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. 2023 Oct 23;24(20):15482. doi: 10.3390/ijms242015482

Figure 1.

Figure 1

Proposed mechanisms of the innate and adaptive immune system in the pathophysiology of celiac disease. Innate immune system. Gluten ingestion triggers gliadin to bind to intestinal epithelium’s CXCR3 receptor, initiating Zonulin release from enterocytes. Zonulin disrupts enterocyte tight junctions, enhancing intestinal permeability. Increased permeability facilitates gluten peptides’ translocation, triggering IL-15 releasing by DCs. IL-15 activates and expands epithelial-damaging CD8+ T IELs. IL-15 may induce NKRs NKG2D and CD94/NKG2C expression on IELs, which then interact with ligands on enterocytes, initiating a cytotoxic attack leading to epithelial damage. Additionally, IL-15 depresses TGF-β from Treg and regulatory FOXP3 T cells, exacerbating the immune response. Adaptive immune system. TG2, generated by IEL-damaged enterocytes, catalyzes the deamidation of neutral glutamine residues into negatively charged glutamic acid residues. This deamidation enhances the potency of gluten peptides, which subsequently bind to MHC class II on DCs. Once presented by antigen-presenting cells, these antigens are recognized by T-cell receptors on CD4+ T helper cells, activating and proliferating them. Activated T cells produce proinflammatory cytokines including IFNγ, IL-21, and IL-2. IFNγ drives CD4+ T cells towards a TH1 cytokine profile, inhibits the TH2 immune response, and reduces regulatory T-cell survival. Also, it may result in reduced BACH2 expression, impairing the formation of functional Tregs. CD4+ T cells can also induce damage through cytotoxic granules containing granzyme B and perforin. Furthermore, CD4+ T cells enhance the activity of CD8+ cytotoxic T IELs, which then increase granzyme B and IFNγ synthesis. TG2 potentially accelerates the degradation of anti-inflammatory PPAR-γ, possibly initiating celiac disease inflammation. Additionally, TG2 may increase transcellular permeability to intact gliadin peptides. Abbreviations: DC, dendritic cells; IL15, interleukin-15; IL10, interleukin-10; IL2, interleukin-2; IL21, interleukin-21; IEL, intraepithelial lymphocytes; IFN-γ, interferon-gamma; MHC, major histocompatibility complex; PPAR-γ, peroxisome proliferator-activated receptor gamma, TG2, tissue transglutaminase 2; TGF-β, Transforming growth factor-beta.