Mechanisms of Continued Tolerance Breakdown in Autoimmunity

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DESCRIPTION (provided by applicant): In chronic inflammation, lymphocytes are not restricted to lymphoid tissues but often infiltrate and accumulate in affected tissues. These lymphocytic infiltrates present in various affected nonlymphoid tissues can form tertiary lymphoid structures by a process called lymphoid neogenesis or ectopic lymphoid organogenesis. These tertiary lymphoid structures are found in many autoimmune diseases including rheumatoid arthritis, Hashimoto's thyroiditis, Sj"gren's syndrome, and Myasthenia gravis. In addition, in chronic infections such as Helicobacter pylori gastritis, hepatitis C, and Borrelia burgdorferi caused Lyme disease, ectopic lymphoid structures can also be frequently found in affected tissues. It has been suggested that the process of lymphoid neogenesis from non-organized infiltrates to GC reaction in autoimmune diseases is associated with increased disease severity and accelerated breakdown in self-tolerance. We hypothesize that lymphocytes in ectopic lymphoid microstructures are reactive or cross-reactive with auto-antigens. The local environment of these specialized tertiary lymphoid structures may trap and enrich antigens that are not initially involved in the disease process and provide an infrastructure to support responses/against self-antigens. Thus, these outposts of lymphoid structures at the inflammatory sites not only play an important role in the loss of self-tolerance, but also are critical in disease progression. We will also test the hypothesis that, due to the unique property of local microenvironment, lymphocytes in ectopic lymphoid structures in inflamed tissues may alter their sensitivity to apoptosis induction and escape the censorship of self-reactive lymphocytes. Therefore, we propose the following specific aims: Aim 1. To evaluate the properties of apoptosis induction in lymphocyte infiltrates in local inflamed tissues. Aim 2. To determine if the local autoreactive response is maintained by reactivity to the initiating antigen. Aim 3. To define the antigen reactivity and ability to transfer disease of hybridomas generated from infiltrating B cells.