Allergy, Anaphylaxis, and Nonallergic Hypersensitivity: IgE, Mast Cells, and Beyond

Abstract

IgE-mediated type I hypersensitivity reactions have many reported beneficial functions in immune defense against parasites, venoms, toxins, etc. However, they are best known for their role in allergies, currently affecting almost one third of the population worldwide. IgE-mediated allergic diseases result from a maladaptive type 2 immune response that promotes the synthesis of IgE antibodies directed at a special class of antigens called allergens. IgE antibodies bind to type I high-affinity IgE receptors (FcεRI) on mast cells and basophils, sensitizing them to get triggered in a subsequent encounter with the cognate allergen. This promotes the release of a large variety of inflammatory mediators including histamine responsible for the symptoms of immediate hypersensitivity. The development of type 2-driven allergies is dependent on a complex interplay of genetic and environmental factors at barrier surfaces including the host microbiome that builds up during early life. While IgE-mediated immediate hypersensitivity reactions are undoubtedly at the origin of the majority of allergies, it has become clear that similar responses and symptoms can be triggered by other types of adaptive immune responses mediated via IgG or complement involving other immune cells and mediators. Likewise, various nonadaptive innate triggers via receptors expressed on mast cells have been found to either directly launch a hypersensitivity reaction and/or to amplify existing IgE-mediated responses. This review summarizes recent findings on both IgE-dependent and IgE-independent mechanisms in the development of allergic hypersensitivities and provides an update on the diagnosis of allergy.

Keywords: Allergy; Anaphylaxis; IgE; Mast cells; Nonallergic hypersensitivity.

Fig. 1

Hierarchy of hypersensitivity reactions involved in immediate hypersensitivity responses (adapted and modified from references [9] and [10]).

Fig. 2

Mechanisms of allergic inflammation. During the sensitization phase in a Th2-favorable environment, barrier epithelial cells respond to allergen challenge. This engenders cytokines that activate type 2 innate lymphoid cells and dendritic cells (DCs). DCs present allergenic peptides to naive T cells, under which the influence of type 2 innate lymphoid cell-secreted cytokines differentiate into IL-4/IL-13-producing Th2 cells. They contact naive B cells via a CD40/CD40L interaction and inducing their switch to IgE-secreting plasma cells. IgE binds to FcεRI present on mast cells and basophils, thereby enhancing its expression. Upon a subsequent allergen encounter, mast cells and blood basophils degranulate, releasing allergic mediators stored in granules and newly synthesized lipid compound (prostaglandins, leukotrienes) responsible for early phase allergic symptoms (vasodilatation, vascular permeability, bronchoconstriction, etc.). In a more delayed phase, they also secrete a whole variety of newly synthesized chemokines/cytokines. Together, they drive an inflammatory response and infiltration of other immune effector cells. When allergen exposure and ensuing epithelial injury persist, a chronic state of tissue injury and remodeling develops.

Fig. 3

Summary of described hypersensitivity mechanisms. The classical IgE-dependent type I hypersensitivity response involves mast cells and basophils that release histamine, promoting anaphylaxis and allergies. Under specific conditions where the allergen and allergen-specific IgG antibodies reach very high concentrations, several cell types in the circulation (neutrophils, monocytes/macrophages, basophils, and platelets) are activated by immune complexes through FcγRIIA and FcγRIII to release PAF and serotonin (platelets) causing anaphylaxis. Complement fragments generated by classical (adaptive) and nonclassical innate pathways can activate mast cells and monocytes/macrophages which can enhance allergies and anaphylaxis. A large variety of positively charged drugs and peptides can interact with various innate receptors such as MRGPRX2/Mrgprb2 receptors and provoke so-called “pseudo-allergic” responses. Physical stimuli such as vibration can activate the ADGRE2 adhesion receptor to cause local hypersensitivity reactions (vibratory urticaria) in the skin.