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Science. 2019 Mar 1;363(6430):993-998. doi: 10.1126/science.aat7186.

Epithelial endoplasmic reticulum stress orchestrates a protective IgA response.

Author information

1
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
2
Amsterdam University Medical Center, University of Amsterdam, Department of Gastroenterology and Hepatology and Tygat Institute for Liver and Intestinal Research, Meibergdreef 9, Amsterdam, Netherlands.
3
Maurice Müller Laboratories (DBMR), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, Murtenstrasse 35, University of Bern, 3010 Bern, Switzerland.
4
Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
5
Division of Neonatology, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
6
Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
7
Amsterdam University Medical Center, University of Amsterdam, Department of Internal Medicine, Tygat Institute for Liver and Intestinal Research, Meibergdreef 9, Amsterdam, Netherlands.
8
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
9
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
10
F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
11
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
12
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
13
Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands.
14
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
15
Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.
16
Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Rosalind-Franklin-Str. 12, 24105 Kiel, Germany.
17
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06519, USA.
18
Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
19
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. rblumberg@bwh.harvard.edu.
#
Contributed equally

Abstract

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.

PMID:
30819965
PMCID:
PMC6637967
DOI:
10.1126/science.aat7186
[Indexed for MEDLINE]
Free PMC Article

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