Ahdi Hypothesis

The adjective "autoimmune" encodes an aetiological claim that is rarely examined: that the immune system has lost its capacity to discriminate self from non-self. The serological evidence on which the term rests, however, establishes only what an antibody binds, not how that binding came about. This preprint proposes that in most chronic immune-mediated diseases directed at endogenous targets the primary event is not a failure of discrimination but a persistent disruption of antigenic homeostasis — the set of tissue-level mechanisms that keep the quantity, location, molecular state, duration of exposure and presentation context of endogenous antigens constant. Under this model, recognition is not erroneous; it is correct recognition of a target that should not have been available in that form, in that place, or for that length of time. A self-sustaining amplification loop accounts for chronicity after the initiating cause has become undetectable. The resulting architecture is referred to as antigenic-homeostasis-driven immunopathology (AHDI). The model makes a specific and falsifiable prediction: for each such disease it should be possible to identify the enzyme that produces the antigenic anomaly, distinct from the enzyme that merely serves as a diagnostic target. The paper sets out the supporting evidence, the diseases where the model fails, four conditions that would refute it, and an experimental programme using existing preclinical cohorts and serum banks.A full exposition of the hypothesis, with a per-disease catalogue of cryptic antigens and enzymes, twelve anticipated objections and the experimental programme, is published as the volume "Oltre il paradigma autoimmune: l'ipotesi AHDI" (2026, in Italian).