It is proposed to investigate the role of the B cell in spontaneous systemic autoimmunity in inbred mice by utilizing congenic mouse strains which are homozygous at the lpr locus. These animals develop diffuse lymphadenopathy and a variety of autoantibodies. Extensive previous work has documented marked T-cell abnormalities in these mice. Their B cells have been less carefully investigated: specifically, the role of the lpr gene in the B cells and the role of the Ly-1+ B-cell subset are unknown. The present proposal will address the function of the B cell in lpr-induced autoimmunity in three specific ways: 1) It will determine the role of lpr gene expression in B cells for autoantibody formation in lpr mice. 2) It will explore the nature of T-B collaboration required for autoantibody formation in lpr mice. 3) It will determine the role of Ly-1+ B cells in autoantibody production in lpr mice. Experiments in all three areas will rely on the generation of double-chimaeric mice in which the donor origin of lymphocytes will be determined by immunoglobulin allotype or surface phenotype markers. It will thus be possible to establish whether normal B cells can be driven into autoantibody production in an lpr environment; whether collaboration for autoantibody production in lpr mice is H-2 restricted; and what relative roles the Ly-1+ and conventional B-cell subsets play in this disease. The latter issue will also be addressed by sorting of autoantibody-forming cells. These studies will provide further understanding of how B cells are induced to form autoantibodies in an important murine model of SLE and should help to focus future research toward the essential immunoregulatory abnormalities in this disease.
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