This proposal will investigate the role of soluble B cell-directed lymphokines in the polyclonal Ig production which is characteristic of human and murine autoimmune disease. These studies will be carried out using mice with genetically determined autoimmune disorders. One model for such a lymphokine is the molecule called BMF (for B cell Maturation Factor). BMF is released from T cell - macrophage immune reactions, and has the defining activity of inducing, in normal resting B lymphocytes and certain B cell tumor lines, all of the biochemical changes involved in going from resting B cells to Ig-secreting plasma cells. B cells responding to BMF also rapidly die. Another B cell-directed lymphokine is BRF (for B cell Replication Factor), which maintains the proliferation of already activated B cells. Disorders in BMF or BRF production or responsiveness in vivo could cause a wide variety of immunological problems ranging from autoimmunity to immunodeficiency. Two specific lines of investigation will be followed here, and are (1) to assay the production of BMF, BRF or similar molecules by the cells of normal and genetically autoimmune mice, and (2) to test the B cells of these same animals for their susceptibility to known preparations of BMF or BRF. Production of factors will be tested by examining in vitro culture supernatants from MLC or mitogen-stimulated cells for their effects on normal B cells and two BMF-responsive B cell tumor lines. Molecules active in these test systems will be compared to standard BMF and BRF. Sensitivity of mutant mouse B cells to BMF and BRF will be tested by careful dose response titrations, using monoclonal T cell-derived BMF and BRF, of cell surface factor receptors, intermediate biochemical changes (both pre- and post-translational) leading to Ig secretion, active Ig secretion itself, cell proliferation, and death. Different B cell populations to be tested will be isolated on the bases of physical characteristics, age of the animal used, and various surface antigen phenotypes. Mutant mice with the single gene defects on several genetic backgrounds, and combined with the nude gene, will be utilized. Overall, these studies could elucidate the mechanisms responsible for one or more types of autoimmune disease, give some indication as to future avenues for research on therapeutic means, and provide fundamental immunological knowledge.
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