Background/Purpose: A single nucleotide polymorphism (SNP) in the IL4R gene (I50V, rs 1805010) has previously been associated with an aggressive destructive course of rheumatoid arthritis (RA). Patients homozygous for the V50 allele, which has been linked to diminished IL-4 signaling, develop more often bone erosions within the first two years of disease. On the other hand, Th17 cells and their cytokine IL-22 have also been associated with cartilage and bone destruction. Development of Th17 cells is negatively regulated by IL-4 signaling through the IL-4R. Because of the functional differences of the two IL4R alleles, we investigated a possible association between I50V IL4RSNP and Th17 cell frequencies in active RA.

Methods: IL4R genotypes were determined in well-defined cohorts of patients with early, treatment-naive RA (n=49) as well as in controls (healthy controls, [n=24] and patients with osteoarthritis [OA, n=15]) by TaqMan SNP assay. IL-17, IL-22 serum levels and ex vivoTh17 cell frequencies were analyzed by ELISA and flow cytometry. To assess the inhibitory effect of IL-4 on Th17 cell development, we primed CD4 T cells for 72 h in the presence or absence of IL-4 and determined Th17 cell frequencies. Clinical and radiographic data were evaluated at baseline and after one year after disease onset. Correlation of clinical data and radiographic progression was performed using Pearson rank correlation test or Chi square test.

Results: Gentotyping revealed 10 patients homozygous for the I50 alleles (I50I), 32 heterozygous patients (I50V), and 7 homozygous VV patients (V50V). Clinical activity was consistently higher in homozygous V50V RA patients during follow-up as compared to the i50V and I50I patients, despite similar treatment regimens. Moreover, the loss of functional IL4R alleles was associated with the presence of erosions. In all study cohorts T cells from V50V individuals responded weaker to IL-4 inhibition of Th17 cell development as compared to their I50I or I50V counterparts. The inhibitory effect of IL-4 on Th17 development in V50V cells was however even less prominent or even completely absent in RA patients as compared to controls. Accordingly, frequencies of Th17 cells were significantly increased in the V50V group of RA patients. RA patients homozygous for the V50 allele variant demonstrated significantly higher IL-17 and IL-22 serum levels as compared to I50I or I50V RA patients and healthy or OA controls.

Conclusion: Together, the data indicate that the V50 allele of the I50V IL4R SNP renders CD4 T cells from RA patients insensitive to IL-4. The V50 allele of the IL-4R might therefore contribute to the increased Th17 cell frequency, clinical activity and radiographic progression in RA.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-i50v-il4r-snp-is-associated-with-increased-th17-cell-frequency-and-poor-clinical-outcome-in-rheumatoid-arthritis/