An Inflammation‐Associated Control Mechanism of Allergy by Proteolysis of IgE

BACKGROUND: Adaptive IgE-mediated reactions are faster than immune responses that depend on IgM, IgA, and IgG. Normal serum IgE concentrations are highly variable among individuals and extremely low in comparison with those of IgM and IgG. Omalizumab is a clinically approved monoclonal antibody that selectively binds free IgE, preventing allergy-specific IgE from binding to FcεRI expressed on mast cells and basophils, thereby inhibiting degranulation and mediator release. We aimed to evaluate proteolysis of IgE within the contexts of acute inflammations in vitro and in patient samples and the biological effects of resulting IgE proteoforms. METHODS: IgE was subjected in vitro to neutrophil proteases. Biochemical and biological IgE proteoform identification was performed and IgE receptor binding capacity and abundance in patient samples were evaluated. RESULTS: Whereas IgG, IgA, and IgM are neutrophil protease-resistant, the IgE heavy chain was cleaved in a bait region by these inflammation-associated proteases. The cleavages occurred on both free and CD23-bound IgE; however, not with FcεRI-bound IgE. Proteolysis generated two proteoforms: a large IgE cleavage fragment (IgEcl) and a smaller IgE carboxyterminal truncation fragment Cεtr. Proteolysed IgE did not bind to its receptors. The Cεtr fragment shared with chemokines high affinity to glycosaminoglycans (GAGs) and synergistically attracted neutrophils. The discovered bait region in IgE corresponded with a shared epitope recognized by omalizumab, and omalizumab prevented IgE proteolysis. Both IgEcl and Cεtr were present in plasma samples from patients suffering from IgE-mediated allergies, chronic spontaneous urticaria, and more abundantly in atopic dermatitis (AD) patients. CONCLUSIONS: This work reveals new mechanistic insights into the immunobiology of IgE and the action of omalizumab with potential clinical impacts. Indeed, IgE-specific cleavage by inflammation-associated granulocyte proteinases may be an important feedback mechanism to control allergic responses.