IgE and mast cells in allergic disease

Abstract

Immunoglobulin E (IgE) antibodies and mast cells have been so convincingly linked to the pathophysiology of anaphylaxis and other acute allergic reactions that it can be difficult to think of them in other contexts. However, a large body of evidence now suggests that both IgE and mast cells are also key drivers of the long-term pathophysiological changes and tissue remodeling associated with chronic allergic inflammation in asthma and other settings. Such potential roles include IgE-dependent regulation of mast-cell functions, actions of IgE that are largely independent of mast cells and roles of mast cells that do not directly involve IgE. In this review, we discuss findings supporting the conclusion that IgE and mast cells can have both interdependent and independent roles in the complex immune responses that manifest clinically as asthma and other allergic disorders.

Figures

Figure 1. Allergen sensitization and IgE production

Initial allergen sensitization results in antigen-specific IgE production (left). In individuals not yet exposed to a new environmental allergen (designated here as an antigen (Ag)), the only IgE present (blue) does not have specificity for the new antigen(s). Such IgE can be bound to the αβγγ form of FcεRI on mast cells or to the αγγ form of FcεRI on the surface of macrophages, monocytes or dendritic cells or to CD23 on airway epithelial cells or other cells (not shown here). The new antigens (orange circles) are captured by dendritic cells or macrophages in the airway lumen or in the epithelium of the airway mucosa or gain access to submucosal dendritic cells through disrupted epithelium or, for some antigens with intrinsic protease activity, by disrupting epithelial cell tight junctions. Antigen-activated dendritic cells mature and migrate to regional lymph nodes or to sites in the local mucosa, where they present processed antigen epitopes to cognate T cells; in the presence of IL-4 or IL-13, which may be derived from a variety of potential cellular sources, this induces such T cells to become differentiated and activated TH2 cells. IL-4 and IL-13, which may be derived from TH2 cells (shown here), basophils, mast cells and/or other sources, also activate immunoglobulin heavy chain gene CSR for antigen-specific IgE production, designated here antigen-specific IgE (epitope A), in B cells. The antigen-specific IgE response is amplified by FAP and other mechanisms (right). Antigen-specific IgE can bind to multiple cell types through various IgE receptors. Antigen-induced aggregation of IgE bound to FcεRI stimulates mast cell degranulation and the release of mediators such as histamine, PGD2 and TNF, which promote recruitment of TH2 cells, the migration, maturation and activation dendritic cells and antigen presentation. IgE and antigen-IgE complexes can cross the epithelium by transcytosis mediated by CD23 on airway epithelial cells (1), allowing them to bind to and activate FcεRI on mast cells and dendritic cells. This process contributes to the perpetuation of allergic inflammation and, potentially, through promotion of IL-4 and/or IL-13 secretion by mast cells (2) and effects of activated mast cells on dendritic cells (3), to additional local IgE CSR and IgE production in B cells, either to additional epitopes of the original antigen (shown here) or to new antigens bound by dendritic cells (square blue symbols). Antigen presentation mediated by binding of antigen-IgE complexes to CD23 on B cells, followed by antigen presentation by these B cells to cognate T cells (not shown here), is called FAP (4), a process that can result in epitope spreading, with production of IgE recognizing new epitopes of the original antigen (for example, epitope B, shown here) or to epitopes of new antigens, if some IgE antibodies to that antigen already exist (not shown), and the subsequent exacerbation of allergic disorders. FcεRI αγγ trimers on other antigen-presenting cells (for example, dendritic cells, monocytes and macrophages) permit these cells to bind and internalize IgE that is bound to complex antigens; epitopes derived from such antigens, including those comprising epitopes for which there is not yet a specific IgE response, are then presented to cognate T cells, which, in the presence of IL-4 and/or IL-13, can become TH2 cells that in turn promote the production of IgE against these new epitopes by B cells (5). ICOS, inducible T cell co-stimulator; ICOSL, ICOS ligand; BCR, B cell receptor.

Figure 2. The early immediate hypersensitivity phase of antigen-induced airway inflammation

The individual IgE molecules that are bound to FcεRI molecules on a single mast cell can be specific for different antigens (red and blue IgE symbols). Binding of IgE to FcεRI αβγγ on mast cells, which are normally located in airway tissues, and basophils, if they have been recruited from the blood to airway tissues, upregulates FcεRI surface expression and sensitizes these cells to respond when later exposed to specific antigens, and, in mast cells, some IgE molecules can enhance cytokine production and survival. The recognition of a particular bivalent or multivalent antigen by at least two IgE molecules bound to adjacent FcεRI molecules induces FcεRI aggregation, activating mast cells (and basophils, if they are present in airway tissues) to initiate an immediate hypersensitivity response by secreting preformed mediators and lipid mediators within minutes of antigen exposure. These mast cells also upregulate the production of many cytokines, chemokines and growth factors. Within minutes of exposure, the rapidly secreted mediators lead to bronchoconstriction, vasodilation, increased vascular permeability and increased mucus production. Mast cell mediators produced rapidly after antigen challenge can also promote dendritic cell migration, maturation and function and can contribute to the transition to the late phase reaction by promoting an influx of circulating leukocytes, both by upregulating adhesion molecules on vascular endothelial cells (for example, through TNF) and by secreting chemotactic mediators (such as LTB4 and PGD2) and chemokines (such as IL-8 and CC-chemokine ligand 2 (CCL2)). These recruited leukocytes can induce further inflammation and bronchoconstriction during the late phase reaction. PAF, platelet activating factor; IFN-γR, IFN-γ receptor; VEGFA, vascular endothelial growth factor

Figure 3. Roles of IgE and mast cells in chronic airway inflammation and tissue remodeling

In chronic allergic inflammation, repetitive or persistent exposure to allergens can result in both the production of IgE against multiple antigen epitopes of several different antigens (Fig. 1, right) and the development of long-term changes in the involved tissues (Box 2), including changes in mast cell number, tissue distribution (with mast cells in the epithelium and the smooth muscle layer, not shown here) and phenotype. Moreover, repetitive epithelial injury caused by chronic allergic inflammation can be exacerbated by exposure to pathogens such as viruses or bacteria or environmental factors, and the consequent repair response results in epithelial and mesenchymal changes that are thought to sustain TH2 cell–associated inflammation, promote sensitization to additional allergens or allergen epitopes (for example, epithelial-cell–derived TSLP can upregulate the expression of co-stimulatory molecules such as OX40, CD40 and CD80 by dendritic cells, not shown here) and regulate the airway remodeling process. These processes in turn result in many functionally relevant changes in the structure of the affected tissue. There is evidence that many of these changes can be influenced by IgE and mast cells, either acting in concert through the IgE–mast-cell axis or independently. For example, both soluble factors, such as INFγ, S1P, adenosine and IL-33, and cells present at the site, such as TH2 cells and Treg cells (which can interact with OX40L on mast cells) can modulate, or tune, IgE-dependent mast cell activation, and some pathogen-associated molecular patterns (PAMPs) and cytokines, including TSLP and IL-33, can activate mast cells independently of IgE to produce different spectra of cytokines or chemokines. Studies in mast-cell–knockin mice have indicated that some actions of mast cells, such as increasing the number of epithelial goblet cells, can occur in a model of chronic asthma by mast-cell–dependent mechanisms that do not require mast cell signaling through the FcεRI γ chain, whereas mast cells must express both the FcεRI γ chain and the IFN γ receptor 1 (IFN-γR1) to mediate increases in lung eosinophils, neutrophils and collagen (not shown here). Amplification of the IgE response by IgE, for example, by FAP (Fig. 1, right) and IgE- and antigen-dependent activation of basophils after their recruitment to the airways can occur independently of mast cells. PRR, pattern recognition receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor