Failed Mucosal Allostasis Distinguishes Murine IgG ‐ From IgE ‐Mediated Recurrent Severe Anaphylaxis

ABSTRACT Background Anaphylaxis is classically framed around IgE‐FcεRI, yet a subset of severe reactions engages an IgG–FcγR‐mediated arm whose consequences for mucosal barrier integrity and epithelial repair remain undefined under recurrence. We propose that mucosal surfaces sustain function during severe anaphylaxis through coordinated operation of immunological composition, structural integrity and reparative capacity—which we term mucosal allostasis—and asked whether the two pathways diverge along this framework. Methods BALB/c mice were resolved into IgE‐ and IgG‐mediated arms using a hybrid active/passive (ASA‐PSA) sensitisation model and subjected to acute or recurrent severe anaphylaxis, with pharmacological reversal enabling matched rechallenge. Lung, small intestine, colon and serum were profiled across cytokine, mediator, junctional, repair and bacterial 16S rDNA panels; ILC subsets and junctional integrity were resolved by flow cytometry and immunohistochemistry. Results Despite comparable systemic clinical severity, the two pathways diverged sharply at the mucosal level. IgE‐mediated recurrence preserved junctional expression and mounted a coordinated AREG/EGF/periostin/TFF3/MUC2 repair programme, whereas IgG‐mediated recurrence dismantled both: Claudin‐1, Occludin, ZO‐1 and E‐cadherin declined in tissue and rose reciprocally in serum, repair mediators failed to engage where junctional injury was greatest, and bacterial DNA translocation rose 48‐fold, alongside a type 2/regulatory to inflammatory shift and an ILC2 to ILC1/NCR + ILC3 reorganisation. Conclusion Recurrent IgE‐ and IgG‐mediated severe anaphylaxis diverge into two mechanistically opposite allostatic phenotypes. IgG‐mediated recurrence produces an allostatic collapse in which structural failure proceeds uncoupled from reparative engagement, identifying barrier–repair coupling as a candidate axis for intervention in refractory anaphylaxis.