Hypersensitivity Reactions

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Hypersensitivity Reactions

What is hypersensitivity?

Hypersensitivity can be defined as a normal but exaggerated or uncontrolled immune response to an antigen that can produce inflammation, cell destruction, or tissue injury. It has traditionally been classified on the basis of time after exposure to an offending antigen. When this criterion is used, the terms immediate hypersensitivity and delayed hypersensitivity are appropriate. Immediate hypersensitivity is antibody mediated; delayed hypersensitivity is cell mediated.

The term immunization, or sensitization, describes an immunologic reaction dependent on the host’s response to a subsequent exposure of antigen. Small quantities of the antigen may favor sensitization by restricting the quantity of antibody formed. An unusual reaction, such as an allergic or hypersensitive reaction that follows a second exposure to the antigen, reveals the existence of the sensitization.

What is an allergy?

Our basic understanding of allergy has evolved from the discovery in 1967 of a previously unknown antibody, immunoglobulin E (IgE). The most significant property of IgE antibodies is that they can be specific for hundreds of different allergens. Common allergens include animal dander, pollens, foods, molds, dust, metals, drugs, and insect stings.

The term allergy originally meant any altered reaction to external substances. A related term, atopy, refers to immediate hypersensitivity mediated by IgE antibodies. The terms allergy and atopy are now often used interchangeably. Atopic allergies include hay fever, asthma, food allergies, and latex sensitivity.

Allergies are very common and are increasing in prevalence in the United States, Western Europe, and Australia. Allergies also occur in families, although not necessarily the same allergy.

Types of Antigens and Reactions

Antigens that trigger allergic reactions are called allergens. These low-molecular-weight substances can enter the body by being inhaled, eaten, or administered as drugs.

Hypersensitivity reactions can occur in response to different types of antigen, including environmental substances, infectious agents, food, and self antigens.

Environmental Substances

Environmental substances in the form of small molecules can trigger several types of hypersensitivity reactions. Dust can enter the respiratory tract, mimicking parasites, and stimulate an antibody response. An immediate hypersensitivity reaction associated with IgE, such as rhinitis or asthma, can result. If dust stimulates immunoglobulin G (IgG) antibody production, it can trigger a different type of hypersensitivity reaction, such as farmer’s lung. If small molecules diffuse into the skin and act as haptens, a delayed hypersensitivity reaction, such as contact dermatitis, will result.

Drugs administered orally, by injection, or on the skin can provoke a hypersensitivity reaction mediated by IgE, IgG, or T lymphocytes.

Metals (particularly nickel) and chemicals can also cause type I hypersensitivity reactions. Low-molecular-weight chemicals usually act as a hapten by binding to body proteins or major histocompatibility complex (MHC) molecules. The complex of antigen and MHC molecules is then recognized by specific T cells, which initiate the reaction.

Food Allergies

According to the National Institute of Allergy and Infectious Diseases (NIAID), food allergy (FA) is an important public health problem that affects adults and children and may be increasing in prevalence. The prevalence of food allergy in Europe and North America has been reported to range from 6% to 8% in children up to the age of 3 years. A recent U.S. study has estimated that 5% of children under 5 years of age and 4% of teens and adults have food allergies.

Food allergy can cause severe allergic reactions and even death from food-induced anaphylaxis. Despite the risk, there is no current treatment for FA; the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis of FA may be problematic because nonallergic food reactions, such as food intolerance, are frequently confused with FAs.

The NIAID guidelines separate diseases defined as FA that include both IgE-mediated reactions to food (food allergies), non–IgE-mediated reactions to certain foods (e.g., celiac disease), and mixed IgE and non-IgE disorders (Table 26-1).

Table 26-1

Classification of Hypersensitivity Reactions

Parameter Type of Reaction
I II III IV
Reaction Anaphylactic Cytotoxic Immune complex T cell–dependent
Antibody IgE IgG, possibly other immunoglobulins Antigen-antibody complexes (IgG, IgM) None
Complement involved No Yes Yes No
Cells involved Mast cells, basophils, granules (histamine) Effector cells (macrophages, polymorphonuclear leukocytes) Macrophages, mast cells Antigen-specific T cells
Cytokines involved Yes No Yes Yes (T cell cytokines)
Comparative description Antibody mediated, immediate Antibody dependent; complement or cell mediated Immune complex mediated (immune complex disease) T cell-mediated, delayed type
Mechanism of tissue injury Allergic and anaphylactic reactions Target cell lysis; cell-mediated cytotoxicity Immune complex deposition, inflammation Inflammation, cellular infiltration
Examples Anaphylaxis
Hay fever

Asthma
Food allergy

Transfusion reactions
Hemolytic disease of newborn
Thrombocytopenia
Arthus reaction
Serum sickness

Systemic lupus erythematosus

Allergy or infection
Contact dermatitis

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Mediator.

Types of Hypersensitivity Reactions

The four types of hypersensitivity reaction (I to IV) are defined by the principal mechanism responsible for a specific cell or tissue injury that occurs during an immune response (Table 26-2). Types I, II, and III reactions are antibody dependent and type IV is cell mediated. Some overlapping occurs among the various types of hypersensitivity reactions, but there are major differences in how each type is diagnosed and treated.

Table 26-2

Mediators of Anaphylaxis

Mediator Primary Action
Histamine Increases vascular permeability; promotes contraction of smooth muscle
Leukotrienes Alter bronchial smooth muscle and enhance effects of histamine on target organs
Basophil kallikrein Generates kinins
Serotonin Contracts smooth muscle
Platelet-activating factor Enhances the release of histamine and serotonin from platelets that affect smooth muscle tone and vascular permeability
Eosinophil chemotactic factor of anaphylaxis Attracts eosinophils to area of activity; these cells release secondary mediators that may limit the effects of primary mediators
Prostaglandins Affect smooth muscle tone and vascular permeability

Type I Reactions

Type I hypersensitivity reactions can range from life-threatening anaphylactic reactions to milder manifestations associated with food allergies.

Etiology

Atopic allergies are mostly naturally occurring, and the source of antigenic exposure is not always known. Atopic illnesses were among the first antibody-associated diseases demonstrating a strong familial or genetic tendency.

Several groups of agents cause anaphylactic reactions. The two most common agents are drugs (e.g., systemic penicillin) and insect stings. Insects of the order Hymenoptera (e.g., common hornet, yellow jacket, yellow hornet, paper wasp) are examples of insects causing the most serious reactions. Immune-mediated IgE adverse food reactions (Box 26-1) can be fatal.

Box 26-1   Diagnosis of IgE-Mediated Food Allergy

The National Institute of Allergy and Infectious Diseases (NIAID) Expert Panel recommends:

• Considering food allergy in individuals presenting with anaphylaxis or any combination of symptoms that occur within minutes to hours of ingesting food, especially in young children and/or if symptoms have followed the ingestion of a specific food on more than one occasion. In addition, infants, young children, and selected older children diagnosed with certain disorders, such as moderate to severe atopic dermatitis (AD), eosinophilic esophagitis (EoE), enterocolitis, enteropathy, and allergic proctocolitis (AP) should be considered for FA.

• Using medical history and physical examination to aid in the diagnosis of FA.

• Confirming parent and patient reports of FA because multiple studies demonstrate that 50% to 90%of presumed FAs are not allergies.

• Performing an SPT (skin puncture test) to assist in the identification of foods that may be provoking IgE-mediated food-induced allergic reactions, but the SPT alone cannot be considered diagnostic of FA.

• Not using intradermal testing or measuring total serum IgE to make a diagnosis of FA.

• Using allergen-specific serum IgE (sIgE) tests for identifying foods that potentially provoke IgE-mediated food-induced allergic reactions, but not using these tests as diagnostic of FA.

• Not using an atopy patch test (APT) in the routine evaluation of noncontact FA.

• Not using the combination of SPTs, sIgE tests, and APTs for the routine diagnosis of FA.

• Eliminating one or a few specific foods from the diet may be useful in the diagnosis of FA, especially in identifying foods responsible for some non–IgE-mediated food-induced allergic disorders, such as food protein–induced enterocolitis syndrome (FPIES), AP, and Heiner syndrome, and some mixed IgE- and non-IgE–mediated food-induced allergic disorders, such as EoE.

• Using oral food challenges for diagnosing FA. The double-blind, placebo-controlled food challenge is the gold standard. However, a single-blind or open-food challenge may be considered diagnostic under certain circumstances. If either of these challenges elicits no symptoms (i.e., the challenge is negative), then FA can be ruled out, but when either challenge elicits objective symptoms (i.e., the challenge is positive) and those objective symptoms correlate with medical history and are supported by laboratory tests, then a diagnosis of FA is supported.

• Not using any of the following nonstandardized tests for the routine evaluation of IgE-mediated FA: basophil histamine release or activation, lymphocyte stimulation, facial thermography, gastric juice analysis, endoscopic allergen provocation, hair analysis, applied kinesiology, provocation neutralization allergen-specific IgG4, cytotoxicity assays, electrodermal test (Vega), mediator release assay (LEAP diet).

Adapted from National Institute of Allergy and Infectious Diseases: Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored expert panel report, 2011(www.niaid.nih.gov/topics/foodAllergy/clinical/Documents/FAguidelinesPatient.pdf).

Immunologic Activity

Mast cells (tissue basophils) are the cellular receptors for IgE, which attaches to their outer surface. These cells are common in connective tissues, lungs, and uterus and around blood vessels. They are also abundant in the liver, kidney, spleen, heart, and other organs. The granules contain a complex of heparin, histamine, and zinc ions, with heparin in a ratio of approximately 6:1 with histamine.

Immediate hypersensitivity is the basis of acute allergic reactions caused by molecules released by mast cells when an allergen interacts with membrane-bound IgE (Fig. 26-1). Acute allergic reactions result from the release of preformed granule-associated mediators, membrane-derived lipids, cytokines, and chemokines when an allergen interacts with IgE that is bound to mast cells or basophils by the alpha chain of the high-affinity IgE receptor (FcεRI-α). This antigen receptor also occurs on antigen-presenting cells, where it can facilitate the IgE-dependent trapping and presentation of allergen to T cells.

Histamine, leukotriene C4, interleukin-4 (IL-4), and interleukin-13 (IL-13) are major mediators of allergy and asthma. All are formed by basophils and released in large quantities after stimulation with interleukin-3; IL-3’s effect is restricted to basophil granulocytes. Basophil granulocytes should be considered as key effector cells in type 2 helper T (Th2) cell immune responses and allergic inflammation. IL-3 strongly induces messenger ribonucleic acid (mRNA) for granzyme B, a major effector of granule-mediated cytotoxicity.

Anaphylactic Reaction

Anaphylaxis is the clinical response to immunologic formation and fixation between a specific antigen and a tissue-fixing antibody. This reaction is usually mediated by IgE antibody and occurs in the following three stages:

It is believed that physical allergies (e.g., to heat, cold, ultraviolet light) cause a physiochemical derangement of proteins or polysaccharides of the skin and transform them into autoantigens responsible for the allergic reaction. Most, if not all, of these reactions are caused by the action of a self-directed IgE.

Atopic Reaction

In a person with atopy, exposure of the skin, nose, or airway to an allergen produces allergen-specific IgG antibodies. In response to the allergen, the T cells (when tested in vitro) exhibit moderate proliferation and production of interferon-γ (IFN-γ) by type 1 helper T (Th1) cells. In comparison, individuals with atopy have an exaggerated response characterized by the production of allergen-specific IgE antibodies and positive reactions to extracts of common airborne allergens when tested with a skin prick test. T cells from the blood of atopic patients respond to allergens in vitro by inducing cytokines produced by Th2 cells (e.g., IL-4, IL-5, IL-13), rather than cytokines produced by Th1 cells (e.g., IFN-γ, IL-2).

There are always exceptions to the rule, but the immunologic hallmark of allergic disease is the infiltration of affected tissue by Th2 cells.

Signs and Symptoms

Although everyone inhales airborne allergens derived from pollen, house dust mites, and animal dander, children and adults without atopy produce an asymptomatic, low-grade immunologic response. In a person with atopy, exposure of the skin, nose, or airway to a single dose of allergen produces symptoms (skin redness, sneezing, wheezing) within minutes. Depending on the amount of allergen, immediate hypersensitivity reactions are followed by a late-phase reaction that reaches a peak 6 to 9 hours after exposure to the allergen and then slowly subsides.

Generalized Reaction

A generalized (anaphylactic) reaction is produced by mediators such as cytokines and vasoactive amines (e.g., histamine) from mast cells. Anaphylactic reactions are dramatic and rapid in onset. The physiologic effects of the primary and secondary mediators on the target organs, such as the cardiovascular or respiratory system, gastrointestinal (GI) tract, or the skin, define the signs and symptoms of anaphylaxis. Several important pharmacologically active compounds are discharged from mast cells and basophils during anaphylaxis (see Table 26-2).

Histamine release leads to constriction of bronchial smooth muscle, edema of the trachea and larynx, and stimulation of smooth muscle in the GI tract, which causes vomiting and diarrhea. The resulting breakdown of cutaneous vascular integrity results in urticaria and angioedema; vasodilation causes a reduction of circulating blood volume and a progressive fall in blood pressure, leading to shock. Kinins also alter vascular permeability and blood pressure.

The body’s so-called natural moderators of anaphylaxis are the enzymes that decompose the mediators of anaphylaxis. Antihistamines have no effect on histamine release from mast cells or basophils. In human beings, antihistamines are effective antagonists of edema and pruritus, probably related to their blockage of a histamine-induced increase in capillary permeability but are relatively less effective in preventing bronchoconstriction.

Allergic Disease in Children

Atopic children characteristically experience a progression of allergic disease called allergy march (see later, ImmunoCAP discussion). The formation of IgE antibodies begins early in life, and sensitization can be detected before clinical symptoms. Sensitization to food allergens such as cow’s milk is manifested as colic or chronic otitis. The highest incidence of sensitization is at age 2 years. After 3 years of age, food sensitivities tend to decrease; sensitization to inhalant allergens typically increases during the preschool years. In most children with asthma, symptoms begin before age 5 years. Risk factors for allergic asthma include a family history of allergy, sensitization to food allergens, total serum IgE higher than 100 kU/L before age 6 years, living in an allergen-rich environment, and smoking.

Testing for Type I Hypersensitivity Reactions

In addition to a patient history and physical examination, an in vivo testing protocol can be used to assist in the identification of foods that may provoke allergic reactions. Skin testing can be performed by a skin puncture test (SPT) to assist in the identification of foods that may provoke IgE-mediated, food-induced allergic reactions or a patch test.

The SPT alone cannot be considered diagnostic of FA. Placing a drop of a solution containing a possible allergen on the skin is the basis of skin testing. A series of scratches or needle pricks allows the solution to enter the skin. If the skin develops a red, raised, itchy area, this is a positive reaction, which usually means that the person is allergic to that particular allergen. Skin testing is a simple outpatient technique to screen for many potential allergens, but may not be suitable for pediatric patients, pregnant women, or other groups. The procedure carries the risk of triggering a systemic reaction (e.g., anaphylactic reaction) or initiating a new sensitivity.

A patch test may be used for the evaluation of contact food allergies. Skin patch testing involves taping a patch that has been soaked in the allergen solution to the skin for 24 to 72 hours. This type of testing is used to detect contact dermatitis.

Laboratory Evaluation of Allergic Reactions

Advantages of in vitro testing include the lack of risk of a systemic hypersensitivity reaction and the lack of dependence on skin reactivity, which can be influenced by drugs, disease, or the patient’s age. Detection of an increased amount of total IgE or allergen-specific IgE in serum indicates an increased probability of an allergic disorder, parasitic infection, or aspergillosis. In vitro laboratory testing can be performed by a variety of methods.

The clinical significance of serum allergen-specific IgE (sIgE) in allergic disorders has long been recognized. The quantitative determination of serum sIgE antibodies is an essential component for differential diagnosis and for identifying the causative allergens for proper medical treatment. The quality and availability of allergens, reagent stability, and degree of automation all influence the method of testing. Based on thousands of test results, a generic curve indicates what an allergen-specific IgE antibody value can mean in relation to symptoms. Although a final diagnosis should always be based on the physicians’ overall impression of the patient, a general rule of thumb is that the higher the IgE antibody value, the greater the likelihood of symptoms appearing.

ImmunoCAP

The U.S. Food and Drug Administration (FDA) has approved ImmunoCAP to provide an in vitro quantitative measurement of IgE in human serum (Fig. 26-2). It is considered to be the gold standard for the analysis of allergen-specific IgE. It is intended for in vitro use as an aid in the clinical diagnosis of IgE-mediated allergic disorders in conjunction with other clinical findings (Table 26-3) .

Table 26-3

Comparison of Tests for Specific IgE

Parameter Skin Prick Testing Intradermal Testing Blood Testing (ImmunoCAP)
Sensitivity (%) 93.6 60.0 87.2
Specificity (%) 80.1 32.3 90.5

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Adapted from Choo-Kang LR: Specific IgE testing: objective laboratory evidence supports allergy diagnosis and treatment, Med Lab Observer MLO 38:10–14, 2006.

ImmunoCAP assays can be performed for hundreds of allergens, such as weeds, trees, pollens, mold, food, and animal dander. It offers testing for over 650 different allergens and 70 allergen components for sensitive and specific quantitative detection of allergen-specific IgE antibodies.

The substances to which a patient is exposed will generally dictate the allergens to test. Some allergens are more common as causes of allergy than others. Factors to consider are the following:

An example of a pediatric allergy, the march (progression) profile, includes testing for allergens to Alternaria alternata (Alternaria tenuis; mold), cat dander, cockroach (German), Dermatophagoides pteronyssinus (Dermatophagoides farinae; mites), dog dander, egg white, codfish, whitefish, cow’s milk, peanut, soybean, wheat, and total serum IgE. Food profile allergens might include corn, egg white, cow’s milk, orange, peanut, shrimp, soybean, and wheat.

Respiratory allergen inhalants can include A. alternata (A. tenuis), cat epithelium and dander, dog dander, elm tree, Hormodendrum hordei (Cladosporium herbarum; fungi), house dust, June grass, Kentucky bluegrass, mountain cedar (juniper) tree, and Russian thistle. Respiratory subtropical Florida allergens include A. alternata (A. tenuis), Aspergillus fumigatus, pine, Australian pine, Bahia grass, Bermuda grass, cat dander, cockroach (German), common short ragweed, D. farinae (D. pteronyssinus; mites), dog dander, Hormodendrum hordei (Cladosporium herbarum; fungi), oak tree, pecan (white hickory) tree, Penicillium notatum, pigweed, and total serum IgE.

The clinical use of inhaled steroids is becoming increasingly popular because of their antiinflammatory effects, although overtreatment may have serious side effects. To ensure the lowest effective dosage throughout treatment, the laboratory can periodically monitor the occurrence in serum of ECP-2 released from inflammatory cells. Eosinophil cationic protein (ECP) released by eosinophils can be detected in body fluids.

Chemiluminescent Enzyme Immunoassay
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