The primary roles of MHC molecules, T cell antigen receptors (TCR) and certain lymphoaccumulation-inducing mutations (lpr,gld) in the pathogenesis of murine lupus have been firmly established. This continuation application on murine models of generalized autoimmunity will further address the molecular basis and biologic pathways by which these genes contribute to the pathogenesis of this complex disorder. The origin and mechanism of action of the autoimmunity promoting/inducing lpr and gld double-negative TCR-alpha beta+ cells will be pursued by assessing their thymic education, V-beta TCR gene expression profiles, and ability to stimulate normal helper T cells to produce T and B cell growth/differentiation-promoting lymphokines. H-2 congenic lines of lupus mice will be developed to further define the role of H-2 haplotypes in this disease, particularly of I-E and its reactive V-beta clonotypes. Our experiments to date of V-beta gene expression profiles in lupus mice indicate disease/age-associated expansions for T cell clones expressing certain V-betas, but their role in disease pathogenesis and means of induction need to be determined. Subtractive approaches with experimentally-induced tolerance-related clonal deletions by neonatal injection of self- or foreign-superantigens will be employed to address this issue. Once disease-associated V-beta clonotypes have been identified, attempts to develop new lupus immunotherapies based on the elimination of such clones in adult mice with anti-V-beta-specific antibodies, or their control by active immunization with synthetic V-beta peptide vaccines, will be undertaken, The recently established SCID mouse/human lupus model will also be used to define human lupus-associated V-beta clonotypes and their autoimmune potential.