Turning Swords Into Plowshares: Transglutaminase to Detoxify Gluten

In CD, increased intestinal permeability allows dietary gluten peptides to cross the epithelial barrier, either via loosened tight junctions or transcytosis. M cells play a potentially important but yet unexplored role in luminal gluten uptake. Having reached the lamina propria, these peptides are deamidated by tissue transglutaminase (tTG), which generates epitopes that bind more efficiently to HLA-DQ2 or -DQ8, which are expressed by antigen-presenting cells (APCs), such as dendritic or B cells. After intracellular processing the HLA-DQ2– or HLA-DQ8–peptide complexes reach the surface of the APCs to stimulate CD4⁺ T cells that finally drive the inflammation, crypt hyperplasia, and villous atrophy found in CD. Prior treatment of gluten with microbial transglutaminase (mTG) and lysine methyl ester exploits the enzyme’s substrate specificity for the immune dominant gluten epitopes to abolish their T-cell stimulatory capabilities.