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02.45 Enhanced bruton’s tyrosine kinase activity in peripheral blood b lymphocytes of autoimmune disease patients
  1. Odilia B.J. Corneth1,
  2. Gwenny M.P. Verstappen2,
  3. Sandra M.J. Paulissen3,
  4. Marjolein J.W. de Bruijn1,
  5. Jasper Rip1,
  6. Melanie Lukkes1,
  7. Jan Piet van Hamburg3,
  8. Erik Lubberts3,
  9. Hendrika Bootsma2,
  10. Frans G.M. Kroese2,
  11. Rudi W. Hendriks1
  1. 1Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands
  2. 2Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
  3. 3Department of Rheumatology, Erasmus MC, Rotterdam, the Netherlands

Abstract

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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