Journal Article

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

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

2011

Overview

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 IL23R(R381) and IL23R(Q381) 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. IL23R(Q381) 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 IL23R(Q381) positive donors. Our study shows conclusively that IL23R(Q381) 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amino Acid Sequence / Amino Acid Substitution - genetics / Analysis / Antibodies / Antigens / Arginine - genetics / Autoimmune diseases / Binding sites / Bioinformatics / Biology / Cell Line, Transformed / Clone Cells / Cloning / Conserved Sequence - genetics / Crohn's Disease / Crohns disease / Cytokines / Cytometry / Disease susceptibility / Drug development / Enzyme-linked immunosorbent assay / Epidemiology / Flow cytometry / Genes / Genetic aspects / Genetic diversity / Genetic Predisposition to Disease / Genetic research / Genetic variance / Genome-wide association studies / Genomes / Genomics / Haplotypes / Humans / Immunology / Infectious diseases / Inflammation / Inflammatory bowel disease / Inflammatory Bowel Diseases - genetics / Interleukin 23 / Interleukin-23 - pharmacology / Leukocytes, Mononuclear - drug effects / Leukocytes, Mononuclear - metabolism / Ligands / Lymphocyte Count / Lymphocytes / Lymphocytes T / Models, Biological / Molecular Sequence Data / Pathophysiology / Phosphorylation / Phosphorylation - drug effects / Polymerase chain reaction / Polymorphism, Single Nucleotide - genetics / Population / Proteins / Psoriasis / Receptors, Interleukin - chemistry / Receptors, Interleukin - genetics / Signal transduction / Signaling / Skin diseases / Species Specificity / STAT Transcription Factors - metabolism / Stat3 protein / Studies / T cells / T-Lymphocytes - drug effects / T-Lymphocytes - metabolism / Tissue Donors / Ulcerative colitis