The functional significance of epitope spreading and its regulation by co‐stimulatory molecules

Abstract

Epitope spreading is a process whereby epitopes distinct from and non-cross-reactive with an inducing epitope become major targets of an ongoing immune response. This phenomenon has been defined in experimental and natural situations as a consequence of acute or persistent infection and secondary to chronic tissue destruction that occurs during progressive autoimmune disease. We have investigated the functional significance of this process in the chronic stages of both autoimmune and virus-induced central nervous system (CNS) demyelinating disease models in the SJL/J mouse. During the relapsing-remitting course of experimental autoimmune encephalomyelitis (R-EAE) induced with defined encephalitogenic myelin peptides, CD4+ T cells specific for endogenous epitopes on both the initiating myelin protein (intramolecular epitope spreading) and distinct myelin proteins (intermolecular epitope spreading) are primed secondary to myelin destruction during acute disease and play a major functional role in mediating disease relapses. Similarly, epitope spreading to endogenous myelin epitopes appears to play a major functional role in the chronic-progressive course of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a virus-induced CD4+ T-cell-mediated immunopathology. In TMEV-IDD, myelin destruction is initiated by virus-specific CD4+ T cells which target virus epitopes persisting in CNS-derived antigen-presenting cells. However, the chronic stage of this progressive disease is associated with the activation of CD4+ T cells specific for multiple myelin epitopes. In both models, the temporal course of T-cell activation occurs in a hierarchical order of epitope dominance, spreading first to the most immunodominant epitope and progressing to lesser immunodominant epitopes. In addition, epitope spreading in R-EAE is regulated predominantly by CD28/B7-1 co-stimulatory interactions, as antagonism of B7-1-mediated co-stimulation using anti-B7-1 F(ab) fragments is an effective ameliorative therapy for ongoing disease. The process of epitope spreading has obvious important implications for the design of antigen-specific therapies for the treatment of autoimmune disease since these therapies will have to identify and target endogenous self epitopes associated with chronic tissue destruction.

Novel p65 Binding Glucocorticoid-induced Leucine Zipper Peptide Suppresses Experimental Autoimmune Encephalomyelitis

“…Peptides and Reagents-GILZ-P 115-137 and a control peptide (control-P) of scrambled residues were synthesized as peptide amides and the PLP 139 -151 (HSLGKWLGHPDKF) and MBP 89 -97 (VHFFKNIVTPRTP) as peptide acids (32). The amino-terminal of GILZ-P, control-P, and MBP 89 -97 were acetylated.…”

Myelin oligodendrocyte glycoprotein peptide-induced experimental allergic encephalomyelitis and T cell responses are unaffected by immunoproteasome deficiency

“…This hypothesis provides an attractive explanation for the phenomenon of "epitope spreading", in which the T cell response changes with time, with a gradual appearance of responses to an ever-widening array of self epitopes. This has been described for CD4 + T cells (Lehmann et al, 1992;Lehmann et al, 1993;Miller et al, 1997;Vanderlugt et al, 1998;Miller et al, 2001), for which it is ascribed to the release of self proteins, and their uptake by specialized antigen presenting cells, where they enter the MHC class II antigen presentation pathway. However, such a mechanism appears unlikely to occur for CD8 + T cells, which generally recognize epitopes which have been synthesized inside the presenting cell.…”

Antigen-Based Immunotherapy Drives the Precocious Development of Autoimmunity

“…Although the initial autoimmune response is limited in its recognition of self-Ags, it subsequently expands to involve other Ags within the target tissue (2,(5)(6)(7)(8)(9)(10)(11)(12)(13). This spreading of T cell autoimmunity often follows a defined chronological pattern during disease progression.…”