CLASS I MOLECULES AND AUTOIMMUNITY

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The overall goal of these studies is to understand the role of class I proteins in autoimmune diseases with a significant B cell involvement. We have found that mice lacking class I molecules by virtue of a deficiency in the class I light chain, beta2 microglobulin (beta2M), show remarkable and unexpected changes in normal and pathological processes many of which are only apparent in the context of mouse strain backgrounds. Among the most striking are aberrations in humorally- mediated diseases, such as systemic lupus erythematosus (SLE). Thus, a deficiency in beta2M prevents the development of the SLE-like syndromes that normally occur in MRL-Fas/+, MRL-Fas/1pr, and BXSB mice. We hypothesize that the class I-like protein, FcRn, acting as the Brambell protection receptor (FcRp), is responsible for all of these effects. To address this hypothesis, we will determine whether a deficiency in FcRn elicits the same phenotype on antibody responses and SLE development as does a deficiency in beta2M, and conversely, whether transgenic over- expression of FcRn exaggerates these processes. If this hypothesis proves correct, FcRn will emerge as a molecule of fundamental importance in humoral immune and autoimmune processes, with novel and intriguing possibilities for clinical intervention. Contrary to other SLE- predisposed strains, BXSB mice carrying the Y-chromosome linked Autoimmune Accelerator locus, Yalpha/alpha, and lacking beta2M develop a premature and much more aggressive form of SLE compared with beta2M- intact controls. Similarly, SJL mice lacking beta2M develop a much more aggressive form of their unusual B cell hyperproliferative disease. We hypothesize that the absence of a potent class I-dependent mechanism mediated by T cells and distinct from FcRn is responsible for exacerbating these two diseases. We will address this hypothesis by investigating whether rendering these strains of mice deficient in FcRn, CD8+T cells, NK1+ T cells, or conventional natural killer cells recapitulates the cellular and pathological changes elicited by a deficiency in beta2M. Altogether, the proposed studies should provide key insights into novel pathobiological pathways controlled by class I molecules, one which accelerates and the other which limits B cell- mediated autoimmune diseases. The insights gained have an excellent changes of extrapolation to clinical situations.