Celiac disease mechanism and therapies (Homo sapiens)

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In celiac disease, gluten peptides breach the intestinal epithelial barrier and are deamidated by tissue transglutaminase 2 (TG2). These modified peptides are presented on HLA-DQ2 or HLA-DQ8 molecules by antigen-presenting cells (APCs), leading to the activation of gluten-specific CD4⁺ T cells. Once activated, these T cells produce inflammatory cytokines such as IFN-γ, IL-2, IL-21, and TNF-α, which contribute to small-intestinal mucosal damage, in part by acting alongside IL-15 secreted by inflamed epithelial cells.

Intraepithelial cytotoxic CD8⁺ T cells are also activated, releasing granzyme B (GZMB) and IFN-γ, amplifying the cycle of inflammation. In the periphery, gluten-specific memory CD4⁺ T cells remain vigilant and rapidly respond to gluten exposure—within 6 hours—by releasing inflammatory mediators like IL-2.

Emerging evidence suggests that bacterial or viral infections may disrupt oral tolerance to gluten. Current therapeutic approaches under investigation target multiple stages of CeD pathogenesis:

• Glutenases and anti-gliadin antibody AGY degrade or neutralize gluten;

• Integrin antagonists and tight junction modulators aim to restore epithelial barrier integrity;

• TG2 inhibitors block gluten peptide deamidation;

• Anti-IL-15 monoclonal antibodies (mAbs) suppress IL-15–driven inflammation;

• CD4⁺ T cell–targeted therapies seek to inhibit the expansion of pathogenic gluten-specific T cells;

• Tolerance-inducing strategies aim to delete or anergize gluten-specific CD4⁺ T cells or promote their differentiation into regulatory T cells (Tregs).