Bridging immune activation and neural regulation: exploring anaphylaxis through the neuroimmunological lens

Anaphylaxis is an acute, potentially fatal systemic hypersensitivity reaction characterized by striking variability in onset and severity. Although it is traditionally attributed to IgE-mediated activation of mast cells and basophils, multiple IgE-independent pathways are increasingly recognized, including IgG-mediated mechanisms, MRGPRX2-dependent mast-cell activation, and complement-derived anaphylatoxin signaling. Beyond the immune mechanisms, accumulating experimental evidence suggests that neuronal circuits may participate early and contribute to disease severity. In this narrative review, we synthesize mechanistic and translational evidence supporting a receptor-level framework in which mast-cell mediators and proteases activate and sensitize TRPV1/TRPA1-expressing sensory neurons through protease-activated receptor (PAR) signaling. Subsequent neuronal activation can trigger the release of neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), which may contribute to vascular leakage and systemic manifestations while further amplifying mast-cell activation, including through MRGPRX2. Together, these interactions support the concept of a self-reinforcing neuroimmune amplification loop that may help explain the rapid onset and clinical heterogeneity of anaphylaxis. We propose this framework as a conceptual model to integrate current evidence, highlight potential adjunct therapeutic strategies beyond epinephrine, and identify key priorities for future translational and clinical research while acknowledging the current limitations of human evidence.