B Lymphocytes in Autoimmune Disease

Rheumatoid arthritis (RA) results from a complex cascade of events that breaks immune tolerance and culminates in the destruction of synovial tissue. Both genetic and environmental factors contribute to disease. B lymphocytes (B cells) play a critical role, producing the autoantibodies that trigger arthritis. The Kendall lab works toward understanding B cells that support arthritis development. We originally used mice deficient in the B cell signaling protein Bruton’s tyrosine kinase (BTK) to test its role in the K/BxN model of spontaneous autoimmune arthritis. The studies indicated significant disease protection, accompanied by loss of autoantibodies, with relative sparing of total IgG. In the course of this work, we made the new discovery that BTK also affects the gut microbiome, commensal organisms that are thought to play an important role in the development of autoimmune diseases, including RA. We found that specialized immune organs in the gut, called Peyer’s patches, are very small, and that they make low levels of IgA antibody that does not bind gut bacteria as well as it should. Further, there is dysregulation of the microbiome that may have a protective effect against autoimmune arthritis. The hypothesis underlying this proposal is that BTK-mediated signaling supports mucosal immunity and regulates microbes that influence autoimmunity, to be tested in Aims which: 1) define the IgA repertoire in Btk-deficient versus –sufficient K/BxN mice, including features such as selection, clonality and evidence of somatic hypermutation, 2) determine the cell-specific role of BTK in regulating the microbiome, differentiating between B cell and myeloid cell functions, and 3) determine whether BTK expression and function in myeloid and B cells differ in RA patients and controls, and whether IgA binding of commensal bacteria are altered. This project has direct clinical importance in understanding how aberrant B cells in autoimmune patients may cause microbiome shifts that modulate disease.