Systematic autoimmune disease are the product of a complex interaction of lymphocytes, soluble macromolecules, and self tissues leading to the pathology of disease. Autoimmune responses often target multiple determinants within an autoantigen in a phenomenon known as epitope spreading. For example, in systemic lupus erythematosus (SLE), autoantibodies are direct at a number of determinants on small nuclear ribonucleoproteins (snRNPs) and on nucleosomes. In the murine model of human multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), disease that is induced with a single self peptide of myelin basic protein soon diversities to multiple sites on the protein during the course of disease. The concept of epitope spreading is a fundamentally important mechanism of the immune system that enhances the ability to clear vital or bacterial infection or to resist tumor challenges. For example, the most efficient means by which to clear an infectious agent is to direct an immune attack against as they sites on the target as possible. One objective of this proposal is to examine the role of B lymphocytes, as autoantigen presenting cells, in the spreading of autoimmunity. Are B cells specific for a short self peptides able to present diverse autoantigenic determinants in eliciting a diverse T cell autoimmune response? The types of self antigens presented in the context of MHC molecules are critical in many aspects of immune responses, from positive and negative selection in the thymus to the activation of autoimmune T cells in the periphery. We have recently identified a novel post translational protein modification that confers immunogenicity to otherwise immunologically inert self peptides. The second objective of this proposal will examine the expression of these post translational modifications in lymphocytes and the role od modified peptides in the autoimmunity of SLE and EAE. Overall, our studies will address mechanisms important in the induction and perpetuation of autoimmune disease. A more thorough understanding of the earlier events in the genesis of autoimmune disease may help identify important elements to exploit for the immunologic intervention of these diseases.

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Yale University
New Haven
United States
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