Hypersensitivity Reactions

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Hypersensitivity Reactions

Learning Objectives

At the conclusion of this chapter, the reader should be able to:

• Define the terms hypersensitivity, allergy, sensitization, and immunization.

• Identify and explain the three categories of antigens.

• Compare the basic differences among and give examples of types I, II, III, and IV hypersensitivity reactions.

• Describe the etiology, immunologic activity, signs and symptoms, laboratory evaluation, and treatment of type I hypersensitivity reactions.

• Discuss examples of type II hypersensitivity reactions, including laboratory evaluation.

• Describe the mechanism of tissue injury, clinical manifestations, and laboratory testing for type III hypersensitivity reactions.

• Describe the characteristics and laboratory evaluation of type IV hypersensitivity reactions.

• Discuss the acquisition and consequences of latex sensitivity.

• Analyze case studies related to hypersensitivity reactions.

• Correctly answer case study related multiple choice questions.

• Be prepared to participate in a discussion of critical thinking questions.

• Describe the principle, clinical applications, or sources of error of a food allergy test, and the direct antiglobulin test.

• Correctly answer end of chapter review questions.

Key Terms

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

image

∗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(http://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.

image
Figure 26-1 Pathways leading to acute and chronic allergic reactions.
Acute allergic reactions are caused by the antigen-induced release of histamine and lipid mediators from mast cells. In the skin and upper airways, basophils (not shown) may also participate in allergic tissue reactions. Chronic allergic reactions, including the late-phase reaction, may depend on a combination of pathways, including recruitment of eosinophils, liberation of mast cell products by histamine-releasing factors, and neurogenic inflammation involving neurotrophins and neuropeptides. Th2, T-helper cell type 2; MHC, major histocompatibility complex. (Adapted from Kay AB: Allergy and allergic disease, N Engl J Med 344:30–38, 2001.)

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

image

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

image
Figure 26-2 ImmunoCAP test—principle, steps, and evaluation. ECP, Eosinophilic cationic protein. (Courtesy Phadia AB, Uppsala, Sweden.)

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.

Treatment

Treatment of patients with allergies involves identifying and eliminating or avoiding possible allergens. Drug therapy and desensitization are two treatment strategies.

Drug Therapy

Drug treatments include the following:

• Epinephrine (adrenaline) can be lifesaving in anaphylaxis. Epinephrine stimulates both α-adrenergic and β-adrenergic receptors, decreases vascular permeability, increases blood pressure, and reverses airway obstruction.

• Antihistamines block specific histamine receptors and play an important role in allergies affecting the skin, nose, and mucous membranes. Antihistamines act much slower than epinephrine in treating anaphylaxis and are not very useful in asthma because histamine is not an important allergic mediator released by mast cells in the lung.

• Specific receptor antagonists block the effects of leukotrienes. One drug, montelukast, reduces the amount of airway inflammation in asthma.

• Corticosteroids, often given topically, are widely used in the prevention of symptoms in patients with allergy.

• Other drugs in development aim to block the Th2 cytokine pathway or prevent IgE binding to FcεRI-α.

Desensitization

Desensitization, or immunotherapy, is a well-established technique to improve allergy symptoms caused by specific allergens (e.g., hay fever; Fig. 26-3). If a patient has a history of life-threatening conditions, and if other treatment alternatives are unsatisfactory, desensitization is used to prevent anaphylaxis resulting from insect stings (e.g., yellow jackets). It is best if only one allergen is incriminated.

image
Figure 26-3 Proposed mechanisms of specific immunotherapy (hyposensitization or desensitization).
Specific immunotherapy is associated with downregulation of the cytokines produced by Th2 cells, upregulation of cytokines produced by Th1 cells, and induction of regulatory T cells. These changes in turn lead to inhibition of allergic inflammation, increases in cytokines that control production of IgE (interferon-g and interleukin-12) and blocking antibodies (IgG), and release of cytokines involved in allergen-specific hyporesponsiveness (IL-10 and transforming growth factor-β). (Adapted from Kay AB: Allergy and allergic disease, N Engl J Med 344:109–113, 2001.)

Specific immunotherapy is associated with downregulation of the cytokines produced by Th2 cells, upregulation of cytokines produced by Th1 cells, and induction of regulatory T (Treg) cells. These changes in produce inhibition of allergic inflammation, increases in cytokines that control the production of IgE (IFN-γ and IL-12), production of blocking antibodies (IgG), and release of cytokines involved in allergen-specific hyporesponsiveness (IL-10 and transforming growth factor-β).

Different routes of desensitization induce different T-cell populations—Th1 and Treg cells in the case of subcutaneous administration and Th2 cells in the case of a sting on the skin.

For desensitization to insect venom, venom is injected subcutaneously in increasing doses at fixed intervals. Treatment starts with very small doses of venom because there is a risk of inducing anaphylactic shock. Over time, the patient is injected with increasing quantities of venom, eventually corresponding to the amount of venom in the insect sting. Once desensitization has been carried out, high levels of allergen-specific IgG will bind venom and prevent it from cross-linking IgE on mast cells. After following the prescribed treatment protocol, more than 90% of patients will not develop anaphylaxis if they are stung again.

Type II Reactions

Type II hypersensitivity reactions are a consequence of IgG or IgM binding to the surface of cells. Three different mechanisms of antibody-mediated injury exist in type II hypersensitivity, as follows:

1. Antibody-dependent, complement-mediated cytotoxic reactions. These are characterized by the interaction of IgG or IgM antibody with cell-bound antigen. This binding of an antigen and antibody can result in the activation of complement and destruction of the cell (cytolysis) to which the antigen is bound. Erythrocytes, leukocytes, and platelets can be lysed by this process. Examples of antibody-dependent, complement-mediated cytotoxic reactions include immediate (acute) transfusion reactions and immune hemolytic anemias (e.g., hemolytic disease of the newborn).

2. Antibody-dependent, cell-mediated cytotoxicity. This depends on the initial binding of specific antibodies to target cell surface antigens. The antibody-coated cells are lysed by effector cells, such as natural killer (NK) cells and macrophages, expressing Fc receptors. The Fc receptors of these effector cells attach to the Fc portion of the antibody that is coating the target cell. Target cell destruction occurs when cytotoxic substances are released by the effector cells. This is the mechanism of injury in antibody-mediated glomerulonephritis and many other diseases. Antibody binding damages solid tissues, in which the antigen may be cellular or part of the extracellular matrix (e.g., basement membrane).

3. Antireceptor antibodies. These disturb the normal function of receptors. Less often, antibodies may modify the function of cells by binding to receptors for hormones (autoimmune hypersensitivity against solid tissue), as illustrated by autoimmune thyroid disease (see Chapter 28). Hyperacute graft rejection is also an example of type II hypersensitivity (see Chapter 31).

Type II Antibody-Dependent, Complement-Mediated Cytotoxic Reactions

Transfusion Reactions

Transfusion reactions are examples of antibody-dependent, complement-mediated cytotoxic reactions. The term transfusion reaction generally refers to the adverse consequences of incompatibility between patient and donor erythrocytes. Transfusion reactions can include hemolytic (red blood cell [RBC]–lysing) reactions occurring during or shortly after a transfusion, shortened posttransfusion survival of RBCs, an allergic response, or disease transmission.

Transfusion reactions can be divided into hemolytic and nonhemolytic types. Hemolytic reactions are associated with the infusion of incompatible erythrocytes. These reactions can be further classified into acute (immediate) or delayed in their manifestations (Box 26-2). Several factors influence whether a transfusion reaction will be acute or delayed, including the following:

Box 26-2   Types of Transfusion Reactions

Immediate Hemolytic

Immediate Hemolytic Reactions

The most common cause of an acute hemolytic transfusion reaction is the transfusion of ABO group–incompatible blood. In patients with preexisting antibodies resulting from prior transfusion or pregnancy, other blood groups may be responsible.

Immunologic Manifestations

Acute hemolytic reactions occur during infusion or immediately after blood has been infused. Infusion of incompatible erythrocytes in the presence of preexisting antibodies initiates an antigen-antibody reaction, with activation of the complement, plasminogen, kinin, and coagulation systems. Other initiators of acute hemolytic reactions include bacterial contamination of blood or infusion of hemolyzed erythrocytes. Many reactions demonstrate extravascular and intravascular hemolysis. If an antibody is capable of activating complement and is sufficiently active in vivo, intravascular hemolysis occurs, producing a rapid increase of free hemoglobin in the circulation. Although uncertain, the cause of the immediate clinical symptoms may be products released by the action of complement on the erythrocytes, which triggers multiple shock mechanisms.

Delayed Hemolytic Reaction

A delayed reaction may not manifest until 7 to 10 days after transfusion. In contrast to an immediate reaction, a delayed reaction occurs in the extravascular spaces. These reactions are associated with decreased RBC survival because of the coating of the RBCs (positive direct antiglobulin test), which promotes phagocytosis and premature removal of RBCs by the mononuclear phagocyte system. If an antibody does not activate complement or activates it very slowly, extravascular hemolysis occurs. Most IgG antibody–coated erythrocytes are destroyed extravascularly, mainly in the spleen.

A delayed hemolytic transfusion reaction may be of two types. It may represent an anamnestic antibody response in a previously immunized recipient on secondary exposure to transfused erythrocyte antigens, or it may result from primary alloimmunization. In an anamnestic response, the antibodies are directed against antigens to which the recipient has been previously immunized by transfusion or pregnancy.

Hemolytic Disease of the Fetus and Newborn

Hemolytic disease of the fetus and newborn (HDFN) results from excessive destruction of fetal RBCs by maternal antibodies. HDFN in the fetus or neonate is clinically characterized by anemia and jaundice. If the hemoglobin breakdown product that visibly produces jaundice (bilirubin) reaches excessive levels in the newborn’s circulation, it will accumulate in lipid-rich nervous system tissue and can result in mental retardation or death.

Etiology

Antigens possessed by the fetus that are foreign to the mother can provoke an antibody response in the mother. Any blood group antigen that occurs as an IgG antibody is capable of causing HDFN.

Although anti-A and anti-B are present in the absence of their corresponding antigens as environmentally stimulated (IgM) antibodies, infrequent IgG forms may be responsible for HDFN because of ABO incompatibility. High titers of anti-A, anti-B of the IgG type in group O mothers often cause mild HDFN. Anti-A and anti-B antibodies are usually 19S (IgM) in character and, as such, are unable to pass through the placental barrier. In addition, the A and B antigens are not fully expressed on the erythrocytes of the fetus and newborn. In a survey of antibodies that have caused HDFN, more than 70 different antibodies were identified.

Signs and Symptoms

Hemolytic disease resulting from ABO incompatibility is usually mild because of fewer A and B antigen sites on the fetal or newborn erythrocytes, weaker antigen strength of fetal or newborn A and B antigens, and competition for anti-A and anti-B between tissues and erythrocytes. The number and strength of A and B antigen sites on fetal erythrocytes are less than on adult RBC membranes. In addition, A and B substances are not confined to the RBCs, so only a small fraction of IgG anti-A and anti-B that crosses the placenta combines with the infant’s erythrocytes.

Manifestations of HDFN caused by other antibodies can range from mild to severe. In addition to possible death in utero, newborns may demonstrate severe anemia and an increase in RBC breakdown products, such as bilirubin. Accumulation of bilirubin causes jaundice and may result in mental retardation if the bilirubin is not cleared from the infant’s body.

Immunologic Mechanisms

For antibody formation to take place, the mother must lack the antigen and the fetus must express the antigen (gene product). The fetus would inherit the gene for antigen expression from the father. HDFN results from the production of maternal antibodies that have been stimulated by the presence of these foreign fetal antigens. The actual production of antibodies depends on a variety of factors: the genetic makeup of the mother, the antigenicity of a specific antigen, and the actual amount of antigen introduced into the maternal circulation.

Transplacental hemorrhage (TPH) can occur at any stage of pregnancy. Immunization resulting from TPH can result from negligible doses during the first 6 months in utero; however, significant immunizing hemorrhage usually occurs during the third trimester or at delivery. Fetal erythrocytes can also enter the maternal circulation as the result of physical trauma from an injury, abortion, ectopic pregnancy, amniocentesis, or normal delivery. Abruptio placentae, cesarean section, and manual removal of the placenta are often associated with a considerable increase in TPH.

An example of the normal pattern of immunization is demonstrated by the case of an Rh(D)-negative mother whose primary immunization (sensitization) was caused by a previously incompatible Rh(D)-positive pregnancy or a blood transfusion, which stimulates the production of low-titered anti-D, predominantly of the IgM class. Subsequent antigenic stimulation, such as fetal-maternal hemorrhage during pregnancy with an Rh(D)-positive fetus, can elicit a secondary (anamnestic) response, characterized by the predominance of increasing titers of anti-D of the IgG class.

Immune antibodies subsequently react with fetal antigens. Erythrocytic antigens, as well as leukocyte and platelet antigens, can induce maternal immunization by the formation of IgG antibodies. In HDFN, the erythrocytes of the fetus become coated with maternal antibodies that correspond to specific fetal antigens. Antibodies to IgG, the only immunoglobulin selectively transported to the fetus, are transferred from the maternal circulation to the fetal circulation through the placenta. The mechanism whereby IgG passes through the placenta has not been definitively established. Most research on transplacental passage supports the hypothesis that all IgG subclasses are capable of crossing the placental barrier between mother and fetus.

When the antigen and its corresponding antibody combine in vivo, increased lysis of RBCs results. Because of this hemolytic process, the normal 45- to 70-day lifespan of the fetal erythrocytes is reduced. To compensate for RBC loss, the fetal liver, spleen, and bone marrow respond by increasing production of erythrocytes. Increased RBC production outside the bone marrow, extramedullary hematopoiesis, can result in enlargement of the liver and spleen and premature release of nucleated erythrocytes from the bone marrow into the fetal circulation. If increased RBC production cannot compensate for the cell being destroyed, a progressively severe anemia develops that can cause the fetus to develop cardiac failure, with generalized edema and death in utero. Less severely affected infants continue to experience erythrocyte destruction after birth, which generates large quantities of unconjugated bilirubin. Bilirubin resulting from excessive hemolysis could result in the accumulation of free bilirubin in lipid-rich tissue of the central nervous system.

Testing for Type II Hypersensitivity

The direct antiglobulin test (DAT) is performed to detect transfusion reactions, HDFN, and autoimmune hemolytic anemia (see later procedure). Polyspecific antihuman globulin (AHG), a mixture of antibodies to IgG and complement components (e.g., C3d), is used for preliminary screening. If positive, the DAT can be repeated using monospecific anti-IgG and anti-C3d reagents for a more exact determination. If there is an autoimmune hemolytic anemia caused by IgM, only the C3d assay would be positive.

The indirect AHG assay is used to determine the presence of an unexpected antibody.

Platelet agglutination assays may be of value if idiopathic thrombocytopenic purpura is suspected. If Goodpasture’s syndrome is suspected, direct fluorescent examination of a renal tissue biopsy would be helpful.

Type II Autoimmune Hypersensitivity Against Solid Tissue

Autoantibodies can also attack and damage components of solid tissues. These antibodies can simply stimulate the target organ function without causing much target organ damage, as in Graves’ disease. In other cases, stimulation of cells by autoantibody leads to tissue damage. As noted, Goodpasture’s syndrome involves IgG autoantibodies and a glycoprotein in the basement membrane of the lung and glomeruli. Anti–basement membrane antibody activates complement, which can trigger an inflammatory response. Goodpasture’s syndrome can be diagnosed by finding antibodies to glomerular basement membrane in patient serum on indirect immunofluorescence (Fig. 26-4) and autoantibodies in serum.

image
Figure 26-4 Indirect immunofluorescence used to detect autoantibodies in patient with Goodpasture’s syndrome.
Kidney tissue is used as the target antigen for this test. Linear staining along the glomerular basement membrane appears to be lit up compared with the renal tubules in the background. (From Nairn R, Helbert M: Immunology for medical students, ed 2, St Louis, 2007, Mosby.)

Type III (Immune Complex) Reactions

Type III hypersensitivity reactions are caused by the deposition of immune complexes in blood vessel walls and tissues. Repeated antigen exposure leads to sensitization with the production of an insoluble antigen-antibody complex. As these complexes are deposited in tissues, the complement system is activated, macrophages and leukocytes are attracted, and immune-mediated damage occurs. Common skin conditions in this category include allergic vasculitis and erythema nodosum. Pulmonary reactions include hypersensitivity pneumonitis, characterized best by farmer’s lung, which is a reaction to thermophilic actinomycetes found in moldy hay. Chemicals such as toluene diisocyanate, phthalic anhydride, and trimetallic anhydride can cause bathtub refinisher’s lung, epoxy resin lung, and plastic worker’s lung, respectively.

Farmer’s lung and the Arthus reaction (Fig. 26-5) are examples of local immune complex diseases. Poststreptococcal glomerulonephritis is an example of a circulating immune complex disease, as in systemic lupus erythematosus (SLE; see Chapter 29). Immune complexes are lattices of antigen and antibody that may be localized to the site of antigen production or may circulate in the blood. Immune complexes are produced as part of the normal immune response and are usually cleared by mechanisms involving complement. However, they cause disease in various situations. Failure to clear immune complexes can result from the saturation of mechanisms involving excessive ongoing production of immune complexes, as well as antigenemia caused by chronic infection.

image
Figure 26-5 Arthus reaction.
In these two reactions of the skin of a rabbit, the larger reaction has an extensive zone of erythema and edema surrounding its necrotic center. (From Markell EK, Voge M: Medical parasitology, ed 5, Philadelphia, 1981, WB Saunders.)

The formation of immune complexes under normal conditions protects the host because they facilitate the clearance of various antigens and invading microorganisms by the mononuclear phagocyte system. In immune complex reactions (disease), antigen-antibody complexes form in the soluble or fluid phase of tissues or in the blood and assume unique biological functions, such as interaction with complement and with cellular receptors.

Other type III (immune complex) reactions include serum sickness and certain aspects of autoimmune diseases (e.g., glomerulonephritis in SLE). Circulating soluble immune complexes are responsible for or associated with various human diseases in which exogenous and endogenous antigens can trigger a pathogenic immune response and result in immune complex disease (Table 26-4).

Table 26-4

Diseases Associated With Immune Complexes

Type Examples
Autoimmune diseases Rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, mixed connective tissue disease, systemic sclerosis, glomerulonephritis
Neoplastic disease Solid and lymphoid tumors
Infectious disease Bacterial infective endocarditis, streptococcal infection, viral hepatitis, infectious mononucleosis

Mechanism of Tissue Injury

Type III reactions are caused by IgG, IgM, and possibly other antibody types. Immune complexes can exhibit a spectrum of biological activities, including suppression or augmentation of the immune response by interacting with B and T cells, inhibition of tumor cell destruction, and deposition in blood vessel walls, glomerular membranes, and other sites. These deposits interrupt normal physiologic processes because of tissue damage secondary to the activation of complement and resulting activities such as mediating immune adherence and attracting leukocytes and macrophages to the sites of immune complex deposition. The release of enzymes and possibly other agents damages the tissues. There are three general anatomic sites of antigen-antibody interactions:

Clinical Manifestations

The persistence of immune complexes in the blood circulation is not inherently harmful. Immune complex disease develops when these circulating complexes are not cleared from the circulation by phagocytosis and are subsequently deposited in certain tissues.

Autoimmune Disorders

SLE is an autoimmune disorder characterized by autoantibodies that form immune complexes with autoantigens, which are deposited in the renal glomeruli (see Chapter 29). As a consequence of this type III hypersensitivity reaction, glomerulonephritis (inflammation of capillary vessels in the glomeruli) develops.

Type IV Cell-Mediated Reactions

Type IV cell-mediated immunity consists of immune activities that differ from antibody-mediated immunity. Cell-mediated immunity is moderated by the link between T lymphocytes and phagocytic cells (i.e., monocyte-macrophages). Lymphocytes (T cells) do not recognize the antigens of microorganisms or other living cells but are immunologically active through various types of direct cell to cell contact and by the production of soluble factors.

Characteristics

• Type IV delayed-type hypersensitivity (DTH) involves antigen-sensitized T cells or particles that remain phagocytized in a macrophage and are encountered by previously activated T cells for a second or subsequent time. T cells respond directly, or by the release of lymphokines, to exhibit contact dermatitis and allergies of infection (Figs. 26-6 and 26-7). One of the mechanisms of cell-mediated immunity is delayed hypersensitivity. Delayed hypersensitivity is a major mechanism of defense against various intracellular pathogens, including mycobacteria, fungi, and certain parasites. In addition, cell-l-mediated immunity is responsible for the immunologic mechanisms contact sensitivity

image
Figure 26-6 Delayed skin reaction.
This reaction exhibited an erythematous but nonedematous zone 15 mm in diameter at 48 hours. A control site, inoculated higher on the forearm, showed no reaction at this time. (From Barrett JT: Textbook of immunology, ed 5, St Louis, 1988, Mosby.)
image
Figure 26-7 Mechanisms of T cell–mediated tissue injury.
T cells may cause tissue injury and disease by two mechanisms: (1) delayed-type hypersensitivity reactions (A), which may be triggered by CD4+ and CD8+ T cells, and in which tissue injury is caused by activated macrophages and inflammatory cells; and (2) direct killing of target cells. (From Abbas AK, Lichtman AH: Basic immunology: functions and disorders of the immune system, ed 3, updated edition, Philadelphia, 2011, Saunders.)

• Rejection of foreign tissue grafts, elimination of tumor cells bearing neoantigens and

• Formation of chronic granulomas

Under some of these conditions, the activities of cell-mediated immunity may not be beneficial. Suppression of the normal adaptive immune response (immunosuppression) by drugs or other means is necessary to overcome an unwanted immunologic response in conditions such as organ transplantation, hypersensitivity, and autoimmune disorders.

DTH can be a physiologic reaction to pathogens that are difficult to clear, such as hepatitis B virus and Mycobacterium tuberculosis. This triggers the most extreme DTH reactions, characterized by granuloma formation, extensive cell death, and appearance of caseous necrosis. DTH can also occur in response to innocuous environmental antigens (e.g., nickel). Antigens must have a low molecular weight to enter the body. DTH reactions also take place against autoantigens. In insulin-dependent (type 1) diabetes, T cells respond to pancreatic islet cell antigens, damaging the islets and eventually preventing insulin secretion.

DTH reactions are initiated when tissue macrophages recognize the presence of danger signals and initiate the inflammatory response. Dendritic cells loaded with antigen migrate to local lymph nodes, where they present antigen to T cells. Specific T cell clones proliferate in response to antigens and migrate to the site of inflammation. T cells and macrophages stimulate one another through the cytokine network. Tumor necrosis factor-α (TNF-α) is secreted by macrophages and T cells and stimulates much of the damage in DTH reactions. Because of the need for antigen presentation by T cells, DTH reactions are often associated with specific human leukocyte antigen (HLA) alleles.

The hallmark of occupational type IV hypersensitivity is allergic contact dermatitis caused by metals (e.g., nickel, mercury, copper), sunscreen agents, disinfectants, perfumes and fragrances, and pesticides. Pulmonary hypersensitivity can be caused by inorganic dust particles, hard metal, and beryllium. Hard metal exposure involves cobalt from the grinding of steel.

Latex Sensitivity

In the health care setting, natural latex can be an allergen in those who have significant cumulative exposure. Since 1985, policies of Standard Precautions have resulted in an exponential increase in the use of latex gloves. The use of latex condoms has also increased. The increase in total exposure to latex and variations in manufacturing apparently have led to an increase in the number of persons with latex sensitivity.

Once sensitized, an individual may experience allergic symptoms when exposed to any product containing latex. At-risk groups sensitized to natural rubber latex include 8% to 17% of health care workers, as well as children who have repeated surgeries. Less than 1% of the general U.S. population (≈3 million) demonstrate latex sensitivity.

Latex contains low-molecular-weight soluble proteins that cause IgE-mediated allergic reactions. Latex allergy can give rise to a broad range of symptoms. Glove wearers may experience type IV, or delayed hypersensitivity, contact dermatitis that ranges from nonspecific pruritus to eczematous, red, weepy skin. These symptoms and the irritant contact dermatitis are caused by the accelerators and chemicals used in glove manufacturing, not by the latex itself. Avoidance of latex gloves is often sufficient to prevent these symptoms.

Anaphylactic reactions to latex have been reported in those who had previously experienced only irritant or allergic contact dermatitis. Direct skin contact with latex may cause a type I, or immediate hypersensitivity, IgE-mediated reaction within 30 to 60 minutes of exposure. Urticaria may be local or generalized and the spectrum of progression is notably unpredictable; some persons have experienced anaphylactic reactions after having minimal or no previous symptoms.

Certain fruits, such as bananas, chestnuts, kiwi, avocados, and tomatoes, show cross-reactivity, perhaps because of a similarity to a latex protein component. These foods have been responsible for anaphylactic reactions in latex-sensitive persons. Many other foods, including figs, apples, celery, melons, potatoes, papayas, and pitted fruits (e.g., cherries, peaches), have caused progressive symptoms, beginning with oral itching. Persons with a history of reactions to these foods are at increased risk of developing latex allergy and those who are sensitive to latex should avoid foods to which they have had previous reactions.

Testing for Delayed Hypersensitivity

The skin test for testing of exposure to tuberculosis (TB) is a classic example of a delayed hypersensitivity reaction. The test is based on the principle that soluble antigens from M. tuberculosis induce a reaction in individuals who have acquired or been exposed to the tuberculosis microorganism or a related organism at some time. It does not mean that the person has tuberculosis.

A small amount of antigen is injected under the skin (intradermally) with a fine-needle syringe. The site is observed at 48 and 72 hours for the presence of induration (lesion ≥10 mm in diameter).

Other antigens that can be skin-tested include diphtheria toxoid, tetanus toxoid, fungal antigens (e.g., Trichophyton, histoplasmin), and Candida albicans.

In cases of persistent dermatitis, a patch test may be performed. An adhesive patch containing the suspected allergen is applied to the skin. The skin is checked for redness with papules or tiny blisters, indicating a positive test result, over 48 hours.

Diagnosis of latex allergy is determined by the patient history and immunologic testing. FDA-approved in vitro tests to measure latex-specific IgE are available (Pharmacia CAP, Pharmacia-UpJohn Diagnostics, Kalamazoo, Mich; AlaSTAT, Diagnostic Products, Los Angeles). The low specificity of these tests, which have a false-negative rate of at least 20% and thus unclear positive predictive value, limits their clinical usefulness. Negative serologic testing with a strongly positive history would suggest the value of skin prick testing to confirm the diagnosis.

Treatment

Strategies to avoid a DTH reaction include avoiding antigen exposure. Antiinflammatory drugs or corticosteroids may be useful. In some patients, TNF-α monoclonal antibodies and recombinant interferon-β may be administered.

CASE STUDY 1

Mr. RM, a 60-year-old man, was stung by a bee while gardening. He had been stung once before, earlier in the summer. Within a few seconds, his hand began to itch and he began to experience abdominal cramping. He subsequently had difficulty breathing. Fortunately, he was able to reach a first aid kit in his garage. Inside the kit was an EpiPen (injectable epinephrine) for his wife because she was allergic to bee venom. He used the pen and began to feel somewhat better. He immediately had his wife drive him to the hospital.

He was asymptomatic on arrival at the hospital. RM had no history of adverse reactions to bee venom or antibiotics. Because of the nature of the incident, a diagnosis of anaphylactic shock caused by bee venom sensitivity was made. An IgE level was ordered. The results indicated a level more than twice the (normal) reference range value. In addition, a follow-up skin test was performed. The patient was extremely positive for bee venom.

Question

See Appendix A for the answers to multiple choice questions.

CASE STUDY 2

Mrs. CC, a 35-year-old gravida 4 para 1+ 2, was seen by her gynecologist when she was 8 weeks pregnant. Her first pregnancy 4 years ago was unremarkable. The patient reported that her second and third pregnancies had resulted in a stillbirth at 36 weeks and a spontaneous abortion at 10 weeks of gestation. Her medical history revealed no history of blood transfusions. She remembered being vaccinated for rubella. Her medical records had been destroyed in a fire at the clinic. Repeat blood grouping and Rh testing and an irregular antibody screen were ordered (Box 26-3).

Box 26-3   Case Study 2: Laboratory Results

Mrs. CC returned in 2 weeks for a repeat anti-D titer. The titer had risen to 1:16. At 17 weeks’ gestation, an amniocentesis was performed. Severe hemolysis was demonstrated and an intrauterine transfusion of the fetus was carried out using fresh, washed, cytomegalovirus screening test–negative, group O, Rh(D)-negative blood. Because of the continuing risk to the fetus, a cesarean section was performed at 36 weeks’ gestation. On delivery, the baby was noted to be jaundiced and pale. The first of three exchange transfusions was performed. Phototherapy was also used to degrade the bilirubin deposited in the skin. The baby made an uneventful recovery with no signs of kernicterus and was discharged from the hospital 5 days after birth.

Question

See Appendix A for the answers to multiple choice questions.

CASE STUDY 3

ZZ’s medical history included frequent sore throats as a child. He had been treated with antibiotics, particularly penicillin. Eventually, he developed a rash. He was told that he had developed an allergy to penicillin and that he should not have it again.

A decade later, he developed a urinary tract infection. He was treated with an antibiotic, trimethoprim, for 8 days. A few days after completing the regimen, he developed a headache and some itchy bumps on his skin. The next day he had sore and swollen joints. His physician confirmed that the rash was urticaria. ZZ also had an elevated temperature and swollen glands in his neck. The diagnosis of a drug allergy was made. The patient was given antihistamines. If this medication failed to alleviate the symptoms, more aggressive steroid therapy would be pursued.

ZZ’s symptoms did not improve and he was started on an oral corticosteroid, prednisone. When the patient returned to his physician 3 weeks later, he was asymptomatic.

CASE STUDY 4

A 19-year-old college student went to the Student Health Services because she had a slowly developing rash on both earlobes, hands and wrist, and around her neck.

Her medical history revealed that she had eczema in childhood. During her early teens, she had facial acne, for which she was given tetracycline. Physical examination revealed a rash of erythema and small blisters, with marked excoriation because of the itching. Her hands were red, scaly, and dry. The rash on her hands looked different than the eruptions on her neck and ears. A contact hypersensitivity was suspected.

Follow-up patch tests included a standard battery of agents—rubber, cosmetics, plant extracts, perfumes, nickel, and makeup. Strongly positive reactions for rubber and nickel were observed.

The student was advised to eliminate contact with rubber (e.g., rubber gloves) used at home or on the job. Her jewelry probably contained nickel and was believed to be the source of the irritation to her earlobes, neck, and wrists. She was advised to wear only nickel-free jewelry. A mild corticosteroid cream was prescribed for use until her symptoms disappeared.

CASE STUDY 5

A 35-year-old woman reported that she had experienced three bouts of urticaria of unknown origin about 10 years ago. The urticaria affected her mucous membranes and skin. She had experienced similar symptoms after repair of a fractured femur caused by a skiing accident. These symptoms were attributed to an antibiotic reaction.

As an emergency room nurse, she observed occasional localized hives following the use of latex gloves. Even when she used hypoallergenic latex gloves, she continued to have hives every few months. Increased urticaria, at times generalized, continued to occur.

Within 30 minutes of having a routine vaginal examination performed by a health care provider wearing latex gloves, she had an anaphylactic reaction that required resuscitation and hospitalization. A vaginal biopsy 1 week later required a latex-free environment for her safety.

A short time later, she was forced to retire from nursing because of symptoms of asthma. She has also developed food allergies to shellfish.

image Rapid Test for Food Allergy

Principle

Rapid Test

The RAPID 3-D Casein Test (Tepnel BioSystems, Stamford, Conn) uses a three-line diagnostic dry strip format. When a food extract containing casein is extracted and applied to a collector comb, blue latex particles coated with antibodies to casein are mobilized. These particles bind casein in the sample and flow along the test strip, where they are trapped by a second, immobilized casein antibody, revealing a blue line. RAPID 3-D kits are available for gluten, peanuts, almonds, hazelnuts, and shellfish.

image Direct Antiglobulin Test

Principle

The DAT is based on the principle that antiglobulin antibodies induce in vitro agglutination of erythrocytes with immunologically bound antibodies. After erythrocytes (RBCs) are washed to remove free plasma protein from the test mixture, they are tested directly with polyspecific reagents containing anti-IgG and anti-C3d. The DAT procedure is clinically important in the diagnosis of conditions such as hemolytic anemia, including hemolytic disease of the newborn.

Chapter Highlights

• The term immunization, or sensitization, is used to describe an immunologic reaction dependent on the response of the host to a subsequent exposure of antigen.

• Hypersensitivity has traditionally been classified as immediate and delayed based on the time after exposure to an offending antigen.

• Type I hypersensitivity reactions can range from life-threatening anaphylactic reactions to milder manifestations associated with food allergies. This reaction is usually mediated by IgE antibody.

• In vitro evaluation of type I hypersensitivity reactions involves various methods. The advantages of in vitro testing include no risk of a systemic hypersensitivity reaction and no dependence on skin reactivity influenced by drugs, disease, or age.

• Type II cytotoxic reactions are characterized by the interaction of IgG or IgM antibody to cell-bound antigen. This binding of an antigen and antibody can result in activation of complement and destruction of the cell (cytolysis) to which the antigen is bound. Erythrocytes, leukocytes, and platelets can be lysed by this process.

• Examples of type III reactions include the Arthus reaction, serum sickness, and certain aspects of autoimmune disease.

Type IV cell-mediated immunity consists of immune activities that differ from antibody-mediated immunity. Cell-mediated immunity is moderated by the link between T lymphocytes and phagocytic cells. Delayed hypersensitivity is a major mechanism of defense against various intracellular pathogens, including mycobacteria, fungi, and certain parasites. In addition, cell-mediated immunity is responsible for the immunologic mechanisms of contact sensitivity, rejection of foreign tissue grafts, elimination of tumor cells bearing neoantigens and formation of chronic granulomas.

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