The Neuroimmune–Allergic Interface: Mechanistic Links Between Allergic and Neurological Disease

The nervous and immune systems form an integrated regulatory network in which neurons, immune cells, vascular structures, and tissue barriers continuously exchange molecular signals. Within this network, allergic and immune dysregulation may intersect with neurological disease through shared genetic defects, mast cell–neural communication, eosinophil-mediated vascular and neural injury, cytokine signaling, kallikrein–kinin activation, and neurovascular barrier mechanisms. This review examines the neuroimmune–allergic interface as a mechanistic framework linking allergic and neurological phenotypes across monogenic, inflammatory, vascular, and mediator-driven disorders. PGM3 deficiency illustrates a pleiotropic shared molecular defect, whereas DOCK8 deficiency and Wiskott–Aldrich syndrome exemplify secondary neurological injury arising from immune dysfunction. Eosinophilic disorders provide clinical evidence of structural neurological injury through vasculitis, thrombosis, and ischemia, whereas direct eosinophil-mediated neuronal cytotoxicity remains less firmly established in humans. Mast-cell and bradykinin-mediated disorders predominantly illustrate functional neuronal and vascular mechanisms, with limited evidence of direct structural neurological injury. We further propose a bidirectional diagnostic framework integrating neurological phenotypes with systemic clues such as severe atopy, eosinophilia, recurrent angioedema, anaphylaxis, elevated basal serum tryptase, and unusual infections. Conversely, severe or atypical allergic phenotypes associated with neurological, developmental, vascular, hematologic, or infectious abnormalities should prompt evaluation for systemic or genetic disease. This framework does not imply that common allergic disease routinely causes neurological pathology. Rather, its clinical value lies in identifying selected patients in whom apparently distinct manifestations share a biologically plausible mechanism, thereby supporting mechanism-based diagnosis, multidisciplinary surveillance, and precision treatment.