IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease

Abstract

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.

Comprehensive proteomics analyses identify PIM kinases as key regulators of IL-15 driven activation of intestinal intraepithelial lymphocytes

“…IL-15 has been shown induce cytolytic effector function in human IEL in the context of certain target cells (Ebert, 1998;Roberts et al, 2001). It has previously been suggested that IL-15 triggers IEL cytotoxic activity by upregulating expression of Granzyme B, and the activating receptor NKG2D, both in human and murine IEL (Meresse et al, 2006, Abadie et al, 2020. However, in our proteomics data, we find only modest upregulation of NKG2D, on a very small proportion of IEL.…”

Genome-Wide Transcriptomic Analysis of Intestinal Mucosa in Celiac Disease Patients on a Gluten-Free Diet and Postgluten Challenge

“…It should be noted that we addressed gluten-induced transcriptomic changes in respect to morphology and inflammation after a 10-week gluten challenge using small and moderate amount (2–4 g) of gluten and did not study, for example, newly diagnosed celiac disease patients who had ingested 10—20 g of gluten for decades. However, we were able to test our data with the published independent data (dataset GSE134900), 31 suggesting that our regression model could be applicable for newly diagnosed celiac disease patients. In addition, our study design can exclude patients with the highest and most acute response to gluten with even lower and shorter gluten challenge.…”

“…Subsequently, we tested the ability of our models to discriminate between healthy controls and celiac patients on independent data. The PCA was performed on dataset GSE134900 31 ( Figure 11 C–E ). F statistics suggest that by using the expression of 4 genes predicted by our models to describe the variance in histomorphology parameters we are able to discriminate between healthy and celiac disease patients better than by using the expression of 4 randomly selected genes ( F = 78 and 36 for VH:CrD and IEL density, respectively, compared with F = 8 for randomly selected genes).…”

An Untargeted Metabolomics Investigation of Jiulong Yak (Bos grunniens) Meat by 1H-NMR

“…We transformed variables that were not-normally distributed according to Box and Cox [28]. Following Abadie et al [29], we looked for molecules, whose concentration varied among muscle types, with ANOVA, followed by Tukey HSD post hoc test (p < 0.05). Due to the low number of samples in TP group, we investigated the differences between LT and TP groups focusing on fold change, as suggested by Wang et al [30].…”