IgE-Mediated Mechanisms in Allergic Disease

Immunoglobulin E (IgE) is a specialised antibody isotype that underpins type I hypersensitivity and chronic allergic inflammation. IgE binds with high affinity to FcεRI receptors on mast cells and basophils, and with lower affinity to CD23 on B cells and other antigen-presenting cells. Crosslinking of receptor-bound IgE by multivalent allergen triggers mast cell degranulation, release of histamine and cytokines, and recruitment of inflammatory cells. In parallel, CD23 engagement regulates IgE homeostasis and antigen presentation. The inherent flexibility of the IgE Fc region enables allosteric transitions that modulate receptor binding and can be exploited by anti-IgE biologics. Dysregulation of these pathways leads to conditions such as asthma, rhinitis, urticaria and anaphylaxis, while targeted interventions against IgE or its receptors have transformed the management of severe allergic disease.

Research from Nature Portfolio

Studies of a next-generation anti-IgE antibody have revealed distinct epitopic interactions that underpin superior suppression of FcεRI-driven responses. Structural analyses demonstrate how ligelizumab binds IgE to block high-affinity receptor engagement more effectively than earlier therapies, reducing basophil activation, IgE production by B cells and anaphylaxis in vivo, while showing differential effects on CD23 binding. Complementary work using a single-domain antibody has defined a strategy for ‘trapping’ IgE in a closed Fc conformation. This agent mimics CD23 binding to induce a half-bent Fc state that precludes interaction with both FcεRI and CD23, displaces receptor-bound IgE and abrogates allergen-mediated basophil activation. Together these findings provide new mechanistic blueprints for designing anti-IgE therapeutics that exploit the intrinsic conformational dynamics of the IgE molecule.

IgE-Mediated Mechanisms in Allergic Disease publication trend

The graph below shows the total number of articles in ige-mediated mechanisms in allergic disease across all publications each year (not limited to Nature Index journals).

Technical terms

IgE: Immunoglobulin E, an antibody class central to type I hypersensitivity and allergic inflammation.

FcεRI: High-affinity receptor for IgE expressed on mast cells and basophils, mediating degranulation upon allergen crosslinking.

CD23: Low-affinity IgE receptor on B cells and antigen-presenting cells, involved in regulation of IgE levels and antigen uptake.

Allosteric modulation: Regulation of IgE function through conformational changes in the Fc region that alter receptor binding.

References

1. IgE, IgE Receptors and Anti-IgE Biologics: Protein Structures and Mechanisms of Action. Annual Review of Immunology (2023).
2. The mechanistic and functional profile of the therapeutic anti-IgE antibody ligelizumab differs from omalizumab. Nature Communications (2020).
3. Trapping IgE in a closed conformation by mimicking CD23 binding prevents and disrupts FcεRI interaction. Nature Communications (2018).
4. Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab. Journal of Biological Chemistry (2017).
5. Current Strategies to Inhibit High Affinity FcεRI-Mediated Signaling for the Treatment of Allergic Disease. Frontiers in Immunology (2019).