MURINE MODELS OF GENERALIZED AUTOIMMUNITY

Scripps Research Institute, La Jolla CA

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Abstract

Systemic lupus erythematosus is a complex, largely genetically-determined, disease with T and B cell tolerance defects leading to autoantibody production against a wide array of self-molecules. Normal T and B cell tolerance occurs centrally or peripherally either as clonal deletion or anergy. Clonal deletions are mediated by apoptosis, a process controlled by an intricate web of promoting and inhibition genes, while the molecular events underyling anergy are unknown. Whereas immature lymphocytes rapidly undergo apoptosis in response to receptor-mediated signals, death of mature cells requires entry into cell cycle, a process also controlled by multiple promoting and inhibiting genes. The relevance of defective activation-induced apoptosis in systemic autoimmunity has been highlighted by the discovery of mutations in the FAS/FASL system in mice with lymphoaccumulation/lupus syndromes. Based on the documented importance of these processes in the induction of tolerance, the central hypothesis in this proposal is that the lupus-associated tolerance defects must be reflected directly or indirectly in the cell-cycle and apoptosis programs, and that detailed analysis of these systems will be instrumental in understanding the etiology of this disorder. This hypothesis will be addressed in the first specific aim by examining activation-induced cell cycle and apoptosis of T and B cells from unmanipulated lupus mice. Expresison levels of the multiple cell cycle-and apoptosis-controlling genes will be measured and correlated with functional and clinical assessments. Emphasis will be given to validating the hypothesis that accumulation of apoptosis-resistant memory T cells in lupus mice is caused by cell cycle arrest. Associated with increased levels of cyclin kinase inhibitors. In the second specific aim, lg transgenic normal and lupus background mice will be used to define mechanisms of B cell tolerance as reflected in cell cycle and apoptosis genes, and to test the hypothesis that lupus mice differ from normals in B cell responses to antigen and memory B cell generation. In the third specific aim, T cell tolerance will be similarly characterized in T cell receptor transgenic normal and lupus mice under conditions leading to activation, anery or deletion. Additional studies using reciprocal adoptive transfers will test the influence of environment on generation and survival of membory T cells.