A variety of immunologic, virologic, hormonal, and genetic abnormalities have been catalogued in murine strains with with systemic lupus erythematosus (SLE)-like syndromes. However, no common link or molecular basis for such abnormalities has yet been identified. Among the various abnormalities, B cell hyperactivity leading to autoantibody production is the common and cardinal feature of all SLE murine strains, as well as of humans with SLE. Whether this B cell abnormality is primary or secondary to helper or suppresor T cell defects remains controversial and and unclear at the present. A large body of recent work indicates that proliferative and differentiative events in B and T cell development are induced by a cascade of antigen-specific and nonspecific soluble mediators elaborated by activated T cells, macrophages, and perhaps other elements of the immune systems. In order to clarify further the essential immunologic abnormalities that lead to autoimmune disorders and perhaps devise means for their molecular analysis, we propose to: (a) measure the effects of soluble T cell-derived factors with known activities on B cells of SLE and normal control murine strains; (b) assess the in vitro elaboration of soluble mediators by limphoid cells of SLE and control strains that might influence B cell differentiative and muturational processes and, if identified, determine their levels, cellular origin, mode of action, and relationship to the disease state: (c) isolate and biochemically characterize the factos, attempt to produce antibodies against them and subsequently assess the in vitro and in vivo effects of the factors and of respective antibodies; and (d) develop new lines of SLE mice defective in expression of acceptor sites for T cell-derived signals so as to ascertain the in vivo importance of the factors and of the target cell component in disease expression. These studies will clarify the means of B cell activation in systemic autoimmune diseases, provide further understanding of the interplay among lymphokines that participate in cellular and humoral immune responses, and may allow, in the future, molecular analysis and modification of this and related disorders.
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