TY - JOUR
T1 - Enhanced Bruton's Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease
AU - Corneth, Odilia B.J.
AU - Verstappen, Gwenny M.P.
AU - Paulissen, Sandra M.J.
AU - de Bruijn, Marjolein J.W.
AU - Rip, Jasper
AU - Lukkes, Melanie
AU - van Hamburg, Jan Piet
AU - Lubberts, Erik
AU - Bootsma, Hendrika
AU - Kroese, Frans G.M.
AU - Hendriks, Rudi W.
N1 - Publisher Copyright: © 2017, American College of Rheumatology
PY - 2017/6
Y1 - 2017/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85019157685&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/art.40059
DO - https://doi.org/10.1002/art.40059
M3 - Article
C2 - 28141917
SN - 2326-5191
VL - 69
SP - 1313
EP - 1324
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
IS - 6
ER -