Project B08
Treg cells as modulators of gluten-induced inflammation in celiac disease
Background
Celiac disease (CeD) is a common inflammatory disease of the small intestine triggered by the ingestion of gluten in genetically susceptible individuals who carry HLA-DQ2 or -DQ8 genotypes. The pathophysiology of CeD is unique. Thus, certain gluten peptides bind to HLA-molecules DQ2 or DQ8 (the necessary but not sufficient genetic predisposition) on antigen-presenting cells in the lamina propria, after their deamidation by the enzyme and CeD autoantigen tissue transglutaminase (TG2). Several cofactors work synergistically to trigger and maintain CeD in those genetically susceptible individuals, including the intestinal microbiota and their metabolites, infections, barrier defects, and alterations of immune cell subsets. CeD is associated with several autoimmune diseases, and impaired mechanisms of tolerance are involved in its pathogenesis.
We hypothesize that specific subsets of Treg cells, which are involved in tissue repair and regeneration, play a role in CeD development and suggest that modulation of these cells represents a novel therapeutic option besides a strict and difficult-to-maintain gluten-free diet.
Strategy
We use the humanized NOD-HLA-DQ8/MHC class II-/- mouse model of CeD in combination with NOD-DEREG mice, as well as duodenal biopsies and PBMCs from patients with active CeD and CeD in remission on the gluten-free diet, or treated with novel drugs to define the role of Treg cells in CeD pathogenesis and to unveil new Treg cell-based therapeutic targets.