Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus.
Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus.
复制标题
非调控Toll样受体7诱导的不同效应B细胞参与系统性红斑狼疮的致病反应。
DOI：
10.1016/j.immuni.2018.08.015
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发表时间：
2018-10-16
期刊：
影响因子：
32.4
通讯作者：
Sanz I
中科院分区：
文献类型：
--
作者：
Jenks SA;Cashman KS;Zumaquero E;Marigorta UM;Patel AV;Wang X;Tomar D;Woodruff MC;Simon Z;Bugrovsky R;Blalock EL;Scharer CD;Tipton CM;Wei C;Lim SS;Petri M;Niewold TB;Anolik JH;Gibson G;Lee FE;Boss JM;Lund FE;Sanz I
系统性红斑狼疮（SLE）的特征在于缺乏IgD和CD 27的B细胞（双阴性; DN）。我们发现DN细胞扩增反映了代表前浆细胞（PC）的CXCR 5 − CD 11 c+细胞（DN 2）的子集。DN 2细胞在患有活动性疾病和肾炎、抗Smith和抗RNA自身抗体的非裔美国患者中占主导地位。它们表达T-bet转录网络;增加Toll样受体-7（TLR 7）;缺乏负TLR调节因子TRAF 5;并且对TLR 7高度反应。DN 2细胞与活化的幼稚细胞（aNAV）共享表型和功能特征以及相似的转录组。它们的PC分化和自身抗体产生由TLR 7以白细胞介素-21（IL-21）介导的方式驱动。克隆共享证实了aNAV、DN 2细胞和PC之间的体内发育联系。本研究确定了自身反应性幼稚B细胞向对先天刺激具有高反应性的PC前体细胞的不同分化命运，以及确定了SLE中滤泡外B细胞活化的突出性，并确定了治疗靶点。滤泡外B细胞在人类系统性狼疮中的作用尚不清楚。詹克斯等人定义了该通路的主要组成部分及其在严重疾病中的重要性。它的激活是由对toll样受体-7的高反应性介导的，并导致产生自身反应性抗体分泌浆母细胞。
Systemic Lupus Erythematosus (SLE) is characterized by B-cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5−CD11c+ cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naïve cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naïve B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B-cell activation in SLE, and identifies therapeutic targets. The role of extrafollicular B cells in human systemic lupus is unknown. Jenks et al. define the main components of this pathway and its prominence in severe disease. Its activation is mediated by hyper-responsiveness to toll-like receptor-7 and leads to the generation of autoreactive antibody-secreting plasmablasts.
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DOI：
10.4049/jimmunol.1400098
发表时间：
2014-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jackson SW;Scharping NE;Kolhatkar NS;Khim S;Schwartz MA;Li QZ;Hudkins KL;Alpers CE;Liggitt D;Rawlings DJ
通讯作者：
Rawlings DJ
影响因子：
13.3
作者：
Chiche, Laurent;Jourde-Chiche, Noemie;Whalen, Elizabeth;Presnell, Scott;Gersuk, Vivian;Dang, Kristen;Anguiano, Esperanza;Quinn, Charlie;Burtey, Stephane;Berland, Yvon;Kaplanski, Gilles;Harle, Jean-Robert;Pascual, Virginia;Chaussabel, Damien
通讯作者：
Chaussabel, Damien
DOI：
10.4049/jimmunol.1400666
发表时间：
2014-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Luo W;Mayeux J;Gutierrez T;Russell L;Getahun A;Müller J;Tedder T;Parnes J;Rickert R;Nitschke L;Cambier J;Satterthwaite AB;Garrett-Sinha LA
通讯作者：
Garrett-Sinha LA
DOI：
10.1084/jem.20150585
发表时间：
2015-09-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kolhatkar NS;Brahmandam A;Thouvenel CD;Becker-Herman S;Jacobs HM;Schwartz MA;Allenspach EJ;Khim S;Panigrahi AK;Luning Prak ET;Thrasher AJ;Notarangelo LD;Candotti F;Torgerson TR;Sanz I;Rawlings DJ
通讯作者：
Rawlings DJ
影响因子：
56.9
作者：
ARPIN, C;DECHANET, J;LIU, YJ
通讯作者：
LIU, YJ