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. We undertook these studies using 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 outcomes of BTK inhibitors. B lymphocytes were profoundly reduced, more than in other models of BTK deficiency. Subset analysis revealed loss of B cells at all developmental stages. Germinal center B cells were also decreased, with downstream effects on numbers of follicular helper T cells 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 in the serum-transfer model of arthritis.
Conclusion: BTK contributes to autoimmune arthritis primarily through its role in B cell signaling and not through innate immune components.
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http://dx.doi.org/10.1002/art.39657 | DOI Listing |
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Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States.
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Department of Rheumatism and Immunology, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), No.4, Renmin Road, Shibei District, Qingdao, 266033, China.
Rheumatoid arthritis (RA) is an autoimmune condition that predominantly affects synovial joints, manifesting with joint swelling, pain, and stiffness. In advanced stages, unchecked inflammation can inflict damage on bone and cartilage, resulting in disabilities and deformities of the joints. Additionally, systemic and extra-articular complications may arise due to the consequences of uncontrolled inflammation.
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