IMMUNOREGULATORY MECHANISMS IN THE RHEUMATIC DISEASES

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Our long term objective has been to elucidate the immunologic mechanisms which are important in the pathogenesis of the autoimmune connective tissue diseases. We have recently made the novel observation that CD8+ lymphocyte subsets from SLE patients paradoxically sustain antibody production. In the next project period, we will determine whether these CD8+ cells found in normal subjects. We will learn whether these cells provide help for B cell activation or are limited to amplifying antibody production by fully differentiated B cells. Using lymphocytes from normal individuals, we will test the hypothesis that up-regulatory effects on antibody production by CD8+ cells reflect an intermediate maturation phase of these cells. This will be accomplished by activating individual CD8+ with monoclonal antibodies against cell surface receptors and determining the conditions which enable them to enhance or suppress antibody production. Signal transduction pathways involved in the generation of regulatory activities will be documented. We will study mobilization of intracellular free calcium and ligand specific activation of protein kinase gained from the study of normal lymphocytes, we will perform comparative studies of CD8+ lymphocytes from SLE patients, family members, discordant twin pairs and normals to determine whether SLE cells are more prone to become amplifiers instead of suppressors. Alternatively, we will determine whether excessive B cell help and impaired suppressor activity result from a deficiency of signals from other cells which are required for the terminal differentiation of CD8+ cells. Elucidation of the specific signals which induce suppression or enhancement and the biochemical mechanisms leading to their regulatory effects in SLE will be most useful in our understanding of the pathogenesis of other chronic inflammatory diseases.