Database of synovial T cell repertoire of rheumatoid arthritis patients identifies cross-reactive potential against pathogens including unencountered SARS-CoV-2.
Database of synovial T cell repertoire of rheumatoid arthritis patients identifies cross-reactive potential against pathogens including unencountered SARS-CoV-2.
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DOI：
10.1136/ard-2022-222763
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发表时间：
2023-03
影响因子：
27.4
通讯作者：
中科院分区：
文献类型：
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作者：
类风湿关节炎(RA)是一种病因复杂的慢性自身免疫性疾病，T细胞介导的获得性免疫反应在滑膜炎症和关节损伤中起主要作用。1在发展效应器功能之前，幼稚的T细胞通常被理解为需要通过其T细胞受体(TCR)传递的初始抗原特异性刺激。TCR介导的识别对于细胞毒性T细胞的靶向细胞溶解也是必需的。以前的研究试图描述不同T细胞群在类风湿关节炎中的功能作用，并证明了它们之间的寡克隆扩张模式。2也有研究表明，一些T细胞克隆可以作为公共剧目在多个患者之间共享。3滑膜T细胞的抗原特异性除了少数表位外，研究还很少，与RA相关的TCR和谱系的开放资源也很少。为了加快对RA的TCR谱系和T细胞抗原特异性的研究，我们在这里报告了使用谱系重建算法从两个大的队列RNA测序数据集中挖掘的滑膜谱系，总计196名RA患者，以及来自外周血和其他关节疾病的额外对照(图1A，在线补充方法)。第一个是GSE89408，用于识别RA患者滑膜中与疾病进展相关的转录组特征(在线补充表S1)。4第二项是PEAC，重点是早期的未接受治疗的患者，并确定有助于在滑膜组织和外周血中建立疾病的转录组特征(在线补充表S2)。5通过在迄今为止尚未导航的免疫谱系维度中探索这些队列，我们建立了第一个在RA患者(http://repertoire.)的滑膜中发现的高频TCR序列的开放可访问的在线数据库生活)。这个参考数据库是一个正在进行的收集和汇编人类类风湿关节炎患者TCR谱系的工作，可以用未来工作中确定的TCR谱系进行搜索，以更好地识别公共序列并确定其抗原特异性。对该数据库的初步分析表明，滑膜(但不是外周血)高频克隆型之间的谱系多样性增加与疾病活动性(疾病活动评分-28，(DAS28))和红细胞沉降率(ESR)(图1B，C，在线补充图S1，在线补充表S3)相关，突出了滑膜寡克隆扩张和临床指标之间的显著相关性。通过TCR聚类分析，我们观察到RA患者的滑膜TCR基序在很大程度上与其他关节疾病中发现的TCR基序不同(在线补充图S2)，这与他们的总体转录组差异一致(在线补充图S3)，但这些基序可以在淋巴病理类型的患者中总体共享(在线补充图S4)。我们还一致地观察到，通过多项指数(图1D，在线补充图S5、S6)评估，这些基序中的几个在高活动度疾病的患者中克隆性扩展和丰富，进一步表明它们可能参与RA的进展。通过与同一患者的配对外周血液样本进行比较，我们观察到
Rheumatoid arthritis (RA) is a chronic autoimmune disease of complex aetiology in which adaptive immune responses mediated by T cells play a major role in driving synovial inflammation and joint damage. 1 Before developing effector functions, naïve T cells are conventionally understood to require an initial antigenspecific stimulus transduced through their T cell receptor (TCR). TCR-mediated recognition is also required for targeted cell lysis by cytotoxic T cells. Previous studies have sought to characterise the functional roles of various T cell populations in RA, and have demonstrated patterns of oligoclonal expansion among them. 2 It has also been shown that some T cell clones may be shared among multiple patients as a public repertoire. 3 However, the antigen specificities of synovial T cells remain poorly studied outside of a few epitopes, and open resources of TCRs and repertoires associated with RA are lacking. To accelerate research efforts into the TCR repertoires and T cell antigen specificities in RA, we report here synovial repertoires mined using a repertoire reconstruction algorithm from two large-cohort RNA sequencing datasets totaling 196 RA patients, as well as additional controls from peripheral blood and other joint disorders (figure 1A, online supplemental methods). The first, GSE89408, had been generated to identify transcriptome signatures in the synovium of patients with RA associated with disease progression (online supplemental table S1). 4 The second, PEAC, focused on early, treatment-naïve patients and identify transcriptome signatures contributing to establishment of disease in synovial tissue and peripheral blood (onlin e supplemental table S2). 5 By exploring these cohorts in the hitherto unnavigated immune repertoire dimension, we built the first openly accessible online database of high-frequency TCR sequences found in the synovium of patients with RA (http://repertoire. life). This reference database is an ongoing effort to collect and compile human TCR repertoires of patients with RA, and can be searched with TCR repertoires identified in future work to better identify public sequences and contextualise their antigen specificity.Initial analysis of this database demonstrated that an increased repertoire diversity among synovial (but not peripheral blood) high-frequency clonotypes was associated with higher disease activity (Disease Activity Score-28,(DAS28)) and erythrocyte sedimentation rate (ESR)(figure 1B, C, online supplemental figure S1, online supplemental table S3), highlighting the significant correlations between synovial oligoclonal expansion and clinical indices. Through TCR clustering analyses, we observed that synovial TCR motifs from patients with RA were largely distinct from those found in other joint diseases (online supplemental figure S2), in a manner consistent with their overall transcriptome differences (online supplemental figure S3), but that these motifs could be shared in aggregate among patients with lymphoid pathotype (online supplemental figure S4). Consistently, we also observed that several of these motifs were clonally expanded and enriched in patients with highly active disease as assessed through multiple indices (figure 1D, online supplemental figures S5, S6), further indicating their potential involvement in RA progression. Through comparison with paired peripheral blood samples from the same patients, we observed that a
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影响因子：
30.5
作者：
Weyand CM;Goronzy JJ
通讯作者：
Goronzy JJ
影响因子：
4.9
作者：
Davignon JL;Combe B;Cantagrel A
通讯作者：
Cantagrel A
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影响因子：
30.5
作者：
Minervina, Anastasia A.;Pogorelyy, Mikhail, V;Kirk, Allison M.;Crawford, Jeremy Chase;Allen, E. Kaitlynn;Chou, Ching-Heng;Mettelman, Robert C.;Allison, Kim J.;Lin, Chun-Yang;Brice, David C.;Zhu, Xun;Vegesana, Kasi;Wu, Gang;Trivedi, Sanchit;Kottapalli, Pratibha;Darnell, Daniel;McNeely, Suzanne;Olsen, Scott R.;Schultz-Cherry, Stacey;Estepp, Jeremie H.;McGargill, Maureen A.;Wolf, Joshua;Thomas, Paul G.
通讯作者：
Thomas, Paul G.
影响因子：
32.4
作者：
Bacher P;Rosati E;Esser D;Martini GR;Saggau C;Schiminsky E;Dargvainiene J;Schröder I;Wieters I;Khodamoradi Y;Eberhardt F;Vehreschild MJGT;Neb H;Sonntagbauer M;Conrad C;Tran F;Rosenstiel P;Markewitz R;Wandinger KP;Augustin M;Rybniker J;Kochanek M;Leypoldt F;Cornely OA;Koehler P;Franke A;Scheffold A
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Scheffold A
影响因子：
16.6
作者：
Savola P;Kelkka T;Rajala HL;Kuuliala A;Kuuliala K;Eldfors S;Ellonen P;Lagström S;Lepistö M;Hannunen T;Andersson EI;Khajuria RK;Jaatinen T;Koivuniemi R;Repo H;Saarela J;Porkka K;Leirisalo-Repo M;Mustjoki S
通讯作者：
Mustjoki S