Enhanced Bruton's Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease. Issue 6 (10th May 2017)

• Record Type: Journal Article
• Authors: Corneth, Odilia B. J.; Verstappen, Gwenny M. P.; Paulissen, Sandra M. J.; de Bruijn, Marjolein J. W.; Rip, Jasper; Lukkes, Melanie; van Hamburg, Jan Piet; Lubberts, Erik; Bootsma, Hendrika; Kroese, Frans G. M.; Hendriks, Rudi W.
• Is Part Of: Arthritis & rheumatology. Volume 69:Issue 6(2017)
• Page Start: 1313
• Page End: 1324
• Publication Date: 2017-05-10
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.40059
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : Objective: Bruton's tyrosine kinase (BTK) transmits crucial survival signals from the B cell receptor (BCR) in B cells. Pharmacologic BTK inhibition effectively diminishes disease symptoms in mouse models of autoimmunity; conversely, transgenic BTK overexpression induces systemic autoimmunity in mice. We undertook this study to investigate BTK expression and activity in human B cells in the context of autoimmune disease. Methods: Using intracellular flow cytometry, we quantified BTK expression and phosphorylation in subsets of peripheral blood B cells from 30 patients with rheumatoid arthritis (RA), 26 patients with primary Sjögren's syndrome (SS), and matched healthy controls. Results: In circulating B cells, BTK protein expression levels correlated with BTK phosphorylation. BTK expression was up‐regulated upon BCR stimulation in vitro and was significantly higher in CD27+ memory B cells than in CD27−IgD+ naive B cells. Importantly, BTK protein and phospho‐BTK were significantly increased in B cells from anti–citrullinated protein antibody (ACPA)–positive RA patients but not in B cells from ACPA‐negative RA patients. BTK was increased both in naive B cells and in memory B cells and correlated with frequencies of circulating CCR6+ Th17 cells. Likewise, BTK protein was increased in B cells from a major fraction of patients with primary SS and correlated with serum rheumatoid factor levels and parotid gland T cell infiltration. Interestingly, targeting T cell activation in patients with primary SS using the CTLA‐4Ig fusion protein abatacept restored BTK protein expression in B cells to normal levels. Conclusion: These data indicate that autoimmune disease in humans is characterized by enhanced BTK activity, which is linked not only to autoantibody formation but also to T cell activity.