Celiac Disease: From Pathogenesis to Novel Therapies

Pathogenesis of celiac disease. Gluten peptides that are highly resistant to intestinal proteases reach the lamina propria, via either epithelial transcytosis or an increased epithelial tight junctional permeability. Cross-linking and particularly deamidation of gluten peptides by TG2 creates potent immunostimulatory epitopes that are presented via HLA-DQ2 or HLA-DQ8 on antigen-presenting cells. Subsequently, CD4⁺ T cells are activated, secreting mainly Th1 cytokines such as IFN-γ, which induces the release and activation of MMPs by myofibroblasts, finally resulting in mucosal remodeling and villus atrophy. Additionally, Th2 cytokines are produced driving the production of (auto-)antibodies to gluten and TG2. Other cytokines such as IL-18, IFN-α, or IL-21 seem to play a role in polarizing and maintaining the Th1 response. Furthermore, IL-15 links the adaptive immune system to innate immune responses (see Figure 2). The scheme is simplified. It does not show that T cells circulate to mesenteric lymph nodes where they encounter and are primed by antigen-presenting cells (mainly dendritic cells) and from where they home back to the lamina propria, a process that is driven by the lymphocyte homing receptors CCR9 and integrin α4β7.

Innate immune responses in celiac disease. Upon stimulation with gliadin peptide p31-49 (and other peptides), epithelial cells, macrophages, and dendritic cells secrete IL-15, which in turn up-regulates both the NKG2D receptor on IELs and its epithelial ligand MICA. The thus stimulated cytotoxic lymphocytes induce increased epithelial apoptosis and permeability. Furthermore, the NKG2C receptor on a subset of natural killer–like IELs is stimulated by its epithelial ligand HLA-E on epithelial cells, resulting in their proliferation and cytotoxicity, whereas stimulation of γδ⁺ CD8⁺ IELs bearing the NKG2A receptor via HLA-E induces TGF-β secretion and therefore a regulatory phenotype. Gliadin (cereal) peptides can also directly elicit innate immune responses in macrophages and dendritic cells via pattern recognition receptors such as Toll-like receptor 4 or other MyD88-dependent pathways. This drives maturation of these cells and secretion of inflammatory cytokines such as IL-1β, IL-8, tumor necrosis factor α, and MCP-1, which can potentiate the adaptive immune response to gluten. APC, antigen presenting cell; pDC, plasmacytoid dendritic cell.

Novel therapeutic approaches. Use of ancestral and/or modified wheat strains with lower immunogenicity. Intraluminal therapies that either bind or degrade ingested gluten peptides in the intestine (glutenases, gluten binders, neutralizing antibodies). Blocking the ZOT receptor with the octapeptide AT-1001 to decrease intestinal permeability is another option. Furthermore, because the deamidation of gluten peptides by TG2 and the subsequent presentation by HLA-DQ2/8 initiates the adaptive immune responses, TG2 inhibitors and DQ2 blocking peptides seem to be an attractive possibility to prevent inflammation. Another promising alternative, especially for patients with refractory celiac disease, is directly targeting the immune cells either by lymphocyte blocking (anti–IL-15, anti-CCR9, anti-α4β7) or tolerance induction.