title: Enhanced Bruton's Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Odilia B J
authors.initials: OBJ
authors.lastname: Corneth
authors.affiliation: University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Gwenny M P
authors.initials: GMP
authors.lastname: Verstappen
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Sandra M J
authors.initials: SMJ
authors.lastname: Paulissen
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marjolein J W
authors.initials: MJW
authors.lastname: de Bruijn
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Rip
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Melanie
authors.initials: M
authors.lastname: Lukkes
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Jan Piet
authors.initials: JP
authors.lastname: van Hamburg
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
authors.affiliation: University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hendrika
authors.initials: H
authors.lastname: Bootsma
authors.affiliation: University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Frans G M
authors.initials: FGM
authors.lastname: Kroese
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D001402:B-Lymphocytes / Q000201:enzymology*; D016022:Case-Control Studies; D006801:Humans; D008213:Lymphocyte Activation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012859:Sjogren's Syndrome / Q000201:enzymology*
chemical_list: D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse