Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis.
Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis.
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DOI：
10.1172/jci.insight.150999
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发表时间：
2021-11-22
期刊：
影响因子：
8
通讯作者：
RAVE-ITN Research Group
中科院分区：
文献类型：
--
作者：
Berti A;Hillion S;Hummel AM;Son YM;Chriti N;Peikert T;Carmona EM;Abdulahad WH;Heeringa P;Harris KM;St Clair EW;Brunetta P;Fervenza FC;Langford CA;Kallenberg CG;Merkel PA;Monach PA;Seo P;Spiera RF;Stone JH;Grandi G;Sun J;Pers JO;Specks U;Cornec D;RAVE-ITN Research Group
抗中性粒细胞胞质抗体相关性血管炎（ANCA相关性血管炎，AAV）中的自身反应性B细胞目前知之甚少。我们的目的是研究循环抗原特异性蛋白酶3反应（PR 3+）B细胞的耐受性检查点。对来自RAVE试验（NCT 00104299）的154名具有严重活性的PR 3-AAV和髓过氧化物酶-AAV（MPO-AAV）的充分表征的参与者和27名健康对照（HC）的PBMC的基线样品进行多色流式细胞术结合生物信息学和功能性体外研究。临床数据和试验结果与PR 3 + B细胞（总细胞和亚群）相关。在PR 3-AAV参与者中，循环B细胞中PR 3 + B细胞的频率较高（中位数4.77%[IQR，3.98%-6.01%]）（中位数3.16%[IQR，2.51%-5.22%]）和AAV受试者与HC受试者相比（1.67%中位数[IQR，1.27%-2.16%]，所有比较P < 0.001），这意味着AAV患者的中枢耐受检查点有缺陷。只有来自患有PR 3-AAV的参与者的PBMC含有能够在体外分泌PR 3-ANCA IgG的PR 3 + B细胞，证明它们在功能上不同于患有MPO-AAV和HC的参与者。无监督聚类鉴定了在PR 3-AAV患者中通过成熟过程积累的非典型自身反应性PR 3+记忆B细胞的细微子集。PR 3 + B细胞在PR 3-AAV参与者的记忆B细胞区室中富集，并与较高的血清CXCL 13水平相关，表明生发中心活性增加。PR 3 + B细胞与全身炎症（C反应蛋白、血沉，P < 0.05）和完全缓解（P < 0.001）相关。这项研究表明，存在缺陷的中央抗原非依赖性和外周抗原依赖性检查点的患者与PR 3-AAV，阐明自身反应性B细胞的选择过程。ClinicalTrials.gov NCT00104299。血管炎基金会、美国国立卫生研究院过敏和传染病研究所和马约教育和研究基金会。
Little is known about the autoreactive B cells in antineutrophil cytoplasmic antibody–associated (ANCA-associated) vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3–reactive (PR3+) B cells. Multicolor flow cytometry in combination with bioinformatics and functional in vitro studies were performed on baseline samples of PBMCs from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-AAV and myeloperoxidase-AAV (MPO-AAV) and 27 healthy controls (HCs). Clinical data and outcomes from the trial were correlated with PR3+ B cells (total and subsets). The frequency of PR3+ B cells among circulating B cells was higher in participants with PR3-AAV (4.77% median [IQR, 3.98%–6.01%]) than in participants with MPO-AAV (3.16% median [IQR, 2.51%–5.22%]) and participants with AAV compared with HCs (1.67% median [IQR, 1.27%–2.16%], P < 0.001 for all comparisons), implying a defective central tolerance checkpoint in patients with AAV. Only PBMCs from participants with PR3-AAV contained PR3+ B cells capable of secreting PR3-ANCA IgG in vitro, proving they were functionally distinct from those of participants with MPO-AAV and HCs. Unsupervised clustering identified subtle subsets of atypical autoreactive PR3+ memory B cells accumulating through the maturation process in patients with PR3-AAV. PR3+ B cells were enriched in the memory B cell compartment of participants with PR3-AAV and were associated with higher serum CXCL13 levels, suggesting an increased germinal center activity. PR3+ B cells correlated with systemic inflammation (C-reactive protein and erythrocyte sedimentation rate, P < 0.05) and complete remission (P < 0.001). This study suggests the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with PR3-AAV, elucidating the selection process of autoreactive B cells. ClinicalTrials.gov NCT00104299. The Vasculitis Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, and the Mayo Foundation for Education and Research.
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DOI：
10.1111/rssb.12298
发表时间：
2019-02-01
影响因子：
5.8
作者：
Li, Ang;Barber, Rina Foygel
通讯作者：
Barber, Rina Foygel
DOI：
10.1038/nri.2017.19
发表时间：
2017-05
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Nemazee D
通讯作者：
Nemazee D
影响因子：
27.4
作者：
Monach PA;Warner RL;Tomasson G;Specks U;Stone JH;Ding L;Fervenza FC;Fessler BJ;Hoffman GS;Iklé D;Kallenberg CG;Krischer J;Langford CA;Mueller M;Seo P;St Clair EW;Spiera R;Tchao N;Ytterberg SR;Johnson KJ;Merkel PA
通讯作者：
Merkel PA
影响因子：
32.4
作者：
Chan, Tyani D.;Wood, Katherine;Brink, Robert
通讯作者：
Brink, Robert
影响因子：
32.4
作者：
Li, H;Jiang, YF;Weigert, M
通讯作者：
Weigert, M