B Lymphocytes in Autoimmune Disease

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 DESCRIPTION (provided by applicant): Rheumatoid arthritis results from a complex cascade of events that breaks immune tolerance and culminates in the destruction of synovial tissue. B lymphocytes (B cells) play a critical role n disease development, producing the autoantibodies that trigger this disease. B cell contributions to arthritis depend upon multiple factors, beginning with loss of B cell tolerance to self-antigen, which occurs at immature stages of B cell development in the bone marrow, prior to T cell interactions. This tolerance is mediated by B cell signaling responses to antigen-binding via the B cell receptor (BCR). Bruton's tyrosine kinase (BTK) is a central component of the BCR- triggered signaling pathway. This protein is not present in T cells, so offers the opportunity to study B cell contributions to lost tolerance in this disease. Understanding B cell signaling components that support arthritis development will advance the field toward specific targeting of pathogenic B cells. We used btk-deficiency to test the role of BTK in the K/BxN model of spontaneous autoimmune arthritis, and found significant disease protection, accompanied by loss of autoantibodies, with relative sparing of total IgG. These findings complement our previous work showing that autoreactive B cells are more sensitive to loss of BTK than normal cells are. Therefore, unlike global B cell immunosuppression offered by general B cell-targeting drugs such as rituximab, these findings suggest that it is possible to target B cell signaling in a way that would preferentially eliminate autoreactive cells without inducing generalized B cell immunodeficiency. The specific hypothesis underlying this proposal is that autoreactive B cells are more dependent on BTK-mediated signal amplification than normal B cells. To understand the mechanisms of action of BTK in promoting autoimmune arthritis, we will use our newly developed mouse models that include 1) an inducible model that allows timed deletion of BTK, to simulate pharmacologic inhibition without the confounding effect of off-target binding, 2) conditional, B cell-specific and dendritic cell-specific BTK knockout models to test cell-specific contributions of BTK, and 3) btk-deficent models as controls for testing of small molecule BTK inhibitors to determine how drug specificity and dosing compare with genetic deficiency, to enhance future drug design. This project has direct clinical importance in understanding how BCR-signaling supports the function of autoreactive B cells in autoimmune arthritis, as a necessary step in developing therapeutic interventions.