The Underappreciated Role of Secretory IgA in IBD

Author:

Bamias Giorgos1ORCID,Kitsou Konstantina1,Rivera-Nieves Jesús23ORCID

Affiliation:

1. GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital , Athens , Greece

2. Gastroenterology Section, San Diego VA Medical Center , La Jolla Village Drive, San Diego, CA , USA

3. Division of Gastroenterology, Department of Medicine, University of California San Diego , La Jolla, CA , USA

Abstract

AbstractEighty percent of antibody secreting cells (ASCs) are found in the intestine, where they produce grams of immunoglobulin (Ig) A daily. immunoglobulin A is actively transcytosed into the lumen, where it plays a critical role in modulating the gut microbiota. Although loss of immune tolerance to bacterial antigens is the likely trigger of the dysregulated immune response that characterizes inflammatory bowel disease (IBD), little effort has been placed on understanding the interface between B cells, IgA, and the microbiota during initiation or progression of disease. This may be in part due to the misleading fact that IgA-deficient humans are mostly asymptomatic, likely due to redundant role of secretory (S) IgM. Intestinal B cell recruitment is critically dependent on integrin α4β7-MAdCAM-1 interactions, yet antibodies that target α4β7 (ie, vedolizumab), MAdCAM-1 (ie, ontamalimab), or both β7 integrins (α4β7 and αE [CD103] β7; etrolizumab) are in clinical use or development as IBD therapeutics. The effect of such interventions on the biology of IgA is largely unknown, yet a single dose of vedolizumab lowers SIgA levels in stool and weakens the oral immunization response to cholera vaccine in healthy volunteers. Thus, it is critical to further understand the role of these integrins for the migration of ASC and other cellular subsets during homeostasis and IBD-associated inflammation and the mode of action of drugs that interfere with this traffic. We have recently identified a subset of mature ASC that employs integrin αEβ7 to dock with intestinal epithelial cells, predominantly in the pericryptal region of the terminal ileum. This role for the integrin had not been appreciated previously, nor the αEβ7-dependent mechanism of IgA transcytosis that it supports. Furthermore, we find that B cells more than T cells are critically dependent on α4β7-MAdCAM-1 interactions; thus MAdCAM-1 blockade and integrin-β7 deficiency counterintuitively hasten colitis in interleukin-10-deficient mice. In both cases, de novo recruitment of IgA ASC to the intestinal lamina propria is compromised, leading to bacterial overgrowth, dysbiosis, and lethal colitis. Thus, despite the safe and effective use of anti-integrin antibodies in patients with IBD, much remains to be learned about their various cell targets.

Funder

National Institutes of Health

San Diego Digestive Diseases Research Center

Chiba University-UC San Diego Program in Mucosal Immunology, Allergy and Vaccines

Publisher

Oxford University Press (OUP)

Subject

Gastroenterology,Immunology and Allergy

Cited by 4 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3