title: Abrogation of Treg function deteriorates rheumatoid arthritis.
abstract: An early prognostic indicator which warns of progressive joint destruction of rheumatoid arthritis (RA) was explored using a novel suspension-array technique in moderate (Steinbrocker stage I and II) and severe (Steinbrocker stage IV) RA patients. DNA microarray analysis of peripheral blood lymphocytes showed significant increase of interleukin (IL)-2 receptor α-chain (CD25) gene expression, a regulatory T cell (Treg) surface marker in severe RA patients. In contrast, suspension array, a comprehensive bead-based enzyme-linked immunosorbent assay (ELISA), revealed decreased production of IL-10 and increased production of interferon (IFN)-γ in sera in the incipient stage of the aggressive disease process. Both in moderate and in severe RA patients, the IFN-γ/IL-10 ratio indicated deterioration of the disease with universal validity. Fluorescence-activated cell sorting (FACS) and reverse-transcription polymerase chain reaction (RT-PCR) analysis showed extant CD4+CD25+ regulatory T cells in severe RA patients, however Foxp3, a regulatory T cell-specific transcription factor, gene expression was absent, while glucocorticoid-induced tumor necrosis factor (TNF) receptor family-related protein (GITR), which transmits a signal that abrogates regulatory T cell functions, was elevated. In the current study, we showed the validity of suspension-array analysis for enabling more complete understanding of RA, and showed that IFN-γ/IL-10 ratio can be a prognostic tool for early lesion and more aggressive RA.
authors.affiliation: Department of Orthopaedic Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. yamagiwa@hyo-med.ac.jp
authors.forename: Tokuyoshi
authors.initials: T
authors.lastname: Yamagiwa
authors.forename: Shigeo
authors.initials: S
authors.lastname: Fukunishi
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tachibana
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yoshiya
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Kashiwamura
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000097:blood; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000097:blood*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology*; D055815:Young Adult
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; C508609:IL10 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; C491405:TNFRSF18 protein, human; D016753:Interleukin-10; D007371:Interferon-gamma