Type I Interferon-Activated STAT4 Regulation of Follicular Helper T Cell-Dependent Cytokine and Immunoglobulin Production in Lupus.
Type I Interferon-Activated STAT4 Regulation of Follicular Helper T Cell-Dependent Cytokine and Immunoglobulin Production in Lupus.
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I型干扰素激活的STAT4对狼疮中滤泡辅助性T细胞依赖性细胞因子和免疫球蛋白产生的调节
DOI：
10.1002/art.41532
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Weinstein JS
中科院分区：
文献类型：
--
作者：
Dong X;Antao OQ;Song W;Sanchez GM;Zembrzuski K;Koumpouras F;Lemenze A;Craft J;Weinstein JS
评估STAT4激活在小鼠和人狼疮期间驱动致病性滤泡辅助T （Tfh）细胞分泌细胞因子IL-21和IFN-γ中的作用。在小鼠狼疮过程中，我们暂时评估了stat4依赖性Tfh细胞信号与细胞因子产生和自身反应性B细胞成熟的关系，并使用RNA-seq进一步评估了Tfh细胞基因转录。与对照组的细胞相比，SLE患者循环中的tfh样细胞中也测定了stat4依赖性信号传导和细胞因子产生，与前者的疾病活动性相关。在狼疮易感小鼠中，IL-21和IFN-γ共同产生的Tfh细胞在检测潜在致病性IgG2c自身抗体之前扩增。Tfh细胞在疾病过程中转录进化，获得stat4依赖的基因特征。Tfh细胞细胞因子合成的维持依赖于STAT4信号，由I型干扰素驱动。来自SLE患者的循环tfh样（cTfh）细胞也分泌IL-21和IFN-γ，且STAT4磷酸化被IFN-β增强，与临床疾病活动性相关。我们确定了IFN- i信号在小鼠和人类狼疮中Tfh细胞驱动STAT4激活和IL-21和IFN-γ产生中的作用。在小鼠和人狼疮中，Tfh细胞中STAT4激活的增强可能是致病B细胞反应的基础。这些数据表明，STAT4在SLE中引导致病细胞因子和免疫球蛋白的产生，为调节自身免疫提供了一个潜在的治疗靶点。
To assess the role of STAT4 activation in driving pathogenic follicular helper T (Tfh) cell secretion of the cytokines IL-21 and IFN-γ during murine and human lupus. We temporally assessed STAT4-dependent Tfh cell signaling with cytokine production and autoreactive B cell maturation during the course of murine lupus, with further assessment of Tfh cell gene transcription using RNA-seq. STAT4-dependent signaling and cytokine production were also determined in circulating Tfh-like cells in patients with SLE, compared to cells from controls, with correlation to disease activity in the former. IL-21 and IFN-γ co-producing Tfh cells expanded prior to the detection of potentially pathogenic IgG2c autoantibodies in lupus-prone mice. Tfh cells transcriptionally evolved during the course of disease with acquisition of a STAT4-dependent gene signature. Maintenance of Tfh cell cytokine synthesis was dependent upon STAT4 signaling, driven by type I interferons. Circulating Tfh-like (cTfh) cells from patients with SLE also secreted IL-21 and IFN-γ, with STAT4 phosphorylation enhanced by IFN-β, in association with clinical disease activity. We identified a role for IFN-I signaling in driving STAT4 activation and production of IL-21 and IFN-γ by Tfh cells in murine and human lupus. Enhanced STAT4 activation in Tfh cells may underlie pathogenic B cell responses in both murine and human lupus. These data indicate that STAT4 guides pathogenic cytokine and immunoglobulin production in SLE, providing a potential therapeutic target to modulate autoimmunity.
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影响因子：
27.4
作者：
Munroe ME;Lu R;Zhao YD;Fife DA;Robertson JM;Guthridge JM;Niewold TB;Tsokos GC;Keith MP;Harley JB;James JA
通讯作者：
James JA
影响因子：
32.4
作者：
Marshall HD;Chandele A;Jung YW;Meng H;Poholek AC;Parish IA;Rutishauser R;Cui W;Kleinstein SH;Craft J;Kaech SM
通讯作者：
Kaech SM
自动发芽中心的克隆进化。
影响因子：
64.5
作者：
Degn SE;van der Poel CE;Firl DJ;Ayoglu B;Al Qureshah FA;Bajic G;Mesin L;Reynaud CA;Weill JC;Utz PJ;Victora GD;Carroll MC
通讯作者：
Carroll MC
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
影响因子：
32.4
作者：
Nakayamada S;Kanno Y;Takahashi H;Jankovic D;Lu KT;Johnson TA;Sun HW;Vahedi G;Hakim O;Handon R;Schwartzberg PL;Hager GL;O'Shea JJ
通讯作者：
O'Shea JJ