As one of the five designated immunoglobulin isotypes, immunoglobulin E (IgE) plays a major role in atopic conditions by inducing immediate hypersensitivity reactions. IgE also contributes significantly to the body’s immune response to parasitic infections, which are more prevalent in the third world countries. A fraction of IgE antibodies is found in the plasma. IgE antibodies are predominantly found in the tissues, firmly attached to effector cells, such as mast cells and basophils, by high-affinity IgE Fc receptor (Fc epsilon RI) and low-affinity IgE receptor (Fc epsilon RII). These two receptors facilitate the immunologic responses that are carried out by IgE.
As a complex cell-surface receptor with a molecular weight of 49 kDa, Fc epsilon RI binds Fc domain of IgE with an affinity of 10 M as oppose to Fc epsilon RII with a notably lower affinity of 10 M.
Fc epsilon RI’s structure is expressed differently based on the effector cell type it is presented on. An alpha beta gamma tetramer is seen on mast cells and basophils, whereas a trimeric, alpha beta isoform is found on other cell types, such as Langerhans and dendritic cells.
Fc epsilon RI activation facilitates immediate hypersensitivity reactions that can manifest as sneezing, urticaria, acute bronchospasm, secretory diarrhea and can even lead to cardiovascular collapse and fatal systemic anaphylactic reactions. These immediate hypersensitivity reactions are carried out by utilizing alpha beta gamma receptors to activate mast cells and basophils. The mechanism behind this reaction starts with binding of antigens to the Fc epsilon RI-bound IgE. This triggers the immediate release of histamine and synthesis of prostaglandins and leukotrienes and stimulates delayed secretion of cytokine and chemokine.
Fc epsilon RI acts as an activator of several signaling complexes such as the SRC-family kinases, which include FYN, LYN, ZAP-70, and SYK, all essential for proper receptor function and downstream activation of other molecules. Following cross-linking of Fc epsilon R, I by antigen, the immunoreceptor tyrosine-based activation motifs (ITAMs) of its gamma chain become phosphorylated. This tyrosine phosphorylation of the receptor, executed by SRC-family kinase LYN, is the initial step that launches the antigen stimulation of mast cells and basophils. Following their phosphorylation, ITAMs bind spleen tyrosine kinase (SYK). SYK is a non-receptor tyrosine kinase with two SRC homology 2 (SH2)-domains and molecular weight of 72 kDa. Upon binding to the activated ITAMs, SYK is phosphorylated by Lyn, which enables it to in-turn transphosphorylase other SYK and other target molecules.
SYK plays a crucial role in augmentation of IgE downstream signaling process. Any disruption in its activity or expression leads to a discernible malfunction in mast cell response mechanism. This discovery has made SYK an ideal therapeutic target for inflammatory and allergic conditions.
Currently, there are a number of clinical trials for asthma, rheumatoid arthritis, and systemic lupus erythematosus that focus on developing drugs to directly or indirectly target SYK.
In the United States (US), allergic reactions result in millions of hospital and office visits each year, which cost billions of dollars. Food, skin, and respiratory allergies are the most common atopic disorders in children. For the past few decades, the prevalence of allergy has increased significantly in the Western countries. For instance, there was a 75% increase in the prevalence of asthma from 1908 to 1994 in the US. The Centers for Disease Control and Prevention reported a 50% increase in the prevalence of food allergy among children from 1997 to 1999 and 2009 to 2011. The US also reports triple the increase in the prevalence of peanut or tree nut allergy between 1997 and 2008. This rise in atopic disorders has not been observed in developing countries. It is suggested that the hygiene, counter-regulatory, GM-CSF, hapten-atopy, antioxidant, lipid, and vitamin D hypotheses presumably contribute to this rapid rate of increase in allergic reactions in the Western countries. But none of the hypotheses can clarify all the aspect of this rise in the prevalence of atopic disease in such short period. There are many critical factors involved in the current allergy epidemic, such as genetic predisposition, the intricate relationship between the immune system and pathogens, and environmental factors.
The hygiene hypothesis proposes that diminished exposure to infectious agents during development is associated with susceptibility to allergic disease. The proposed mechanism behind this hypothesis is the imbalance in the activation process of T helper (Th) 2 cells over Th1 cells. Th2 cells are the known culprit for the development atopic disorders.
This hypothesis was first proposed in 1989 through an epidemiological study of hay fever. The study revealed that the children who encountered fewer infectious agents as a result of changes in lifestyle, such as higher standards of personal hygiene, reduced family size, and upgraded amenities, were more susceptible to hay fever. This suggests that allergic disease might be prevented by early childhood infections.
When expressed by immature dendritic cells and mononuclear phagocytic cells, Interleukin 10 (IL-10) plays a vital role in stimulation and maintenance of tolerance to benign allergens. But in allergic rhinitis and asthma, airway IL-10 expression is reduced. This, in turn, results in inflammation, in response to non-harmful allergens. The counter-regulatory hypothesis suggests that infections lead to increased expression of IL-10, which lowers predisposition towards allergy. The current lifestyle in Western countries has reduced exposure to infectious agents. This has diminished the benefits of this counter-regulatory feedback, making people more susceptible to atopic disorders.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is produced by many cell types, including T cells, macrophages, and endothelial cells, following their activation. GM-CSF in-turn stimulates the proliferation and activation of neutrophils, monocytes, lymphocytes, macrophages, and dendritic cells.GM-CSF hypothesis suggests that overexpression of GM-CSF is associated with severe tissue damage in various places in the body. In allergic disorders, GM-CSF causes continual survival of eosinophils by inhibiting their apoptosis.
Hapten-atopy hypothesis proposes that high-level exposure to chemicals in early stages of development is associated with increased allergic disorders.Haptens are small molecules with low molecular weight (less than 500 Da) that are typically not capable of generating an immune response but can bind to bigger molecules and turn them into allergens. Exposure to dietary haptens through processed food, formula milk, and oral medications has drastically increased in the past four decades. It is suggested that this rise in exposure has contributed to the increased prevalence of atopic disorders during this period.
There are two contradictory theories behind the role antioxidants play in atopic disease. Some studies propose that a low intake of antioxidants, such a green vegetables and fresh fruits and fish, contributes to the increased prevalence of atopic disorders, while others suggest that increased antioxidant intake has caused the increase in allergic disorders.
The consumption of foods containing n-3 polyunsaturated fat, found in tuna, herring, mackerel, salmon, sardines, and trout has reduced in the past few decades. At the same time, there has been a rise in consumption of processed foods that are rich in n-6 polyunsaturated fat, which presumably activates IgE production causing atopic disorders. This theory is defined as the lipid hypothesis. Vitamin D hypothesis proposes that the prevalence of allergic disorders is higher in patients who were supplemented with vitamin D as infants.
IgE plays a vital role in allergic disorders by inducing immediate hypersensitivity reactions. The activation of Fc epsilon RI, located on the surface of mast cells, facilitates immediate hypersensitivity reactions that can manifest as sneezing, urticaria, acute bronchospasm, secretory diarrhea, cardiovascular collapse, or fatal systemic anaphylactic reactions. Fc epsilon RI activates SYK (an SRC-family kinase), which plays a critical role in augmentation of the mast cell downstream signaling process. Thus SYK is an ideal therapeutic target for inflammatory and allergic conditions.
More than 600 million people in the world suffer from allergic rhinitis (AR), which is a chronic inflammatory disease. The symptoms include sneezing, itching, rhinorrhea, nasal congestion. The pathophysiology of AR involves an immediate and a late-phase response involving the nasal mucosa. The immediate response is IgE-mediated, whereas the late response is carried out by activated eosinophils and T cells that contribute to the chronic inflammatory process. Mast cells and T cells release cytokines (IL-4 and IL-13), which in-turn assist with the synthesis of IgE by B cells. The IgE that is synthesized in the local mucosa and IL-4 both help augment the Fc epsilon RI expression in the mast cells and basophils. Fc epsilon RI presence can in-turn bind a greater number of IgE-Ag complexes. This increases mast cell sensitivity to the allergen, further enhancing the presence of cytokines and chemical mediators.
Asthma affects approximately 300 million people in the world and is caused by chronic, inflammation, hyperactivity, and reversible obstruction of the airway. It presents with shortness of breath, cough, and wheezing. Non-allergic asthma, which is not associated with atopy, presents with negative skin tests to typical aeroallergens and tends to present with a later onset in life. Allergic asthma, accounting for two-thirds of all asthma cases, is illustrated by increased IgE levels and sensitization to allergens. This is when cross-linking of antigens to the Fc epsilon RI-bound IgE on the surface of mast cells, basophils, and dendritic cells trigger their activation.
Anaphylaxis is a potentially fatal systemic hypersensitivity reaction. Anaphylaxis carried out by an immunologic mechanism is referred to as allergic anaphylaxis. In allergic anaphylaxis, Fc epsilon RI binds IgE and activates mast cells and basophils. The activation of these effector cells in-turn leads to the release of inflammatory mediators, which are responsible for the pathophysiology of anaphylaxis such as vasodilation, increased vascular, bronchoconstriction, pulmonary and coronary vasoconstrictor.
Atopic dermatitis, also known as eczema, is an inflammatory skin disorder, which presents with dry and pruritic lesions on the flexure surfaces of extremities as well as head and neck area. Similar to the other immediate hypersensitivity reactions, Fc epsilon RI-activated mast cells release proinflammatory mediators. This, in turn, leads to an inflammatory response in the skin forming the eczematous lesions.
Food allergy is most commonly triggered by the IgE-mediated hypersensitivity reaction and presents with local or systemic symptoms that begin minutes or hours after ingestion of the offending food. The proposed pathogenesis involves IgE production against normal food constituents, such as glycoproteins. IgE binds Fc epsilon RI and triggers the downstream signaling cascade, which leads to the production of increased levels of inflammatory mediators. These mediators, in turn, cause an inflammatory response and lead to symptoms involving the skin, gastrointestinal and respiratory tracts, eyes, and the heart, ranging from mild to a severe fatal anaphylactic response.