Disease relevance of IL23R

• An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated [1].
• A genome-wide association study identifies IL23R as an inflammatory bowel disease gene [1].
• METHODS: We describe the first patient, to our knowledge, with PCM and a well-defined primary immunodeficiency in the beta 1 subunit of the interleukin (IL)-12/IL-23 receptor, a disorder previously shown to be specifically associated with impaired interferon (IFN)-gamma production, mycobacteriosis, and salmonellosis [2].
• Therefore, targeting of IL-23 or the IL-23 receptor is a promising therapeutic approach for autoimmune diseases [3].
• No association was found between IL23R or ATG16L1 and celiac disease [4].
• This concurrent analysis of 3 distinct AS populations and their regional controls demonstrates a disease association with the IL-23R locus and implicates the same polymorphisms associated with IBD and psoriasis [5].

High impact information on IL23R

• Individuals homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased risk of disease (OR(common) 1.66, Pcomb=1.33x10-8) [6].
• Patients with mutations in IL12RB1, the gene encoding IL-12Rbeta1, suffer from combined IL-12R/IL-23R deficiency and are unusually susceptible to nontuberculous mycobacteria and salmonellae [7].
• Moreover, T-bet was found to directly regulate transcription of the IL-23R, and, in doing so, influenced the fate of Th17 cells, which depend on optimal IL-23 production for survival [8].
• Anti-IL-12Rbeta1 and anti-IL-23R Abs block IL-23 responses of an NK cell line and Ba/F3 cells expressing the two receptor chains [9].
• The human IL-23R gene is on human chromosome 1 within 150 kb of IL-12Rbeta2 [9].

Biological context of IL23R

• Here, we demonstrate that at least six spliced isoforms of IL-23R (IL-23R1 to 6) can be generated through alternative splicing [10].
• The standard form of IL-23R is encoded by at least 12 exons [10].
• Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (OR(common) 1.44, Pcomb=3.13x10-6) [6].
• We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23 [1].

Anatomical context of IL23R

• Differential expressions of IL-23R spliced variants are observed in natural killer and CD3+ CD4+ T cells [10].
• Identification and expression analysis of alternatively spliced isoforms of human interleukin-23 receptor gene in normal lymphoid cells and selected tumor cells [10].
• We now show for the first time that suppression of T-bet ameliorates EAE by limiting the differentiation of autoreactive Th1 cells, as well as inhibiting pathogenic Th17 cells via regulation of IL-23R [8].

Other interactions of IL23R

• The ability of cells to respond to IL-23 or IL-12 correlates with expression of IL-23R or IL-12Rbeta2, respectively [9].
• IL23R was associated with CD and UC only in the absence of CARD15 mutations, whereas ATG16L1 was associated with CD in the presence and absence of CARD15 mutations [11].

References