Figure 7: A keystone mechanism in celiac disease (CD) pathogenesis: the lamina propria adaptive CD4+ T-cell response to gluten orchestrated by HLA-DQ2/8 molecules. In active CD, gluten peptides left undigested by luminal and brush border enzymes can enter into the intestinal mucosa. Because of their primary sequence rich in Q-X-P motifs, gluten peptides are preferential substrates for tissue transglutaminase II (Ttgase). This enzyme is activated by tissue damage and can deamidate neutral glutamine residues into negatively charged glutamic acid (left box). Negative charges in gluten peptides, as well as the presence of proline residues at specific positions, facilitate their binding into the peptide pocket of HLA-DQ2 (or HLA-DQ8) expressed by antigen-presenting cells (APCs; including likely CD11c+ dendritic cells, 33 and CD123+ plasmacytoid dendritic cells 126; right box). Gluten presentation promotes the activation of a gliadin-specific TH1 CD4+ response in the intestinal lamina propria. Interferon (IFN-γ) can participate in the induction of mucosal damage 11.