Hosomi et al. show that intestinal epithelial cell–specific deletion of X-box–binding protein 1, an unfolded protein response–related transcription factor, results in CHOP-dependent increased expression of specific natural killer group 2 member D (NKG2D) ligands. This activates NKG2D-expressing intraepithelial group 1 ILCs and promotes small intestinal inflammation.

SummaryBackgroundInflammatory bowel disease (IBD) can be exacerbated by stress and depression. Type D personality, characterised by high negative affectivity and social inhibition, represents a vulnerability towards stressors and is associated with adverse outcomes in coronary heart disease.AimsTo assess the prevalence of Type D personality in IBD patients and investigate potential associations with disease course.MethodsWe tested for associations between Type D (Type D Scale‐14), depressive symptoms (Hospital Anxiety and Depression Scale's depression subscore ≥11) and recurrent IBD amongst Swiss IBD cohort patients. We built regression models for cross‐sectional and Cox proportional hazards models for time‐to‐event analyses. IBD disease course was assessed by the future occurrence of active disease (Crohn's Disease Activity Index ≥150/Modified Truelove & Witts activity index ≥10) and several IBD‐relevant endpoints.ResultsAmongst 2275 patients (1005 ulcerative colitis, 1270 Crohn's disease), 672 (29.5%) had Type D. Type D was a significant risk factor for future active disease (adjusted hazard ratio, aHR: 1.60, corrected P value, q = 0.007) and predicted the future presence of depressive symptoms (aHR: 3.30, P < 0.001). The combination of Type D and depressive symptoms further increased the risk for active disease (aHR: 3.98, q < 0.001). However, Type D associated depressive symptoms seemed to be the main contributor to this effect as Type D's predictive power decreased considerably in models corrected for depressive symptoms (aHR: 1.32, CI: 0.97‐1.79, q = 0.292).ConclusionsType D personality's prevalence amongst IBD patients was comparable with its prevalence in the general population. Type D was strongly associated with depressive symptoms and showed modest independent associations with IBD prognosis.

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.