Abstract Background The incidence of autoimmune diseases has risen markedly over recent decades, yet the initiatingevents of most conditions remain unexplained. Current mechanistic models focus on adaptive immuneperpetuation — the loss of tolerance to specific self-antigens — while the prior question of how and whenautoimmunity is first triggered has received comparatively little attention. Existing frameworks do not account forthe temporal and contextual specificity of disease onset, the organ selectivity of autoimmune targeting, or the roleof modern iatrogenic exposures in disrupting physiological immune homeostasis. Hypothesis We propose a unified mechanistic framework operating at two levels. At the first level, iatrogenicinitiation is driven by the protein corona formed on Al(OH) 3 nanoparticles upon entering the vascularcompartment: PS80 enriches the corona with ApoE, enabling LDLR-mediated transcytosis to organ-specifictissues where aluminum activates NLRP3, generates danger signals, and exposes cryptic autoantigens.Pre-existing anti-PS80/PEG IgM antibodies amplify this innate response through structural pattern mimicry ofexposed repetitive endogenous structures. At the second level, a concurrent or prior gram-negative bacterialinfection consolidates the innate response into organ-specific autoimmune disease through molecular mimicrybetween bacterial OMPs and host tissue proteins — acting as the antigenic specifier, not as the initiator. TheApoE genotype and individual LDLR expression profile are proposed as the primary determinants of which organis targeted at the initiation level. Mechanistic sequence The framework proposes a six-step sequence organised across two causal levels. Level 1(Steps 1–3) operates independently of bacterial infection: vaccination with Al(OH) 3 and PS80 forms anApoE-enriched corona that directs aluminum to LDLR-rich tissues; NLRP3 activation exposes crypticautoantigens; and anti-PS80/PEG IgM amplify innate activation through pattern mimicry, potentially producingtransient sterile autoimmunity. Level 2 (Steps 4–5) consolidates this innate response into defined organ-specificautoimmune disease: gram-negative bacterial OMPs provide the molecular mimicry targets that specify theautoimmune phenotype, with active infection amplifying but not being required for this consolidation. Step 6 isadaptive perpetuation independent of all initiating stimuli. Conclusion This framework integrates five previously published mechanistic hypotheses into a single coherenttwo-level model. It offers a biologically plausible, falsifiable explanation for the organ specificity, abrupt onset,and rising incidence of autoimmune diseases in the context of modern vaccination schedules and widespreadpolyethoxylated excipient exposure. It predicts specific associations between gram-negative bacterial infections,aluminum-adjuvanted vaccines, and defined autoimmune diseases, as tabulated in the companion Master Table ofAutoimmunity.
Añaños et al. (Fri,) studied this question.