Expanding the Immunologic and Neuronal Landscape of IgE‐Mediated Anaphylaxis

Anaphylaxis is a life-threatening immunoglobulin E (IgE)-mediated type I hypersensitivity reaction with rising prevalence and burden. It involves mast cell degranulation upon cross-linking of antigen on mast cell-bound IgE. Mechanisms of IgE-mediated anaphylaxis remain incompletely understood, particularly the induction of systemic symptoms (hypothermia, hypotension). We consider two hypotheses driving anaphylaxis. In the first case, circulating antigen reaches mast cells systemically, causing widespread degranulation and downstream effects. In a second scenario, a subset of mast cells "view" antigen, initiating local activation and extensive neuronal signaling to activate distal mast cells and trigger tissue responses. Support for systemic antigen is evident in food allergy, with allergenicity determined by antigen stability in the face of digestion, and antigen translocation across the gut epithelium and within circulation, possibly through chylomicrons. Emerging research implicates neuronal signaling in modulating systemic responses, with mast cells communicating bidirectionally with neurons via released mediators. These interactions lower activation thresholds, amplify inflammation, and engage key downstream receptors and pathways. In vivo models demonstrate such mast cell neuromodulation underlying systemic manifestations of IgE-mediated anaphylaxis, including pruritus and hypothermia. The evidence suggests that both scenarios are likely at play in anaphylaxis, warranting further investigation.