We are studying the cellular and molecular basis of autoimmune diseases with two purposes. First, we want to establish the pathogenic role and antigen-specificity of T cells that cause autoimmune diseases such as multiple sclerosis, myasthenia gravis, insulin-dependent diabetes, among others. Second, we would like to determine the feasibility of specific antigen-of ainduced apoptosis as a means of treating such autoimmune diseases. To these ends, we have made progress in the following areas: 1) we have characterized a transgenic T cell receptor mouse model of myasthenia gravis which has a powerful response to a peptide from the acetylcholine receptor; In this model, we have established that act topic expression of the T-cell receptor chains encoded by the transgene have a toxic effect on B lymphocytes. 2) we are studying sets of apoptosis-related genes for association with autoimmunity to establish genetic determinants of autoimmunity; and 3) we are initiating studies of antigen-specific therapy to prevent the formation of blocking antibodies following factor VIII administration to hemophiliacs. We will also be initiating studies of a new transgenic mouse model for autoimmune thyroiditis. As part of these studies we are also trying to understand the regulation of antigen-induced death by T cell receptor stimulation. These studies should yield important new insights into the pathogenesis and treatment of autoimmune diseases which is a widespread health problem in the U.S. particularly among working women.