Autoantibodies to the U1RNP and Sm proteins are serologic hallmarks of systemic lupus erythematosus (SLE). Indirect evidence suggests that the production of these autoantibodies is T cell dependent and antigen driven. How T cell tolerance to the Sm proteins is abrogated in SLE is unknown. Using a model autoantigen, we have identified T cells in the repertoire of normal mice that react with 'cryptic' self-peptides. These T cells remain quiescent because the peptide for which they are specific is not normally produced or presented in sufficient numbers by antigen presenting cells to activate T cells. In this proposal, we will investigate the presence of cryptic peptides within the Sm D protein able to elicit autoreactive T cell responses in normal and autoimmune (MRL) mice. T cell responses to Sm D peptides that arise in spontaneous murine SLE will be compared to those that result after immunization with Sm D peptides. The ability of Sm D specific cells to augment spontaneous autoimmunity (as determined by the time-course of development of autoantibodies) will be determined. As murine and human Sm D proteins share identical amino acid sequences, T cell responses of SLE patients with Sm D antibodies will be examined in proliferation assays using Sm D peptides. These studies will examine the potential role of cryptic self-peptides in the induction of lupus-like autoimmunity. We have also demonstrated that B lymphocytes elicited with foreign molecular mimics can bind, process and present self-peptide in the priming of autoimmune T cells. We now postulate that self antigen- specific B cells elicited by cryptic peptides are critical APCs for the priming of autoimmune T cells and the subsequent expansion of the autoimmune response. A striking feature of SLE is that autoantibodies to self proteins frequently target multiple proteins present on the same intracellular particle, suggesting that the particle itself drives the expansion of the immune response. The role of B cell subsets (including autoantigen-specific B cells) in initial activation of naive T cells will be determined in adoptive transfer experiments using mice genetically deficient in B lymphocytes ('B-less' mice) and in mice transgenic for rheumatoid factor specific B lymphocytes. In addition, the role of Sm D-specific B cells in the subsequent expansion of the immune response to other proteins of the SmRNPs will be examined. Collectively, these studies will provide a model for the induction of lupus-like autoimmunity.
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