B-lymphocyte-intrinsic and -extrinsic defects in secretory immunoglobulin A production in the neural crest-conditional deletion of endothelin receptor B model of Hirschsprung-associated enterocolitis.
B-lymphocyte-intrinsic and -extrinsic defects in secretory immunoglobulin A production in the neural crest-conditional deletion of endothelin receptor B model of Hirschsprung-associated enterocolitis.
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先天性巨结肠相关小肠结肠炎神经嵴条件性删除内皮素受体 B 模型中分泌性免疫球蛋白 A 产生的 B 淋巴细胞内在和外在缺陷。
DOI：
10.1096/fj.201801913r
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Gosain,Ankush
中科院分区：
文献类型：
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作者：
Medrano,Giuliana;Cailleux,Frederic;Guan,Peihong;Kuruvilla,Korah;Barlow-Anacker,AmandaJ;Gosain,Ankush
先天性巨结肠是新生儿肠梗阻的常见原因。Hirschsprung相关性小肠结肠炎（HAEC）是HSCR的一种严重且危及生命的并发症，影响高达60%的患者。内皮素受体B（Ednr B）突变的动物模型可靠地模拟人HSCR和HAEC。我们以前证明了肠道生态失调和肠道特异性缺乏B淋巴细胞产生的分泌型伊加（sIgA），粘膜免疫的主要效应分子，在小鼠与纯合子神经嵴细胞条件性缺失EdnrB（EdnrBNCC−/−）。为了确定sIgA缺乏的机制，我们研究了B淋巴细胞发育和功能的内在和外在方面。内皮素轴组分[内皮素-1（ET-1）、内皮素-3（ET-3）、内皮素受体A（EdnrA）、EdnrB]的表达在发育时间过程中被确定。体外测定B淋巴细胞存活和IG产生。研究了聚合物IG受体（pIgR）介导的伊加转运至肠腔。结果表明，内皮素轴成分（EdnrA、EdnrB、ET-1、ET-3）在发育中的髓外造血器官中表达，部分脾B淋巴细胞表达EdnrB。与野生型（WT）B淋巴细胞相比，EdnrBNCC−/−小鼠的脾B淋巴细胞在存活率方面没有表现出内在缺陷。脾B淋巴细胞的体外刺激表明EdnrBNCC−/−与WT小鼠相比伊加、IgG和IgM的产生减少。此外，EdnrBNCC−/−小鼠的小肠pIgR降低了约50%。这些结果表明，在HAEC的EdnrBNCC−/−模型中，抗体产生的内在B淋巴细胞缺陷以及伊加转运的外在缺陷。我们的结果与人HAEC观察到的管腔sIgA减少和其他炎性肠病的小鼠模型一致，其中pIgR减少与失调的微生物群一致。最后，我们的研究结果表明，靶向生态失调的微生物组和pIgR介导的sIgA转运是预防和治疗HAEC的潜在治疗方法。Medrano，G.，Cailleux，F.，Guan，P.，Kuruvilla，K.，Barlow-Anacker，A. J.，Gosain，A. Hirschsprung相关小肠结肠炎内皮素受体B神经嵴条件性缺失模型中分泌性免疫球蛋白A产生的B淋巴细胞内在和外在缺陷
Hirschsprung disease (HSCR) is a common cause of intestinal obstruction in the newborn. Hirschsprung-associated enterocolitis (HAEC) is a significant and life-threatening complication of HSCR, affecting up to 60% of patients. Animal models of endothelin receptor B (EdnrB) mutation reliably model human HSCR and HAEC. We previously demonstrated intestinal dysbiosis and a gut-specific deficiency of B-lymphocyte–produced secretory IgA (sIgA), the primary effector molecule of mucosal immunity, in mice with homozygous neural crest cell–conditional deletion of EdnrB (EdnrBNCC−/−). To determine mechanisms for sIgA deficiency, we examined intrinsic and extrinsic aspects of B-lymphocyte development and function. Expression of the endothelin axis components [endothelin-1 (ET-1), endothelin-3 (ET-3), endothelin receptor A (EdnrA), EdnrB] were determined over a developmental time course. B-lymphocyte survival and Ig production were assayed in vitro. Polymeric Ig receptor (pIgR)–mediated IgA transport into the intestinal lumen was interrogated. We found endothelin axis component (EdnrA, EdnrB, ET-1, ET-3) expression in developing extramedullary hematopoietic organs and that some splenic B lymphocytes express EdnrB. Splenic B lymphocytes from EdnrBNCC−/− mice showed no intrinsic defect in survival vs. wild-type (WT) B lymphocytes. In vitro stimulation of splenic B lymphocytes demonstrated decreased IgA, IgG, and IgM production in EdnrBNCC−/− vs. WT mice. Additionally, small intestinal pIgR was decreased ∼50% in EdnrBNCC−/− mice. These results suggest an intrinsic B-lymphocyte defect in antibody production as well as an extrinsic defect in IgA transport in the EdnrBNCC−/− model of HAEC. Our results are consistent with human HAEC observations of decreased luminal sIgA and mouse models of other inflammatory bowel diseases, in which decreased pIgR is seen in concert with a dysregulated microbiota. Finally, our results suggest targeting the dysbiotic microbiome and pIgR-mediated sIgA transport as potential therapeutic approaches in prevention and treatment of HAEC.—Medrano, G., Cailleux, F., Guan, P., Kuruvilla, K., Barlow-Anacker, A. J., Gosain, A. B-lymphocyte–intrinsic and –extrinsic defects in secretory immunoglobulinA production in the neural crest–conditional deletion of endothelin receptor B model of Hirschsprung-associated enterocolitis.