在类风湿关节炎中，Th17 细胞频率增加和临床预后不良与 IL4R 基因中的遗传变异 rs1805010 相关。

Increased Th17 cell frequency and poor clinical outcome in rheumatoid arthritis are associated with a genetic variant in the IL4R gene, rs1805010.

机构信息

Medizinische Klinik and Poliklinik IV, University of Munich, Munich, Germany.

出版信息

Arthritis Rheumatol. 2014 May;66(5):1165-75. doi: 10.1002/art.38343.

DOI:10.1002/art.38343

PMID:24782180

Abstract

OBJECTIVE

The minor allele of the IL4R gene single-nucleotide polymorphism, rs1805010, confers impaired interleukin-4 (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 as being prominent in RA patients and being associated with cartilage and bone destruction. The purpose of the present study was to investigate whether rs1805010 modulates Th17 cell development and, hence, subsequent clinical outcome in RA.

METHODS

A total of 90 patients with early, active RA (mean ± SD Disease Activity Score in 28 joints 4.6 ± 1.1) and 39 control subjects (24 healthy subjects and 15 patients with osteoarthritis [OA]) were genotyped. Serum levels of IL-17 and IL-22 as well as frequencies of Th17 cells were analyzed by enzyme-linked immunosorbent assay and flow cytometry. Clinical and radiographic data were collected and evaluated at baseline and 1 year after disease onset.

RESULTS

Twenty-six percent of the RA patients were homozygous for the major allele of rs1805010, 60% were heterozygous, and 14% were homozygous for the minor allele. The RA patients who were homozygous for the minor allele demonstrated significantly higher clinical activity associated with the presence of erosions after 1 year of followup as compared to the other RA patients. The inhibitory effect of IL-4 on Th17 cell development in these patients was significantly less prominent. Accordingly, the frequencies of Th17 cells and serum levels of IL-17 and IL-22 were significantly increased.

CONCLUSION

The data indicate that the rs1805010 minor allele 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.

摘要

目的

白细胞介素 4 受体（IL4R）基因单核苷酸多态性的 IL4R 基因的次要等位基因 rs1805010 导致白细胞介素 4（IL-4）信号受损，并与类风湿关节炎（RA）的侵袭性破坏性病程相关。IL-4 抑制 Th17 细胞的发育，Th17 细胞最近被确定为 RA 患者中突出的细胞群体，并与软骨和骨破坏相关。本研究旨在探讨 rs1805010 是否调节 Th17 细胞的发育，进而影响 RA 的后续临床结果。

方法

共纳入 90 例早期活动期 RA 患者（平均 ± 标准差 28 关节疾病活动评分 4.6 ± 1.1）和 39 名对照者（24 名健康对照者和 15 名骨关节炎[OA]患者）进行基因分型。通过酶联免疫吸附试验和流式细胞术分析血清 IL-17 和 IL-22 水平以及 Th17 细胞频率。在疾病发病后 1 年收集并评估临床和放射学数据。

结果

26%的 RA 患者为 rs1805010 的主要等位基因纯合子，60%为杂合子，14%为次要等位基因纯合子。与其他 RA 患者相比，携带 rs1805010 次要等位基因纯合子的 RA 患者的临床活动明显更高，且 1 年后出现侵蚀。IL-4 对这些患者 Th17 细胞发育的抑制作用明显减弱。相应地，Th17 细胞频率、血清 IL-17 和 IL-22 水平均显著升高。