Characterizing the role of IgG antibodies in anaphylaxis

Anaphylaxis is a severe and potentially fatal allergic reaction. The current paradigm in humans states that anaphylaxis is triggered by allergen-specific IgE antibodies (Abs). Several reports in mice indicate that IgG Abs can also trigger anaphylaxis. The goal of my thesis was to better understand the pathways through which IgG mediate anaphylaxis. We first evaluated this in an adjuvant-free mouse model of active systemic anaphylaxis. We observed a contribution of the 'classical’ pathway mediated by IgE, FcγRI, mast cells and histamine. However, anaphylaxis was largely mediated by an ‘alternative’ pathway driven by IgG, FcγRIII, macrophages and PAF. We then examined whether human IgG can also trigger anaphylaxis. Omalizumab, an IgG1 anti-IgE mAb, has been reported to induce adverse events, including anaphylaxis. We found that Omalizumab forms immune complexes with IgE that engage FcγRs and induce both skin inflammation and anaphylaxis when injected into mice expressing all human FcγRs (hFcγRKI). We then developed an Fc-engineered version of Omalizumab which cannot bind FcγRs, and demonstrated that this Ab is as potent as Omalizumab at blocking IgE-mediated allergic reactions, but does not induce FcγR-mediated anaphylaxis. Finally, I describe ongoing work in a new model of peanut anaphylaxis in which hFcγRKI mice are sensitized with IgG from allergic subjects. Preliminary data indicate that these IgG induce anaphylaxis in this model; Surprisingly, anaphylaxis is increased in mice deficient for all FcγRs. We are now investigating the mechanism(s), in particular the implication of the complement pathway, and the role of the inhibitory receptor FcγRIIB.