I made these notes in relation to IL23R a couple of years ago and thought you might find them of interest - I hope most of it is still relevant:
IL23R Interleukin 23 Receptor is located on Chromosome 1p31.3
IL23R is a cytokine receptor present on T-cells, NK lymphocytes, monocytes, and dendritic cells. These cells identify foreign substances and defend the body against infection and disease. IL23R is a critical cytokine receptor on a subset of CD4+ T-cells called T helper 17 (Th17) cells. The receptor for IL-23 is formed by the IL12Rβ1 subunit and an IL23 specific subunit, IL23R. Note that Th17 cells express a high level of the cytokine IL-17 in response to stimulation.
The primary articular site of inflammation in the spondylarthropathies are the entheses (tendon-bone attachments) and the aortic root and valve (which are structurally similar to entheses). Recent studies have shown that IL23 acts on previously unidentified IL23R+ ROR-γt+ CD3+ CD4- CD8- Sca1+ entheseal resident T cells, which normally act to repair and remodel these sites. In response to high levels of gut derived circulating IL-23 these cells elaborate inflammatory mediators including IL-6, IL-17, IL-22 and CXCL1 with the specific and characteristic development of enthesitis and entheseal new bone formation in the initial complete absence of synovitis. Thus, dysregualtion of IL-23 results in lesions at precise and predictable anatomical sites. Moreover, these cells express the molecule PLZF, which allows them to respond to cytokines extremely rapidly, and indeed entheses respond within hours to IL23 in vitro.
At the cell surface IL23R binds with IL23 and triggers intracellular signalling that promotes inflammation. Genetic alleles of IL23R substantially affect susceptibility to AS, Crohn’s Disease, and psoriasis and this may in part explain the clinical association of these diseases. IL23R polymorphism is also associated with MS susceptibility. It is known that up to 70% of AS patients have subclinical ileal inflammation resembling Crohn’s and that about 10% of AS patients have clinical IBD. The strong association with susceptibility to disease suggests that IL23/IL23R targeted therapies may even be capable of disease prevention.
One of the alleles of IL23R appears to reduce the likelihood of developing AS. This allele results from the substitution of a single amino acid, glutamine for arginine at protein position 381, written R381Q or Arg381Gln. The same allele is protective against Crohn’s disease and psoriasis. Researchers believe that the role of IL23R in triggering inflammation in the intestinal wall may underlie its connection with Crohn’s and probably with AS. Accumulating evidence suggests that IL-23 is a likely master regulator of mucosal immunity during gastrointestinal infection and inflammation.
Genome wide association studies have previously shown that a single nucleotide polymorphism (SNP) in the IL23R gene (R381Q ) is significantly higher among healthy controls than in patients with psoriasis, Crohn’s Disease, sarcoidosis or AS. The associated SNP (rs11209026) which consists of a guanine (G) to adenine (A) substitution at the DNA level results in an arginine (R) to glutamine (Q) substitution at position 381 (R381Q) within the cytoplasmic domain of IL23R.
The possible Genotypes are : GG - Typical odds of AS; AG - moderately lower odds of AS and AA - substantially lower odds of AS.
Th17 cells generated from A allele carriers and G allele carriers are capable of producing similar amounts of Th17 cytokines. However, IL-23 mediated effector function was impaired, as Th17 helper cells from the protective A allele carriers had significantly reduced IL-23 induced IL-17A production and reduced STAT3 phosphorylation compared to the common G allele carriers.
The functional consequences of carrying the protective gene variant are elaborated in the 2011 paper “Functional studies of the IBD susceptibility gene IL23R implicate reduced receptor Function in the protective genetic variant R381Q” by Pidasheva, S et al.
‘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.’
That is, the IL23R R381Q SNP protects against multiple immune mediated diseases by impairing IL-23 mediated Th17 responses, namely, reduced IL17A production and STAT3 phosphorylation.
Early studies of Han Chinese suggested there was NO association of IL23R with AS, presumably because there was no polymorphism within the IL23R gene at rs11209026 . In a contradictory result from another study (2009) the difference in the genotypes rs11209032 and the differences in the genotypes and allele frequencies of rs6677188 between AS cases and controls in a Han population WERE significant. The two SNP’s rs11209032 and rs 6677188 were in strong linkage disequilibrium.
A more recent study has implicated rare IL23R variants with AS aetiopathogenesis, and has identified a low frequency nsSNP with predicted loss of function effects that is protectively associated with AS in Han Chinese, suggesting that decreased IL-23R function protects against AS. These findings further support an important role for IL23-signalling in AS.
A new injectible monoclonal antibody treatment, Stelara, is an Anti-IL12p40 antibody given (45mg) every 3 months (cost ~$5000 /shot) and it is currently only approved for psoriasis but may be available soon for psoriatic arthritis.
(1)The allele G frequency of rs11209032 is higher in AS groups than in the controls (A vs. G: OR = 1.173, 95% CI = 1.107–1.243, P < 0.001). (2) The allele A of rs1004819 is higher in the AS groups than in the controls in both all-pooled population (A vs. G: OR = 1.147, 95% CI = 1.022–1.287, P = 0.02) and Europe-pooled population (A vs. G: OR = 1.199, 95% CI = 1.007–1.429, P = 0.042). (3) The allele frequency T of rs1343151, G of rs10489629, and A of rs11209026 is lower in AS groups than in the controls. (4) No significant differences are found in allele frequency of rs10889677 polymorphism between cases and controls by random effects model. The conclusion is that the genetic susceptibility to AS is associated with the IL-23R gene polymorphisms. The protective SNPs include rs1343151, rs10489629, and rs11209026 while rs1004819 and rs11209032 may be the susceptibility SNPs.