T CELL ANTIGEN RECEPTOR GENES IN AUTOIMMUNITY

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The pathogenesis and molecular basis of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis remain unknown. These diseases are believed to be caused by immunologic disturbances related to defects in tolerance induction or immunoregulation, both profoundly affected by T cells. The T cell-dependence of both systemic and organ-specific autoimmunity has been demonstrated conclusively in many experimental systems and an important, perhaps pivotal, role for specific autoreactive T cell clonotypes in initiating the disease process is highly suspected. Mouse autoimmune systems have provided excellent models to study the role of T cell antigen receptor (TCAR) genes in autoimmunity. In this study, we will attempt to further define the role of TCAR genes in autoimmunity by assessing possible abnormalities in germline TCAR gene repertoire and TCAR gene expression at prediseased and diseased stages of mice with spontaneous lupus/arthritis syndromes. A collection of TCAR cDNA clones containing all, or nearly all, the murine alpha, beta, gamma variable (V) region sequences will be derived and used initially for definitive analysis of the genomic composition and polymorphisms of these genes in auto-immune-prone mice that correlate with disease. Allelic variations in germline-encoded TCAR genes could affect the ability of a given strain's TCAR repertoire to respond to certain antigens, and also affect its tendency to product autoreactive, potentially pathogenic, T cell clonotypes. Analysis of the thymically-selected and expressed TCAR gene repertoires in lymphoid organs of autoimmune mice will also be, initially at the mRNA level, to identify V gene usage patterns characteristic of autoimmune T cell populations, including clonal expansions or deletions, and possible expression of unique or mutated TCAR genes. Once abnormal expression patterns are identified, anti- "variotypic" (V region-specific) monoclonal antibodies will be elicited and used to more precisely define, at the single-cell level, aberrant clonotypes in lymphoid organs and lymphoid cell infiltrates of afflicted tissues of autoimmune mice. Anti- "variotypic" antibodies will also be assessed for their in vitro and in vivo effects on autoimmune responses and disease. These studies will provide a better understanding of TCAR repertoire "shaping" during thymic selection and its possible role in the development of autoreactive T cell clones. Identification of aberrancies in this central event is expected to have a significant impact on our ability to molecularly define autoimmune diseases and to devise specific and accurate means for their management.