title: Activation of Syk in peripheral blood B cells in patients with rheumatoid arthritis: a potential target for abatacept therapy.
abstract: OBJECTIVE
  B cells play a pivotal role in the pathogenesis of autoimmune diseases. Although Syk functions as a key molecule in B cell receptor signaling, the pathologic role of Syk in B cells in rheumatoid arthritis (RA) remains unclear. The purpose of this study was to assess the relevance of activation of Syk in B cells to the pathologic development of RA and to the responsiveness of RA patients to treatment with biologics.
  
  
  METHODS
  Healthy subjects (n = 36) and patients with moderate or severe RA disease activity (n = 70) were studied. The phosphorylation of Syk (pSyk) in peripheral blood B cells was measured by flow cytometry, and its correlation with clinical characteristics and changes after administration of biologic agents was evaluated.
  
  
  RESULTS
  Levels of pSyk in peripheral blood B cells were preferentially higher in patients with RA compared to healthy subjects. Patients with significantly higher pSyk levels were strongly positive for anti-citrullinated protein antibodies (ACPAs). High pSyk levels were not correlated with the severity of disease activity. Treatment with abatacept, but not tumor necrosis factor inhibitors, significantly reduced the levels of pSyk in RA peripheral blood B cells. Abatacept also significantly reduced the proportion of follicular helper T (Tfh) cells.
  
  
  CONCLUSIONS
  Levels of pSyk in peripheral blood B cells were significantly elevated in patients with RA, and these patients also exhibited strong positivity for ACPAs. These data suggest that abatacept seems to inhibit the phosphorylation of Syk in B cells, as well as the development of Tfh cells, thus highlighting the relevance of B cell-T cell interactions as a potential target of abatacept therapy in RA.
authors.affiliation: University of Occupational and Environmental Health Japan, Kitakyushu, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Iwata
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakayamada
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Fukuyo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kubo
authors.forename: Naoki
authors.initials: N
authors.lastname: Yunoue
authors.forename: Sheau-Pey
authors.initials: SP
authors.lastname: Wang
authors.forename: Maiko
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Saito
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000069594:Abatacept; D000368:Aged; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D012720:Severity of Illness Index; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D018796:Immunoconjugates; D000069594:Abatacept; D020794:Receptor Protein-Tyrosine Kinases; C084944:TYRO3 protein, human