The ARA theory of compartmental autoimmunity: Access–Recognition–Amplification as a sequential architecture of autoimmune phenotypes

Abstract

"Autoimmunity" groups together, under a single term, mechanistically heterogeneous processes that existing models of molecular mimicry and loss of tolerance fail to explain through a shared mechanism. It is proposed that autoimmunity is not a mechanistically homogeneous natural kind, but a common clinical phenotype reachable by divergent etiological pathways. It is argued that the primary causal hypothesis is not molecular resemblance between an exogenous antigen and a self-antigen, but access: the arrival of a damaging supramolecular architecture — of microbial origin, iatrogenic origin, or both at once — in a protected anatomical compartment, and the consequent exposure of an autoantigen normally hidden or tolerized. This proposal is organized under the Access–Recognition–Amplification (ARA) framework: mimicry is only one of the possible modalities by which the immune response comes to recognize and fix upon a self antigen, not the only one, and treating it as synonymous with "recognition" obscures mechanisms — such as bystander co-presentation, enzymatic neoepitope generation, or dual BCR–TLR activation by nucleic-acid complexes — that require no structural resemblance at all. An eight-step sequential architecture (the Compartmental Sequence) is developed that mechanistically instantiates the three stages of the ARA framework; its submodels are specified (VECT — Vascular Escape–Corona–Transcytosis — for excipient-mediated access; seven modalities of Access, including apoptotic relocalization of autoantigen; six modalities of Recognition grouped into three families, plus a hapten-carrier submechanism formalized in celiac disease; two mechanisms of Amplification, including a cross-cutting axis of biopersistent-load reactivation); and it is applied to a bank of more than thirty cases — bacterial, iatrogenic, and idiopathic autoimmune — evaluated under explicit causality standards (Oldstone [1]; Witebsky/Rose-Bona [2]) and with associated falsifiable predictions. The bank also includes boundary cases that test the framework at its extremes: phenotypes with demonstrated Access but no established Recognition (ALS), phenotypes with established causal Recognition but no identified pathological Access (idiopathic pemphigus vulgaris, anti-AChR myasthenia gravis, anti-MuSK myasthenia gravis, and AQP4-IgG-positive NMOSD); a further, amplification-first boundary profile in which Amplification is well specified while Access and Recognition remain unresolved (idiopathic dermatomyositis); and a paraneoplastic and pharmacological family of candidate exceptions to Access-necessity, assessed in §9.1 against an explicit threshold for when such a candidate counts as genuine (checkpoint-inhibitor-associated ANCA vasculitis; cancer-associated anti-TIF1-γ dermatomyositis). It is further proposed that this architecture is of general scope — not restricted to the cases addressed here — but that universality is explicitly put forward as a prediction of the theory, open to refutation, not as an already-demonstrated premise; one boundary case developed in this document, thymoma-associated myasthenia gravis, is the strongest positive candidate identified to date for such a refutation — a demonstrated primary failure of central tolerance, not yet shown to form a sufficient causal chain to pathogenic Recognition — and §9.1 specifies in advance the evidence that would elevate it to a confirmed exception. The framework distinguishes nominal exposure from effective compartmental Access, formalizes Access imprinting and phase-dependent partial or full autonomy, and treats host state as a modifier of each transition and of reversibility. ARA is situated as the autoimmune sister grammar of ADA within the provisional broader program of Spatially Compartmentalized Disorders, while retaining its own mechanisms, scope and evidentiary standards.