This project will continue to focus on the cellular and genetic mechanisms leading to autoimmunity in two classes of murine models based on primary single gene mutations. One class of model is represented by the viable motheaten (me ) mutation, and seems to result from the aberrant expansion and lymphokine- mediated autostimulation of a normally minor population of B cells marked by the Ly-1 surface antigen. In the second class of models, which includes the lymphoproliferation (1pr) and generalized lymphoproliferative disease (gld) mutations, B cell hyperactivity appears secondary to T cell hyperplasia. The following two specific aims will be addressed: 1. What cellular interactions, including those with other cells and with soluble molecules such as lymphokines, are involved in the development of autoimmunity? This question will be approached by studying cell and organ chimeras between genetically marked and thus distinguishable normal and autoimmune donors, and by creating mice bearing both a primary autoimmunity-inducing mutation and other genes leading to the loss of specific immunological cells or reactivities. 2. What other genes influence the pattern or severity of autoimmunity caused by the primary autoimmunity-inducing mutations? Mice homozygous for one of the primary autoimmunity genes and congenic for various MHC, Ig, or T cell receptor alleles, or with the primary genes on different genetic backgrounds (via congenic lines) or combinations of backgrounds (via RI strains), will be used to address this issue. The parameters of autoimmunity to be assayed in these mice include: spontaneous antibody secretion (by polyclonal and specific ELISA assays), cell phenotype (by immunofluorescent staining and FACS analysis), lymphokines production (by in vitro cellular assays and analysis of lymphokine mRNA levels), and clinical course and immunopathology). These studies should yield significant basic information on the mechanisms of genetically determined immunological disease, and provide additional animal models for further research.
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