Interleukin-13 Receptor α1-Mediated Signaling Regulates Age-Associated/Autoimmune B Cell Expansion and Lupus Pathogenesis.
Interleukin-13 Receptor α1-Mediated Signaling Regulates Age-Associated/Autoimmune B Cell Expansion and Lupus Pathogenesis.
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DOI：
10.1002/art.42146
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发表时间：
2022-09
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年龄相关/自身免疫B细胞（abc）是一种新兴的B细胞亚群，在SLE中异常扩张。ABC的产生和分化表现出明显的性别二态性，TLR7的参与是这些性别差异的关键因素。ABC的产生也受IL-21及其与IFNγ和IL-4的相互作用控制。本文研究了IL-13Rα1（一种传递IL-4/IL-13信号的x连锁受体）是否能调控ABCs和狼疮的发病机制。将缺乏DEF6和SWAP-70 （Double-Knock-out=DKO）的小鼠与IL-13Rα1KO小鼠杂交，使其在雌性中优先发生狼疮。IL-13Rα1KOs也与Yaa-DKO雄性杂交，导致TLR7过表达，发病严重。采用流式细胞仪（FACS）和RNA-seq法测定abc。通过血清学和组织学分析评估狼疮的发病机制。白细胞介素13r α1在abc细胞中的表达水平高于滤泡B细胞。无论是DKO女性还是Yaa-DKO男性，IL-13Rα1的缺失都降低了ABCs的积累、向浆母细胞的分化以及自身抗体的产生。IL-13Rα1的缺乏也延长了生存期，延缓了组织炎症的发展。IL-13Rα1缺乏减少了体外产生的abc，令人惊讶的是，这一效应可以在单独IL-21的反应中观察到。RNAseq显示，缺乏IL-13Rα1的abc下调了B细胞的一些特征，但上调了髓细胞标志物和促炎介质。这些研究揭示了IL-13Rα1在控制ABC生成和分化中的新作用，表明IL-13Rα1通过调节il -21介导的一组信号事件来参与这些作用。这些研究也提示除了TLR7外，x连锁基因也参与了狼疮中abc的调控。
Age-Associated/Autoimmune B cells (ABCs) are an emerging B cell subset that aberrantly expand in SLE. ABC generation and differentiation exhibit marked sexual dimorphism and TLR7 engagement is a key contributor to these sex differences. ABC generation is also controlled by IL-21 and its interplay with IFNγ and IL-4. Here we investigated whether IL-13Rα1, an X-linked receptor that transmits IL-4/IL-13 signals, can regulate ABCs and lupus pathogenesis. Mice lacking DEF6 and SWAP-70 (Double-Knock-out=DKO) that develop lupus preferentially in females were crossed with IL-13Rα1KO mice. IL-13Rα1KOs were also crossed to Yaa-DKO males, which overexpress TLR7 and develop severe disease. ABCs were assessed by FACS and RNA-seq. Lupus pathogenesis was evaluated by serologic and histological analyses. ABCs express higher levels of IL-13Rα1 than follicular B cells. Absence of IL-13Rα1 in either DKO females or Yaa-DKO males decreased the accumulation of ABCs, their differentiation into plasmablasts, and autoantibody production. Lack of IL-13Rα1 also prolonged survival and delayed the development of tissue inflammation. IL-13Rα1 deficiency diminished the in vitro generation of ABCs, an effect that, surprisingly, could be observed in response to IL-21 alone. RNAseq revealed that ABCs lacking IL-13Rα1 downregulated some B cell characteristics but upregulated myeloid markers and proinflammatory mediators. These studies uncover a novel role for IL-13Rα1 in the control of ABC generation and differentiation suggesting that IL-13Rα1 contributes to these effects by regulating a subset of IL-21-mediated signaling events. These studies also suggest that X-linked genes besides TLR7 participate in the regulation of ABCs in lupus.
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DOI：
10.4049/jimmunol.1700372
发表时间：
2017-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Barik S;Ellis JS;Cascio JA;Miller MM;Ukah TK;Cattin-Roy AN;Zaghouani H
通讯作者：
Zaghouani H
影响因子：
27.4
作者：
Kwon YC;Lim J;Bang SY;Ha E;Hwang MY;Yoon K;Choe JY;Yoo DH;Lee SS;Lee J;Chung WT;Kim TH;Sung YK;Shim SC;Choi CB;Jun JB;Kang YM;Shin JM;Lee YK;Cho SK;Kim BJ;Lee HS;Kim K;Bae SC
通讯作者：
Bae SC
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：
16.6
作者：
Langefeld CD;Ainsworth HC;Cunninghame Graham DS;Kelly JA;Comeau ME;Marion MC;Howard TD;Ramos PS;Croker JA;Morris DL;Sandling JK;Almlöf JC;Acevedo-Vásquez EM;Alarcón GS;Babini AM;Baca V;Bengtsson AA;Berbotto GA;Bijl M;Brown EE;Brunner HI;Cardiel MH;Catoggio L;Cervera R;Cucho-Venegas JM;Dahlqvist SR;D'Alfonso S;Da Silva BM;de la Rúa Figueroa I;Doria A;Edberg JC;Endreffy E;Esquivel-Valerio JA;Fortin PR;Freedman BI;Frostegård J;García MA;de la Torre IG;Gilkeson GS;Gladman DD;Gunnarsson I;Guthridge JM;Huggins JL;James JA;Kallenberg CGM;Kamen DL;Karp DR;Kaufman KM;Kottyan LC;Kovács L;Laustrup H;Lauwerys BR;Li QZ;Maradiaga-Ceceña MA;Martín J;McCune JM;McWilliams DR;Merrill JT;Miranda P;Moctezuma JF;Nath SK;Niewold TB;Orozco L;Ortego-Centeno N;Petri M;Pineau CA;Pons-Estel BA;Pope J;Raj P;Ramsey-Goldman R;Reveille JD;Russell LP;Sabio JM;Aguilar-Salinas CA;Scherbarth HR;Scorza R;Seldin MF;Sjöwall C;Svenungsson E;Thompson SD;Toloza SMA;Truedsson L;Tusié-Luna T;Vasconcelos C;Vilá LM;Wallace DJ;Weisman MH;Wither JE;Bhangale T;Oksenberg JR;Rioux JD;Gregersen PK;Syvänen AC;Rönnblom L;Criswell LA;Jacob CO;Sivils KL;Tsao BP;Schanberg LE;Behrens TW;Silverman ED;Alarcón-Riquelme ME;Kimberly RP;Harley JB;Wakeland EK;Graham RR;Gaffney PM;Vyse TJ
通讯作者：
Vyse TJ
影响因子：
7.3
作者：
Junttila IS
通讯作者：
Junttila IS