Ugarte-Berzal, Estefania, Martens, Erik, Ganseman, Eva, Gouwy, Mieke, Vaz Sousa Pereira, Rafaela, Breynaert, Christine, Schrijvers, Rik, Proost, Paul, Opdenakker, Ghislain, Guntermann, Christine and Wets, Dries (2025) An inflammation-associated control mechanism of allergy by proteolysis of IgE. Allergy. ISSN 0105-4538

Abstract

Background: Acute IgE-mediated reactions are faster than adaptive immune responses which 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 FcRI expressed on mast cells and basophils, thereby inhibiting degranulation and mediator release.
Methods: Proteolysis of IgE in vitro and in patient samples and biological effects of resulting IgE proteoforms were evaluated.
Results: Whereas IgG 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 CD-23-bound IgE, however, not with FcεRI-bound IgE. Proteolysis generated two proteoforms: a large IgE fragment (IgEcl) and a smaller IgE carboxyterminal 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 site in IgE corresponded with a shared epitope recognized by Omalizumab and Omalizumab prevented IgE proteolysis. Both IgEcl and Cεtr were present in plasma 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 action of Omalizumab and into IgE immunology with clinical impacts. Indeed, IgE-specific cleavage by granulocyte proteinases may be an important feedback mechanism to control allergic responses.

Item Type:	Article
Keywords:	Metalloproteinases, MMP-9, neutrophils, proteolysis, IgE
Date Deposited:	23 Aug 2025 00:45
Last Modified:	23 Aug 2025 00:45
URI:	https://oak.novartis.com/id/eprint/54993