02.45 Enhanced bruton’s tyrosine kinase activity in peripheral blood b lymphocytes of autoimmune disease patients

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 naive 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.