The Role of IgE in Upper and Lower Airway Disease: More Than Just Allergy!

Abstract

Immunoglobulin E (IgE) is a well-known key factor in allergic airway disease; however, its central role in non-allergic airway inflammation is often underestimated. In some airway diseases, IgE is produced as a result of allergic sensitization. However, in others, IgE production occurs despite the lack of a specific allergen. Although multiple pathways contribute to the production of IgE in airway disease, it is its activity in mediating the inflammatory response that is associated with disease. Therefore, an understanding of IgE as the unifying component of upper and lower airway diseases has important implications for both diagnosis and treatment. Understanding the role of IgE in each upper and lower airway disease highlights its potential utility as a diagnostic marker and therapeutic target. Further classification of these diseases by whether they are IgE mediated or non-IgE mediated, rather than by the existence of an underlying allergic component, accounts for both systemic and localized IgE activity. Improvements in diagnostic methodologies and standardization of clinical practices with this classification in mind can help identify patients with IgE-mediated diseases. In doing so, this group of patients can receive optimal care through targeted anti-IgE therapeutics, which have already demonstrated efficacy across numerous IgE-mediated upper and lower airway diseases.

Keywords: Asthma; Immunoglobulin E; Lower airway disease; Nasal polyps; Rhinitis; Upper airway disease.

Fig. 1

Mechanism of IgE-mediated upper and lower airway disease. In response to allergen exposure, dendritic cells present allergen-specific antigens to naïve T cells, which are activated and differentiate into Th2 cells. These Th2 cells produce key cytokines (IL-4, IL-13), prompting B cells to produce allergen-specific IgE. Alternatively, exposure to external stimuli such as bacteria, fungi, viruses, and particulates promotes epithelial release of IL-25, TSLP, and IL-33. These factors stimulate ILC2 cells to produce IL-5, IL-13, and to a lesser extent, IL-4, which in turn promote B cell production of IgE. Finally, superantigens, including Staphylococcal enterotoxins, can directly cross-link antigen-presenting cells with naïve T cells, bypassing the antigen presentation step, yielding polyclonal IgE. Once produced, local IgE acts on the FcεRI receptors of tissue-resident mast cells and basophils, prompting the release of histamine, leukotrienes, tryptase, and prostaglandin, which manifest as edema, vasodilation, and bronchoconstriction as part of the early response. IgE also binds to FcεRII receptors on B cells for enhanced antigen presentation. Later release of key cytokines recruits proinflammatory cells, including eosinophils and basophils, to the site of inflammation, and additionally promotes the overexpression of mucus-producing goblet cells and contributes to airway hyperresponsiveness. Crosstalk within the inflammatory pathway promotes a self-propagating cycle of chronic inflammation. The lower left side of the figure depicts the fibroblasts and mast cells within the supporting connective tissue of the nasal cavity, while the lower right side depicts the smooth muscle cell layer surrounding the lower respiratory airway. DC, dendritic cell; FcεRI, high-affinity immunoglobulin E receptor; FcεRII, low-affinity immunoglobulin E receptor; IgE, immunoglobulin E; IL, interleukin; ILC, innate lymphoid cell; PGD2, prostaglandin D2; Th2, T helper 2; TSLP, thymic stromal lymphopoietin

Fig. 2

B cell activation. In response to Th2-derived IL-4 and IL-13, naïve B cells migrate to B cell follicles for proliferation and formation of germinal centers. In incompletely organized germinal centers, as found in the Th2-centric response, naïve B cells undergo somatic hypermutation and class-switch recombination as part of direct switching to IgE⁺ B cells. In mature germinal centers, naïve B cells undergo indirect switching, passing through an intermediate IgG₄⁺ B cell phase before transforming into IgE⁺ B cells. In either case, IgE⁺ B cells can then leave the germinal center, becoming either memory B cells or long-lived plasma cells. Memory B cells are dividing cells that produce minimal IgE but allow the prompt production of specific IgE-secreting plasma cells following a secondary allergen exposure in the absence of cytokines. It is not well established where IgE memory resides, and this remains a topic under active investigation within the field. Plasma cells do not divide, but produce far more specific IgE. Figure adapted from Akdis M and Akdis CA. Nat Immunol 2012;13(4):312–314 and Davies JM, et al. J Allergy Clin Immunol 2013;131(4):972–976. IgE immunoglobulin E, IgG immunglobulin G, IgM immunoglobulin M, IL interleukin, ILC innate lymphoid cell, MHCII major histocompatibility complex class II, TCR T cell antigen receptor, Th2 T helper 2