Epitopes of Autoantigens and their Role in Initiation and Propagation of Systemic Autoimmunity
Abstract
Abstract
The presence of autoantibodies is the hallmark of systemic autoimmune diseases. Although their pathogenetic and aetiological relationship is not fully understood, autoantibodies are important tools for establishing the diagnosis, classification and prognosis of autoimmune diseases. Autoantibodies in systemic autoimmune rheumatic diseases target mainly multicomponent intracellular complexes containing both protein antigens and (ribo)-nucleic acid(s), such as the spliceosome or Ro/La RNPs. In this article we focus on their B-cell antigenic determinants (epitopes). We first provide a brief overview of the types of B-cell epitope that have been identified. They include primary, secondary, tertiary and quarternary structured epitopes, as well as cryptotopes, neoepitopes and mimotopes. New insights into the pathogenetic role of epitopes in systemic autoimmunity are also examined. In this regard, using the defined structures of the B-cell antigenic epitopes, complementary epitopes can be designed according to the ‘molecular recognition’ theory. The complementary epitopes can be used as probes to study pathogenetic and immunoregulatory aspects of the anti-idiotypic response. The origin of humoral autoimmunity and the spreading of the epitopes during the evolution of the autoimmune response are also discussed. Finally, the ability of post-translational modifications to induce autoreactive immune attack via the generation of neoepitopes is presented.
Keywords
Autoimmunity, rheumatic diseases, B-cell epitopes, La/SSB, Ro/SSA
Disclosure: The authors have no conflicts of interest to declare.
Received: 29 July 2009 Accepted: 16 August 2009
Correspondence: Athanasios G Tzioufas, Department of Pathophysiology, School of Medicine, 75, M Asias St, 11527, Athens, Greece. E: agtzi@med.uoa.gr
Historically, studies of disease mechanisms in systemic autoimmunity have focused on characterisation of autoantibodies and identification of their antigenic targets. The understanding of fine autoantibody specificities in systemic autoimmune rheumatic diseases is important in both the basic and clinical settings. In fact, many autoantibodies to intracellular autoantigens are essential for the evaluation of patients with systemic rheumatic diseases: they are included in the diagnostic or classification criteria of certain systemic autoimmune disorders;1,2 some are associated with disease activity indices, particularly in systemic lupus erythematosus (SLE);3 and some might be correlated with specific clinical manifestations observed in the spectrum of a given systemic disease (i.e. anti-Ro/SSA antibodies with skin involvement in subacute cutaneous lupus erythematosus [SCLE]). 4 In basic research focusing on autoimmune diseases, the most exciting question remains unaddressed: why are these particular autoantigens, among the many molecules expressed in the organism, selected as targets of the immune system? The answer to this question is certainly a significant step towards our understanding of the origin of autoimmunity. Over the past few years, different laboratories have tried to define the fine specificity of autoantibodies to intracellular antigens by identifying those structures within the antigen moiety recognised most frequently by autoantibodies (antigenic determinants or B-cell epitopes). The identification of Bcell epitopes may provide useful information on putative mechanisms regarding the generation of autoantibodies, including molecular mimicry (molecular similarity that leads to cross-reactivity between antigens from a foreign agent and self-proteins) and epitope spreading (expansion of an autoantibody’s target from a single determinant to a number of distinct and non-cross-reactive epitopes on a given autoantigen). 5 In addition, characterisation of epitopes with high sensitivity and specificity may facilitate the development of immunoassays based on synthetic peptides that eventually can be used as substrates for the detection of autoantibodies. Finally, the association of a specific epitope with the clinical picture or certain clinical findings may be proved valuable for potential therapeutic applications, including the generation of peptide-based vaccines.
Classification and Characteristics of B-cell Epitopes of Autoantigens
B-cell epitopes are diverse in structure and immune reactivity and can be classified accordingly. On the basis of epitope nature, they can be classified as linear or continuous, consisting of sequential amino acids in the primary structure of the protein, and conformational or discontinuous epitopes, formed by distant regions in the protein sequence coming together in its secondary, tertiary or quarternary structure (in the case of ribonucleoprotein complexes). Additional types include cryptic epitopes (cryptotopes). These are usually linear epitopes hidden in the native structure of the autoantigen. They become accessible to antibody binding after disruption of the 3D structure (e.g. by denaturation, proteolytic degradation or chemical modification of the autoantigen). Modified epitopes (neoepitopes) incorporate post-translationally modified amino acids such as phosphorylated serine, threonine or tyrosine, acetylated lysine, deamidated glutamine, glycosylated asparagine, serine or threonine and citrullinated arginine in their structure. Such modified amino acids have been reported in a variety of human nuclear proteins, including the Sm antigens D1 and D3, 6 fibrillarin7 and nucleolin.8
B-cell Epitopes of Autoantigens as Tools to Study the Autoimmune Response
Complementary Epitopes and Anti-idiotypic Antibodies
The idiotypic network theory was proposed by the 1984 Nobel laureate Niels Jerne.9 He hypothesised that antibodies can act as antigens and elicit antiantibodies (called anti-idiotypic antibodies). If anti-idiotypic antibodies target the antigen-binding sites of the idiotypic antibodies, they can either compete with the antigen for the same binding site (Ab2 anti-idiotypic antibodies according to Jerne’s classification) or elicit anti-idiotypic antibodies with similar antigenic specificity to the idiotypic antibodies.10 Thus, anti-idiotypic antibodies can either neutralise idiotypic antibodies or elicit the generation of antibodies with the original antigenic specificity. In this regard, after an antigenic stimulus, an anti-idiotypic network is established regulating the production of antibodies directed against the antigen that initiated the immune response.
