Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex–Mediated Inflammatory Arthritis

Abstract

Objective Bruton’s Tyrosine Kinase (BTK) is a B cell signaling protein that also contributes to innate immunity. BTK-inhibitors prevent autoimmune arthritis, but have off-target effects, and the mechanisms of protection remain unknown. These studies used genetic deletion to investigate the role of BTK in adaptive and innate immune responses that drive inflammatory arthritis. Methods Btk-deficient K/BxN mice were generated to study the role of BTK in a spontaneous model that requires both adaptive and innate immunity. The K/BxN serum transfer model was used to bypass the adaptive system and elucidate the role of BTK in innate immune contributions to arthritis. Results Btk-deficiency conferred disease protection to K/BxN mice, confirming BTK-inhibitor outcomes. B lymphocytes were profoundly reduced, more than in other Btk-deficient models. Subset analysis revealed loss at all developmental stages. Germinal center B cells were also decreased, with downstream effects on T follicular helper numbers, and greatly reduced autoantibodies. In contrast, total IgG was only mildly decreased. Strikingly, and in contrast to small molecule inhibitors, Btk-deficiency had no effect on the serum transfer model of arthritis. Conclusions BTK contributes to autoimmune arthritis primarily via its role in B cell signaling, not innate immune components.

Tyrosine kinase signaling pathways in neutrophils

“…132 However, similar to integrin and Fc-receptor signaling, p190RhoGAP was not required for autoantibody-induced arthritis. 23 Interestingly, Btk-deficient mice also showed normal arthritis development in the K/B×N serum-transfer model, 133 indicating either that Tec-family kinases are not involved in this process or that another Tec-family member is able to compensate for the lack of Btk in experimental mice.…”

Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies

“…Infiltrating CD8+ T cells can be seen on joint cytology (87). Underlying mechanisms of T cell-driven autoimmunity (90) and/or innate immune hyperactivation (91, 92) have been proposed. In these cases, IVIG alone can be insufficient management (87, 90), progression despite methotrexate has been described (87), nonsteroidal anti-inflammatories (NSAIDs) may provide some benefit (89, 90), and there is no systematic guidance for the use of T cell or innate immune targeted strategies to date.…”

The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy

“…Our lab recently used the K/BxN spontaneous and serum transfer models to further investigate the role of Btk in arthritis, and discovered that its primary contribution is in the B cell compartment, especially germinal center development and function. Interestingly, autoantibodies were severely reduced while total IgG remained at near normal levels in Btk-deficient K/BxN mice, and spontaneous autoimmune arthritis was strikingly reduced (87). However, Btk-deficient recipients of K/BxN serum transfer developed arthritis at the same rate as Btk-sufficient littermates, indicating that innate contributions to arthritis are not affected by loss of Btk.…”