HLA-DRB1 共享表位等位基因与疾病活动度与类风湿关节炎患者 CD4+ T 细胞中 T 细胞受体多样性减少相关。
HLA-DRB1 Shared Epitope Alleles and Disease Activity Are Correlated with Reduced T Cell Receptor Repertoire Diversity in CD4+ T Cells in Rheumatoid Arthritis.
机构信息
From the Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.
K. Sakurai, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; K. Ishigaki, MD, PhD, Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; H. Shoda, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; Y. Nagafuchi, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; Y. Tsuchida, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; S. Sumitomo, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; H. Kanda, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; A. Suzuki, PhD, Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; Y. Kochi, MD, PhD, Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; K. Yamamoto, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, and Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; K. Fujio, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo.
出版信息
J Rheumatol. 2018 Jul;45(7):905-914. doi: 10.3899/jrheum.170909. Epub 2018 Apr 15.
OBJECTIVE
Shared epitope (SE) alleles are the most significant genetic susceptibility locus in rheumatoid arthritis (RA); however, their target populations in CD4+ T cells are not well elucidated. We analyzed the association between SE alleles and the T cell receptor (TCR) repertoire diversity of naive and memory CD4+ T cells using next-generation sequencing (NGS).
METHODS
The TCR beta chains in naive and memory CD4+ T cells from the peripheral blood of 22 patients with RA and 18 age- and sex-matched healthy donors (HD) were analyzed by NGS. The Renyi entropy was used to evaluate TCR repertoire diversity and its correlations with SE alleles and other variables were examined. Serum cytokine levels were measured by multiplex ELISA.
RESULTS
The TCR repertoire diversity in memory CD4+ T cells was reduced in SE allele-positive patients with RA compared with HD, and showed a significant negative correlation with the SE allele dosage in RA. The TCR repertoire diversity of naive and memory T cells was also negatively correlated with disease activity, and the SE allele dosage and disease activity were independently associated with reduced TCR repertoire diversity. TCR repertoire diversity showed a significant positive correlation with the serum interleukin 2 levels.
CONCLUSION
SE alleles and disease activity were negatively correlated with the TCR repertoire diversity of CD4+ T cells in RA. Considering the pivotal role of CD4+ T cells in RA, restoring the altered TCR repertoire diversity will provide a potential RA therapeutic target.
目的
共享表位（SE）等位基因是类风湿关节炎（RA）中最显著的遗传易感性位点；然而，其在 CD4+T 细胞中的靶人群尚未得到充分阐明。我们使用下一代测序（NGS）分析了 SE 等位基因与幼稚和记忆 CD4+T 细胞的 T 细胞受体（TCR） repertoire 多样性之间的关联。
方法
通过 NGS 分析了 22 例 RA 患者和 18 例年龄和性别匹配的健康供体（HD）外周血中幼稚和记忆 CD4+T 细胞的 TCRβ链。使用 Renyi 熵评估 TCR repertoire 多样性，并检查其与 SE 等位基因和其他变量的相关性。通过多重 ELISA 测量血清细胞因子水平。
结果
与 HD 相比，SE 等位基因阳性的 RA 患者记忆 CD4+T 细胞的 TCR repertoire 多样性降低，并且与 RA 中的 SE 等位基因剂量呈显著负相关。幼稚和记忆 T 细胞的 TCR repertoire 多样性也与疾病活动呈负相关，SE 等位基因剂量和疾病活动与降低的 TCR repertoire 多样性独立相关。TCR repertoire 多样性与血清白细胞介素 2 水平呈显著正相关。
结论
SE 等位基因和疾病活动与 RA 中 CD4+T 细胞的 TCR repertoire 多样性呈负相关。考虑到 CD4+T 细胞在 RA 中的关键作用，恢复改变的 TCR repertoire 多样性将为 RA 的潜在治疗靶点提供依据。
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