Article thumbnail

Functional Studies on the IBD Susceptibility Gene IL23R Implicate Reduced Receptor Function in the Protective Genetic Variant R381Q

By Svetlana Pidasheva, Sara Trifari, Anne Phillips, Jason A. Hackney, Yan Ma, Ashley Smith, Sue J. Sohn, Hergen Spits, Randall D. Little, Timothy W. Behrens, Lee Honigberg, Nico Ghilardi and Hilary F. Clark


Genome-wide association studies (GWAS) in several populations have demonstrated significant association of the IL23R gene with IBD (Crohn's disease (CD) and ulcerative colitis (UC)) and psoriasis, suggesting that perturbation of the IL-23 signaling pathway is relevant to the pathophysiology of these diseases. One particular variant, R381Q (rs11209026), confers strong protection against development of CD. We investigated the effects of this variant in primary T cells from healthy donors carrying IL23RR381 and IL23RQ381 haplotypes. Using a proprietary anti-IL23R antibody, ELISA, flow cytometry, phosphoflow and real-time RT-PCR methods, we examined IL23R expression and STAT3 phosphorylation and activation in response to IL-23. IL23RQ381 was associated with reduced STAT3 phosphorylation upon stimulation with IL-23 and decreased number of IL-23 responsive T-cells. We also observed slightly reduced levels of proinflammatory cytokine secretion in IL23RQ381 positive donors. Our study shows conclusively that IL23RQ381 is a loss-of-function allele, further strengthening the implication from GWAS results that the IL-23 pathway is pathogenic in human disease. This data provides an explanation for the protective role of R381Q in CD and may lead to the development of improved therapeutics for autoimmune disorders like CD

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (2006). A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
  2. (2008). A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease.
  3. (2002). A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.
  4. (2008). Contribution of positively charged flanking residues to the insertion of transmembrane helices into the endoplasmic reticulum.
  5. (2006). Defective Th1 cytokine gene transcription in CD4+ and CD8+ T cells from WiskottAldrich syndrome patients.
  6. (2007). Development, cytokine profile and function of human interleukin 17-producing helper T cells.
  7. (2007). Flow cytometry-based methods for studying signaling in human CD4+CD25+FOXP3+ Tr e g u l a t o r yc e l l s .
  8. (2006). Functional consequences of NOD2 (CARD15) mutations.
  9. (2008). Future of psoriasis: an industry perspective on research.
  10. (2002). Generation and maintenance of cloned human T cell lines. Curr Protoc Immunol Chapter 7:
  11. (2008). Genetic mapping in human disease.
  12. (2009). Genetic variants in IL-23R and ATG16L1 independently predispose to increased susceptibility to Crohn’s disease in a Canadian population.
  13. (1996). Genetics versus environment in inflammatory bowel disease: results of a British twin study.
  14. (2007). Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.
  15. (2010). Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci.
  16. (2007). Genomewide association study for Crohn’s disease in the Quebec Founder Population identifies multiple validated disease loci.
  17. (2009). Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells.
  18. (2006). IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration.
  19. (1985). Il-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo.
  20. (2007). IL23R R381Q and ATG16L1 T300A are strongly associated with Crohn’s disease in a study of New Zealand Caucasians with inflammatory bowel disease.
  21. (2008). Impaired autophagy of an intracellular pathogen induced by a Crohn’s disease associated ATG16L1 variant.
  22. (2011). Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses.
  23. (2005). Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
  24. (2003). Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17.
  25. (2008). Linking genetic susceptibility to Crohn’s disease with Th17 cell function: IL-22 serum levels are increased in Crohn’s disease and correlate with disease activity and IL23R genotype status.
  26. (2008). New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition.
  27. (2007). Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS
  28. (2000). Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.
  29. (2011). Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease.
  30. (2008). Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn’s disease and analysis of the IL17F p.His161Arg polymorphism in IBD.
  31. (2007). Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility.
  32. (2007). Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
  33. (2005). Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease.
  34. (2007). Single-cell phosphoprotein analysis by flow cytometry.
  35. (2007). Systematic association mapping identifies NELL1 as a novel IBD disease gene.
  36. (2009). Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa.
  37. (2008). The biological functions of T helper 17 cell effector cytokines in inflammation.
  38. (2006). The epidemiology of inflammatory bowel disease in Canada: a population-based study.
  39. (2008). The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis.
  40. (1988). Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking.
  41. (2009). Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study.
  42. (2007). Update on the incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County,
  43. (2007). Wellcome Trust Case Control Consortium