Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen.
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.
Lehmann
P V
PV
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024.
Forsthuber
T
T
Miller
A
A
Sercarz
E E
EE
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D006168:Guinea Pigs; D007108:Immune Tolerance; D007114:Immunization; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009113:Muramidase / Q000276:immunology; D004676:Myelin Basic Protein / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; D004676:Myelin Basic Protein; D009113:Muramidase