Immunization with myelin basic protein (MBP) induces experimental allergic encephalomyelitis (EAE), a prototype of CD4+ T-cell mediated autoimmune disease. In rodents, MBP-reactive T-cell clones are specific for a single, dominant determinant on MBP and use a highly restricted number of T-cell receptor genes. Accordingly, EAE has been prevented by various receptor-specific treatments, suggesting similar strategies may be useful for therapy of human autoimmune disease. Here we report that in (SJL x B10.PL)F1 mice, immune dominance of a single determinant, MBP:Ac1-11, is confined to the inductive phase of EAE. In mice with chronic EAE, several additional determinants of MBP in peptides 35-47, 81-100 and 121-140 recall proliferative responses. Most importantly, reactivity to the latter determinants was also detected after induction of EAE with MBP peptide Ac1-11 alone; this demonstrates priming by endogenous MBP determinants. Thus, determinants of MBP that are cryptic after primary immunization can become immunogenic in the course of EAE. Diversification of the autoreactive T-cell repertoire due to 'determinant spreading' has major implications for the pathogenesis of, and the therapeutic approach to, T-cell driven autoimmune disease.

Insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice results from the T-lymphocyte-mediated destruction of the insulin-producing pancreatic beta-cells and serves as a model for human IDDM. Whereas a number of autoantibodies are associated with IDDM, it is unclear when and to what beta-cell antigens pathogenic T cells become activated during the disease process. We report here that a T-helper-1 (Th1) response to glutamate decarboxylase develops in NOD mice at the same time as the onset of insulitis. This response is initially limited to a confined region of glutamate decarboxylase, but later spreads intramolecularly to additional determinants. Subsequently, T-cell reactivity arises to other beta-cell antigens, consistent with intermolecular diversification of the response. Prevention of the spontaneous anti-glutamate decarboxylase response, by tolerization of glutamate decarboxylase-reactive T cells, blocks the development of T-cell autoimmunity to other beta-cell antigens, as well as insulitis and diabetes. Our data suggest that (1) glutamate decarboxylase is a key target antigen in the induction of murine IDDM; (2) autoimmunity to glutamate decarboxylase triggers T-cell responses to other beta-cell antigens, and (3) spontaneous autoimmune disease can be prevented by tolerization to the initiating target antigen.

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In this review, we first consider the inherent structural constraints for binding of a peptide to MHC class II molecules. Such parameters at the site of TCR recognition are dependent upon the efficient generation of the antigenic determinant during natural processing of the whole protein antigen. Strikingly, only a minor fraction of such potential determinants on an antigen are presented in an immunodominant manner, while the remaining peptides are silent (cryptic). Why one determinant is selected while the majority are neglected is still unresolved, but we review the experimental evidence pertaining to this choice. Thus, features of the antigen remote from the actual determinant can either steer processing toward disclosure or revelation of a determinant, or interfere with the binding of peptides to MHC (hinderotopy). The evidence is reviewed for "MHC-guided processing," where the unfolding antigen binds at an early stage to an MHC molecule through its most available and affine agretope and then is trimmed down to final size, while the rest of the molecule, including cryptic determinants, is discarded. Different MHC molecules can compete for determinants at an early stage of processing when the antigen is close to its original length. There are shifts in the hierarchy of display of dominant and cryptic determinants, and these shifts relate to local inflammatory states, to changes in the state or composition of the APC population, and to aspects of exogenous vs endogenous processing. The impact of this differential display of determinants on tolerance and autoimmunity is discussed.

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