IgE Occupancy and Antigen Valency Cooperate to Control FcεRI Aggregation Geometry and Signaling Efficiency

Authors

• Birgit Linhart, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria.
• Rachel M. Grattan, Department of Pathology, University of New Mexico, Albuquerque, NM.
• Jon Christian David, Department of Computer Science, University of New Mexico, Albuquerque, NM.
• Elton D. Jhamba, Department of Pathology, University of New Mexico, Albuquerque, NM.
• Christian Lupinek, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria.
• Margarete Focke-Tejkl, Center for Molecular Allergology, Karl Landsteiner University of Health Sciences, Krems, Austria.
• Michael L. Paffett, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM.
• Shayna R. Lucero, Department of Pathology, University of New Mexico, Albuquerque, NM.
• Rudolf Valenta, Center for Molecular Allergology, Karl Landsteiner University of Health Sciences, Krems, Austria. Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria.
• Lydia Tapia, Department of Computer Science, University of New Mexico, Albuquerque, NM.
• Bruna Jacobson, Department of Computer Science, University of New Mexico, Albuquerque, NM.
• Bridget S. Wilson, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM. Department of Pathology, University of New Mexico, Albuquerque, NM.
• Diane S. Lidke, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM. Department of Pathology, University of New Mexico, Albuquerque, NM.

Document Type

Article

Publication Date

10-30-2025

Abstract

The crosslinking of IgE-bound FcεRI by multivalent allergens initiates mast cell and basophil signaling underlying Type 1 allergy. Yet, how allergen properties and IgE occupancy impact receptor aggregation and downstream signaling remain unclear. We used Phl p 1-specific IgE and recombinant fusion proteins presenting a Phl p 1-derived peptide in defined valencies and positions (MB1N, MB2N, MB4N, MB1N1C) to probe antigen-dependent signaling. Tetravalent MB4N evoked stronger degranulation and Ca2+ response than bivalent antigens, MB2N and MB1N1C. MB4N was also capable of signaling at low IgE occupancy and in Lyn-deficient cells. Monte Carlo simulations predicted that MB4N forms larger, complex receptor aggregates, while MB2N and MB1N1C produce dimers and linear chains. Consistently, addition of MB4N showed larger aggregates by electron microscopy and slower mobility by single particle tracking, compared to bivalent antigens. Thus, allergen valency and epitope spatial arrangement dictate FcεRI aggregate organization and subsequent effector cell activation.

Recommended Citation

Linhart B, Grattan RM, David JC, Jhamba ED, Lupinek C, Focke-Tejkl M, Paffett ML, Lucero SR, Valenta R, Tapia L, Jacobson B, Wilson BS, Lidke DS. IgE occupancy and antigen valency cooperate to control FcεRI aggregation geometry and signaling efficiency. bioRxiv [Preprint]. 2025 Oct 30:2025.10.28.685118. doi: 10.1101/2025.10.28.685118. PMID: 41279798; PMCID: PMC12636472.