Antibody secreting cells are critically dependent on integrin α4β7/MAdCAM-1 for intestinal recruitment and control of the microbiota during chronic colitis.
Antibody secreting cells are critically dependent on integrin α4β7/MAdCAM-1 for intestinal recruitment and control of the microbiota during chronic colitis.
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DOI：
10.1038/s41385-021-00445-z
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发表时间：
2022-01
影响因子：
8
通讯作者：
Rivera-Nieves J
中科院分区：
文献类型：
--
作者：
Tyler CJ;Guzman M;Lundborg LR;Yeasmin S;Zgajnar N;Jedlicka P;Bamias G;Rivera-Nieves J
T 细胞和 B 细胞利用整合素 α4β7 在稳态条件下迁移至肠道。这些细胞在炎症条件下是否不同地依赖 α4β7 归巢尚未得到充分研究。这可能对我们理解抗整合素疗法在炎症性肠病（IBD）中的作用方式有一定的影响。在这里，我们使用 IL-10−/− 小鼠、β7 缺陷型 IL-10−/− 小鼠、IgA 缺陷型 IL-10−/− 小鼠以及 MAdCAM-1 抗体阻断，研究了 α4β7 整合素在慢性结肠炎期间的作用。我们发现α4β7主要由B细胞表达。 β7 缺陷和 MAdCAM-1 阻断特异性地耗尽结肠 LP 中的抗体分泌细胞 (ASC)（不是 T 细胞），导致粪便全免疫球蛋白缺乏、严重结肠炎和微生物群组成的改变。结肠炎并不是由于调节缺陷造成的，因为树突状细胞 (DC)、调节性 T 细胞、视黄醛脱氢酶 (RALDH) 表达、活性和调节性 T/B 细胞细胞因子在菌株/治疗之间都具有可比性。最后，IgA 缺陷密切再现了 β7 缺陷型 IL-10−/− 小鼠的临床表型和改变的微生物群组成。因此，管腔 IgA 缺陷会在 β7 缺陷状态下加速结肠炎。鉴于 IgA ASC 对 α4β7:MAdCAM-1 肠道归巢的关键/非冗余依赖性，B 细胞可能代表了抗整合素治疗中未被重视的靶点。
T and B cells employ integrin α4β7 to migrate to intestine under homeostatic conditions. Whether those cells differentially rely on α4β7 for homing during inflammatory conditions has not been fully examined. This may have implications for our understanding of the mode of action of anti-integrin therapies in inflammatory bowel disease (IBD). Here, we examined the role of α4β7 integrin during chronic colitis using IL-10−/− mice, β7-deficient IL-10−/−, IgA-deficient IL-10−/− mice, and antibody blockade of MAdCAM-1. We found that α4β7 was predominantly expressed by B cells. β7 deficiency and MAdCAM-1 blockade specifically depleted antibody secreting cells (ASC) (not T cells) from the colonic LP, leading to a fecal pan-immunoglobulin deficit, severe colitis, and alterations of microbiota composition. Colitis was not due to defective regulation, as dendritic cells (DC), regulatory T cells, retinaldehyde dehydrogenase (RALDH) expression, activity, and regulatory T/B-cell cytokines were all comparable between the strains/treatment. Finally, an IgA deficit closely recapitulated the clinical phenotype and altered microbiota composition of β7-deficient IL-10−/− mice. Thus, a luminal IgA deficit contributes to accelerated colitis in the β7-deficient state. Given the critical/nonredundant dependence of IgA ASC on α4β7:MAdCAM-1 for intestinal homing, B cells may represent unappreciated targets of anti-integrin therapies.
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影响因子：
7.3
作者：
Brynjolfsson SF;Persson Berg L;Olsen Ekerhult T;Rimkute I;Wick MJ;Mårtensson IL;Grimsholm O
通讯作者：
Grimsholm O
影响因子：
4.9
作者：
Keubler LM;Buettner M;Häger C;Bleich A
通讯作者：
Bleich A
DOI：
10.1093/ecco-jcc/jjx121
发表时间：
2018-01-05
期刊：
Journal of Crohn's & colitis
影响因子：
--
作者：
Hassan-Zahraee M;Banerjee A;Cheng JB;Zhang W;Ahmad A;Page K;von Schack D;Zhang B;Martin SW;Nayak S;Reddy P;Xi L;Neubert H;Fernandez Ocana M;Gorelick K;Clare R;Vincent M;Cataldi F;Hung K
通讯作者：
Hung K
影响因子：
2.5
作者：
Gorfu G;Rivera-Nieves J;Ley K
通讯作者：
Ley K
影响因子：
--
作者：
Nowicka, Malgorzata;Krieg, Carsten;Robinson, Mark D
通讯作者：
Robinson, Mark D