title: Expression and function of inducible costimulator on peripheral blood CD4+ T cells in Behçet's patients with uveitis: a new activity marker?
abstract: OBJECTIVE
  Inducible costimulator (ICOS) is an important costimulatory molecule involved in T-cell activation. In this study, the role of ICOS in the pathogenesis of uveitis in Behçet's disease (BD) was investigated.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) were obtained from BD patients with uveitis in the active or remission phase and in healthy subjects. Total RNA was isolated from PMBCs, and mRNA expression was analyzed on an oligonucleotide microarray. ICOS expression on CD4(+) T cells was determined by flow cytometry, and the functional costimulatory effect of ICOS/B7RP-1 interaction was assessed on stimulation with concanavalin A (conA) or IRBP in the presence or absence of anti-ICOS mAb.
  
  
  RESULTS
  As the result of microarray analysis, ICOS in PBMCs showed the greatest difference in expression in BD patients with uveitis compared with healthy control subjects. ICOS expression on CD4(+) T cells in BD patients with uveitis was significantly higher than that in healthy individuals, both before and after conA stimulation. Among the BD patients, ICOS expression on CD4(+) T cells was significantly higher in those with active uveitis than in those with remitted uveitis. Blockade of ICOS/B7-related protein-1 (B7RP-1) interaction by anti-ICOS mAb significantly decreased IFN-γ, IL-17, and TNF-α production by PBMCs when stimulated with conA or IRBP in BD with active uveitis.
  
  
  CONCLUSIONS
  High ICOS expression in BD patients with uveitis contributed to the upregulation of IFN-γ, IL-17, and TNF-α production, suggesting that abnormal ICOS costimulation may play an immunopathologic role in the pathogenesis of uveitis in BD.
authors.affiliation: Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Usui
authors.forename: Masaru
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Yamakawa
authors.forename: Aya
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kezuka
authors.forename: Juan
authors.initials: J
authors.lastname: Ma
authors.forename: Ryusaku
authors.initials: R
authors.lastname: Matsuda
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okunuki
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Goto
mesh_terms: D000328:Adult; D019138:Antibodies, Blocking; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology; D001528:Behcet Syndrome / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005136:Eye Proteins / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology; D014605:Uveitis / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D019138:Antibodies, Blocking; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D015415:Biomarkers; D003208:Concanavalin A; D016207:Cytokines; D005136:Eye Proteins; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D012333:RNA, Messenger; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C556692:ICOS protein, human