Figure 2. A schematic presentation of celiac disease induction via CTLA-4 dysfunction. (A) Gluten is ingested and digested, reaching the gut lumen as gliadin peptides. (B) Gliadins are rich in glutamine and proline, and thus are a prime substrate for deamidation and cross-linking by luminal and mucosal transglutaminases, thus, turning those naïve molecules into immunogenic ones. Transglutaminase capacity to deamidated or transamidate, results in increased post-translation modified proteins (PTMP). Luminal digestive peptidases cannot further break down those bonds, hence, inducing gut inflammation, mucus disruption, and intestinal epithelial damage. (C) Gluten increases intestinal permeability by binding to epithelial CXCR3 receptors, resulting in zonulin release. Gliadin-transglutaminase transformed peptides can potentially infiltrate through the open junctions or trans-enterocytically into the lamina propria. A breach in the epithelial barrier exposes the highly immunoreactive sub-epithelium to luminal foreign antigens, stimulating the local immune system. (D) In the lamina propria, gliadin-transglutaminase cross-linked complexes induce pro-inflammatory cytokines. (E) Two types of DC are present, sub-epithelial DCs that send protrusions into the lumen and sense the gut microbiota, and the lamina propria DCs that migrate to lymph nodes, where they present antigens and activate T cells. (F) Immune checkpoint inhibitors block co-inhibitory pathways unleashing effector T cells and depleting regulatory T cells. CTLA-4 polymorphism, such as CT60, manifest itself in less soluble CTLA-4, which leads to a more aggressive response. (G) Uncontrolled activation and proliferation of cytotoxic T lymphocytes (CTLs) further aggravate barrier perturbation, secreting IFNγ and TNFα cytokines, leading to severe intestinal damage

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When Genetic Polymorphism Meets an Immune Checkpoint Inhibitor in Celiac Disease

Aaron Lerner, Carina Benzvi

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