title: Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis.
abstract: BACKGROUND
  There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested.
  
  
  METHODS
  The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors.
  
  
  RESULTS
  There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity.
  
  
  CONCLUSIONS
  Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.
authors.affiliation: Division of Pediatric Rheumatology, and Special Immunology, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Almanzar
authors.forename: Matthias
authors.initials: M
authors.lastname: Klein
authors.forename: Marc
authors.initials: M
authors.lastname: Schmalzing
authors.forename: Deborah
authors.initials: D
authors.lastname: Hilligardt
authors.forename: Nady
authors.initials: N
authors.lastname: El Hajj
authors.forename: Hermann
authors.initials: H
authors.lastname: Kneitz
authors.forename: Vanessa
authors.initials: V
authors.lastname: Wild
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Sandrine
authors.initials: S
authors.lastname: Benoit
authors.forename: Henning
authors.initials: H
authors.lastname: Hamm
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Tony
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
authors.forename: Matthias
authors.initials: M
authors.lastname: Goebeler
authors.forename: Martina
authors.initials: M
authors.lastname: Prelog
mesh_terms: D000328:Adult; D000368:Aged; D000954:Antigens, Surface / Q000378:metabolism; D015415:Biomarkers; D016207:Cytokines / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056747:Immunomodulation; D018655:Lymphocyte Count; D008231:Lymphopenia; D008297:Male; D008745:Methylation; D008875:Middle Aged; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000954:Antigens, Surface; D015415:Biomarkers; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human