Bruton's typrosine kinase and autoreactive B lymphocytes: Roles in development, survival, and disease
Nyhoff, Lindsay Elizabeth
Bruton’s tyrosine kinase (BTK) is a tec-family kinase present in B lymphocytes and innate immune cells. BTK is an important regulator of B cell autoreactivity. Innate-like autoreactive-prone B1, anergic An1, and transgenic anti-insulin B cells all rely upon BTK. Autoreactive B cells drive Type 1 diabetes (T1D) development and are preferentially targeted by disruption of BTK. We hypothesized that the same strategy could be extended to systemic autoimmunity, typified by rheumatoid arthritis (RA). We found that genetic deletion of BTK in a model of spontaneous arthritis results in a severe block in B cell development, subsequent reduction of germinal center formation and reduced autoantibody production, culminating in disease protection. In contrast, the development of immune-complex mediated arthritis, which relies upon the innate immune system, was not alleviated by genetic deletion of BTK. We have well established that BTK-deficiency results in loss of autoreactive B cells; however, whether these cells require BTK for maturation only, or also for their survival, remained unknown. Our group has developed the first loxP-flanked Btk mouse model, paired with an inducible Cre-ERT2 for kinetic studies of BTK function. We achieve 90% knockdown within five days after tamoxifen-induced Cre activation. We find that the B cell phenotype typical of murine Btk-deficiency emerges quickly, including a developmental block at T2, and decreased follicular B cells. Surprisingly, B1 B cells are not reduced, in contrast to their near-absence in Btk-deficient models. BTK-negative B1 cells remain able to produce natural IgM, but cannot respond to T-independent immunization. Furthermore, transgenic anergic anti-insulin B cells, which are reduced 95% by conventional Btk-deficiency, also maintain large mature populations after deletion of Btk protein, and remain able to internalize insulin. These findings suggest that autoimmune-prone B cell populations require BTK-mediated signaling for development, but not for survival or certain functions, and may have implications for the use of BTK-inhibitors currently in clinical trials for treatment of autoimmunity.