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.
The immune system provides defense against infections and cancer. B lymphocytes are part of the immune system. One of their primary functions is to produce antibodies to help in this fight. However, nearly one in 12 people have B cells that mistake healthy tissue for a dangerous invader. This mistake leads to dozens of autoimmune diseases that affect 23 million Americans, including our Veterans. Rheumatoid arthritis (RA) is one of the most common of these autoimmune diseases, with a disproportionate impact on young and middle-aged women. This demographic represents a group of Veterans that has grown rapidly in recent decades, as more opportunities have opened for women in the Armed Forces. This proposal focuses on the effects of a new class of drugs that fight autoreactive B cells, and that will have increasing importance in treating our Veterans with RA and other autoimmune diseases in the near future.
| Nyhoff, Lindsay E; Clark, Emily S; Barron, Bridgette L et al. (2018) Bruton's Tyrosine Kinase Is Not Essential for B Cell Survival beyond Early Developmental Stages. J Immunol 200:2352-2361 |
