Background The minor allele of the interleukin-4 receptor (IL4R) gene single nucleotide polymorphism (SNP), I50V (rs1805010), confers impaired IL-4 signaling and has been associated with an aggressive destructive course of rheumatoid arthritis (RA). IL-4 inhibits the development of Th17 cells, a cell population recently identified to be prominent in RA patients and to associate with cartilage and bone destruction.
Objectives Here, we investigated whether the I50V IL4R SNP modulates Th17 cell development and, hence, subsequent clinical outcome in RA.
Methods Patients with early, active RA (n=90; DAS28 4.6±1.1) and controls (healthy subjects, [n=24], osteoarthritis patients [OA, n=15]) were genotyped. To assess the inhibitory effect of IL-4 on Th17 cell development, we primed CD4 T cells from all patient and control genotype groups for 72 h in the presence or absence of IL-4 and determined Th17 cell frequencies. Further, in all groups, IL-17, IL-22 serum levels were assessed by ELISA, and Th17 cell frequencies were analyzed ex vivo and after activation by flow cytometry. Clinical and radiographic data were collected and evaluated at baseline and one year after disease onset.
Results Gentotyping revealed that 26% of the patients were homozygous for the major allele of I50V IL4R SNP (I50/I50), 60% were heterozygous (I50/V50), and 14% were homozygous for the minor allele (V50/V50). RA patients homozygous for the minor allele (V50/V50) demonstrated significantly higher clinical activity associated with the presence of erosions after one year of follow-up as compared to the other patients. The inhibitory effect of IL-4 on Th17 development in those V50/V50 patients with the impaired IL-4R signaling was significantly less prominent or even absent. Accordingly, frequencies of Th17 cells were significantly increased in the V50/V50 group of RA patients correlating with high disease activity. Those patients demonstrated consistently higher IL-17 and IL-22 serum levels as compared to I50/I50 or I50/V50 RA patients, and controls.
Conclusions The data indicate that the minor allele of I50V IL4R SNP (V50/V50) contributes to increased Th17 cell frequency, enhanced clinical activity and accelerated radiographic progression in RA by rendering CD4 T cells from RA patients insensitive to the attenuating effect of IL-4 on Th17 cell development. Here, we provide a potential genetic basis for the Th17 cell-driven inflammatory process underlying early RA.
Disclosure of Interest None declared
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