Allergies occur due to hypersensitivity of the immune system to substances in the environment that is normally harmless. There are four different kinds of hypersensitivity. Types IIII are antibody mediated. Antibodies, also called immunoglobulins, recognize antigens, foreign substances that induce an immune reaction in the body. Antigens that provoke an allergic reaction are called allergens. The five major immunoglobulin classes, or isotypes, found in serum are IgA, IgD, IgE, IgG, and IgM. Most allergies fall under the type I hypersensitivity category. This type of hypersensitivity manifests quickly, so it is also called an immediate hypersensitivity. It occurs thanks to IgE antibodies, so it is also called IgEmediated hypersensitivity.
IgE binds to the FcƐ receptor, which is found on mast cells and basophils. When an antigen binds to IgE specific to itself, it crosslinks these receptors, activates the cell, and this induces release of chemical mediators from the mast cells which lead to allergic disease.
However, before you can have an allergic response to a substance, you need to be exposed and sensitized to it via the production of IgE antibodies specific to it. It is the reexposure to the same stimulus after the production of IgE that causes the allergic response. Note that you may or may not be sensitized to a substance the first time you are exposed to it! And even not every sensitization will lead to symptomatic allergic responses. The IgE is produced by Bcells after they classswitch, usually from producing IgM antibodies.
How does sensitization work? Upon exposure to an antigen, the immune response that leads to IgE production is driven mostly by two kinds of signals. One involves signals favouring differentiation of Tcells into the TH2 phenotype. Th1 and Th2 are two classes of helper Tcells. Th1 cells generate responses against bacteria and viruses that are intracellular pathogens, while Th2 mounts responses against extracellular parasites. The other kind of signal involves cytokines (IL4 and IL13) and signals from TH2 cells that stimulate Bcells to class switch, changing their antibody production to the production of IgE, and amplifies the TH2 response. Dendritic cells, which are a type of antigenpresenting cell, ingest the antigen. They then travel to the lymph node to prime Tcells. The dendritic cell presents the antigen on a MHC class II protein. Once it finds a naïve Tcell built to recognize the antigen, it can prime it so that it will differentiate. Note that the Tcell is naïve because it has never recognized the antigen before, however, of the enormous variety of naïve Tcells hanging around, this specific one is a match for that antigen before it ever makes contact with it.
The differentiation of Tcells into a TH2 phenotype as opposed to a different phenotype depends on the cytokines it’s exposed to before and during antigen presentation by dendritic cells, as well as the antigen itself, its dose, and the route of presentation. Cytokines favouring the development of TH2 cells include IL4, IL5, IL9, and IL13. IL4 or IL13 are also the first signal that causes class switching of Bcells to IgE production. Note that mast cells and basophils can also promote the production of IgE by B cells. Mast cells and basophils express the highaffinity IgE receptor FcƐ receptor on their surfaces. They are activated by an antigen crosslinking IgE bound to these receptors. This causes them to degranulate, releasing preformed granules with histamine, which makes you itchy, and other pharmacological mediators. It also makes them synthesize prostaglandins, leukotrienes, and plateletactivating factor. They then express cellsurface CD40 ligand and secrete IL4. This allows them to contribute to further classswitching of Bcells.
Another means of amplification of the allergic reaction is capture of IgE by the FcƐ receptor on dendritic cells. These IgEs are a perfect trap for the antigen, and the dendritic cell can now process it more efficiently to present it to more naïve Tcells. The immediate reaction caused by the degranulation of mast cells is followed by sustained inflammation, which results from recruitment of additional Th2 cells, eosinophils, and basophils.
So, if IgE causes so much trouble, why do we have it? IgE evolved primarily to help with adaptive immunity against parasitic worm infection, which is common in developing countries. In industrialized parts of the world however, the prevalence of these parasitic worms is low and so IgE mostly causes trouble with allergies. The immune system’s defenses against multicellular parasites are, as you’d expect, stationed where these organisms are likely to enter the body. Hence, these defenses are located under the skin and in the mucosal tissues of the gut and airways. The immune cells located in these regions are specialized to secrete cytokines promoting TH2 responses.