Figure 1: Gluten has a dual effect on the small intestine mucosa. Innate response (left). Toxic peptides, such as the 19-mer, induce an unspecific immune response characterized by the presence of IL-15 produced by the enterocytes, that in turn activates the NF- B in the adjacent cells, which enhances the IL-15 production and iNOS induction and feedback of the innate response. Molecule expression as MICA and/or HLA-E is increased in the enterocytes and IL-15-triggered apoptosis on these cells to induce expression of NKG2D and NKG2C molecules (ligands MICA and HLA-E, resp.) in intraepithelial lymphocytes. Finally, IL-15 can weaken the bonds tight-junctions between the enterocytes. Adaptive response (right): is facilitated by increased intestinal permeability allowing passage of immunogenic peptides such as the 33-mer to the lamina propria, which are deamidated by the enzyme tissue transglutaminase (TG2). Furthermore, IL-15 activates dendritic cells, which increases the surface expression of costimulatory molecules, necessary for effective antigen presentation by HLA-DQ2-restricted/DQ8, to T lymphocytes. These lymphocytes trigger a Th1 response, with a predominance of IFN and the absence of IL-10, and the release by stromal cells, growth factors, and keratinocytic metalloprotease of Th1 cytokine profile is responsible for the injury, characterized by intraepithelial lymphocytosis, crypt hyperplasia, and villous flattening, but can also attract new proinflammatory cells in the lamina propria. (Adapted with permission from Dr. E. Arranz).