Objective Bruton’s tyrosine kinase (BTK) transmits crucial survival signals from the B cell receptor (BCR) in B cells. Pharmacological BTK inhibition effectively diminishes disease symptoms in mouse models of autoimmunity and, conversely, transgenic BTK overexpression induces systemic autoimmunity in mice. We investigated 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 peripheral blood B cell subsets and activation and presence of T cell subsets in patients with rheumatoid arthritis (RA; n=30) and primary Sjogren’s Syndrome (pSS; n=26) and matched healthy controls.
Results In circulating B cells BTK protein expression levels correlated with BTK phosphorylation. BTK expression was upregulated upon BCR stimulation in vitro and significantly higher in CD27+ memory B cells than in CD27-IgD+ naive B cells. Importantly, BTK protein and phosphorylated-BTK were significantly increased in B cells from RA patients expressing anti-citrullinated protein antibodies (ACPA+) but not in ACPA- patients. BTK was increased both in naïve and memory B cells and correlated with the frequencies of circulating CCR6+ T helper-17 cells. Likewise, BTK protein was increased in B cells from a major fraction of pSS patients and correlated with B cell activation, serum rheumatoid factor levels and parotid gland T cell infiltration. Interestingly, targeting T cell activation in pSS patients by abatacept (CTLA4-Ig) treatment restored BTK protein expression in B cells to normal levels.
Conclusions These data indicate that human autoimmune disease is characterised by enhanced BTK activity, which is not only linked to autoantibody formation but also to T cell activity.
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