Self antigen is the target of most nephritogenic immune responses, yet little is known abut the proximal events that generate, regulate, and induce expression of autoreactive lymphocytes. Effective therapy for severe autoimmune disease thus remains limited to nonspecific and toxic immunosuppression. The goal of the proposed studies is to gain a better understanding of the immunologic mechanisms that normally regulate nephritogenic humoral autoimmunity, as a basis for developing more specific interventions to eliminate or inactivate autoreactive cells and/or reestablish tolerance. These studies emphasize autoantibodies that target renal basement membrane (BM) antigens because BM proteins are the only confirmed renal targets in human autoimmune nephritis, BM is targeted in both systemic and organ-restricted autoimmunity, and regular of immune responses to these complex matrix antigens has been virtually ignored to date. The proposed studies will test the hypothesis that unmutated nephritogenic anti-laminin and anti-DNA B cells similar to those activated in systemic lupus are present but tolerant in the normal host; that their expression can be induced by inherited autoimmune susceptibility and/or environmental challenge; and that nephritogenic anti-alpha3(IV)NC1 collagen B cells persist as nontolerant (""""""""ignorant"""""""") lymphocytes in the periphery of nonautoimmune hosts until activated by specific immunization in a permissive genetic background. The Ig transgenic approach is used for this purpose because it permits enrichment for the autoreactive B cell population of interest while preserving complex immunologic microenvironments in vivo. Six established Ig-tg lines that encode lupus anti-laminin (LamH) or nephritogenic and anti-DNA (238H) Ig will be used to determine the presence, phenotype, functional state and pathogenecity of autoreactive B cells in the nonautoimmune B6 and autoimmune MRL genetic backgrounds. Laminin epitopes recognized by autoantibodies will be determined, using spontaneous Ig recovered from nontolerant mice and Ig rescued from tolerance mice by in vitro or in vivo bcl-2 expression. Finally, B6 mice will be rendered transgenic for an anti-alpha3(IV)NC1 Mab that recognizes Goodpasture's epitope, to determine the tolerance phenotype of B cells specific for a cryptic and organ-restricted BM antigen targeted in severe human nephritis. The autoantibody transgenic model thus provides a well defined experimental system in which to study immunologic mechanisms and etiologic influences and to test novel therapeutic interventions for autoimmune renal disease.
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