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

IntroductionRheumatoid 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.MethodsPeripheral 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.ResultsIn 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.ConclusionsThese 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.

IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis

“…This is in keeping with other studies that report the presence of IL-17A in only a proportion of patients. 20,21 The reason why IL-17A is only present in a subgroup of patients remains unclear. However, RA is a heterogeneous disease and the presence of IL-17A clearly defines a specific subgroup of patients who appear to have more aggressive disease, with evidence that the presence of IL-17 results in more joint erosion 22 and may predict vascular function in RA.…”

SERUM IL17 AND IL4R rs1805010 GENOTYPES: RELATIONSHIP WITH RHEUMATOID ARTHRITIS DISEASE ACTIVITY IN EGYPTIAN PATIENTS

“…However, only GG carriers showeda positive correlation with statistical significance between serum IL17 and Larsen scale. Our results highlight the poor effect of IL4RG allele on RA progression, a process in which IL-17 seems to be a crucial player.Interestingly, IL4 has been shown todecrease autoimmune inflammation, bone and joint destruction not only through above mentioned mechanisms but also by suppression of Th17/IL17 axis and effects Guenova et al, 2015;Leipe et al, 2014 andWallis et al, 2011). The current findings might be explained by the reduced ability of IL4 to suppress Th17 cells in carriers of G allele.…”

“…Amino acid substitution due to rs1805010 GG genotype, reduces STAT6 activation, hence weakens the downstream signals through IL4R. Thus, production of IL4 is significantly diminished and TH17/IL17 suppression is diminished as well, in such patients Guenova et al, 2015;Leipe et al, 2014 andWallis et al, 2011). Finally, there were non-significant differences in serum levels of IL17 between patients on different treatment regimens in all three genotypes.…”

Association between IL-4 gene polymorphisms, IL-4 serum levels, and ankylosing spondylitis

“…Moreover, this cytokine, produced by activated CD4 + T cells, can promote Th2 cell maturation (Limón-Camacho et al, 2012). However, genetic polymorphisms in IL-4 that affect expression of the IL-4 protein contribute to a T cell imbalance, thereby potentially influencing its anti-inflammatory role and the development of AS (Wallis et al, 2011;Inanir et al, 2013).…”