Expression and function of inducible costimulator on peripheral blood CD4+ T cells in Behçet's patients with uveitis: a new activity marker?
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.
Usui
Yoshihiko
Y
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.
Takeuchi
Masaru
M
Yamakawa
Naoyuki
N
Takeuchi
Aya
A
Kezuka
Takeshi
T
Ma
Juan
J
Matsuda
Ryusaku
R
Okunuki
Yoko
Y
Akiba
Hisaya
H
Goto
Hiroshi
H
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
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