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.
Highlights
Rheumatoid arthritis (RA) is suspected to be driven by pathogenic Th17 cells that secrete interleukin (IL)-17 and can be regulated by IL-4
In the healthy individuals there was a significant increase in the IL-17 level after the addition of Th17-stimulatory cytokines over baseline T cell stimulation with anti-CD3 (P < 0.01), and there was a significant decrease in the measured IL-17 level with the addition of IL-4 to the Th17-stimulatory conditions (Figure 1)
The results indicate that a polymorphism in IL-4 receptor (IL-4R) in part controls production of IL-17 by Th17 cells cultured from healthy individuals
Summary
Rheumatoid arthritis (RA) is suspected to be driven by pathogenic Th17 cells that secrete interleukin (IL)-17 and can be regulated by IL-4. CD4+ lymphocytes were thought to contain two distinct lineages of effector cells, the Th1 and Th2 subsets that are defined by secretion of either interferon (IFN)-g or interleukin (IL)-4. This paradigm has been modified to include a third CD4+ T-cell population, the Th17 cells [1,2]. Th17 cells are critical for autoimmune inflammation in a variety of murine models of human disease, such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) [3,4,5]. The cytokines IL-6 and tumor growth factor (TGF)-b are crucial for the generation of Th17 cells in the mouse [6,7,8], while IL-1b, IL-6 and IL-23 induce and maintain the differentiation of human Th17 cells [9,10].
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