to pathogens

It is likely that ES is a normal feature of a protective immune response and not just an abnormal reaction of the immune system confined to autoimmune disease. In order to clear infections and malignancies the immune system has evolved to attack as many targets as possible. In other words, the immune system depends on diversification. It is well recognized that, with time, there is a progressive and ordered appearance of Abs of different specificities, to for example human immunodeficiency virus (HIV), hepatitis B virus (HBV) and Borrelia burgdorferei infection. In HIV infection the combination of antibody profiles, HIV antigen levels, clinical condition and CD4 T cell count can indicate the state of progression of the disease.

An infection model provides an example of the role of B cells in ES. It demonstrates that the breakdown of T-cell tolerance to a peptide from one protein of a particle can be sufficient to allow ES among B cells and the subsequent expansion of the Ab response to other parts of the particle. 1 T cells from mice primed with the nucleocapsid (core) protein of HBV (HbcAg) can drive Ab production against HBV surface Ag (HbsAg) provided that the primed mice are boosted with intact virus. Core Ag-specific T cells seem to help B cells produce antibodies against both HbcAg and HbsAg. The latter does not occur if the two proteins are physically dissociated; if instead of being boosted with intact virus, mice are boosted with purified preparations of HbcAg and HbsAg.

ES is a phenomenon sought after and exploited in vaccine design. For example, infants are unable to mount a protective response to Haemophilus influenzae B capsular polysaccharide antigens. So to make an effective vaccine for children, the polysaccharide is conjugated to tetanus toxoid (to which infants are successfully vaccinated). It is thought that B cells binding to the polysaccharide component of the vaccine can be activated by T helper cells specific for the linked tetanus toxoid.

ES in autoimmunity

Evidence that autoimmune responses are dynamic with evolving specificities has been demonstrated in a variety of experimentally induced or spontaneous animal models of autoimmunity at both T- and B-cell level. In these animal models it is possible to trace the progression of disease, and potentially to identify the circumstances necessary for pathogenic ES.

Murine models

Murine relapsing experimental autoimmune encephalomyelitis (R-EAE) is a well-characterized model of chronic T-cell initiated experimental autoimmunity, which bears some resemblance to multiple sclerosis (MS). It is induced by immunization of genetically susceptible mice with myelin basic protein (MBP) or proteolipid protein, and has provided much of the initial evidence in support for ES in autoimmunity and also evidence that ES can be T-cell mediated. Within this animal model the following have been demonstrated:
  

Intramolecular, intrastructural/intermolecular epitope spreading may occur.
There is a predictable, reproducible sequential epitope spreading cascade. 2
Central nervous system myelin damage is necessary for the initiation of ES. 3
ES in EAE has functional importance, as it is required for disease relapses. 46

Similar findings are reported in NOD mice (non obese diabetic mice, a murine model for type I diabetes). An immune response to GAD65 (a 65-kDa isoform of glutamic acid decarboxylase) is believed to initiate islet cell destruction. As the animals progress to overt diabetes, the immunoreactivity spreads to other pancreatic cell Ags such as carboxypetidase H, insulin and heat shock protein 65.7,8 Induction of tolerance to GAD65 results in a reduced incidence of diabetes in NOD mice and importantly prevents the activation of autoreactive response to other pancreatic cell Ags. 9

Human disease

Many instances of human organ-specific autoimmunity involve clusters of target molecules. For example, autoAbs in systemic lupus erythematosus (SLE) often arise in grouped, or linked sets, that target macromolecular complexes, such as chromatin, snRNPs, or Ro/La (SS-A/SS-B). This observation was made more than 25 years ago, when it was demonstrated that the nRNP and Sm Ags are physically associated, and that autoAbs to these Ags often occur together in patients' sera.10,11 Variations in defined patterns of autoAb response can be of diagnostic value, such as the subset of patients with cutaneous lupus and mild systemic disease that mount responses to Ro (SS-A) in the absence of other detectable autoAb, i.e. subacute cutaneous lupus erythematosus. In contrast, many patients with primary Sjogren's syndrome and SLE produce IgG Abs specific for both the Ro and La (SS-B) Ags, which are physically associated.

Examples within dermatology

Chan et al.12 have reviewed the probable examples of ES in cutaneous autoimmune disease. Patients with bullous pemphigoid may have circulating Abs against several basement membrane zone (BMZ), upper lamina lucida/hemidesmosome, Ags, and not infrequently to both BP180 and BP230, 13 two proteins which are structurally associated but without cross-reactive sites. BP180 (or collagen XVII) is extracellular and is accessible to immune cells and Abs without prior cell disruption and BP230 is not. BP180 is therefore now believed to harbour the immunodominant epitope.

Pathogenic anti-BMZ Abs have arisen following nonAb-mediated damage to the cutaneous BMZ for example, bullous pemphigoid occurring on the background of lichen planus (LP), 1417 nodular prurigo 1821 or psoriasis, 2224 mucous membrane pemphigoid following Stevens-Johnson syndrome 25 or in association with other immunobullous diseases such as dermatitis herpetiformis associated with bullous pemphigoid. 2628 Paraneoplastic pemphigus, which is characterized by a panoply of epidermal intercellular and BMZ antibodies, has been described in association with clinical and histological features of LP. 29 The authors propose that cell-mediated immunity in LP predisposes to ES with the development of subsequent and progressive cutaneous autoimmunity (presumably, in the context of immune dysregulation secondary to malignancy).

Changing autoAb profiles, as demonstrated in immunobullous disease, provide some circumstantial evidence, but as yet there are few studies looking at the temporal variations in immune responses of autoreactive cells in humans. There are studies to suggest that ES may occur in the immune response to specific myelin proteins in patients with MS. 3032 One study 32 involved five cases and four normal controls, and found heterogeneous MBP epitope reactivity patterns, with roughly 40% maintaining a broad T-cell response throughout, 40% seeming to display ES and the remaining 20% maintaining a focused response. These results are difficult to interpret because of the small subject numbers and because responsiveness to MBP is probably not the only factor in the pathogenesis of relapsing episodes of demyelination.

Why does autoimmunity occur so infrequently?

It would seem that the manner of T-cell activation favours ES (see Fig. 1 and Table 3). There is increased likelihood of T cell activation, not only with increased Ag concentration, but also with increased density of major histocompatibility complex (MHC) and costimulatory molecules [which lead to increased avidity of the T-cell receptor/antigen presenting cell (APC) interaction]. Although many organs are protected by low level MHC expression, MHC is up-regulated in an inflamed area. In contrast with foreign Ags (which are usually removed by the immune response), organ-specific self-determinants will continue to be released leading to a self-perpetuating process. If so, why does autotimmunity occur so infrequently?

ES, it seems, is not always harmful. During the course of adjuvant arthritis, which is induced in Lewis rats by the subcutaneous injection of heat killed Mycobacterium tuberculosis, the immune response diversifies to involve certain epitopes of the 65 kDa heat-shock protein (Bhsp65). This diversification appears to mediate a natural remission from the acute arthritis. 33 The same mechanism is also induced in WKY rats but because of genetic dissimilarities these rats process Bhsp65 differently. This response has already often been induced by microbial flora in Fisher rats, explaining their resistance to adjuvant arthritis. 34 Potentially therefore, ES may also lead to recovery/protection from autoimmune disease. The recruitment of a new determinant could induce a Th2 response or a cytokine milieu unfavourable for continued autoimmunity. This might help to account for the natural recovery from acute autoimmune phenomena (such as haemolytic anaemia, cryoglobulinaemia, vasculitis, Giullain-Barré syndrome and post-streptococcal glomerulonephritis) that are turned off when the infectious agent is cleared. These experiments may also provide tantalizing clues as to why different individuals in the same (or different) environments differ in their susceptibility to autoimmune disease, questions raised, for example, in the endemic South American pemphigus foliaceus, fogo selvagem.

In immunobullous disease, diversity may be associated with a less aggressive disease course, for example the transition from pemphigus vulgaris to the more benign pemphigus foliaceus. Some individuals with pemphigus vulgaris, who present initially with pure mucosal disease and Ab only against restricted desmoglein (Dsg) 3 epitopes, later go on to develop cutaneous disease aswell, associated with immune reactivity against Dsg 1. This may evolve because certain secondary epitopes on Dsg 3 are cross-reactive with Dsg 1. 35 In pemphigus this ES may occur with loss of reactivity to the primary, dominant epitope on Dsg 3, resulting in the conversion of pemphigus vulgaris to pure cutaneous pemphigus foliaceus with Abs targeting Dsg 1 only. 36

What are the implications of ES on research into new treatment strategies

Over the last couple of decades, one of the focuses in the study of the aetiopathogenesis of autoimmunity has been to identify disease-specific autoantigenic epitopes. It was hoped that, in the context of a highly restricted autoimmune response, the identification of stimulatory T- and B-cell epitopes would eventually lead to the development of highly specific and curative therapies. For example, avoiding suppression of the whole immune system by using peptide immunotherapy to actively induce tolerance to the antigenic epitope, or by deleting T cells bearing receptors with the specific autoreactive V region product only. But the ES model proposes that inflammatory self-recognition is maintained by a shifting of autoreactivity from primary initiating self-epitopes to cascades of secondary epitopes, defined by the host's genotype and other factors, that sustain the self-recognition process through disease progression. Does the discovery of ES model make these approaches less valid?

In fact, there is evidence to suggest that dominant T-cell epitopes are also the most potent tolerogens. 37 Altering the reactivity to the dominant epitope may provide sufficient T-cell immune deviation (change in the predominant T-helper signal type), to alter significantly the immune milieu and switch off the dysregulated immune response. Additionally there is evidence from specific immunotherapy experiments in murine allergy models that treatment with the immunodominant peptide can tolerate an animal to the whole multideterminant molecule, a role for intramolecular epitope suppression (sometimes also referred to as intramolecular bystander suppression). 38 This data may mean that the identification of immunodominant epitopes involved in autoimmunity and allergy remains worthwhile in order to tolerize patients and turn off dysregulated immunity.

Because the response to a single Ag can be heterogeneous, strategies to target an individual's entire repertoire of Ag-specific T cells may be required. One such strategy would be the novel approach, using APCs, genetically engineered both to present the Ag and to express Fas ligand, to simultaneously target the range of antigen-specific T cells and induce their apoptosis, 39 regardless of intramolecular ES.

Conclusion

ES is a practical and functionally important element of a healthy immune system, with considerable evidence to support its role in protection from infectious agents. But it also seems to play a role in the pathogenesis of autoimmunity, probably in the context of inherent abnormalities in control mechanisms for the prevention of autoimmunity or genetic predisposing factors (to date the most convincing association with autoimmunity remains the MHC haplotype). A combination of factors is likely to be responsible for the development of autoAb responses. A combination of these factors probably also influences the direction of spread of epitope reactivity and could account for the heterogeneous features of autoimmune diseases such as SLE or even different phenotypes of anti-BP180 reactivity associated with bullous pemphigoid, mucous membrane pemphigoid, linear IgA disease and pemphigoid gestationis, for example. Different autoAg epitopes may be important for each individual depending on MHC background, the sets of foreign Ag encountered and the timing of MHC up-regulation. Understanding the reasons for, and mechanisms of, epitope spreading covers questions involving the entire spectrum of immune reactivity, tolerance, T and B cell activation; the very basis of the immune reaction to infectious agents, cancers, transplants and to self.

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