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

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.