Michael Scaglione

Michael Scaglione

PI: Peggy Kendall, MD, Department of Medicine

Bruton’s Tyrosine Kinase (BTK) Regulation of Autoantibody Production in Spontaneous Arthritis

Rheumatoid arthritis (RA) is a chronic disorder caused when the immune system damages the body’s joints, and can be driven by autoreactive antibodies. Autoreactive B cells produce this damaging autoantibody when they are activated via the B-cell receptor (BCR) and differentiate into plasma cells. Therefore, BCR signaling proteins are an exciting target for treating autoimmune arthritis by disrupting autoreactive B-cell activation and reducing autoantibody production. Our lab has found that when a BCR signaling protein known as Bruton’s tyrosine kinase (BTK) is lost, autoreactive B cells fail to fully develop while beneficial types of B cells develop normally. BTK inhibitors have already had some success in treating autoimmune arthritis, but it is unclear which stages of B cell activation and differentiation are impacted. Understanding the role of BTK in the generation and function of autoreactive B cells is a critical step in the development of precise RA treatments that minimize suppression of functional immune cells. We hypothesize that BTK loss before autoreactive B cells are activated will reduce autoantibody production and protect against arthritis while BTK loss after autoreactive plasma cells differentiate will not reduce antibody production. We assessed the impact of BTK loss on spontaneous autoantibody production using a mouse model of autoimmune arthritis and investigated the role of BTK in B cell development at specific stages of an immune response. Revealing when autoreactive B cells are preferentially dependent on BTK for development will provide insight into how to create more precise therapies for treating autoimmune arthritis.