The investigator's long term goal is to define the fundamental mechanism of the prototypic systemic autoimmune disease, Systemic Lupus Erythematosus (SLE). Theetiological mechanism of SLE remains elusive because the primary antigen that triggers the pathogenic autoimmune response in this disease is unknown. In spite of this obstacle, the investigators have cloned the select T-helper cells that induce the production of the pathogenic variety of anti-DNA autoanitbodies in SLE. Analysis of the structure and specificities of the receptors expressed by these particular T-cells and the pathogenic autoantibody producing B-cells that are representative of the disease, as well as studies of their regulation may lead to an understanding of the etiologic mechanism of lupus in humans. The specific goals of this application involve: (1) PATHOGENIC T-CELLS: (a) Determine the V region sequences of the receptors (TcRs) expressed by the pathogenic anti-DNA autoantibody-inducing T-cells from lupus patients to detect any clonal restriction/recurrent usage or any special featuure in their junctional region (CDR3) sequences that would provide clues for their antigenic specificities. (b) Determine the specificities of these lupus T-helper cells that preferentially interact with pathogenic autoantibody- producing B-cells, using synthetic peptides and autologous B-cell clones. (c) Determine the in vivo pathogenic relevance of theseautoimmune T-helper cell clones using immunodeficient SCID mice. (2) PATHOGENIC B-CELLS: (a) Clone human lupus B-cells that produce pathogenic anti-DNA autoantibodies of IgG class and cationic charge. Determine the in vivo pathogenic relevance of such autoantibodies and their representation in human lupus nephritis. (b) Define the structural basis of cationic charge, antigenic specificities, idiotypic cross-reactions and clonalrelationships among the pathogenic anti- DNA autoantibodies. (c) Define the intrinsic B-cell defect in SLE that leads to an excessive production of heat shock proteins. These studies will help us todesign specific therapies that would intervene in the basic steps leading to systemic autoimmune disease.
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