IL-21 Rescues the Defect of IL-10-Producing Regulatory B Cells and Improves Allergic Asthma in DOCK8 Deficient Mice.
IL-21 Rescues the Defect of IL-10-Producing Regulatory B Cells and Improves Allergic Asthma in DOCK8 Deficient Mice.
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IL-21 挽救 DOCK8 缺陷小鼠产生 IL-10 的调节性 B 细胞的缺陷并改善过敏性哮喘
DOI：
10.3389/fimmu.2021.695596
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发表时间：
2021
影响因子：
7.3
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Jiang J;Qin T;Zhang L;Liu Q;Wu J;Dai R;Zhou L;Zhao Q;Luo X;Wang H;Zhao X
人类DOCK8基因突变会导致一种以哮喘和食物过敏等过敏性疾病为特征的联合免疫缺陷综合征。然而，潜在的机制尚不清楚。产生IL-10的调节性B(Breg)细胞在变态反应性和自身免疫性疾病患者中发挥强大的免疫抑制功能。DOCK8缺乏的B细胞对TLR9信号的反应减弱，这表明DOCK8缺乏的人产生IL-10的Breg细胞可能存在缺陷，这可能是导致过敏的原因之一。在这里，我们分离了DOCK8缺陷患者的外周血单个核细胞，并建立了Dock8 KO小鼠模型，以研究DOCK8缺陷对Breg细胞的影响。DOCK8缺陷患者和Dock8 KO小鼠在产生IL-10的Breg细胞中存在数量和质量上的缺陷；这些缺陷是由Dock8-/-CD4+T细胞异常引起的。我们发现，重组小鼠(RM)IL-21在体外和Dock8KO小鼠体内都恢复了Bregs的功能，导致在小鼠哮喘模型中肺内炎性细胞的浸润减少。总体而言，这些结果为基于Breg或基于IL-21的过敏性疾病治疗策略的潜在设计提供了新的见解，包括与DOCK8缺乏相关的哮喘。
Mutations in human DOCK8 cause a combined immunodeficiency syndrome characterized by allergic diseases such as asthma and food allergy. However, the underlying mechanism is unclear. Regulatory B (Breg) cells that produce IL-10 exert potent immunosuppressive functions in patients with allergic and autoimmune disorders. DOCK8-deficient B cells show diminished responses to TLR9 signaling, suggesting a possible defect in IL-10-producing Breg cells in those with DOCK8 deficiency, which may contribute to allergies. Here, we isolated peripheral blood mononuclear cells from DOCK8-deficient patients and generated a Dock8 KO mouse model to study the effect of DOCK8 deficiency on Breg cells. DOCK8-deficient patients and Dock8 KO mice harbored quantitative and qualitative defects in IL-10-producing Breg cells; these defects were caused by abnormal Dock8-/- CD4+ T cells. We found that recombinant murine (rm)IL-21 restored the function of Bregs both in vitro and in Dock8 KO mice, leading to reduced inflammatory cell infiltration of the lungs in a murine asthma model. Overall, the results provide new insight into the potential design of Breg-based or IL-21-based therapeutic strategies for allergic diseases, including asthma associated with DOCK8 deficiency.
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影响因子：
30.5
作者：
Schneider, Caitlin;Shen, Connie;Gopal, Angelica A.;Douglas, Todd;Forestell, Benjamin;Kauffman, Keith D.;Rogers, Dakota;Artusa, Patricio;Zhang, Qian;Jing, Huie;Freeman, Alexandra F.;Barber, Daniel L.;King, Irah L.;Saleh, Maya;Wiseman, Paul W.;Su, Helen C.;Mandl, Judith N.
通讯作者：
Mandl, Judith N.
影响因子：
12.4
作者：
Braza, F.;Chesne, J.;Brouard, S.
通讯作者：
Brouard, S.
影响因子：
24.8
作者：
Krishnaswamy JK;Gowthaman U;Zhang B;Mattsson J;Szeponik L;Liu D;Wu R;White T;Calabro S;Xu L;Collet MA;Yurieva M;Alsén S;Fogelstrand P;Walter A;Heath WR;Mueller SN;Yrlid U;Williams A;Eisenbarth SC
通讯作者：
Eisenbarth SC
影响因子：
4.4
作者：
Singh, Anurag;Carson, William F.;Schramm, Craig M.
通讯作者：
Schramm, Craig M.
影响因子：
4.4
作者：
Lampropoulou, Vicky;Hoehlig, Kai;Fillatreau, Simon
通讯作者：
Fillatreau, Simon