title: Combinatorial control of Th17 and Th1 cell functions by genetic variations in genes associated with the interleukin-23 signaling pathway in spondyloarthritis.
abstract: OBJECTIVE
  Recent genome-wide association studies have revealed numerous genetic associations between specific single-nucleotide polymorphisms (SNPs) and immune-mediated inflammatory diseases. The current challenge is to identify associations of the genetic variants with effector mechanisms implicated in pathogenesis. This study was undertaken to investigate the link between genetic variation at loci associated with spondyloarthritis (SpA) and the effector function of CD4+ T lymphocyte subsets involved in chronic inflammatory disease.
  
  
  METHODS
  Expression of Th17 and Th1 cytokines and transcription factors was measured in CD4+ T cells isolated from patients with SpA. Correlation analyses were performed to assess potential associations of these expression levels with the patient's genotype at loci genetically linked to SpA.
  
  
  RESULTS
  The effector functions of Th17 and Th1 cells in patients with SpA were found to be under combinatorial control by multiple SNPs at genes associated with the interleukin-23 (IL-23)/Th17 pathway. Patients with SpA carrying risk-associated alleles of genes in the IL-23/Th17 pathway expressed the highest levels of genes involved in the differentiation and function of Th17 and Th1 cells, whereas the presence of protective alleles was associated with low-level expression of these genes. In contrast, variation at loci that were genetically linked to SpA, but not associated with the IL-23 pathway, did not affect the expression of Th17- and Th1-specific genes, suggesting that these SNPs may contribute to the pathogenesis of SpA through distinct cellular mechanisms.
  
  
  CONCLUSIONS
  These results show that genetic variations at genes associated with the IL-23 signaling pathway may influence the effector functions of Th17 and Th1 cells in patients with SpA. These findings provide a framework to delineate the mechanisms by which genetic variants contribute to pathology.
authors.affiliation: Institut Pasteur and CNRS URA 1961, Paris, France.
authors.forename: Maryaline
authors.initials: M
authors.lastname: Coffre
authors.forename: Mathilde
authors.initials: M
authors.lastname: Roumier
authors.forename: Magda
authors.initials: M
authors.lastname: Rybczynska
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sechet
authors.forename: Helen K W
authors.initials: HK
authors.lastname: Law
authors.forename: Laure
authors.initials: L
authors.lastname: Gossec
authors.forename: Maxime
authors.initials: M
authors.lastname: Dougados
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bianchi
authors.forename: Lars
authors.initials: L
authors.lastname: Rogge
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D025242:Spondylarthropathies / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016207:Cytokines; D053759:Interleukin-23