title: B-cell linker protein expression contributes to controlling allergic and autoimmune diseases by mediating IL-10 production in regulatory B cells.
abstract: BACKGROUND
  Regulatory B cells that exhibit the cell-surface CD1d(hi)CD5(+) phenotype and produce IL-10 are termed B10 cells. Although B10 cells exert potent suppressive functions in patients with various allergic and autoimmunity disorders, the precise signaling mechanisms required for B10 cell functions remain unknown. B-cell linker protein (BLNK) is an essential component of the B-cell antigen receptor signaling pathway and is required for optimal B-cell development.
  
  
  OBJECTIVE
  We sought to elucidate the signaling pathways that are responsible for IL-10 production in B10 cells and in vivo mechanisms of how impaired B10 cell functions influence allergic and autoimmune responses.
  
  
  METHODS
  For in vitro assays, splenic CD1d(hi)CD5(+) B cells from BLNK-deficient (BLNK(-/-)) mice were analyzed for intracellular signaling pathways and cytokine production. Contact hypersensitivity (CHS) and experimental autoimmune encephalomyelitis were examined by using BLNK(-/-) mice.
  
  
  RESULTS
  Although the CD1d(hi)CD5(+) B-cell population was present in BLNK(-/-) mice, IL-10 production was impaired both in vitro and in vivo. BLNK(-/-) mice had exaggerated CHS and experimental autoimmune encephalomyelitis responses, which were normalized by adoptive transfer of splenic CD1d(hi)CD5(+) B cells from wild-type mice. In mice with CHS, BLNK(-/-) mice exhibited decreased B-cell and regulatory T-cell percentages and increased CD8(+) T-cell percentages in the skin and lymph nodes. In vitro BLNK was required for LPS-induced signal transducer and activator of transcription 3 phosphorylation in CD1d(hi)CD5(+) B cells. Finally, secreted IL-10 leads to autocrine expansion of IL-10-producing B cells.
  
  
  CONCLUSIONS
  BLNK serves as a critical signaling component for B10 cell function by mediating IL-10 production.
authors.affiliation: Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Guihua
authors.initials: G
authors.lastname: Jin
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Hamaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Doanh
authors.initials: D
authors.lastname: Le Huu
authors.forename: Nobuko
authors.initials: N
authors.lastname: Ishiura
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Naka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D019898:Autocrine Communication; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology*; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018956:CD5 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006967:Hypersensitivity / Q000235:genetics* / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D053612:Janus Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055610:Antigens, CD1d; C113939:B cell linker protein; D018956:CD5 Antigens; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D053612:Janus Kinases