Epithelial endoplasmic reticulum stress orchestrates a protective IgA response.
Joep GrootjansNiklas KrupkaShuhei HosomiJuan D MatuteThomas HanleySvetlana SaveljevaThomas GensollenJarom HeijmansHai LiJulien P LimenitakisStephanie Christine Ganal-VonarburgShengbao SuoAdrienne M LuomaYosuke ShimodairaJinzhi DuanDavid Q ShihMargaret E ConnerJonathan N GlickmanGwenny M FuhlerNoah W PalmMarcel R de ZoeteChristien J van der WoudeGuo-Cheng YuanKai W WucherpfennigStephan R TarganPhilip RosenstielRichard A FlavellKathy D McCoyAndrew J MacphersonArthur KaserRichard S BlumbergPublished in: Science (New York, N.Y.) (2019)
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.