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

Research output: Contribution to journalArticleAcademicpeer-review


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
Externally publishedYes


  • Animals
  • Autophagy
  • Autophagy-Related Proteins/genetics
  • Endoplasmic Reticulum Stress
  • Epithelial Cells/immunology
  • Humans
  • Immunity, Mucosal
  • Immunoglobulin A/immunology
  • Inflammation
  • Intestinal Mucosa/immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plasma Cells/immunology
  • Tissue Culture Techniques
  • X-Box Binding Protein 1/genetics


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