This application is designed to test the """"""""receptor presentation"""""""" hypothesis as a mechanism for recruiting autoreactive B lymphocytes in systemic lupus erythematosus (SLE). There is a growing body of evidence, even from studies of Ig transgenic animal models, that spontaneous recruitment of autoreactive B cells in SLE is a rare clonal event. Novel data from this laboratory have associated recruitment with the acquisition of somatic mutations that produce class II MHC-restricted epitopes in Ig V regions. This finding is reinforced by evidence from others, indicating that peptides from autoreactive V regions are immunogenic and may influence disease in autoimmune-prone mice. Accordingly, we propose that autoreactive B cells in SLE are recruited by T helper cells that are specific for peptide epitopes, derived from somatically-altered segments of the B cell receptor that are self-presented by class II MHC on the B cell surface. To test the receptor presentation hypothesis, we will identify and determine the functional significance of somatic mutations that are shared by members of large autoreactive hybridoma lineages. A specialized mouse will be generated to permit identification and evaluation of all somatic mutations in autoreactive clones, and thus provide a firm test of the hypothesis and plausible alternatives. The premise that T cells from autoimmune-prone mice attain a state of tolerance to germline-encoded antibody V region peptides will be examined. And we will generate a novel transgenic animal in which a reproducible, clonally defined autoantibody response can occur, so that B cell recruitment can be systematically studied and experimentally manipulated, with all of the power historically applied to studies of anti-hapten immune responses. The information obtained from, and model systems generated by, this work will significantly advance our capabilities and comprehension of elusive events that initiate B cell clonal expansion in SLE.
