Les interactions entre l’interleukine-15, l’haplotype HLA-DQ8 et le gluten conduisent au développement de la maladie cœliaque chez la souris

Coeliac disease is a chronic inflammatory enteropathy characterized by autoimmune features. This disease occurs in genetically predisposed individuals expressing HLA-DQ2 or HLA-DQ8 haplotypes and is triggered following gluten consumption. The disease is characterized by the development of intestinal villous atrophy leading to malabsorption. The only current therapy is the adherence to a gluten-free diet, but the diet is not always effective and is heavy in concessions. Therefore, the development of alternative therapies is urgent but is a slowly evolving pipeline, mainly due to the absence of a physiologically relevant animal model. The aim of this thesis is to answer this unmet need by developing an animal model capable of recapitulating the main characteristics of the disease. Chapter 1 depicts a portrait of the disease in four points, gradually leading the reader into the details of its pathogenesis. This introduction begins with a review of the physiology and intestinal immunity and then draws a clinical portrait of the disease. Third, the reader evolves in a more detailed part of the pathogenesis helping him to discern its cellular and molecular actors. Finally, the introduction ends with a review of the literature on current animal models. Chapter 2 outlines the thesis objectives based on key data from the literature, in particular, patients present at least one copy of the HLA-DQ2 or HLA-DQ8 haplotype and more than two-thirds over-express the proinflammatory cytokine interleukin-15 at the level of their intestinal mucosa. It is therefore reasonable to hypothesize that gluten, HLA haplotype and interleukin-15 together contribute to the pathogenesis. Although suspected, their roles and interactions still require the provision of tangible evidence in vivo. Chapter 3 details these interactions based on the proposed new mouse model. This model is characterized by the overexpression of interleukin-15 in the intestinal epithelium and lamina propria and by the expression of the HLA-DQ8 haplotype. This work demonstrates that the exposure of this mouse to gluten is accompanied by villous atrophy and the complete serological, cellular and transcriptional signature of the disease. We also demonstrate that simultaneous overexpression of interleukin-15 in both mucosal compartments is a prerequisite for the development of atrophy. This study also highlights the need for CD4+ T cells and interferon-gamma in the activation of intraepithelial lymphocytes and the development of villous atrophy. Finally, this research establishes the central role played by the HLA-DQ8 haplotype and the enzyme tissue transglutaminase II in the occurrence of these lesions. In general, the results from this model presented in Chapter 3 reflects the complexity of the interactions between gluten, genetics and IL-15 in the development of coeliac disease. Finally, chapter 4 concludes this work and chapter 5 discusses future directions for this powerful preclinical model that will undoubtedly contribute to a better understanding of coeliac disease and will allow the identification of new potential therapeutic targets.

Keyphrases: gluten, HLA-DQ8, transglutaminase-2, autoimmunity, coeliac disease, mouse model, gluten, HLA-DQ8, transglutaminase-2, interleukin-15, cytotoxic CD8+ T cells, CD4+ T cells