The Microbiome Activates CD4 T-cell-mediated Immunity to Compensate for Increased Intestinal Permeability.
The Microbiome Activates CD4 T-cell-mediated Immunity to Compensate for Increased Intestinal Permeability.
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DOI：
10.1016/j.jcmgh.2017.06.001
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发表时间：
2017-09
影响因子：
7.2
通讯作者：
Turner JR
中科院分区：
文献类型：
--
作者：
Edelblum KL;Sharon G;Singh G;Odenwald MA;Sailer A;Cao S;Ravens S;Thomsen I;El Bissati K;McLeod R;Dong C;Gurbuxani S;Prinz I;Mazmanian SK;Turner JR
尽管存在显著的相关性，但慢性肠屏障丧失并不足以在人类受试者或实验动物中诱发疾病。我们假设代偿性粘膜免疫激活可能保护肠通透性增加的个体免受疾病的侵害。我们使用了一个模型，其中肠屏障丧失是由肠上皮特异性表达组成活性肌球蛋白轻链激酶（CA-MLCK）引发的。在这里，我们询问本构紧密结屏障丧失是否影响对肠道病原体的易感性。在CA-MLCK转基因或野生型小鼠中评估急性或慢性刚地弓形虫或鼠伤寒沙门菌感染。在肠道通透性增加的情况下，无菌小鼠或缺乏特异性免疫细胞群的小鼠被用来研究微生物激活免疫对病原体易位的影响。CA-MLCK小鼠急性弓形虫和鼠伤寒沙门氏菌跨上皮屏障的易位减少。这种保护是由于粘膜免疫激活的增强，需要CD4+ T细胞和白细胞介素17A，而不是免疫球蛋白a。CA-MLCK小鼠的保护性粘膜免疫激活依赖于节段丝状细菌（SFB），因为在无菌的CA-MLCK小鼠中，对早期鼠伤寒沙门氏菌入侵的保护丧失了，但可以通过含有SFB而不是缺乏SFB的微生物群进行常规恢复。相比之下，慢性鼠伤寒沙门氏菌感染在CA-MLCK小鼠中更为严重，这表明尽管激活了保护性粘膜免疫，屏障缺陷最终导致疾病进展加快。上皮紧密连接通透性的增加与共生菌协同作用，促进肠道CD4+ t细胞扩增和白细胞介素17A的产生，从而限制肠道病原体的侵袭。
Despite a prominent association, chronic intestinal barrier loss is insufficient to induce disease in human subjects or experimental animals. We hypothesized that compensatory mucosal immune activation might protect individuals with increased intestinal permeability from disease. We used a model in which intestinal barrier loss is triggered by intestinal epithelial-specific expression of constitutively active myosin light chain kinase (CA-MLCK). Here we asked whether constitutive tight junction barrier loss impacts susceptibility to enteric pathogens. Acute or chronic Toxoplasma gondii or Salmonella typhimurium infection was assessed in CA-MLCK transgenic or wild-type mice. Germ-free mice or those lacking specific immune cell populations were used to investigate the effect of microbial-activated immunity on pathogen translocation in the context of increased intestinal permeability. Acute T gondii and S typhimurium translocation across the epithelial barrier was reduced in CA-MLCK mice. This protection was due to enhanced mucosal immune activation that required CD4+ T cells and interleukin 17A but not immunoglobulin A. The protective mucosal immune activation in CA-MLCK mice depended on segmented filamentous bacteria (SFB), because protection against early S typhimurium invasion was lost in germ-free CA-MLCK mice but could be restored by conventionalization with SFB-containing, not SFB-deficient, microbiota. In contrast, chronic S typhimurium infection was more severe in CA-MLCK mice, suggesting that despite activation of protective mucosal immunity, barrier defects ultimately result in enhanced disease progression. Increased epithelial tight junction permeability synergizes with commensal bacteria to promote intestinal CD4+ T-cell expansion and interleukin 17A production that limits enteric pathogen invasion.
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影响因子：
2.7
作者：
Cong, Hua;Mui, Ernest J.;Witola, William H.;Sidney, John;Alexander, Jeff;Sette, Alessandro;Maewal, Ajesh;El Bissati, Kamal;Zhou, Ying;Suzuki, Yasuhiro;Lee, Daniel;Woods, Stuart;Sommerville, Caroline;Henriquez, Fiona L.;Roberts, Craig W.;McLeod, Rima
通讯作者：
McLeod, Rima
影响因子：
30.3
作者：
Johansson ME;Jakobsson HE;Holmén-Larsson J;Schütte A;Ermund A;Rodríguez-Piñeiro AM;Arike L;Wising C;Svensson F;Bäckhed F;Hansson GC
通讯作者：
Hansson GC
影响因子：
32.4
作者：
Khounlotham M;Kim W;Peatman E;Nava P;Medina-Contreras O;Addis C;Koch S;Fournier B;Nusrat A;Denning TL;Parkos CA
通讯作者：
Parkos CA
影响因子：
29.4
作者：
Gradel, Kim O.;Nielsen, Hans L.;Nielsen, Henrik
通讯作者：
Nielsen, Henrik
影响因子：
3.1
作者：
Gerlach, Katharina;McKenzie, Andrew N.;Weigmann, Benno
通讯作者：
Weigmann, Benno