The long-term objectives of this proposal are to develop a better understanding of the cellular events leading to the production of pathogenic autoantibodies in Systemic Lupus Erythematous. Ultimately through this understanding a more rational approach to alter these events can be planned. For these purposes the role of an autoreactive T cell clone, termed ARTC-1 and derived from the lupus prone MRL-1pr/1pr mouse, in murine lupus will be examined. This will include analysis of the events involved in activation of ARTC-1 and the factors responsible for ARTC-1 induced B cell proliferation and immunoglobulin production. Particular emphasis will be devoted to the capacity of ARTC-1 to induce B cells to produce immunoglobulin with nephritogenic properties. This work will involve six approaches: 1) Further characterization of the requirements for activation of ARTC-1 using L cell transfectants expressing class II molecules; 2) Analysis of the capacity of ARTC-1 to induce B cell proliferation and immunoglobulin production, using both T cells and membranes isolated from activated T cells; 3) Examination of the lymphokines produced by ARTC-1 by determination of soluble lymphokines ARTC-1 produces and the lymphokine mRNA expressed by ARTC-1 after activation; 4) Characterization of the immunoglobulin products resulting for ARTC-1 induced B cell activation by analysis of the class, subclass, charge and ligand binding properties of Ig products derived from ARTC-1 B cell interaction; 5) Production and characterization of an ARTC-1 hybridoma, and 6) Production and characterization of a monoclonal anti- clonotypic antibody specific for ARTC-1. The result of these studies (1-4) will be compared to those performed with other T cell lines derived form MRL-1pr/1pr mice. Ultimately, the probes derived from the latter studies of (V-VI) will be used to examine the role of cells like ARTC-1 in the pathogenesis of murine lupus in vivo, if these cells are prominent in vivo, strategies using the reagents derived for the proposed studies, will be planned to either delete or alter the function of cells line ARTC-1 in vivo.
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