Seven chain adaptive immune receptor repertoire analysis in rheumatoid arthritis reveals novel features associated with disease and clinically relevant phenotypes

In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. In comparison to controls, we show that RA patients have multiple and strong differences in the BCR repertoire including reduced diversity as well as altered isotype, chain and segment frequencies. We demonstrate that therapeutic TNF inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific TCR repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases. Overall design: Three complementary study designs were conducted to characterize the immune repertoire of RA, including case-control, case-case and longitudinal analyses Please note that the gender information for each sample (included in mixed sample records) is provided in the corresponiding sample description field.类风湿关节炎（rheumatoid arthritis, RA）中，针对自身抗原的T细胞与B细胞克隆活化可引发滑膜慢性炎症。本研究针对RA患者体内构成适应性免疫受体库（adaptive immune receptor repertoire, AIRR）的七条免疫受体链开展了深入的定量分析。与健康对照相比，RA患者的B细胞受体（B cell receptor, BCR）库存在多处显著差异，包括多样性降低、同种型、链型及片段使用频率异常。研究证实，肿瘤坏死因子（tumor necrosis factor, TNF）靶向治疗可部分逆转上述异常，但应答者与无应答者之间的潜在生化反应特征存在显著差异。将AIRR数据与人类白细胞抗原（human leukocyte antigen, HLA）分型结果相结合，本研究鉴定出与疾病风险变异相关的特异性T细胞受体（T cell receptor, TCR）库。整合上述特征，本研究进一步构建了分子分类器，证实AIRR可作为诊断工具发挥应用价值。对人类AIRR的七条链进行同步测序，可揭示与疾病及临床相关表型（包括治疗应答情况）相关的全新特征。上述研究结果彰显了AIRR在免疫相关疾病精准医疗领域的独特应用潜力。研究整体设计：本研究采用三种互补的研究方案以表征RA的免疫库，包括病例-对照研究、病例-病例研究及纵向分析。请注意，每份样本（含混合样本记录）的性别信息已在对应的样本描述字段中提供。