Continuing Education Activity

As one of the five designated immunoglobulin isotypes, immunoglobulin E (IgE) plays a significant 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 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. This activity describes the pathophysiology of an allergic reaction and highlights the interprofessional team's role in managing these patients.

Objectives:

• Identify the function of the IgE molecule.
• Describe the pathophysiology of an allergic reaction.
• Review the presentation of a patient suffering from an allergic reaction.
• Outline interprofessional team strategies for improving care coordination and communication to advance the management of an allergic reaction and improve outcomes.

Introduction

Immunoglobulin E(IgE), named in 1968, is the last of the five human immunoglobulins to be discovered and is typically associated with the diverse manifestations of allergic diseases.[1] As one of the five designated immunoglobulin isotypes, immunoglobulin E (IgE) plays a major role in atopic conditions by inducing immediate hypersensitivity reactions.[2] IgE also contributes significantly to the body’s immune response to parasitic infections, which are more prevalent in 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).[3] 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 the Fc domain of IgE with an affinity of 10 M instead of Fc epsilon RII with a notably lower affinity. Fc epsilon RI’s structure is expressed differently based on the effector cell type on which it is presented. For example, an alpha-beta gamma tetramer is seen on mast cells and basophils. In contrast, 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, and secretory diarrhea and can even lead to cardiovascular collapse and fatal systemic anaphylactic reactions. These immediate hypersensitivity reactions utilize alpha beta gamma receptors to activate mast cells and basophils. The mechanism behind this reaction starts with the 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 the delayed secretion of cytokine and chemokine.[4]

Function

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 RI 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 a molecular weight of 72 kDa. Upon binding to the activated ITAMs, SYK is phosphorylated by Lyn, which enables it to in-turn transphosphorylase to other SYK and other target molecules.[5][6][7]

SYK plays a crucial role in the augmentation of the IgE downstream signaling process. Any disruption in its activity or expression leads to a discernible malfunction in the mast cell response mechanism. This discovery has made SYK an ideal therapeutic target for inflammatory and allergic conditions. Several clinical trials for asthma, rheumatoid arthritis, and systemic lupus erythematosus focus on developing drugs to directly or indirectly target SYK.

Role of IgE in exerting anti-parasite function: Anti-parasitic IgE and IgE expressed on effector cells such as eosinophils have been shown to confer defense against different parasites (e.g., Schistosoma mansoni). Furthermore, IgE engaged with FcεRI or CD23 can improve parasite clearance by human eosinophils, platelets, and macrophages through antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). Besides, elevated serum titers of parasite antigen-specific IgE have been associated with resistance to parasitic infection.[1]

Issues of Concern

In the United States (US), allergic reactions result in millions of hospital and office visits each year, which cost billions of dollars.[8] Children's most common atopic disorders are food, skin, and respiratory allergies. For the past few decades, allergies have increased significantly in 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 allergies among children from 1997 to 1999 and 2009 to 2011.[9] The US also reports a three times increase in peanut or tree nut allergy prevalence between 1997 and 2008.[10]

This rise in atopic disorders has not been observed in developing countries. It is suggested that hygiene, counter-regulatory, GM-CSF, hapten-atopy, antioxidant, lipid, and vitamin D hypotheses presumably contribute to this rapid increase in allergic reactions in Western countries.[11] But none of the hypotheses can clarify all the aspects of this rise in the prevalence of atopic disease in such a short period. Many critical factors are 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 of atopic disorders.[12] 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 due to 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 early childhood infections might prevent allergic diseases.[13]

When expressed by immature dendritic cells and mononuclear phagocytic cells, Interleukin 10 (IL-10) is vital in stimulating and maintaining 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 the 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.[14][15]

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 stimulates the proliferation and activation of neutrophils, monocytes, lymphocytes, macrophages, and dendritic cells. The 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 the continual survival of eosinophils by inhibiting their apoptosis.[16][17][18]

The hapten-atopy hypothesis proposes that high-level exposure to chemicals in the 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. Over the past four decades, exposure to dietary haptens through processed food, formula milk, and oral medications has drastically increased. It is suggested that this rise in exposure has contributed to the increased prevalence of atopic disorders during this period.[19][20][21]

There are two contradictory theories behind the role antioxidants play in atopic disease. Some studies propose that a low intake of antioxidants, such as green vegetables, fresh fruits, and fish, contributes to the increased prevalence of atopic disorders. In contrast, others suggest that increased antioxidant intake has caused an increase in allergic disorders.[22]

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 the consumption of processed foods rich in n-6 polyunsaturated fat, which presumably activates IgE production, causing atopic disorders. This theory is defined as the lipid hypothesis. The Vitamin D hypothesis proposes that the prevalence of allergic disorders is higher in patients supplemented with vitamin D as infants.[23]

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. In addition, Fc epsilon RI activates SYK (an SRC-family kinase), which plays a critical role in the augmentation of the mast cell downstream signaling process. Thus SYK is an ideal therapeutic target for inflammatory and allergic conditions.

Hyper IgE syndromes include rare primary immunodeficiency disorders distinguished by a triad of atopic dermatitis and chronic skin and lung infections with raised IgE levels. There is an impaired IL-10 and IL-21 signaling and eosinophilia. Job syndrome( autosomal dominant hyper IgE syndrome) is due to a deficiency of Th 17 cells due to STAT3 mutation. These patients usually present with non-inflamed abscesses, retained baby teeth, and fractures from minor trauma, along with the clinical features described above. Treatment is supportive, consisting of prophylactic antibiotics against staphylococcal infection, eczema care, and intravenous immunoglobulin or subcutaneous immunoglobulin depending upon the severity of presentation.[24]

Clinical Significance

More than 600 million people worldwide suffer from allergic rhinitis (AR), a chronic inflammatory disease. The symptoms include sneezing, itching, rhinorrhea, and nasal congestion. The pathophysiology of AR involves an immediate and 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 assist with the synthesis of IgE by B cells. The IgE synthesized in the local mucosa and IL-4 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. f IgE-Ag complexes increase mast cell sensitivity to the allergen, further enhancing the presence of cytokines and chemical mediators.[25][26]

Asthma affects approximately 300 million people worldwide and is caused by chronic inflammation, hyperactivity, and reversible airway obstruction. It presents with shortness of breath, cough, and wheezing. Non-allergic asthma, 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 which happens when there is a cross-linking of antigens to the Fc epsilon RI-bound IgE on the surface of mast cells, basophils, and dendritic cells triggers their activation.[27][28]

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, and pulmonary and coronary vasoconstriction.[29]

Atopic dermatitis, also known as eczema, is an inflammatory skin disorder that presents with dry and pruritic lesions on the flexure surfaces of extremities and head and neck areas. Like the other immediate hypersensitivity reactions, Fc epsilon RI-activated mast cells release pro-inflammatory mediators, leading to an inflammatory response in the skin forming eczematous lesions.[30]

The IgE-mediated hypersensitivity reaction most commonly triggers food allergy. It presents with local or systemic symptoms that begin minutes or hours after ingesting 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, leading to 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 severe fatal anaphylactic response.[31]

Preclinical research suggests that IgE may have therapeutic potential for treating solid tumors. IgE can augment Fc-mediated effector functions by engaging receptors on immune cells like monocytes, neutrophils, macrophages, eosinophils, basophils, and mast cells. IgE can also engage antigen-presenting cells to enhance antigen uptake and presentation. Antibody-dependent cell-mediated cytotoxicity (ADCC) and degranulation result in the release of toxic and pro-inflammatory mediators; these mediators, along with antibody-dependent cell-mediated phagocytosis (ADCP), enhance anti-tumor activity. IgE can also engage antigen-presenting cells to improve antigen uptake and presentation. IgE impacts cancer cells, like anti-cancer IgG antibodies, decreasing cancer cell growth signaling.[1] 

Preclinical research suggests that IgE may have therapeutic potential for many treatments of solid tumors. Mouse/human chimeric IgE (MOv18) is specific for the ovarian cancer antigen, folate receptor alpha (FRα)-mediated ADCC, and ADCP of ovarian cancer cells by human peripheral blood mononuclear cells (PBMCs). In light of this study's findings, a phase 1 clinical trial has been conducted on MOv18 IgE for advanced solid tumors. Evidence of anti-tumor activity was seen in a patient with ovarian cancer at a total MOv18 IgE dose of 0.7mg. Shrinkage of peritoneal metastases was evident. These results support the safety of IgE as a treatment for cancer for the first time and provide primary evidence for its anti-tumor efficacy. One patient experienced anaphylaxis with tryptase elevation. The most common adverse drug reaction was manageable urticaria without systemic manifestations. However, substantial research is needed to validate these results and integrate the use of IgE in patients with cancer in clinical practice.[32]

Other Issues

• IgE plays a central role in the pathogenesis of atopic disorders.
• The binding of IgE to the Fc epsilon RI receptor on the surface of mast cells induces an immediate hypersensitivity reaction in allergic rhinitis, atopic dermatitis, asthma, food allergies, and anaphylaxis.
• The prevalence of these allergic disorders in Western countries has increased significantly in the past few decades. This rapid increase in atopic disorders has been attributed to hygiene, counter-regulatory, GM-CSF, hapten-atopy, antioxidant, lipid, and vitamin D hypotheses.[33]
• Primary immunodeficiency disorders, such as Job syndrome, require a high index of suspicion for diagnosis; management of these disorders is complex, requiring multidisciplinary care.[24]

Enhancing Healthcare Team Outcomes

The management of allergic patients is best done with an interprofessional team that includes clinicians, immunologists, and pharmacists. The key is to prevent allergies, and this requires patient education. Caregivers and parents should be told to avoid triggers of allergic reactions. In addition, for those with allergies, carrying rapidly injectable epinephrine pens can be lifesaving. A systematic review and meta-analysis demonstrated the significant contribution of pharmacists to achieving clinical outcomes, adherence to medications, and drug-related problems s in efficiently managing autoimmune disorders.[34] [Level 2a]

Nursing, Allied Health, and Interprofessional Team Interventions

Nursing can educate patients about the signs and symptoms of allergies and avoid triggers. The pharmacist can educate the patients about drugs that can trigger drug-induced hypersensitivity reactions. Clinicians, including nurse practitioners, may participate in the proper diagnosis. An allergist/immunologist may use the basophil activation test (BAT) and skin tests to evaluate IgE-mediated allergic reactions to food, insect, drugs, and chronic urticaria.[35]

Nursing, Allied Health, and Interprofessional Team Monitoring

Clinical nurse specialists can monitor for the signs of anaphylaxis, such as urticaria, hypotension, and shortness of breath. Pharmacists can monitor the patients for adverse drug reactions from drug therapy. Immunologists can monitor patients with severe asthma and add omalizumab (Anti-IgE) therapy when indicated according to GINA guidelines.[36][37]