Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

• Published in: Science (American Association for the Advancement of Science) Vol. 363; no. 6430; pp. 993 - 998
• Main Authors: Grootjans, Joep, Krupka, Niklas, Hosomi, Shuhei, Matute, Juan D., Hanley, Thomas, Saveljeva, Svetlana, Gensollen, Thomas, Heijmans, Jarom, Li, Hai, Limenitakis, Julien P., Ganal-Vonarburg, Stephanie C., Suo, Shengbao, Luoma, Adrienne M., Shimodaira, Yosuke, Duan, Jinzhi, Shih, David Q., Conner, Margaret E., Glickman, Jonathan N., Fuhler, Gwenny M., Palm, Noah W., de Zoete, Marcel R., van der Woude, C. Janneke, Yuan, Guo-Cheng, Wucherpfennig, Kai W., Targan, Stephan R., Rosenstiel, Philip, Flavell, Richard A., McCoy, Kathy D., Macpherson, Andrew J., Kaser, Arthur, Blumberg, Richard S.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.03.2019; The American Association for the Advancement of Science
• Subjects: Animals; Autophagy; Autophagy-Related Proteins - genetics; Commensalism; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Epithelial cells; Epithelial Cells - immunology; Epithelium; Gastrointestinal tract; Humans; Immunity, Mucosal; Immunoglobulin A; Immunoglobulin A - immunology; Immunoglobulins; Inflammation; Intestinal Mucosa - immunology; Lamina propria; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiota; Microorganisms; Mucosa; Peritoneum; Phagocytosis; Plasma cells; Plasma Cells - immunology; Stress; Tissue Culture Techniques; X-Box Binding Protein 1 - genetics
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aat7186

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.