title: A polymorphism in the interleukin-4 receptor affects the ability of interleukin-4 to regulate Th17 cells: a possible immunoregulatory mechanism for genetic control of the severity of rheumatoid arthritis.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is now suspected to be driven by pathogenic Th17 cells that secrete interleukin (IL)-17 and can be regulated by IL-4. A single-nucleotide polymorphism (SNP), I50V, in the coding region of the human IL-4 receptor (IL-4R) is associated with rapid development of erosive disease in RA. The present study was undertaken to determine whether this SNP renders the IL-4R less able to transduce signals that regulate IL-17 production.
  
  
  METHODS
  Peripheral blood mononuclear cells were activated under Th17-stimulating conditions in the presence or absence of IL-4, and IL-17 production was measured by both enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Serum IL-17 was also measured by ELISA. Paired comparisons were performed using the two-tailed t-test. IL-4 receptor gene alleles were determined by polymerase chain reaction.
  
  
  RESULTS
  In healthy individuals, IL-4 significantly inhibited IL-17 production by cells from subjects with the I/I genotype (P = 0.0079) and the I/V genotype (P = 0.013), but not the V/V genotype (P > 0.05). In a cross-sectional sample of patients with established RA, the magnitude of the in vitro effect of IL-4 was lower and was not associated with a specific IL-4R allele. Serum IL-17 levels were higher in RA patients than in healthy individuals, as was the percentage of CD4+ cells that produced IL-17.
  
  
  CONCLUSIONS
  These results indicate that an inherited polymorphism of the IL-4R controls the ability of the human immune system to regulate the magnitude of IL-17 production. However, in established RA, this pattern may be altered, possibly due to secondary effects of both RA itself as well as immunomodulatory medications. Ineffective control of Th17 immune responses is a potential mechanism to explain why IL-4R is an important severity gene in RA, but this issue will require careful study of a cohort of new-onset RA patients.
authors.affiliation: Division of Rheumatology and Rheumatic Diseases Research Core Center, Department of Internal Medicine, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Wallis
authors.forename: Laura A
authors.initials: LA
authors.lastname: Cooney
authors.forename: Judith L
authors.initials: JL
authors.lastname: Endres
authors.forename: Min Jie
authors.initials: MJ
authors.lastname: Lee
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ryu
authors.forename: Emily C
authors.initials: EC
authors.lastname: Somers
authors.forename: David A
authors.initials: DA
authors.lastname: Fox
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002469:Cell Separation; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D019948:Receptors, Interleukin-4 / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D020381:Interleukin-17; D019948:Receptors, Interleukin-4; D015847:Interleukin-4