Autoantibodies to a variety of self antigens are specific diagnostic markers for many autoimmune diseases, and their pathogenic role is well established in a subset of these disorders. The events underlying autoantibody production nevertheless remain obscure. Studies of B cell self-tolerance and auto immunity have been confounded by the complexity of different self antigens and the enormous variability in the frequency, affinity, and isotype of antigen-specific B cells. To circumvent these problems, a transgenic mouse model will be employed. The development of tolerance or autoimmunity to a single neo-self antigen, hen egg lysozyme, will be studied using transgenic animals that express lysozyme in different forms, levels, and tissues. In parallel, established and new lines of transgenic mice expressing rearranged immunoglobulin genes will provide a source of homogenous antigen specific B cells, expressing lysozyme-binding receptors with a distinct affinity or isotype. Lysozyme-specific helper T cells will be obtained from similar TCR gene transgenic mice.
In AIMS l and 2, these animals will be used to track mechanisms for censoring self-reactive B and T cells in vivo, and define whether autoantibodies to particular classes of autoantigens result from natural limits in B and T cell censoring or by circumstances that allow self-reactive B cells to resist censoring. Transgenic animal models developed in AIMS 1 and 2 will then be used in AIM 3 to determine if additional immunoregulatory mechanisms exist to control self-reactive B and T-cells that escape censoring. Two distinct and relevant scenarios will be studied, where autoreactive B and T-cells escape censoring and can potentially initiate autoimmunity to lysozyme expressed as a cell membrane autoantigen either systemically or localized to the thyroid gland. The role of autoreactive B cells and autoantibody of different isotypes in development of systemic or thyroid pathology will be determined. These studies should provide important insights into the pathogenesis of a range of human autoimmune diseases, such as systemic lupus erythematosus and Grave's disease.
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