title: The proportion of regulatory T cells in the peripheral blood reflects the relapse or remission status of patients with Churg-Strauss syndrome.
abstract: BACKGROUND
  Churg-Strauss syndrome (CSS) is a rare, systemic, necrotizing vasculitis that develops in some asthma patients. We previously reported that maintenance of the proportion of type 1 regulatory T (Tr1) cells in patients with chronic eosinophilic pneumonia and asthma might inhibit the development of CSS through the action of cytokines, such as interleukin (IL)-10 and IL-2, produced by Tr1 and responder T cells. We also reported that IL-17-producing CD4+ helper T cells (Th17 cells) are involved in the pathogenesis of CSS because a higher proportion of Th17 cells was observed in CSS patients during relapses than during remissions. However, few studies have addressed the role of both Tr1 cells and Th17 cells in the status of CSS.
  
  
  METHODS
  We recruited 40 patients (25 in remission and 15 in relapse) for participation in this study. CSS was diagnosed on the basis of American College of Rheumatology criteria. Remission was defined as the absence of any clinical symptoms of active vasculitis. Tr1 cells were defined as CD4+CD25+ T cells that predominantly produce IL-10 when costimulated with phorbol myristate acetate (PMA) and ionomycin. Naturally occurring Treg (nTreg) cells were defined as CD4+CD25+ T cells that expressed Forkhead box P3 (FOXP3) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). Th17 cells were identified as CD4+ T cells that mainly produced IL-17 and IL-22. Peripheral blood mononuclear cells (PBMCs) obtained from the subjects were costimulated with PMA and ionomycin, and intracellular cytokines were detected after fixing and permeabilizing the cells. Indoleamine 2,3-dioxygenase (IDO) expression was measured in PBMCs that had been treated with IFN-γ and then stimulated overnight with lipopolysaccharide (LPS) or lipopeptide Pam3CSK.
  
  
  RESULTS
  Lower expression of CTLA-4 was observed on the surface of CD4+CD25+ T cells obtained from patients with relapsed CSS versus patients in remission. Both FOXP3-expressing nTreg cells and IL-10-producing Tr1 cells were detected in a lower proportion in patients with a relapse compared to patients in remission, but the proportion of CD4+ T cells producing IL-17 was higher during relapse than during remission. In addition, the proportion of CD4+ T cells that produced IL-25, which promotes Th2 inflammation, was also higher in the relapsed patients. We observed a lower percentage of CD14+ monocytes expressing both TLR2 and TLR4 obtained from patients with a relapse of CSS versus patients in remission. Stimulation of CD14+ monocytes with LPS or Pam3CSK reduced IDO expression by the cells from patients with relapsed CSS. The level of IDO expression was positively correlated with the proportion of Tr1 cells in the peripheral blood and inversely correlated with the percentage of Th17 cells.
  
  
  CONCLUSIONS
  CSS relapse may be linked to increased numbers of CD4+ T cells producing IL-25, which promotes Th2 inflammation, and to a decline in the Tr1 cell subpopulation resulting from lower IDO expression in monocytes. Thus, the proportions of Tr1 cells and Th17 cells reflect the status of CSS.
authors.affiliation: Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara Hospital, Sagamihara, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saito
authors.forename: Naomi
authors.initials: N
authors.lastname: Tsurikisawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsuburai
authors.forename: Chiyako
authors.initials: C
authors.lastname: Oshikata
authors.forename: Kazuo
authors.initials: K
authors.lastname: Akiyama
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060908:CTLA-4 Antigen; D015267:Churg-Strauss Syndrome / Q000175:diagnosis* / Q000188:drug therapy / Q000276:immunology; D003430:Cross-Sectional Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012008:Recurrence; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D000305:Adrenal Cortex Hormones; D015703:Antigens, CD; D015415:Biomarkers; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020381:Interleukin-17; D007378:Interleukins; D055666:Lipopeptides; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D000097043:Interleukin-22; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; C486701:IL25 protein, human; C508075:Pam(3)CSK(4) peptide