Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

Joep Grootjans, Niklas Krupka, Shuhei Hosomi, Juan D. Matute, Thomas Hanley, Svetlana Saveljeva, Thomas Gensollen, Jarom Heijmans, Hai Li, Julien P. Limenitakis, Stephanie C. Ganal-Vonarburg, Shengbao Suo, Adrienne M. Luoma, Yosuke Shimodaira, Jinzhi Duan, David Q. Shih, Margaret E. Conner, Jonathan N. Glickman, Gwenny M. Fuhler, Noah W. PalmMarcel R. De Zoete, C. Janneke Van Der Woude, Guo Cheng Yuan, Kai W. Wucherpfennig, Stephan R. Targan, Philip Rosenstiel, Richard A. Flavell, Kathy D. McCoy, Andrew J. Macpherson, Arthur Kaser, Richard S. Blumberg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

48 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)993-998
Number of pages6
Issue number6430
Publication statusPublished - 1 Mar 2019

Bibliographical note

Funding Information:
This work was supported by NIH grants DK044319, DK051362, DK053056, and DK088199; the Harvard Digestive Diseases Center (HDDC) DK034854 (R.S.B.); the Wellcome Trust Senior Investigator Award 106260/Z/14/Z, Evelyn Trust 13/27 (A.K.); the HORIZON2020/European Research Council Consolidator Grant 648889 (A.K.); the National Institute for Health Research Cambridge BRC Cell Phenotyping Hub (A.K.); Rubicon grant 825.13.012, Netherlands Organization for Scientific Research (J.G.); JSPS KAKENHI grant number 2689323 and 16K19162, Japan Foundation for Applied Enzymology (S.H.); NIH and NIAID grants R01AI24998 and R21AI117220 (M.E.C); Deutsche Forschungsgemeinschaft grant KR 4749/1-1 (N.K.); NIH NCI grant R01 CA238039 (K.W.W.); DFG ExC Precision Medicine in Chronic Inflammation, H2020 SYSCID #733100 and DFG CRC1182, C2 (P.R.); and Pediatric Scientist Development Program K12-HD000850 (J.D.M.). The Howard Hughes Medical Institute supports R.A.F.

Publisher Copyright:
© 2019 The Authors, some rights reserved. All rights reserved.


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