Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.

OBJECTIVEDAFNE (Dose Adjustment For Normal Eating), a structured education program in flexible insulin therapy, has been widely adopted in the U.K. after validation in a randomized trial. To determine benefits in routine practice, we collected biomedical and psychological data from all participants attending during a 12-month period.RESEARCH DESIGN AND METHODSHbA1c, weight, self-reported hypoglycemia awareness, severe hypoglycemia frequency, PAID (Problem Areas In Diabetes), HADS (Hospital Anxiety and Depression Scale), and EuroQol Group 5-Dimension Self-Report Questionnaire scores were recorded prior to DAFNE and after 1 year.RESULTSComplete baseline and follow-up HbA1c data were available for 639 (54.9%) of 1,163 attendees. HbA1c fell from 8.51 ± 1.41 (mean ± SD) to 8.24 ± 1.29% (difference 0.27 [95% CI 0.16–0.38]; P < 0.001), with a greater mean fall of 0.44% from baseline HbA1c >8.5%. Severe hypoglycemia rate fell from 1.7 ± 8.5 to 0.6 ± 3.7 episodes per person per year (1.1 [0.7–1.4]) and hypoglycemia recognition improved in 43% of those reporting unawareness. Baseline psychological distress was evident, with a PAID score of 25.2 and HADS scores of 5.3 (anxiety) and 4.8 (depression), falling to 16.7 (8.5 [6.6–10.4]), 4.6 (0.7 [0.4–1.0]), and 4.2 (0.6 [0.3–0.8]), respectively (all P < 0.001 at 1 year). Clinically relevant anxiety and depression (HADS ≥8) fell from 24.4 to 18.0% and 20.9 to 15.5%, respectively.CONCLUSIONSA structured education program delivered in routine clinical practice not only improves HbA1c while reducing severe hypoglycemia rate and restoring hypoglycemia awareness but also reduces psychological distress and improves perceived well-being.

SUMMARY Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germ-line-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD.

Coeliac disease (CeD) is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that selectively occurs in a subset of genetically susceptible HLA-DQ8 and HLA-DQ2 individuals 1 , 2 . The need to develop non-dietary treatments is now widely recognized 3 , but it is hampered by the lack of a pathophysiologically relevant gluten- and HLA-dependent preclinical model. Furthermore, while human studies have led to major advances in our understanding of CeD pathogenesis 4 , direct demonstration of the respective roles of disease-predisposing HLA molecules, and adaptive and innate immunity in the development of tissue damage is missing. To address these unmet needs, we engineered a mouse model that reproduces the dual overexpression of IL-15 in the gut epithelium and the lamina propria (LP) characteristic of active CeD, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy (VA) upon gluten ingestion. We show that overexpression of IL-15 in both the epithelium and LP is required for the development of VA, demonstrating the location-dependent central role of IL-15 in CeD pathogenesis. Furthermore, our study reveals that CD4 + T cells and HLA-DQ8 are required for VA development, because of their critical role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell (IEC) lysis. Finally, it establishes that IFN-γ and transglutaminase 2 (TG2) are central for tissue destruction. This mouse model, by reflecting the complex interplay between gluten, genetics and the IL-15-driven tissue inflammation, represents a powerful preclinical model for the characterization of cellular circuits critically involved in intestinal tissue damage in CeD, and the identification and testing of new therapeutic strategies.