Immunology (Lippincott Illustrated Reviews Series) 2nd Edition

Chapter 14: Hypersensitivity Reactions

I. OVERVIEW

Excessive or inappropriate immune responses sometimes lead to host tissue damage resulting from prolonged or repeated antigen exposure. These reactions, called hypersensitivity reactions, cause tissue injury by the release of chemical substances that attract and activate cells and molecules resulting in inflammation. These reactions are classified into four hypersensitivity types depending on the mechanism(s) that underlie the tissue damage (Table 14.1); the first three types involve antigen–antibody reactions, whereas the fourth is antibody-independent, involving cell-mediated immune responses only.

• Type I (also called immediate hypersensitivity) hypersensitivity reactions are rapid, occurring within minutes of exposure to an antigen, and always involve IgE-mediated degranulation of basophils or mast cells.

• Type II hypersensitivity reactions are initiated by the binding of antibody to a cell membrane or to the extracellular matrix.

• Type III hypersensitivity reactions involve the interaction of antibodies with soluble molecules to make soluble antigen–antibody complexes that become deposited in tissues.

• Type IV hypersensitivity reactions are those in which cells of the immune system directly attack host cells in the absence of antibody. These reactions include contact dermatitis (CD, also called contact sensitivity, CS); delayed-type hypersensitivity (DTH); and, occasionally, cytotoxic T-lymphocyte (CTL) responses.

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II. TYPE I HYPERSENSITIVITY

Commonly called allergic or immediate hypersensitivity reactions, type I responses occur within minutes to hours of antigen exposure. Some individuals develop IgE antibodies in response to relatively harmless environmental antigens or allergens. IgE molecules readily bind to Fc receptors (FcRε or CD23) on the surfaces of mast cells and basophils (Fig. 14.1). Unlike other FcRs, FcRεs bind antigen-free immunoglobulin (IgE), and the IgE-CD23 complexes function as antigen-specific cell-surface receptors. Cross-linking of surface-bound IgE molecules generates intracellular signals via CD23, leading to mast cell or basophil degranulation and the release of vasoactive amines (e.g., histamine) and other inflammatory mediators. Histamine and other inflammatory mediators cause vascular endothelial cell junctions to loosen (vasodilation) and increase vascular permeability, resulting in fluid accumulation in the tissues (edema). Histamine also induces smooth muscle contraction in arterial and arteriole walls (vasoconstriction) to accelerate fluid distribution from the central trunk of the body into peripheral tissues.

A. Localized reactions

Because mast cells accumulate in respiratory passages, intestinal walls, and the skin, type I reactions are often most pronounced in these tissues. Sites affected are typically those where the initiating antigen is most often encountered. Antigens that enter the body by inhalation localize primarily to the nasopharyngeal and bronchial tissues, where smooth muscle contraction and vasodilation increase mucous production and the constriction of respiratory passages (Fig. 14.2). In combination, these responses can produce the severe and potentially fatal disorder known as asthma. Allergens that contact other tissues may produce IgE-mediated inflammatory responses, causing rashes, redness, and edema—the classic “wheal and flare” appearance. Food or ingested allergens primarily affect the gastrointestinal tract.

CLINICAL APPLICATION

Asthma

Eighteen months ago, Jenny Q., a 31-year-old female, received a Persian cat (Felis domesticus) as a birthday present. Jenny became sensitized to the major cat allergen (the salivary protein Fel d1) and reported persistent symptoms of nasal congestion, rhinorrhea, sneezing, and nasal pruritus (itching). An oral antihistamine was prescribed, and she was advised to limit her exposure to the cat. These measures were effective in alleviating her symptoms for a time. After several months, Jenny presents to the emergency room with breathing difficulty, wheezing, and chest tightness. Physical examination reveals diffuse wheezing during both expiration and inspiration. Spirometry testing in the emergency room reveals reduced peak expiratory flow rate. Jenny mentions that the cat still lives with her and sleeps in her bedroom. Acute asthma associated with cat allergen exposure is diagnosed. This is an example of IgE-mediated Type I hypersensitivity. If the cat is removed from her house or if she limits her exposure to the cat by keeping it out of her bedroom and uses her medications, her prognosis is good.

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Figure 14.1

Type I reactions. These reactions result from the interaction of surface-bound IgE with antigen. Presentation of antigen (often referred to as allergen) to antigen-specific CD4+ T cells allows them to provide signals to antigen-specific B cells that cause their maturation into IgE secreting plasma cells. IgE enters into the circulation, is rapidly bound by CD23 (FcRε) on tissue mast cells and basophils, and serves as antigen (allergen)-specific receptors on those cells. Subsequent encounter with multivalent (having multiple identical epitopes) allergen cross-links CD23 on mast cells and basophils inducing a signaling cascade, leading to degranulation. The released substances cause contraction of vascular (and other) smooth muscle, dilation of vascular endothelium (vasodilation), leukocyte chemotaxis, and activation.

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Figure 14.2

Asthma. Asthma is a reversible airway obstruction often caused by the release of inflammatory mediators from mast cells upon encounter with allergen. These inflammatory mediators cause the loosening of tight junctions in the bronchiole epithelium, increased capillary permeability, and spasmatic contraction of smooth muscle surrounding the bronchi. This temporarily decreases the size of the bronchial lumen, resulting in shortness of breath. Bronchospasms triggered by nonimmunologic stimuli such as cold, viral infections, and exercise, also stimulate the same airway inflammation.

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Figure 14.3

Anaphylaxis and shock. Exposure to allergen may cause the rapid release of vasoactive amines from mast cells and basophils as well as a flood of cytokines, resulting in the contraction of smooth muscle in the vasculature and vasodilation of capillary endothelium. Blood pressure decreases, resulting in vascular shock. In addition, the release of mediators increases the contraction of smooth muscles in the bronchi and bronchioles of the respiratory tract, making breathing difficult.

B. Systemic reactions

In some cases, such as injected allergens (e.g., venom or toxins), antigen may be disseminated by the bloodstream, resulting in systemic inflammation. In 1902, at the request and sponsorship of Albert I of Monaco, Charles Richet and Paul Portier investigated jellyfish nematocyst toxin that sometimes induced a life-threatening response. Their experiments were conducted on the Prince of Monaco’s yacht (ah, the past glamour of science!). They found that initial injection of dogs with a small amount of toxin had little effect. However, when a second injection of the same amount of the toxin was administered several weeks later, the dogs suffered immediate shock and even death. Termed anaphylaxis (“against protection”), this clinical shock syndrome is characterized by vascular smooth muscle constriction (vasoconstriction) combined with gap formation between adjacent capillary endothelial cells (vasodilation) that results in severe fluid loss and leads to shock. This kind of response can also occur in humans when an allergen, to which the individual is highly sensitive, enters the body (Fig. 14.3).

III. TYPE II HYPERSENSITIVITY

Type II hypersensitivity reactions are initiated by the interaction of antibody (IgM or IgG, not IgE) with cell membranes or with the extracellular matrix. Complement may also be involved. The antigens that are recognized may be intrinsic to the cell membrane or extracellular matrix, or they may be exogenous molecules, such as a drug metabolite adsorbed onto the cell membrane or extracellular matrix.

CLINICAL APPLICATION

Anaphylaxis

Andrew V., an 8-year-old boy, with a history of allergy to walnuts, developed diffuse hives and difficulty breathing after eating a brownie at a school party. The teacher was aware of Andrew’s history of walnut allergy and immediately checked the ingredients listed on the brownie package. She noted that the label stated “may contain peanuts and tree nuts.” She immediately rushed Andrew to the school nurse’s office where the nurse immediately administered a dose of epinephrine using an EpiPen® (Mylan, Inc., Napa, California) and a dose of oral antihistamine. The nurse also called for emergency help to transfer Andrew to the nearest medical facility for further follow-up and therapy.

Andrew’s conditions are consistent with anaphylaxis, which is potentially life threatening. Symptoms of anaphylaxis may involve many organ systems including skin, respiratory, gastrointestinal, and cardiovascular. Cardiac arrest can occur. Patients with severe food allergies are educated in avoidance and should carry EpiPen® for immediate treatment in case of inadvertent exposure to the allergen.

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Figure 14.4

Fc receptors. Receptors for Fc portion of immunoglobulin are expressed by various cell types. With the exception of FcRε (CD23), FcRs bind only antigen-bound antibody. IgE readily binds to FcRε (CD23) in the absence of antigen.

A. Interaction of antibody with cells

Cell-surface or extracellular matrix epitope binding by antibodies (usually IgM or IgG) results in a conformational change in the Fc portion of the antibody molecule (Fig. 14.4). The conformational change in the Fc portion of the antibody molecule is recognized by cellular FcRs and by complement; and several immune-mediated destructive mechanisms may then come into play, targeted on the site(s) of antibody binding.

1. Antibody-dependent cell-mediated cytotoxicity (ADCC): This is complement independent but requires the cooperation of leukocytes (Fig. 14.5). FcR-bearing cells (e.g., monocytes, neutrophils, eosinophils, and natural killer [NK] cells) bind to cells that have IgG or IgM antibodies bound to surface epitopes on a cell.

2. Complement: Complement activated by IgM and IgG antibodies generates active components of the classical pathway, namely, C3b and C4b (discussed previously in Chapter 5). These components are then deposited on the surfaces of antibody-coated cells or extracellular matrix to function as opsonins. Phagocytes recognize bound antibody through their FcRs and bound complement components through their complement receptors. In this manner, both complement and antibody function as opsonins to increase phagocytosis and the destruction of microorganisms (Fig. 14.6).

3. Blood group antibodies: These exemplify type II hypersensitivity reactions. Hemolytic anemias may result from the binding of IgM antibodies to carbohydrate structures on erythrocytes (notably anti-A or anti-B antibodies) resulting in their phagocytosis and in the presence of complement, their rapid lysis (hemolysis) (Fig. 14.7). Antibodies (IgG) to certain protein molecules on erythrocytes (e.g., Rh factor[s]) do not activate complement; erythrocytes are destroyed by phagocytosis (Fig. 14.7).

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Figure 14.5

Antibody-dependent cell-mediated cytotoxicity. Specific binding of immunoglobulin to cell surface epitopes causes a conformation change in the Fc portion of the antibody molecule. FcγRIII, expressed by natural killer (NK) cells, recognize and bind the altered antibody, causing the NK cell to release perforin granules that cause lysis of the antibody-coated cell.

B. Interaction of antibody with the extracellular matrix

Antibodies that bind to extracellular matrix proteins (e.g., basement membrane) may activate the classical pathway of complement, generating anaphylotoxins (e.g., C5a, C4a, C3a, in descending order of potency, not in order of appearance) that recruit neutrophils and monocytes. FcR engagement with the bound antibody results in the release of reactive oxygen intermediates, resulting in inflammation and tissue injury (Fig. 14.8).

C. Antibody-mediated disruption of cellular function

Sometimes antibodies bind to cell surface receptors without activating complement or binding to FcRs. This binding blocks the receptor’s ability to interact with its natural ligand (Fig. 14.9). The antibody-receptor interaction may be stimulatory (e.g., Graves disease) or inhibitory (e.g., myasthenia gravis) to the receptor’s signaling pathway(s).

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Figure 14.6

Type II hypersensitivity reactions. These reactions may involve complement-mediated lysis. Antibodies that invoke the classical and terminal or lytic pathways of complement activation recognize epitopes on cell membranes and cause formation of the membrane attack complex, transmembrane pore formation, and loss of electrolyte balance, causing lysis.

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Figure 14.7

“Natural” antibodies against blood group AB antigens. These naturally occurring IgM antibodies bind to erythrocyte membranes, rendering them susceptible to phagocytosis or complement-mediated lysis.

IV. TYPE III HYPERSENSITIVITY

Circulating antigen–antibody complexes may lead to inflammation at their sites of deposition, often resulting in blood vessel inflammation (vasculitis). Immune complexes may cause injury resulting from the interaction with exogenous (e.g., microbes, viruses, or chemically modified self-proteins) or endogenous antigens (e.g., serum proteins). Type III reactions may occur locally or systemically.

A. Localized reactions

Localized type III hypersensitivities, also known as Arthus reactions, result from acute immune complex vasculitis causing tissue necrosis. These reactions are elicited 4 to 6 hours after the intradermal introduction of a small amount of antigen. Antibody diffuses from the vasculature to form large immune precipitates that activate complement to induce a painful localized edematous inflammatory lesion (Fig. 14.10). Lesions range from necrotizing vasculitis with polymorphonuclear cell infiltration to the formation of a sterile abscess.

B. Systemic reactions

Systemic immune complex disease, in some cases termed serum sickness, occurs with the wide dissemination of antigen–antibody complexes throughout the body. Very large immune complexes are rapidly cleared from the body by phagocytic cells and are relatively harmless. Smaller, circulating immune complexes have less chance to be seen by phagocytes and remain in the circulation longer. These complexes have the greatest pathologic consequences.

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Figure 14.8

Antibodies against matrix proteins. Autoreactive IgG (autoimmune; see Chapter 16) antibodies may react with epitopes on extracellular matrix, such as the basement membrane, and trigger the classical pathway of complement. Sequential activation of complement components C4, C3, and C5 result in the release of C5a, C3a, and C4a (in descending order of potency) activate phagocytes (such as neutrophils and monocytes) to damage the basement membrane.

1. Exogenous antigens: Administered either in large amounts or for a prolonged period, these may induce antibody responses. Soluble antigen–antibody complexes immobilized along the endothelium activate complement to cause vascular injury. Complement components (e.g., C5a, C4a, and C3a) attract polymorphonuclear cells to the site, and these cells exacerbate the vascular injury (Fig. 14.11).

Serum sickness used to be solely a consequence of treatment with animal-derived antisera. Before the advent of antibiotics, sera from immunized animals were often administered to human patients to ameliorate infection or the effects of bacterial toxins, such as diphtheria toxin. Horses were commonly immunized with heat-inactivated toxin (called a toxoid). Intravenously administered horse antiserum is very efficient at neutralizing the harmful effects of bacterial toxins. Horse serum proteins persist in the patient’s circulation and, unfortunately, are very good immunogens in humans. After 7 to 10 days, patients may develop symptoms of immune complex disease, corresponding to the advent of a primary antibody response to horse serum proteins. Serum sickness is a self-limiting disease because the foreign antigen (antiserum) is cleared from the body.

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Figure 14.9

Disruption of cellular function by antibody. Autoantibodies (see Chapter 16) may be produced against the acetylcholine receptor (in a condition known as myasthenia gravis), blocking the interaction of the acetylcholine receptor with its obligate ligand (acetylcholine) and leading to increased muscle weakness and death.

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Figure 14.10

Arthus or acute immune complex vasculitis. This localized type III hypersensitivity reaction results from the tissue deposition of antigen–antibody complexes. Circulating antibodies leave the vasculature to interact with antigens introduced into the tissue.

CLINICAL APPLICATION

Drug-induced immune complex disease

An 18-year-old female presents in the emergency room with a 2-day history of fever (39°C), cough, and labored breathing. A diagnosis of lobar pneumonia is made. She is admitted to the hospital, and because a gram-negative organism is suspected, a 10-day course of oral penicillin G is prescribed. Within 48 hours, her temperature is 37.4°C (37°C is normal), and by 96 hours, her respiration has improved and she feels remarkably better. Sputum cultures grow penicillin-sensitive Streptococcus pneumoniae, confirming the initial diagnosis. On the 8th day of treatment, she develops edematous eyelids and hives (urticaria) on her abdomen. Penicillin is immediately discontinued, and antihistamine is administered. Nevertheless, she develops tightness in the throat, swollen face, and widespread urticaria. Laboratory tests show an elevated leukocyte count with 67% lymphocytes (30% is normal), plasma cells are present in blood smears, and complement levels are decreased. She has developed a type III hypersensitivity response to penicillin. She is advised by her physician that she must avoid use of penicillin and penicillin derivatives in the future.

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Figure 14.11

Accumulation of immune complexes within the vasculature. Antibodies are produced against circulating antigens. Binding of antigen conformationally changes the Fc portion of antibody, which can then bind to endothelial Fc receptors. More antibody and antigen are bound, forming an immune complex that activates the classical pathway of complement.

2. Endogenous antigens: These may also cause immune-complex disease. Unlike exogenous antigens, continually produced endogenous antigens are responsible for chronic antigen exposure, chronic immunization, and prolonged immune-complex disease. Autoimmune diseases are often accompanied by immune-complex disease. Each year, 50 new cases per million of the population of systemic lupus erythematosus (SLE) are diagnosed. This disease occurs approximately eight times more often in women than in men. SLE is a complex, multifaceted autoimmune disease. Individuals with SLE produce autoantibodies to several different self-antigens. As a consequence, immune complexes are deposited in the vascular beds that activate complement and cause vasculitis.

V. TYPE IV HYPERSENSITIVITY

Type IV hypersensitivity reactions result from the interaction of T cell-initiated inflammation and do not involve antibody. Inflammatory responses result from the manner in which T cells encounter and respond to antigen. CD4+ T cells may be sensitized and respond to topically applied antigen (contact dermatitisCD, also called contact sensitivity) and by antigen-injected antigen (delayed [-type] hypersensitivity, DTH). Alternatively, CD8+ T cells may encounter cell-surface antigen and directly cause the lysis of that cell (CTL).

CLINICAL APPLICATION

Acute rheumatic fever

“Strep” throat is an acute infection of the palatine tonsils often caused by Streptococcus pyogenes, making swallowing painful. For most individuals, streptococcal tonsillitis is a self-limiting illness. However, a small number of untreated individuals develop polyarthritis and complications arising from antibody responses to antigen (M protein) expressed in the cell wall of S. pyogenes. A minority of these individuals develop antibodies that cross-react with antigens expressed on heart valves, myocardial and smooth muscle sarcolemma, and myosin (anti-M antibodies), a disease known as acute rheumatic fever (ARF). Because recurrent attacks of S. pyogenes result in increased severity of ARF, prophylactic measures are indicated. When S. pyogenes infection is confirmed by throat culture, antibiotic therapy (penicillin) is prescribed to help eliminate S. pyogenes and to minimize the development of a systemic antibody response.

A. Contact dermatitis

Chemically reactive substances may be absorbed through the epidermis, where they bind to proteins. Potential contact sensitizers include synthetic chemicals, plant products, and certain metals (e.g., nickel). Generally, contact sensitizers are, by themselves, too small (,10,000 Da) to be recognized by the immune system. Contact sensitizers interact with self-proteins to form immunogenic neoepitopes or neoantigens on these proteins. Immunologists often refer to substances that are immunogenic only when bound to another molecule as haptens. First acute exposure to a contact sensitizer often occurs without apparent incident but serves to immunize the immune system. After seven or more days, reexposure or chronic exposure elicits a localized inflammation of the dermis. Clinical signs, like those seen for DTH, typically appear 24 to 72 hours after reexposure (Fig. 14.12).

CLINICAL APPLICATION

Poison ivy

Toxicodendron radicans, commonly known as poison ivy, is a woody vine that secretes a toxic oil known as urushiol. T. diversiloba (poison oak) and T. vermix (poison sumac) also secrete this compound. The name comes from urushi, a Japanese wood lacquer produced from the sap of T. vernicifluum. Minute amounts of urushiol (1 ng) are sufficient to elicit contact dermatitis in previously exposed individuals. Over 85% of individuals who had contact with urushiol will develop a type IV hypersensitivity to this compound.

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Figure 14.12

Contact dermatitis. Certain chemical compounds (e.g., 2,4-dinitrophenyl or DNP) by themselves do not invoke an immune response (haptens). However, they may penetrate the epidermis and covalently bind to self-proteins (hapten-protein conjugate). Following phagocytosis and presentation by resident dendritic cells in the context of MHC class II, CD4+ T cells entering the site may be activated and release chemokines to attract and cytokines (e.g., IFN-γ) that induce type IV hypersensitivity.

CLINICAL APPLICATION

Canary girls and the munitions factory

As men fought in “the war to end all wars,” World War I, Britain found itself with severe shortages of war supplies and labor. The only way to find sufficient labor for production needs was to hire young women to manufacture and load trinitrotoluene (TNT) into explosive shells. TNT is a pale yellow crystalline solid that is readily absorbed through the skin. Munitions workers who handled the chemical found that their skin turned bright yellow (and red hair turned green) and were nicknamed “canary girls.” With time, many developed severe dermatitis, and over 100 workers died from TNT exposure. By themselves, TNT and derivatives of related compounds such as trinitrophenyl, dinitrophenyl, and nitrophenyl cannot stimulate an immune response. These compounds, termed haptens, penetrate the epidermis and readily bind to body proteins, where they may induce a hapten-specific type IV immune response. The plight of the canary girls led to increased awareness of industrial and environmental hazards and aided the cause that led to women’s suffrage in Britain in 1918.

B. Delayed (-type) hypersensitivity

Delayed (-typehypersensitivity (DTH) responses occur in sensitized individuals upon nontopical reencounter with antigen. In general, Type IV DTH hypersensitivity responses are stimulated by intracellular parasites such as bacteria (e.g., Mycobacterium tuberculosis, M. leprae, Leishmania monocytogenes), fungi (e.g., Candida albicans), and some viruses (e.g., mumps virus, a paramyxovirus). DTH responses occur upon reexposure to the stimulating antigen. Reexposure generally must occur more than 1 week after the initial antigenic encounter (Fig. 14.13). Like contact dermatitis responses, DTH responses are delayed, occurring 24 to 72 hours after restimulation. Unlike contact dermatitis responses, DTH responses are not limited to the dermis but can occur at almost any anatomical site in the body.

CLINICAL APPLICATION

Mantoux test

Tuberculosis (TB) is a potentially severe contagious disease caused by Mycobacterium tuberculosis. TB is spread from person to person through the air. According to the Centers for Disease Control and Prevention and the World Health Organization, one-third of the world’s population is infected with TB. More than 2 million people worldwide die from TB each year. Among people older than 5 years of age, TB disease is the leading cause of death due to infectious disease around the world.

The Mantoux skin test is a useful screening test to identify people who have been infected with TB. It involves injection of 5 TU (tuberculin units) of purified protein derivative (tuberculin), usually 0.1 mL, intradermally. Induration (swelling) is assessed at 48 to 72 hours. The induration is caused by cell infiltration and occasionally vesiculation and necrosis. A positive response is an example of type IV hypersensitivity (DTH) and indicates that the subject has had prior exposure to M. tuberculosis.

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Figure 14.13

Delayed (-type) hypersensitivity. Proteins or intracellular organisms are phagocytosed and presented by resident dendritic cells in the context of MHC class II. CD4+ T cells enter the site, recognize the foreign substance, and release chemokines to attract and cytokines (e.g., IFN-γ) to activate phagocytic cells to cause a type IV hypersensitivity.

CLINICAL APPLICATION

Hypersensitivity pneumonitis

John M., a previously healthy 46-year-old male with no prior history of immune-related illnesses presents with a persistent cough and shortness of breath associated with headache and malaise. Four weeks ago, his physician prescribed an antibiotic for some findings on his lung exam. The antibiotic did not alleviate his symptoms. At that time, his chest radiograph and screening spirometry were normal. For the last 6 months, he has worked in a new location. Others at his workplace began to complain of similar symptoms, and an air quality analysis was performed, revealing fungal spore counts of more than 500 per cubic meter of air (reference: ,200). Radiographs show diffuse patchy lung infiltrate consistent with the diagnosis of hypersensitivity pneumonitis, an example of type IV hypersensitivity mediated by CD4+ T cells. John is prescribed a course of oral corticosteroids, and it is recommended that he find an alternative work location. John follows this advice, and his symptoms resolve quickly. He has remained symptom-free since that time.

C. T cell-mediated cytotoxicity

In some instances, type IV hypersensitivity reactions are caused by CD8+ T lymphocytes. These CTLs respond to reactive chemical agents (haptens) that pass through the cell membrane and bind to cytoplasmic proteins to produce neoantigens (Fig. 14.14). Peptides derived from haptenated cytoplasmic proteins (ubiquitin, proteasome, TAP pathway) are presented by MHC class I molecules to sensitize and elicit a CTL response.

Chapter Summary

• All four hypersensitivity responses occur upon second exposure or chronic exposure to antigen. Only type IV hypersensitivity reactions are antibody independent.

• Hypersensitivity reactions cause tissue injury by the release of chemical substances that attract and activate cells and molecules resulting in inflammation.

• Type I hypersensitivity reactions are rapid, occurring within minutes of exposure to an antigen, and always involve IgE-mediated degranulation of basophils or mast cells.

• Anaphylaxis (“against protection”) is characterized by vascular smooth muscle constriction (vasoconstriction) combined with gap formation between adjacent capillary endothelial cells (vasodilation) that results in severe fluid loss and leads to shock.

• Type II hypersensitivity reactions are initiated by the binding of antibody to a cell membrane or to the extracellular matrix. Type II reactions are initiated by the interaction of antibody (IgM or IgG) with cell membranes or with the extracellular matrix. The antigens that are recognized may be intrinsic to the cell membrane or extracellular matrix, or they may be exogenous molecules such as a drug metabolite adsorbed onto the cell membrane or extracellular matrix.

• Type III hypersensitivity reactions involve the interaction of antibodies with soluble molecules to make soluble antigen–antibody complexes that become deposited in tissues. Circulating antigen–antibody complexes may lead to inflammation at their sites of deposition, often resulting in blood vessel inflammation (vasculitis). Immune complexes may cause injury resulting from the interaction with exogenous antigens (e.g., microbes, viruses, or chemically modified self-proteins) or endogenous antigens (e.g., serum proteins).

• Type IV hypersensitivity reactions involve direct attack of host cells by leukocytes in the absence of antibody. Included are contact dermatitis, delayed (-type) hypersensitivity (DTH), and, sometimes, cytotoxic T-lymphocyte (CTL) responses. Type IV reactions result from T cell-initiated inflammation. Inflammatory responses result from the manner in which T cells encounter and respond to antigen. CD4+ T cells may be sensitized and respond to topically applied antigen (contact dermatitis), or they may be sensitized by injected antigen (DTH), or CD8+ T cells may encounter cell-surface antigen and directly cause cellular lysis (CTL).

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Figure 14.14

Type IV hypersensitivity mediated by cytotoxic CD8+ T lymphocytes. DNP that penetrates the epidermis may covalently bond to self-proteins present on cell surfaces. CD8+ T cells enter the site, where they recognize and kill the hapten-modified cell and release substances that invoke an inflammatory response.

Study Questions

14.1. A previously healthy 45-year-old male presents with rhinorrhea, nasal congestion, and persistent respiratory symptoms several months after returning to his home in New Orleans after Hurricane Katrina. He has noticed mold growing along the walls of his house. Skin testing for sensitivity to common mold spores gave positive results to several of them in less than 30 minutes. These findings indicate an example of

A. contact dermatitis.

B. delayed (-type) hypersensitivity.

C. immediate hypersensitivity.

D. serum sickness.

E. type II hypersensitivity.

The correct answer is C. Type I (immediate) hypersensitivity is caused by the cross-linking of FcR (also known as CD23) -bound IgE antibodies on cell surfaces, which triggers the release of vasoreactive amines from mast cell granules. Antigens (allergens) are often airborne and elicit type I reactions that cause respiratory distress. Neither contact dermatitis nor delayed (-type) hypersensitivity reactions involve antibody. Both serum sickness and type II hypersensitivity involve immune complexes.

14.2. A 25-year-old female with a history of penicillin allergy unknown to her physician was given a single injection of penicillin for the treatment of syphilis. Within minutes, she developed diffuse urticaria (hives), tachycardia (rapid heart rate), and hypotension (decrease in blood pressure). This patient has experienced

A. anaphylaxis.

B. anergy.

C. antibody-mediated cytotoxicity.

D. asthma.

E. contact sensitivity.

The correct answer is A. This individual displays the hallmarks of a classical anaphylactic reaction to penicillin. Anergy is the impairment of effector immune responsiveness. Antibody-mediated cytotoxicity is most often localized to tissues bearing epitopes to which the antibody binds. Asthma causes respiratory distress because of the contraction of bronchiole-associated smooth muscle in response to the release of vasoactive mediators from mast cells. Contact sensitivity results from the epicutaneous application of a reactive antigen/hapten; in the present question, the antigen (penicillin) was administered intramuscularly.

14.3. Which of the following is/are initiated by the interaction of host cell membranes with IgM or IgG antibody but never IgE antibody?

A. Arthus reactions

B. Serum sickness

C. Type I hypersensitivity reactions

D. Type II hypersensitivity reactions

E. Type IV hypersensitivity reactions

The correct answer is D. Type II hypersensitivity reactions occur with host cell membranes or with the extracellular matrix. Arthus reactions and serum sickness are type III hypersensitivities that result from the interaction(s) of antibody with soluble antigen(s). IgE is not involved, thus ruling out type I hypersensitivity.

14.4. An 8-year-old female with a known allergy to peanuts inadvertently ingests a cereal containing traces of peanuts. Within 1 hour, she develops diffuse erythema (redness of the skin) and urticaria associated with respiratory symptoms of shortness of breath and diffuse wheezing. These findings suggest which of the following events?

A. Type I hypersensitivity reaction

B. Arthus reaction

C. FcR-bearing cells binding to host cells coated with IgG

D. IgG binding to extracellular matrix of the respiratory passages

E. IgM-mediated interaction with cell membranes of lymphocytes

The correct answer is A. This individual has experienced an immediate or type I hypersensitivity. The clue here is that this reaction occurred within 1 hour of antigen (peanut) ingestion. Her presentation shows hallmarks of IgE-mediated anaphylactic reactions. Arthus reactions and those mediated by IgM and IgG neither cause mast cell degranulation nor do they cause rapid respiratory distress.

14.5. The 8-year-old patient recovered from the event described in Study Question 14.4. The next day, she went to play with a friend who had recently returned from a family trip to Asia. The friend gave her a Japanese lacquered box as a gift. Two days later, she developed itchiness in her hands, and her mother noticed that they were bright red. Her mother also noticed clear fluid vesicles on her right forearm. These findings suggest which type of hypersensitivity?

A. Type I, mediated by CD4+ T cells

B. Type I, mediated by CD8+ T cells

C. Type II, mediated by CD8+ T cells

D. Type III, mediated by CD4+ T cells

E. Type IV, mediated by CD4+ T cells

The correct answer is E. Urushiol, common to poison ivy and poison oak, is a component of Japanese lacquer. The urticaria (itchiness) and fluid vesicles on her forearm are hallmarks of contact dermatitis, a type IV hypersensitivity mediated by CD4+ T cells. Type I and type II hypersensitivities are mediated by antibodies; type IV is not.

14.6. A 45-year-old female with a history of hepatitis C viral infection presents with decreased renal function, hypertension (increased blood pressure), and anemia. Laboratory findings reveal decreased serum C3. Her urine sediment contains leukocytes, erythrocytes, and red blood cell casts (a proteinaceous mold of the renal tubules that includes erythrocytes). Her renal biopsy is consistent with glomerulonephritis. These findings suggest which type of hypersensitivity?

A. Type I, mediated by CD4+ T cells

B. Type II, mediated by IgM antibodies

C. Type III, mediated by IgG antibodies

D. Type IV, mediated by CD4+ T cells

E. Type IV, mediated by IgG (and sometimes IgM) antibodies

Study Questions

The correct answer is C. Glomerulonephritis is often associated with immune complex deposition, a type III hypersensitivity. Red blood cell casts are indicative of glomerulonephritis, and reduced C3 levels indicate a high level of cleavage and activation of C3. Type I hypersensitivity is mediated by IgE, not by CD4+ T cells. Type II hypersensitivity responses usually involve IgG. Type IV hypersensitivities do not involve antibodies.

14.7. A 35-year-old male presents with headache, fatigue, light-headedness, dyspnea (difficulty in breathing), and tachycardia (rapid heart rate). Laboratory findings reveal decreased hemoglobin and a positive direct Coombs test (presence of antibodies on erythrocyte surfaces). The patient is currently taking an antibiotic for symptoms of upper respiratory infection. These findings suggest which type of hypersensitivity?

A. Type I, mediated by IgG antibodies

B. Type II, mediated by IgG antibodies

C. Type III, mediated by IgG antibodies

D. Type III, mediated by IgG or IgM antibodies

E. Type IV, mediated by CD4+ T cells

The correct answer is B. Type II reactions involve antibodies directed against self-cells (such as erythrocytes) or membranes. Certain drugs react with erythrocytes to form neoantigens. Type I responses are against foreign antigens (e.g., allergens), cause IgE responses, and do not invoke a Coombs reaction. Type III reactions involve soluble antigen–antibody complexes, and type IV reactions do not involve antibody.