Characterization and modulation of autoantigen-specific T cells in systemic lupus erythematosus by the pathogenetically significant SmD183-119 peptide

A characteristic feature of systemic lupus erythematosus is the presence of autoantibodies against nuclear antigens. Anti-dsDNA antibodies can be detected in the majority of patients, and there is an association between antibody titers and disease activity. We recently identified an epitope at the C-terminus of the SmD1 protein (peptide aa 83-119) against which 70% of all SLE patients have antibodies. Immunization with the SmD183-119 peptide in (NZB x NZW)F1 mice (BWF1), an animal model for SLE, not only led to disease acceleration but also to increased formation of anti-dsDNA antibodies. T cells reacting against SmD183-119 were detected in untreated BWF1 mice and in SLE patients, but not in healthy individuals, where T cell reactivity is likely suppressed by tolerance mechanisms. The proposed project aims to characterize SmD183-119-specific T cells in animal models and analyze their pathogenetic significance.
The hypothesis that the SmD183-119 peptide provides T cell support for the B cell response against dsDNA will be tested. By activating SmD183-119-specific T cells, an autoimmune response will be induced in an animal model, and the response of the B and T cells will be analyzed. Then, attempts will be made to induce specific tolerance in the activated, SmD183-119-specific T cells or to alter their response profile. The impact of this modulation on disease progression will be investigated.