Fig. 1

Adapted simplified pathogenesis of celiac disease [3, 5, 9]. Prolamin overcomes the epithelial barrier via a transcellular transport as a soluble IgA-prolamin complex bound to an epithelial receptor (CD71). The interaction of prolamin with a chemokine receptor CXCR3 leads to the release of Zonulin, a protein that increases the permeability of the epithelium, due to opening of Tight-junctions and hence allows paracellular transport of prolamin. CD71, CXCR3 and Zonulin are upregulated in patients with celiac disease. Prolamin that reaches the lamina propria gets deamidated by transglutaminase 2 (TG2) and hence binds more strongly to human leukocyte antigens (HLA)-DQ2 and DQ8 molecules on antigen-presenting cells. These presented prolamins activate CD4⁺T-cells, which then secrete proinflammatory cytokines. Furthermore, T-cells induce the expression of Interleukin (IL) 15 and autoantibodies against TG2 by innate immune cells. IL 15 has a very important role regarding the remodeling process of the intestinal surface. It leads to an upregulation of nonconventional HLA molecules, MICA on enterocytes, and activates NKG2D receptors on intraepithelial lymphocytes (IELs). The interaction of MICA and NKG2D promotes the downstream effect of IEL-mediated epithelial damage. Another source of IL 15 are epithelial and dendritic cells after contact with prolamin. To sum up, the contact of prolamin with the epithelial layer activates the innate and humoral immune system, which induces the destruction of the surface of the small intestine