Immune Disorders

Immune Disorders The immune system is an absolutely essential component of the body’s defenses. However, if the immune system functions abnormally—either by overreacting or by underreacting—the malfunction may cause significant disease, even death. If the immune system functions excessively, the body develops any of a variety of immune hypersensitivities, such as allergies. Further, if the immune system attacks the body’s own tissues, autoim­ mune diseases develop. If the immune system fails, an immuno­ deficiency disease (im’ū-nō-dē-fish’en-sē) results. AIDS is a prime example. In this chapter, we discuss each of these three categories of derangements of the immune system. Hypersensitivities LE A R N I N G O U TC O M E 18.1 Compare and contrast the four types of hypersensitivity. Hypersensitivity (hī’per-sen-si-tiv’i-tē) may be defined as any immune response against a foreign antigen that is exaggerated beyond the norm. For example, most people can wear wool, smell perfume, or dust furniture without experiencing itching, wheezing, runny nose, or watery eyes. When these symptoms do occur, the person is said to be experiencing a hypersensitivity response. In the following sections, we examine each of the four main types of hypersensitivity response, designated as type I through type IV. Type I (Immediate) Hypersensitivity LE A R N I N G O U TC O M E S 18.2 Describe the two-part mechanism by which type I hypersensitivity occurs. 18.3 Explain the roles of three inflammatory chemicals (medi- ators) released from mast cell granules. 18.4 Describe three disease conditions resulting from type I hypersensitivity mechanisms. Type I hypersensitivities are localized or systemic (whole body) reactions that result from the release of inflammatory molecules (such as histamine) in response to an antigen. These reactions are termed immediate hypersensitivity because they develop within seconds or minutes following contact with antigens. They are also commonly called allergies,1 and the antigens that stimulate them are called allergens (al’er-jenz). In the next two subsections, we will examine the two-part mechanism of a type I hypersensitivity reaction: sensitization upon initial contact with an allergen and the degranulation of sensitized cells. Sensitization upon Initial Exposure to an Allergen All of us are exposed to antigens in the environment, against which we typically mount immune responses that result in the 1From Greek allos, meaning “other,” and ergon, meaning “work.” M18_BAUM7206_05_SE_C18.indd 522 production of antibodies of the gamma class (IgG). But when regulatory proteins (cytokines, especially interleukin 4) from type 2 helper T (Th2) cells stimulate B cells in allergic individuals, the B cells become plasma cells that produce class epsilon antibodies (IgE; FIGURE 18.1a). Typically, IgE is directed against parasitic worms, which rarely infect most Americans, so IgE is found at low levels in the blood serum. However, in allergic individuals, plasma cells produce a significant amount of IgE in response to allergens. The precise reason why only some people produce high levels of IgE (and thereby suffer from allergies) is a matter of intense research. Many researchers report evidence for the hygiene hypothesis, which holds that children exposed to environmental antigens—such as dust mites, molds, parasitic worms, and pet hair—are less likely to develop allergies than children who have been sheltered from common environmental antigens. Conversely, other researchers have discovered evidence that environmental factors sensitize people, making them hypersensitive and more likely to develop allergies. In any case, following initial exposure to allergens, the plasma cells of allergic individuals secrete IgE, which binds very strongly with its stem to three types of defense cells—mast cells, basophils, and eosinophils—sensitizing these cells to respond to future exposures to the allergen. Degranulation of Sensitized Cells When the same allergen reenters the body, it binds to the active sites of IgE molecules on the surfaces of sensitized cells (described shortly). This binding triggers a cascade of internal biochemical reactions that causes the sensitized cells to release the inflammatory chemicals from their granules into the surrounding space—an event called degranulation (dē-granū-lā’shŭn; FIGURE 18.1b). It is these inflammatory mediators that generate the characteristic symptoms of type I hypersensitivity reactions: respiratory distress, rhinitis (inflammation of the nasal mucous membranes, commonly called “runny nose”), watery eyes, inflammation, and reddening of the skin. The Roles of Degranulating Cells in an Allergic Reaction Mast cells are specialized relatives of white blood cells, deriving from other stem cells in the bone marrow. They are distributed throughout the body in connective tissues other than blood. These large, round cells are most often found in sites close to body surfaces, including the skin and the walls of the intestines and airways. Their characteristic feature is cytoplasm packed with large granules that are loaded with a mixture of potent inflammatory chemicals. One significant chemical released from mast cell granules is histamine (his’tă-mēn), a small molecule related to the amino acid histidine. Histamine stimulates strong contractions in the smooth muscles of the bronchi, gastrointestinal tract, uterus, and bladder, and it also makes small blood vessels dilate (expand) and become leaky. As a result, tissues in which mast cells degranulate become red and swollen. Histamine also stimulates nerve endings, causing itching and pain. 11/23/16 3:37 AM       H ypersensitivities ◀ FIGURE 18.1 The mechanisms of a type I hypersensitivity reaction. (a) Sensitization. After normal processing of an antigen Allergen (antigen) 1 Antigen-presenting cell (APC) phagocytizes and processes antigen. MHC-II 2 APC presents epitope (carried by MHC-II) to Th2 cell Th2 cell IL-4 B cell 3 IL-4 from Th2 cell stimulates selected B cell clone. 4 B cells become plasma cells that secrete IgE. Plasma cell IgE against allergen 5 IgE stem binds to mast cells, basophils, and eosinophils. IgE Mast cell Basophil Eosinophil (a) Sensitization Subsequent exposure to allergen (allergen) by an antigen-presenting cell 1 , Th2 cells are stimulated to secrete interleukin 4 (IL-4) 2 . This cytokine stimulates a B cell 3 , which becomes a plasma cell that secretes IgE 4 , which then binds to and sensitizes mast cells, basophils, and eosinophils 5 . (b) Degranulation. When the same allergen is subsequently encountered, its binding to the IgE molecules on the surfaces of sensitized cells triggers rapid degranulation and the release of inflammatory chemicals from the cells. Finally, histamine is an effective stimulator of bronchial mucus secretion, tear formation, and salivation. Other triggers of allergies released by degranulating mast cells include kinins (kī’ninz), which are powerful inflammatory chemicals, and proteases (prō’tē-ās-ez)—enzymes that destroy nearby cells, activating the complement system, which in turn results in the release of more chemicals that cause inflammation. Proteases account for more than half the proteins in a mast cell granule. In addition, the binding of allergens to IgE on mast cells activates other enzymes that trigger the production of leukotrienes (loo-kō-trī’ēnz) and prostaglandins (prostă-glan’dinz), lipid molecules that are powerful inflammatory agents. TABLE 18.1 summarizes the inflammatory molecules released from mast cells. Basophils, the least numerous type of leukocyte in blood, contain cytoplasmic granules that stain intensely with basic dyes (see Chapter 15, Figure 15.5a) and are filled with inflammatory chemicals similar to those found in mast cells. Sensitized basophils bind IgE and degranulate in the same way as mast cells when they encounter allergens. The blood and tissues of allergic individuals also accumulate many eosinophils, leukocytes that contain numerous cytoplasmic granules that stain intensely with a red dye called eosin and that function primarily to destroy parasitic worms. The process during type I hypersensitivity reactions that results in the accumulation of eosinophils in the blood—a condition termed eosinophilia—begins with mast cell degranulation, which releases peptides that stimulate the release of eosinophils from the bone marrow. Once in the bloodstream, TABLE 18.1 Inflammatory Molecules Released from Mast Cells Molecules Role in Hypersensitivity Reactions H Released During Degranulation Kinins P Sensitized mast cell, basophil, or eosinophil roteases Causes smooth muscle contraction, increased vascular permeability, and irritation Cause smooth muscle contraction, inflammation, and irritation Damage tissues and activate complement Synthesized in Response to Inflammation Leukotrienes P Histamines, kinins, proteases, leukotrienes, prostaglandins, and other inflammatory molecules istamine rostaglandins Cause slow, prolonged smooth muscle contraction, inflammation, and increased vascular permeability Some contract smooth muscle; others relax it (b) Degranulation M18_BAUM7206_05_SE_C18.indd 523 11/23/16 3:37 AM ter a       Ch p 18   Immune Disorders SEM (a) 25 µm SEM (b) 15 µm (c) SEM 125 µm P ▲ FIGURE 18.2 Some common allergens. (a) Spores of the fungus Aspergillus on stalks. (b) ollen of Ambrosia trifida (ragweed), the most common cause of hay fever in the United States. (c) Two house dust mites. Mites’ fecal pellets and dead bodies may become airborne and trigger allergic responses. eosinophils are attracted to the site of mast cell degranulation, where they themselves degranulate. Eosinophil granules contain unique inflammatory mediators and produce large amounts of leukotrienes, which increase movement of white blood cells from blood vessels and stimulate smooth muscle contraction, thereby contributing greatly to the severity of a hypersensitivity response. Clinical Signs of Localized Allergic Reactions 2From Latin urtica, meaning “nettle.” M18_BAUM7206_05_SE_C18.indd 524 ▲ FIGURE 18.3 Urticaria. These red, itchy patches on the skin are prompted by the release of histamine in response to an allergen. What causes fluid to accumulate in the patches seen in urticaria? Figure 18.3 The fluid accumulates because histamine from degranulated mast cells causes blood capillaries to become more permeable. Type I hypersensitivity reactions are usually mild and localized. The site of the reaction depends on the portal of entry of the antigens. For example, inhaled allergens may provoke a response in the upper respiratory tract commonly known as hay fever—a local allergic reaction marked by a runny nose, sneezing, itchy throat and eyes, and excessive tear production. Among the more common allergens are fungal (mold) spores; pollens from grasses, flowering plants, and some trees; and feces and dead bodies of house dust mites (FIGURE 18.2). If inhaled allergen particles are sufficiently small, they may reach the lungs. A type I hypersensitivity in the lungs can cause an episode of severe difficulty in breathing known as asthma, characterized by wheezing; coughing; excessive production of a thick, sticky mucus; and constriction of the smooth muscles of the bronchi. Asthma can be life threatening: without medical intervention, the increased mucus and bronchial constriction can quickly cause suffocation. Other allergens—including latex; wool; certain metals; and the venom or saliva of wasps, bees, fire ants, deer flies, fleas, and other stinging or biting insects—may cause a localized inflammation of the skin. As a result of the release of histamine and other mediators, plus the ensuing leakage of serum from local blood vessels, the individual suffers raised, red areas called hives, or urticaria2 (er’ti-kar’i-ă; FIGURE 18.3). These lesions are very itchy because histamine irritates local nerve endings. Clinical Signs of Systemic Allergic Reactions Following a sensitized individual’s contact with an allergen, many mast cells may degranulate simultaneously, releasing massive amounts of histamine and other inflammatory mediators into the bloodstream. The release of chemicals may exceed the body’s ability to adjust, resulting in a condition called acute anaphylaxis3 (an’ă-fĭ-lak’sis), or anaphylactic shock. The clinical signs of acute anaphylaxis are those of rapid suffocation. Bronchial smooth muscle, which is highly sensitive to histamine, contracts violently. In addition, increased 3From Greek ana, meaning “away from,” and phylaxis, meaning “protection.” 11/23/16 3:37 AM Diagnosis of Type I Hypersensitivity ­ Clinicians diagnose type I hypersensitivity with a test variously called ImmunoCAP Specific IgE blood test, CAP RAST, or Pharmacia CAP, in which suspected allergens are mixed with samples of the patient’s blood. The specifics of the test are beyond the scope of this chapter, but basically the test detects the amount of IgE directed against each allergen. High levels of a specific IgE indicate a hypersensitivity against that allergen. Alternatively, physicians diagnose type I hypersensitivity by injecting into the skin a very small quantity of a dilute solution of the allergens being tested. In most cases, the individual is screened for more than a dozen potential allergens simultaneously, using the forearms as injection sites. When the individual tested is sensitive to an allergen, having been previously exposed to that allergen, local histamine release causes redness and swelling at the injection site within a few minutes (FIGURE 18.4). Prevention of Type I Hypersensitivity Prevention of type I hypersensitivity begins with identifying the allergens responsible and avoiding them. Filtering the air and avoiding rural areas during pollen season can reduce upper       H leakage of fluid from blood vessels causes swelling of the larynx and other tissues. The patient also experiences contraction of the smooth muscle of the intestines and bladder. Without immediate administration of epinephrine (ep’i-nef’rin; discussed shortly), an individual in anaphylactic shock may suffocate, collapse, and die within minutes. A common cause of acute anaphylaxis is a bee sting in an allergic and sensitized individual. The first sting produces sensitization and the formation of IgE antibodies, and successive stings—which may occur years later—produce an anaphylactic reaction. Other allergens commonly implicated in acute anaphylaxis are certain foods (notoriously peanuts), vaccines containing egg proteins, antibiotics such as penicillin, iodine dyes, local anesthetics, blood products, and certain narcotics such as morphine. ypersensitivities respiratory allergies provoked by some pollens. Encasing bedclothes in mite-proof covers, frequent vacuuming, and avoiding home furnishings that trap dust (such as wall-to-wall carpeting and heavy drapes) can reduce the severity of other household allergies. A dehumidifier can reduce mold in a home. The best way for individuals to avoid allergic reactions to pets is to find out whether they are allergic before they get a pet. If an allergy develops afterward, they may have to find a new home for the animal. Food allergens can be identified and then avoided by using a medically supervised elimination diet in which foods are removed one at a time from the diet to see when signs of allergy cease. Peanuts and shellfish are among the foods more commonly implicated in anaphylactic shock; allergic individuals must avoid consuming even minute amounts. For example, individuals sensitized against shellfish can suffer anaphylactic shock from consuming meat sliced on an unwashed cutting board previously used to prepare shellfish. Some vaccines contain small amounts of egg proteins and should not be given to individuals allergic to eggs. Health care workers should assess a patient’s medical history carefully before administering penicillin, iodine dyes, and other potential allergens. Therapies such as antidotes and respiratory stimulants should be immediately available if a patient’s sensitivity status is unknown. In addition to avoidance of allergens, type I hypersensitivity reactions can be prevented by immunotherapy (im’yū-nōthār’ă-pē), commonly called “allergy shots,” which involves the administration of a series of injections of dilute allergen, usually once a week for many months. It is unclear just how allergy shots work, but they may change the helper T cell balance from Th2 cells to Thl cells, reducing the production of antibodies, or they may stimulate the production of IgG, which binds antigen before the antigen can react with IgE on mast cells, basophils, and eosinophils. Immunotherapy reduces the severity of allergy symptoms by roughly 50% in about two-thirds of patients with upper respiratory allergies; however, the series of injections must be repeated every two to three years. Treatment of Type I Hypersensitivity ▲ FIGURE 18.4 Skin tests for diagnosing type I hypersensitivity. The presence of redness and swelling at an injection site indicates sensitivity to the allergen injected at that site. M18_BAUM7206_05_SE_C18.indd 525 One way to treat type I hypersensitivity is to administer drugs that specifically counteract the inflammatory mediators released when cells degranulate. Thus, antihistamines are administered to counteract histamine. However, because histamine is but one of many mediators released in type I hypersensitivity, antihistamines do not completely eliminate all clinical signs in diseases such as asthma. For asthmatics, physicians typically prescribe an inhalant containing glucocorticoid (glookō-kōr’ti-koyd) and a bronchodilator (brong-kō-dī’lā-ter), which counteract the effects of many inflammatory mediators. The hormone epinephrine quickly neutralizes many of the lethal mechanisms of anaphylaxis by relaxing smooth muscle tissue in the lungs, contracting smooth muscle of blood vessels, and reducing vascular permeability. Epinephrine is thus the drug of choice for the emergency treatment of both severe asthma and anaphylactic shock. Patients who suffer from severe type I hypersensitivities may carry a prescription epinephrine 11/23/16 3:37 AM ter a       Ch p 18   Immune Disorders kit so that they can inject themselves before their allergic reactions become life threatening.  ­ ­ Type II (Cytotoxic) Hypersensitivity functions, including transportation of glucose and ions across the cytoplasmic membrane. There are several sets of blood group antigens that vary in complexity. The ABO group system is most famous and consists of just two antigens arbitrarily given the names A antigen and B antigen. Each person’s red blood cells have either A antigen, B antigen, both A and B antigens, or neither antigen. Individuals with neither antigen are said to have blood type O. As you probably know, blood can be transfused from one person to another; however, if blood is transfused to an individual with a different blood type, then the donor’s blood group antigens may stimulate the production of antibodies in the recipient. These bind to and eventually destroy the transfused cells. The result can be a potentially life-threatening transfusion reaction. Note that it is a blood recipient’s own immune system that causes problems; the donated cells merely trigger the response. Transfusion reactions, the most problematic of which involve the ABO group, develop as follows:  ­ LE A R N I N G O U TC O M E S 18.5 Discuss the mechanisms underlying transfusion reactions. 18.6 Construct a table comparing the key features of the four blood types in the ABO blood group system. 18.7 Describe the mechanisms and treatment of hemolytic disease of the newborn. The second major form of hypersensitivity results when cells are destroyed by an immune response—typically by the combined activities of complement and antibodies. This cytotoxic hypersensitivity is part of many autoimmune diseases, which we will discuss later in this chapter, but the most significant examples of type II hypersensitivity are the destruction of donor red blood cells following an incompatible blood transfusion and the destruction of fetal red blood cells. We begin our discussion by focusing on these two manifestations of type II hypersensitivity. The ABO System and Transfusion Reactions Red blood cells have many different glycoprotein and glycolipid molecules on their surface. Some surface molecules of red blood cells, called blood group antigens, have various • If the recipient has preexisting antibodies to foreign antigens, then the donated blood cells will be destroyed immediately—either the antibody-bound cells will be phagocytized by macrophages and neutrophils, or the antibodies will agglutinate the cells and complement will rupture them, a process called hemolysis (FIGURE 18.5). Hemolysis releases hemoglobin into the bloodstream, which may cause severe kidney damage. At the same time, the membranes of the ruptured blood cells trigger blood Type A antigens on red blood cells of patient Donated red blood cells with B antigen Anti-B antibody 1 Transfusion Complement Hemoglobin 2 Agglutination and complement binding 3 Hemolysis ▲ FIGURE 18.5 Events leading to hemolysis. One of the negative consequences of a ­ transfusion reaction (here illustrated by a transfusion of type B blood into a patient with type A blood): When antibodies against a foreign ABO antigen combine with the antigen on transfused red blood cells the cells are agglutinated, and the complexes bind complement 2 . The resulting hemolysis releases large amounts of hemoglobin into the bloodstream 3 and produces additional negative consequences throughout the body. , ­ 1 M18_BAUM7206_05_SE_C18.indd 526 11/23/16 3:37 AM       H ypersensitivities To prevent transfusion reactions, laboratory personnel must cross-match ABO blood types between donors and recipients. Before a recipient receives a blood transfusion, the red cells and serum of the donor can be mixed with the serum and red cells of the recipient. If any signs of clumping are seen, then that blood is not used, and an alternative donor is sought. TABLE 18.2 presents the characteristics of the ABO blood group and the compatible donor-recipient matches that can be made. The Rh System and Hemolytic Disease of the Newborn Many decades ago, researchers discovered the existence of an antigen common to the red blood cells of humans and rhesus monkeys. They called this antigen, which transports anions and glucose across the cytoplasmic membrane, rhesus (rē’sŭs) antigen, or Rh antigen. Laboratory analysis of human blood samples eventually showed that the Rh antigen is present on the red blood cells of about 85% of humans; that is, about 85% of the population is Rh positive (Rh+), and about 15% of the population is Rh negative (Rh-). In contrast to the situation with ABO antigens, preexisting antibodies against Rh antigen do not occur. Although a transfusion reaction can occur in an Rh-negative patient who TABLE 18.2 receives more than one transfusion of Rh-positive blood, such a reaction is usually minor because Rh antigen molecules are less abundant than A or B antigens. Instead, the primary problem posed by incompatible Rh antigen is the risk of hemolytic4 disease of the newborn (hē-mō-lit’ik; FIGURE 18.6). This hypersensitivity reaction develops when an Rh mother is pregnant with an Rh+ baby (who inherited an Rh gene from the father). Normally, the placenta keeps fetal red blood cells separate from the mother’s blood, so fetal cells do not enter the mother’s bloodstream. However, in 20–50% of pregnancies—especially during the later weeks of pregnancy, during a clinical or spontaneous abortion, or during childbirth—fetal red blood cells escape into the mother’s blood. The Rh - mother’s immune system recognizes these Rh+ fetal cells as foreign and initiates an antibody immune response by developing antibodies against the Rh antigen. Initially, only IgM antibodies are produced, and because IgM is a very large molecule that cannot cross the placenta, no problems arise during this first pregnancy. However, IgG antibodies can cross the placenta, so if during a subsequent pregnancy the fetus is Rh +, anti-Rh IgG molecules produced by the mother cross the placenta and destroy the fetus’s Rh+ red blood cells. Such destruction may be limited, or it may be severe enough—especially in a third or subsequent pregnancy—to cause grave problems. One classic feature of hemolytic disease of the newborn is severe jaundice from excessive bilirubin (bil-i-roo’bin), which is a yellowish blood pigment released during the degradation of hemoglobin from lysed red blood cells. The liver is normally responsible for removing bilirubin, but because of the immaturity of the fetal liver and overload from the hemolytic process, the bilirubin may instead be deposited in the brain, causing severe neurological damage or death during the last weeks of pregnancy or shortly after the baby’s birth. In the past, when prevention of hemolytic disease of the newborn was impossible, this terrible disease occurred in about 1 of every 300 births. Today, however, physicians can routinely and drastically reduce the number of cases of the disease by administering anti-Rh immunoglobulin (IgG), called RhoGAM, to Rh-negative women at 28 weeks into their pregnancy and also within 72 hours following abortion, miscarriage, or childbirth. Any fetal red cells that may have entered the mother’s body are destroyed by RhoGAM before the fetal cells can trigger an immune response. As a result, sensitization of the mother does not occur, and future pregnancies are safer. ­ clotting within blood vessels, blocking them and causing circulatory failure, fever, difficulty in breathing, coughing, nausea, vomiting, and diarrhea. If the patient survives, recovery follows the elimination of all the foreign red blood cells. • In most people, production of antibodies against foreign ABO antigens is stimulated not by exposure to foreign blood cells but instead by exposure to antigenically similar molecules found on a wide range of plants and bacteria. Individuals encounter and make antibodies against these antigens on a daily basis, but only upon receipt of a mismatched blood transfusion do the antigens cause problems. • If the recipient has no preexisting antibodies to the foreign blood group antigens, then the transfused cells circulate and function normally, but only for a while—that is, until the recipient’s immune system mounts a primary response against the foreign antigens and produces enough antibody to destroy the foreign cells. This happens gradually over a long enough time that the severe symptoms and signs mentioned above do not occur. ABO Blood Group Characteristics and Donor-Recipient Matches ABO Blood Group ABO Antigen(s) Present Antibodies Present Can Donate To Can Receive From A A Anti-B A or AB A or O B B Anti-A B or AB B or O AB A and B None AB A, B, AB, or O (universal recipient) O None Both anti-A and anti-B A, B, AB, or O (universal donor) O 4From M18_BAUM7206_05_SE_C18.indd 527 Greek haima, meaning “blood,” and lysis, meaning “destruction.” 11/23/16 3:37 AM 18   Immune Disorders ter a       Ch p During delivery, Rh antigens enter mother’s circulation through breaks in the placenta. – Mother makes anti-Rh antibodies, which have no effect on this baby, who has been born. Rh– mother + – Anti-Rh antibodies Placenta + Rh+ antigens – + – Fetal RBC with Rh+ antigens – – – – Mother’s Rh– RBC (a) First pregnancy Mother’s anti-Rh antibodies cross the placenta and destroy fetal blood cells. Mother’s anti-Rh antibodies still circulate. – Anti-Rh antibodies – Placenta + + + + – Rh+ fetus – + – Fetal RBC with Rh+ antigens – + Fetal red blood cells destroyed – – hemolytic disease of the newborn. (a) During an V T utor ▲ FIGURE 18.6 Events in the development of ideo (b) Subsequent pregnancy initial pregnancy, Rh red blood cells from the fetus enter the Rh- mother’s circulation, often during childbirth. As a result, the mother produces anti-Rh antibodies. (Antigens and antibodies are not shown to scale.) (b) During a subsequent pregnancy with another Rh child, anti-Rh IgG molecules cross the placenta and trigger destruction of the fetus’s red blood cells. How is it possible that the child of an Rh - mother is Rh +? Figure 18.6 The father of the child is Rh positive. Type III (Immune Complex–Mediated) Hypersensitivity LE A R N I N G O U TC O M E S 18.8 Outline the basic mechanism of type III hypersensitivity. 18.9 Describe hypersensitivity pneumonitis and glomerulonephritis. M18_BAUM7206_05_SE_C18.indd 528 erythematosus. The formation of complexes of antigen bound to antibody, called immune complexes, initiates several molecular processes, including complement activation. Normally, immune complexes are removed from the body via phagocytosis. However, in type III (immune complex–mediated) hypersensitiv­ ity reactions, small immune complexes escape phagocytosis and circulate in the bloodstream until they become trapped in organs, joints, and tissues (such as the walls of blood vessels). In these sites, they react with complement, resulting in inflammation, and cause neutrophils to release enzymes that damage nearby tissues. FIGURE 18.7 illustrates the mechanism of type III reactions. Type III hypersensitivities may be localized or may affect a number of body systems simultaneously. There is no cure for these diseases, though steroids that suppress the immune system may provide some relief. Two localized conditions resulting from immune complex–mediated hypersensitivity are hypersensitivity pneumonitis and glomerulonephritis; two systemic disorders are rheumatoid arthritis and systemic lupus erythematosus. ­ Rh+ fetus 18.10 List the signs and symptoms of rheumatoid arthritis. 18.11 Discuss the cause and signs of systemic lupus Hypersensitivity Pneumonitis Type III hypersensitivities can affect the lungs, causing a form of pneumonia called hypersensitivity pneumonitis (noomō-nī’tus). Individuals become sensitized when minute mold spores or other antigens are inhaled deep into the lungs, stimulating the production of antibodies. A hypersensitivity reaction occurs when the subsequent inhalation of the same antigen stimulates the formation of immune complexes that then activate complement. One form of hypersensitivity pneumonitis, called farm­ er’s lung, occurs in farmers chronically exposed to spores from moldy hay. Many other syndromes in humans develop via a similar mechanism and are usually named after the source of the inhaled allergen. Thus, pigeon breeder’s lung arises following exposure to the dust from pigeon feces, mushroom grower’s lung is a response to the soil or fungal spores encountered in the growing of mushrooms, and librarian’s lung results from inhaling dust from old books. Glomerulonephritis Glomerulonephritis (glō-mār’ū-lō-nef-rī’tis) occurs when immune complexes circulating in the bloodstream are deposited in the walls of glomeruli, which are networks of minute blood vessels in the kidneys. Immune complexes damage the glomerular cells, leading to enhanced local production of cytokines that trigger nearby cells to produce more of the proteins that underlie the cells, impeding blood filtration. Sometimes, the immune complexes are deposited in the center of the glomeruli, where they stimulate local cells to divide and compress nearby blood vessels, again interfering with kidney function. The net result is kidney failure; the glomeruli lose 11/23/16 3:37 AM       H ypersensitivities 1 Antigens combine with antibodies to form antigen-antibody complexes. Antigen ◀ FIGURE 18.7 The mechanism of type III (immune complex–mediated) hypersensitivity. After immune complexes form 1 , some complexes are not phagocytized and lodge in tissues (in this case, the wall of a blood vessel) 2 . These complexes then activate complement 3 , which leads to inflammation and attracts neutrophils 4 . The release of enzymes from these neutrophils leads to the destruction of tissue 5 . Antibody (IgG) Antigen-antibody complex their ability to filter wastes from the blood, ultimately resulting in death. Rheumatoid Arthritis (RA) 2 Phagocytes remove most of the complexes, but some lodge in the walls of blood vessels. 3 There, the complexes activate complement. Inactive complement Active complement 4 Antigen-antibody complexes and activated complement attract and activate neutrophils, which release enzymes. Rheumatoid arthritis (RA) (roo’mă-toyd ar-thrī’tis) is a type III hypersensitivity that is also an autoimmune disease— the immune system attacks the body’s own antigens. RA commences when B cells secrete IgM that binds to certain IgG molecules. IgM-IgG complexes are deposited in the joints, where they activate complement and mast cells, which release inflammatory chemicals. The resulting inflammation causes the tissues to swell, thicken, and proliferate into the joint, resulting in severe pain. As the altered tissue extends into the joint, the inflammation further erodes and destroys joint cartilage and the neighboring bony structure until the joints begin to break down and fuse; as a result, affected joints become distorted and lose their range of motion (FIGURE 18.8). The course of rheumatoid arthritis is often intermittent; however, with each recurrence, the lesions and damage get progressively more severe. The trigger of RA is not well understood. The fact that there are no animal models (because the disease appears to affect humans only) significantly hinders research on its cause. Many cases demonstrate that RA commonly follows an infectious disease in a genetically susceptible individual. Possession of certain immunity (MHC) genes appears to increase susceptibility. Neutrophil Enzymes 5 Enzymes and inflammatory chemicals damage underlying tissues. ▲ FIGURE 18.8 The crippling distortion of joints characteristic of rheumatoid arthritis. M18_BAUM7206_05_SE_C18.indd 529 11/23/16 3:37 AM 18   Immune Disorders Systemic Lupus Erythematosus (SLE) Type IV (Delayed or Cell-Mediated) Hypersensitivity LE A R N I N G O UTC O M E S 18.12 18.13 18.14 18.15 Outline the mechanism of type IV hypersensitivity. Describe the significance of the tuberculin test. Identify four types of grafts. Compare four types of drugs commonly used to prevent graft rejection. When certain antigens contact the skin of sensitized individuals, they provoke inflammation that begins to develop at the site only after 12–24 hours. Such delayed hypersensitivity reactions result not from the action of antibodies but rather from interactions among antigen, antigen-presenting cells, and T cells; thus, a type IV reaction is also called a cell- mediated hypersensitivity reaction. The delay in this cell-mediated response reflects the time it takes for macrophages and T cells to migrate to and divide at the site of the antigen. We begin our discussion of type IV reactions by considering two common examples: the tuberculin response and allergic contact dermatitis. Then we will consider two type IV hypersensitivity reactions involving the interactions between the body and tissues grafted to (transplanted into) it—graft rejection and graft-versus-host disease—before considering donor-recipient matching and tissue typing. ­ ­ Another example of type III hypersensitivity that is also an autoimmune disorder is systemic lupus erythematosus (SLE) (loo’pŭs er-ĭ-thē’mă-tō-sus), often shortened to lupus. Patients with lupus produce antibodies against numerous self-antigens found in normal organs and tissues. As a result, the immune system attacks multiple organs, giving rise to many different pathological lesions and clinical manifestations. One consistent feature of SLE is the development of such self-reactive antibodies, called autoantibodies, against nucleic acids, especially DNA. These autoantibodies combine with free DNA released from dead cells to form immune complexes that are deposited in glomeruli, causing glomerulo nephritis and kidney failure. Thus, SLE is an immune complex–mediated hypersensitivity reaction. Immune complexes may also be deposited in joints, where they give rise to arthritis. The disease’s curious name—systemic lupus erythematosus— stems from two features of the disease: Systemic simply reflects the fact that it affects different organs throughout the body, lupus is Latin for “wolf,” and erythematosus refers to a redness of the skin, so these last two words describe the characteristic red, butterfly-shaped rash that develops on the face of many patients, giving them what is sometimes described as a wolflike appearance (FIGURE 18.9). This rash is caused by deposition of nucleic acid–antibody complexes in the skin and is worse in skin areas exposed to sunlight. Although autoantibodies to nucleic acids are characteristic of SLE, many other autoantibodies are also produced. Autoantibodies to red blood cells cause hemolytic anemia, autoantibodies to platelets give rise to bleeding disorders, antilymphocyte antibodies alter immune reactivity, and autoantibodies against muscle cells cause muscle inflammation and, in some cases, damage to the heart. Because of its variety of symptoms, SLE can be misdiagnosed. The trigger of lupus is unknown, though some drugs can induce a lupus-like disease. It is likely that SLE has many causes. Physicians treat lupus with immunosuppressive drugs that reduce autoantibody formation and with glucocorticoids that reduce the inflammation associated with the deposition of immune complexes. Scientists are currently testing a battery of novel drugs for treating lupus. ­ Physicians treat rheumatoid arthritis by administering anti-inflammatory drugs such as ibuprofen to prevent additional joint damage and immunosuppressive drugs to inhibit the antibody immune response. ­ ter a       Ch p The Tuberculin Response ▲ FIGURE 18.9 The characteristic facial rash of systemic lupus erythematosus. Its shape corresponds to areas most exposed to sunlight, which worsens the condition. M18_BAUM7206_05_SE_C18.indd 530 The tuberculin response (too-ber’kyū-lin) is an important example of a delayed hypersensitivity reaction in which the skin of an individual exposed to tuberculosis (TB) or tuberculosis vaccine reacts to a shallow injection of tuberculin—a protein solution obtained from Mycobacterium tuberculosis (mī’kō-baktēr’ē-ŭm too-ber-kyū-lō’sis). Health care providers use the tuberculin test, also called a Mantoux test (mahn-too’) after the French physician who perfected it, to diagnose contact with antigens of M. tuberculosis. When tuberculin is injected into the skin of a healthy, never-infected or unvaccinated individual, no response 11/23/16 3:37 AM       H ypersensitivities A tuberculin response is mediated by memory T cells. When an individual is first infected by or immunized against M. tuberculosis, the resulting cell-mediated immune response generates memory T cells that persist in the body. When a sensitized individual is later injected with tuberculin, phagocytic cells migrate to the site and attract memory T cells, which secrete a mixture of cytokines that attract still more T cells and macrophages, giving rise to a slowly developing inflammation. The macrophages ingest and destroy the injected tuberculin, allowing the tissues to eventually return to normal. Allergic Contact Dermatitis ▲ FIGURE 18.10 A positive tuberculin test, a type IV hypersensitivity response. The hard, red swelling 10 mm or greater in diameter that is characteristic of the tuberculin response indicates that the individual has been vaccinated against Mycobacterium tuberculosis or is now or has previously been infected with the bacterium. occurs. In contrast, when tuberculin is injected into someone currently or previously infected with M. tuberculosis or an individual previously immunized with tuberculosis vaccine, a red, hard swelling (10 mm or greater in diameter) indicating a positive tuberculin test develops at the site (FIGURE 18.10). It isn’t possible to determine whether a positive response is due to current infection, previous infection, or immunization. Inflammation in response to tuberculin reaches its greatest intensity within 24–72 hours and may persist for several weeks before fading. Microscopic examination of the lesion reveals that it is infiltrated with lymphocytes and macrophages. CLINICAL CASE STUDY The First Time’s Not the Problem H ­ Steven, an eight-year-old boy, is brought to your office Monday morning by his father to have his upper arm checked for a possible infection. Dad is worried because the area of a bee sting on the boy’s arm is getting redder, itchier, and more tender. The father gave him some children’s acetaminophen yesterday, which relieved the discomfort somewhat. There is no history of medical problems or allergies, and the child takes no regular medication. e is otherwise feeling well, and his father tells you he is playing and eating normally. There is no previous history of bee stings, and Steven proudly tells you he “hardly even cried” when he got stung. M18_BAUM7206_05_SE_C18.indd 531 Urushiol (ŭ-rū’shē-ŏl), the oil of poison ivy (Toxicodendron radi­ cans, toks’si-kō-den’dron rā’dē-kanz) and related plants, is a small molecule that becomes antigenic when it binds to almost any protein it contacts—including proteins in the skin of most people who rub against the plant. The body regards these chemically modified skin proteins as foreign, triggering a cell-mediated immune response and resulting in an intensely irritating skin rash called allergic contact dermatitis (der-mătī’tis). In severe cases, cytotoxic T lymphocytes (Tc cells) destroy so many skin cells that acellular, fluid-filled blisters develop (FIGURE 18.11). Other small molecules that don’t trigger an immune response by themselves combine chemically with skin proteins and induce allergic contact dermatitis. Examples include formaldehyde; some cosmetics, dyes, drugs, and metal ions; and chemicals used in the production of latex for hospital gloves and tubing. Because T cel ls mediate a l lerg ic contac t der mat itis, epinephrine and other drugs used to treat immediate There is a half-dollar-sized area on his left upper arm that is puffy and red, but there is no streaking or drainage, and the area does not appear to be infected. Steven’s temperature is normal, and his lungs are clear. 1. What type of hypersensitivity reaction is Steven manifesting? 2. What other over-the-counter medication might relieve the itching? 3. What mechanism is causing the signs and symptoms you are seeing? 4. Since the area is not infected, what future health risk for his son should the father be made aware of? 5. What can be done to determine future risk from a bee sting? 6. How would you recognize a severe allergic reaction? 7. What precautions can the family take to protect the boy from future reactions? 11/23/16 3:37 AM ter a       Ch p 18   Immune Disorders Autograft Isograft Genetically identical sibling or clone A special case of type IV hypersensitivity is the rejection of grafts (or transplants), which are tissues or organs, such as livers, kidneys, or hearts, that have been transplanted, whether between sites within an individual or between a donor and an unrelated recipient. Even though advances in surgical technique enable surgeons to move grafts freely from site to site, grafts perceived as foreign by a recipient may undergo graft rejection, a highly destructive phenomenon that can severely limit the success of organ and tissue transplantation. Graft rejection is a normal immune response against foreign major histocompatibility complex (MHC) proteins on the surface of graft cells. The likelihood of graft rejection depends on the degree to which the graft is foreign to the recipient, which in turn is related to the type of graft. Scientists name graft types according to the degree of relatedness between the donor and the recipient (FIGURE 18.12). A graft is called an autograft (aw’tō-graft) when tissues are moved to a different location within the same individual. Autografts do not trigger immune responses because they do not express foreign antigens. Examples of autografts include the grafting of skin from one area of the body to another to cover a burn area or the use of a leg vein to bypass blocked coronary arteries. Isografts (ī’sō-graftz) are grafts transplanted between t wo genet ically ident ical individuals, that is, bet ween ident ical siblings or clones. Because these individuals M18_BAUM7206_05_SE_C18.indd 532 ­ Graft Rejection have identical MHC proteins, the immune system of the recipient cannot differentiate between the grafted cells and its own normal body cells. As a result, isografts are not rejected. Allografts (al’ō-graftz) are grafts transplanted between genetically distinct members of the same species. Most grafts performed in humans are allografts. Because the MHC proteins of the allograft are different from those of the recipient, allografts typically induce a strong type IV hypersensitivity, resulting in graft rejection. Rejection must be stopped with immunosuppressive drugs if the graft is to survive. Xenografts (zēn’ō-graftz) are grafts transplanted between individuals of different species. Thus, the transplant of a baboon’s heart into a human is a xenograft. Because xenografts are usually very different from the tissues of the recipient, both biochemically and immunologically, they usually provoke a rapid, intense rejection that is very difficult to suppress. Therefore, xenografts from mature animals are not commonly used therapeutically. ­ hypersensitivity reactions are ineffective. T cell activities and inflammation can, however, be suppressed by corticosteroid treatment. Good strategies for dealing with exposure to poison ivy include washing the area thoroughly and immediately with a strong soap and washing all exposed clothes as soon as possible. ▲ FIGURE 18.12 Types of grafts. The names are based on the degree of relatedness between donor and recipient. Autografts are grafts moved from one location to another within a single individual. In isografts, the donor and recipient are either genetically identical siblings or clones. In allografts, the donor and recipient are genetically distinct individuals of the same species. In xenografts, the donor and recipient are of different species. ­ Note the large, acellular, fluid-filled blisters that result from the destruction of skin cells. Genetically different member of same species Graft-Versus-Host Disease Physicians often use bone marrow allografts as a component of the treatment for leukemias and lymphomas (cancers of leukocytes). In this procedure, physicians use total body irradiation combined with cytotoxic drugs to kill tumor cells in the patient’s bone marrow. In the process, the patient’s existing leukocytes are also destroyed, which completely eliminates the body’s ability to mount any kind of immune response. Physicians then inject the patient with donated bone marrow, which produces a new set of leukocytes. Ideally, within a few months, a fully functioning bone marrow is restored. Unfortunately, when they are transplanted, donated bone marrow T cells may regard the patient’s cells as foreign, ­ hypersensitivity response. The response in this case is to poison ivy. Xenograft ­ ▲ FIGURE 18.11 Allergic contact dermatitis, a type IV Allograft 11/23/16 3:37 AM       H ypersensitivities mounting an immune response against them and giving rise to a condition called graft-versus-host disease. If the donor and recipient mainly differ in MHC class I molecules, the grafted T cells attack all of the recipient’s tissues, producing especially destructive lesions in the skin and intestine. If the donor and recipient differ mainly in MHC class II molecules, then the grafted T cells attack the antigen-presenting cells of the host, leading to immunosuppression and leaving the recipient vulnerable to infections. The same immunosuppressive drugs used to prevent graft rejection (discussed shortly) can limit graft-versus-host disease. Donor-Recipient Matching and Tissue Typing Although it is usually not difficult to ensure that donor and recipient have identical blood groups, MHC compatibility is much harder to achieve. The reason is the very high degree of MHC variability, which ensures that unrelated individuals differ widely in their MHCs. In general, the more closely donor and recipient are related, the smaller their MHC difference. Given that in most cases an identical sibling is not available, it is usually preferable that grafts be donated by a parent or sibling possessing MHC antigens similar to those of the recipient. In practice, of course, closely related donors are not always available. And even though a paired organ (such as a kidney) or a portion of an organ (such as liver tissue) may be available from a living donor, unpaired organs (such as the heart) almost always come from an unrelated cadaver. In such cases, attempts are made to match donor and recipient as closely as possible by means of tissue typing. Physicians examine the white cells of potential graft recipients to determine what MHC proteins they have. When a donor organ becomes available, it too is typed. Then the potential recipient whose MHC proteins most closely match those of the donor is chosen to receive the graft. Though a perfect match is rarely achieved, the closer the match, the less intense the rejection process and the greater the chance of successful grafting. A match of 50% TABLE 18.3 or less of the MHC proteins is usually acceptable for most organs, but near absolute matches are required for successful bone marrow transplants. TABLE 18.3 summarizes the major characteristics of the four types of hypersensitivity. Next, we turn our attention to the actions of various types of immunosuppressive drugs used in situations in which the immune system is overactive. The Actions of Immunosuppressive Drugs The development of potent immunosuppressive dr ugs has played a large role in the dramatic success of modern transplantation procedures. These drugs can also be effective in combating certain autoimmune diseases (discussed shortly). In the following discussion, we consider four classes of immunosuppressive drugs: glucocorticoids, cytotoxic drugs, cylosporine, and lymphocyte-depleting therapies. Glucocorticoids, sometimes called corticosteroids and commonly referred to as steroids, have been used as immunosuppressive agents for many years. Glucocorticoids such as prednisone (pred’ni-sōn) and methylprednisolone suppress the response of T cells to antigen and inhibit such mechanisms as T cell cytotoxicity and cytokine production. These drugs have a much smaller effect on B cell function. Cytotoxic drugs inhibit mitosis and cytokinesis (cell division). Given that lymphocyte proliferation is a key feature of specific immunity, blocking cellular reproduction is a powerful, although very nonspecific, method of immunosuppression. Among the cytotoxic drugs that have been used, the following are noteworthy: • Cyclophosphamide (sī-klō-fos’fă-mīd) cross-links daughter DNA molecules in mitotic cells, preventing their separation and blocking mitosis. It impairs both B cell and T cell responses. • Azathioprine (ā-ză-thī’ō-prēn) is a purine analog; it competes with purines during the synthesis of nucleic acids, The Characteristics of the Four Types of Hypersensitivity Reactions Name Cause Time Course Characteristic Cells Involved Type I Immediate hypersensitivity Antibody (such as IgE) on sensitized cells’ membranes binds antigen, causing degranulation After initial sensitization, seconds to minutes reviously sensitized mast cells, basophils, or eosinophils Type II Cytotoxic hypersensitivity Antibodies and complement lyse target cells Minutes to hours lasma cells secrete antibodies that act against other body cells Type III Immune complex–mediated hypersensitivity Nonphagocytized complexes of antibodies and antigens trigger complement activation, leading to inflammation, and cause neutrophils to release damaging enzymes Several hours Neutrophils Type IV Delayed (cell-mediated) hypersensitivity T cells attack the body’s cells Several days Activated T cells M18_BAUM7206_05_SE_C18.indd 533 P P Descriptive 11/23/16 3:37 AM 18   Immune Disorders thus blocking DNA replication and suppressing both primary and secondary antibody responses.  ­ ­ ­ Three other cytotoxic drugs used for immunosuppression include mycophenolate mofetil, which inhibits purine synthesis, and brequinar sodium and leflunomide, each of which inhibits pyrimidine synthesis and thereby inhibits cellular replication. Drugs such as cyclosporine (sī-klō-spōr’ēn), a polypeptide derived from fungi, prevent production of interleukins and interferons by T cells, thereby blocking Th1 responses. Because cyclosporine acts only on activated T cells and has no effect on resting T cells, it is far less toxic than the nonspecific drugs previously described. When it is given to prevent allograft rejection, only activated T cells attacking the graft are suppressed. Because steroids have a similar effect, the combination of glucocorticoids and cyclosporine is especially potent and can enhance survival of allografts. Scientists have developed techniques involving relatively specific lymphocyte­depleting therapies in an attempt to reduce the many adverse side effects associated with the use of less specific immunosuppressive drugs. One technique involves administering an antiserum called antilymphocyte globulin, which is specific for lymphocytes. Another, more specific, antilymphocyte technique uses monoclonal antibodies against CD3, which is found only on T cells. An even more specific monoclonal antibody is directed against the interleukin 2 receptor (IL-2R), which is expressed mainly on activated T cells. Such immunosuppressive therapies are effective in reversing graft rejection. Because they target a narrow range of cells, they produce fewer undesirable side effects than less specific drugs. TABLE 18.4 lists some drugs and their actions for each of the four classes of the immunosuppressive drugs. TELL ME WHY During the war in Afghanistan in 2012, an army corporal with type AB blood received a life-saving blood transfusion from his sergeant, who had type O blood. Later, the sergeant was involved in a traumatic accident and needed blood desperately. The corporal wanted to help but was told his blood was incompatible. Explain why the corporal could receive blood from but could not give blood to the sergeant. Just as today’s military must control its arsenal of sophisticated weapons to avert losses of its own soldiers from “friendly fire,” the immune system must be carefully regulated so that it does not damage the body’s own tissues. However, an immune system does occasionally produce antibodies and cytotoxic T cells that target normal body cells—a phenomenon called autoim­ munity. Although such responses are not always damaging, they can give rise to autoimmune diseases, and some of these hypersensitivities are life threatening. Causes of Autoimmune Diseases LE A R N I N G O UTC O M E 18.16 Briefly discuss eight hypotheses concerning the causes of autoimmunity and autoimmune diseases. Most autoimmune diseases appear to develop spontaneously and at random. Nevertheless, scientists have noted some common features of autoimmune disease. For example, they occur more often in older individuals, and they are also much more common in women than in men, although the reasons for this gender difference are unclear. Hypotheses to explain the etiology of autoimmunity abound. They include the following: • Estrogen may stimulate the destruction of tissues by cytotoxic T cells. • During pregnancy, some maternal cells may cross the placenta and colonize the fetus. These cells are more likely to survive in a daughter than in a son and might trigger an autoimmune disease later in the daughter’s life. • Conversely, fetal cells may also cross the placenta and trigger autoimmunity in the mother. • Environmental factors may contribute to the development of autoimmune disorders. Some autoimmune diseases—type 1 diabetes mellitus (dī-ă-bē’tēz mĕ-lī’tĕs) and rheumatoid arthritis, for example—develop in a few patients following their recovery from viral infections, though other individuals who develop these diseases have no history of such viral infections. The Four Classes of Immunosuppressive Drugs Class Glucocorticoids Examples P TABLE 18.4 Autoimmune Diseases ­ ter a       Ch p rednisone, methylprednisolone Action Anti-inflammatory; kill T cells Cytotoxic drugs Cyclophosphamide, azathioprine, mycophenolate mofetil, brequinar sodium, leflunomide Block cell division nonspecifically Cyclosporine Cyclosporine Blocks T cell responses Lymphocyte-depleting therapies Antilymphocyte globulin, monoclonal antibodies Kill T cells nonspecifically, or kill activated T cells, or inhibit IL-2 reception M18_BAUM7206_05_SE_C18.indd 534 11/23/16 3:37 AM       Autoimmune Diseases • Some autoimmune diseases develop when T cells encounter self-antigens that are normally “hidden” in sites where T cells rarely go. For example, because sperm develop within the testes during puberty, long after the body has selected its T cell population, men may have T cells that recognize their own sperm as foreign. This is normally of little consequence because sperm are sequestered from the blood. But if the testes are injured, T cells may enter the site of damage and mount an autoimmune response against the sperm, resulting in infertility. • Infections with a variety of microorganisms may trigger autoimmunity as a result of molecular mimicry, which occurs when an infectious agent has an epitope that is very similar or identical to a self-antigen. In responding to the invader, the body produces antibodies that are autoantibodies (antibodies against self-antigens), which damage body tissues. For example, children infected with some strains of Streptococcus pyogenes (strep-tōkok’ŭs pī-oj’en-ēz) may produce antibodies to heart muscle and so develop heart disease. Other strains of streptococci trigger the production of antibodies that cross-react with glomerular basement membranes and so cause kidney disease. It is possible that some virally triggered autoimmune diseases also result from molecular mimicry. • Other autoimmune responses may result from failure of the normal control mechanisms of the immune system. For example, harmful, self-reactive T lymphocytes are normally destroyed via apoptosis triggered by a cell-surface receptor; however, if defects in the receptor are present, they can permit abnormal T cells to survive and cause disease. Examples of Autoimmune Diseases LE A R N I N G O U TC O M E 18.17 Describe a serious autoimmune disease associated with each of the following: blood cells, endocrine glands, nervous tissue, and connective tissue. ­ ­ Regardless of the specific mechanism that causes an autoimmune disease, immunologists categorize them into two major groups: systemic autoimmune diseases such as lupus (discussed previously) and single-organ autoimmune diseases, which affect a single organ or tissue. Among the many single-organ M18_BAUM7206_05_SE_C18.indd 535 autoimmune diseases recognized, common examples affect blood cells, endocrine glands, nervous tissue, or connective tissue. ­ • Genetic factors may play a role in autoimmune diseases. MHC genes that in some way promote autoimmunity are found in individuals with autoimmune diseases, whereas MHC genes that somehow protect against autoimmunity may dominate in other individuals. MHC genes may also trigger autoimmune disease by preventing the elimination of some self-reactive T cells in the thymus. Autoimmunity Affecting Blood Cells Individuals with autoimmune hemolytic anemia (a type II hypersensitivity) produce antibodies against their own red blood cells. These autoantibodies speed up the destruction of the red blood cells, and the patient becomes severely anemic. Different hemolytic anemia patients make antibodies of different classes. Some patients make IgM autoantibodies, which bind to red blood cells and activate the classical complement pathway; the red blood cells are lysed, and degradation products from hemoglobin are released into the bloodstream. Other hemolytic anemia patients make IgG autoantibodies, which serve as opsonins that promote phagocytosis. In this case, red blood cells are removed by macrophages in the liver, spleen, and bone marrow. Even though these latter patients have no hemoglobin in their urine, they are still severely anemic. The precise causes of all cases of autoimmune hemolytic anemia are unknown, but some cases follow infections with viruses or treatment with certain drugs, both of which alter the surface of red blood cells such that they are recognized as foreign and trigger an immune response. Autoimmunity Affecting Endocrine Organs Other common targets of autoimmune attack are the endocrine (hormone-producing) organs. For example, patients can develop autoantibodies or produce T cells against cells of the islets of Langerhans within the pancreas or against cells of the thyroid gland. In most cases, the ensuing autoimmune reaction results in damage to or destruction of the gland and in hormone deficiencies as endocrine cells are killed. Immunological attack on the islets of Langerhans results in a loss of the ability to produce the hormone insulin, which leads to the development of type 1 diabetes mellitus (also known as juvenile­onset diabetes). As with other autoimmune diseases, the exact trigger of type 1 diabetes is unknown, but many patients endured a severe viral infection some months before the onset of diabetes, which may be the trigger for this type IV hypersensitivity. Additionally, some patients are known to have a genetic predisposition to developing type 1 diabetes that is associated with the possession of certain class I MHC molecules. Some physicians have been successful in delaying the onset of type 1 diabetes by treating at-risk patients with immunosuppressive drugs before damage to the islets of Langerhans becomes apparent. An autoimmune response can lead to stimulation rather than to inhibition or destruction of glandular tissue. An example of this is Graves’ disease, which involves the thyroid gland. This major endocrine gland located in the neck secretes iodine-containing hormones, which help regulate metabolic rate in the body. Like other autoimmune diseases, Graves’ disease may be triggered by a viral infection in individuals 11/23/16 3:37 AM ter a       Ch p 18   Immune Disorders with certain genetic backgrounds. Affected patients (usually women) make autoantibodies that bind to and stimulate receptors on the cytoplasmic membranes of thyroid cells, which elicits excessive production of thyroid hormone and growth of the thyroid gland. Such patients develop an enlarged thyroid gland, called a goiter, and protruding eyes, rapid heartbeat, fatigue, and weight loss despite increased appetite. Physicians treat Graves’ disease with antithyroid medicines or radioactive iodine. Patients whose condition doesn’t improve with those treatments may require surgical removal of most of the thyroid tissue. Autoimmunity Affecting Nervous Tissue Of the group of autoimmune diseases affecting nervous tissue, the most frequent is multiple sclerosis (MS) (sklĕ-rō’sis), which is another type IV hypersensitivity. The exact cause of MS is unknown, but it appears that a cell-mediated immune response against a bacterium or virus generates cytotoxic T cells that mistakenly attack and destroy the myelin sheaths that normally insulate brain and spinal cord neurons and increase the speed of nerve impulses along the length of the neurons. Consequently, MS patients experience deficits in vision, speech, and neuromuscular function that may be quite mild and intermittent or may be progressive, paralytic, and perhaps fatal. Autoimmunity Affecting Connective Tissue Rheumatoid arthritis (discussed previously) is another crippling autoimmune disease resulting from a type III hypersensitivity. Autoantibodies are formed against connective tissue in joints. TELL ME WHY Why can’t scientists use the postulates of Robert Koch to determine the specific cause of Graves’ disease? Immunodeficiency Diseases LE A R N I N G O U TC O M E 18.18 Differentiate primary from acquired immunodefi- ciencies, and cite one disease caused by each form of immunodeficiency. • Primary immunodeficiency diseases, which are detectable near birth and develop in infants and young children, result from some genetic or developmental defect. • Acquired (secondary) immunodeficiency diseases develop in later life as a direct consequence of some other recognized cause, such as malnutrition, severe stress, or infectious disease. Next, we consider each general type of immunodeficiency disease in turn. Primary Immunodeficiency Diseases Many different inherited defects have been identified in all of the body’s lines of defense, affecting first and second lines of defense as well as antibody and cell-mediated immune responses. One of the more important inherited defects in the second line of defense is chronic granulomatous disease, in which children have recurrent infections characterized by the inability of their phagocytes to destroy bacteria. The reason is that these children have an inherited inability to make reactive forms of oxygen, which are necessary to destroy phagocytized bacteria. Most primary immunodeficiencies are associated with defects in the components of the third line of defense—adaptive immunity. For example, some children fail to develop any lymphoid stem cells whatsoever, and as a result they produce neither B cells nor T cells and cannot mount immune responses. The resulting defects in the immune system cause severe combined immunodeficiency disease (SCID). Other children suffer from T cell deficiencies alone. For example, DiGeorge syndrome results from a failure of the thymus to develop. Consequently, there are no T cells. Individuals with DiGeorge syndrome generally die of viral infections while remaining resistant to most bacteria—a phenomenon that underscores the importance of T cells in protecting against viruses. Physicians can treat DiGeorge syndrome with a thymic stem cell transplant. B cell deficiencies also occur in children. The most severe of the B cell deficiencies, called Bruton-type agammaglobulinemia5 (ā-gam’ă-glob’ū-li-nē’mē-ă), is an inherited disease in which affected babies, usually boys, cannot make immunoglobulins. These children experience recurrent bacterial infections but are usually resistant to viral, fungal, and protozoan infections. Inherited deficiencies of a single immunoglobulin class are more common than a deficiency of all classes. Among these, IgA deficiency is the most common. Because affected children cannot produce secretory IgA, they experience recurrent infections in the respiratory and gastrointestinal tracts. TABLE 18.5 summarizes some major primary immunodeficiency diseases. ­ ­ You may have noticed that during periods of increased emotional or physical stress you are more likely to have a cold. You are not imagining this phenomenon; stress has long been known to decrease the efficiency of the immune system. Similarly, chronic defects in the immune system typically first become apparent when affected individuals become sick more often from infections of opportunistic pathogens. Such opportunistic infections are the hallmarks of immunodeficiency diseases, which are conditions resulting from defective immune mechanisms. Researchers have characterized a large number of immunodeficiency diseases in humans, which are of two general types: M18_BAUM7206_05_SE_C18.indd 536 5Agammaglobulinemia means “an absence of gamma globulin (IgG).” 11/23/16 3:37 AM       Immunodeficiency Diseases worldwide pandemic, no affliction has affected modern life as much. TABLE 18.5 Some Primary Immunodeficiency Diseases Defect Manifestation Signs and Symptoms of AIDS Chronic granulomatous disease Ineffective phagocytes Uncontrolled infections Severe combined immunodeficiency disease (SCID) Lack of T cells and B cells No resistance to any type of infection, leading to rapid death DiGeorge syndrome Lack of T cells and thus no cell-mediated immunity Overwhelming viral infections Bruton-type agammaglobulinemia Lack of B cells and thus lack of immunoglobulins Overwhelming bacterial infections AIDS is not a single disease but a syndrome, that is, a group of signs, symptoms, and diseases associated with a common pathology. Currently, epidemiologists define AIDS as the presence of several opportunistic or rare infections along with infection by human immunodeficiency virus (HIV) or as a severe decrease in the number of CD4+ cells (6 200/ml of blood)6 and a positive test showing the presence of antibodies against HIV. The infections include diseases of the skin, such as shingles and disseminated (widespread) herpes ( FIGURE 18.13a); diseases of the nervous system, ­ Disease Acquired Immunodeficiency Diseases LE A R N I N G O U TC O M E S 18.19 Describe five acquired conditions that suppress immunity. 18.20 Define AIDS, and differentiate a disease from a syndrome. 18.21 Describe HIV, including its structure, possible origin, replication cycle (particularly the roles of gp120 and gp41), and transmission. 18.22 Describe the relationship of the helper T cell population to the course of AIDS. 18.23 Describe the diagnosis, treatment, and prevention of AIDS, and list four behaviors that increase the risk of infection with HIV. (a) (b) ▲ FIGURE 18.13 Diseases associated with AIDS. (a) Dissemi- nated herpes. (b) Kaposi’s sarcoma, a cancer of blood vessels. ­ Unlike inherited primary immunodeficiency diseases, acquired immunodeficiency diseases affect individuals who had a previously healthy immune system. Acquired immunodeficiencies result from a number of causes. In all humans, the immune system (but especially T cell production) deteriorates with increasing age; as a result, immunity, especially cell-mediated immunity, is normally less effective in older individuals than in younger individuals. This is the reason why the incidence of both viral diseases and certain types of cancer are increased in the older population. Severe stress can also lead to immunodeficiencies by prompting the secretion of increased quantities of corticosteroids, which are toxic to T cells and thus suppress cell-mediated immunity. This is why, for example, cold sores may “break out” on the faces of students during final exams: The causative human herpesviruses, which are kept under control by a fully functioning cell-mediated immune response, escape immune control in stressed individuals. Malnutrition and certain environmental toxins can also cause acquired immunodeficiency diseases by inhibiting the normal production of B cells and T cells. The most significant example of the result of an acquired immunodeficiency is acquired immunodeficiency syndrome (AIDS). From the time of its discovery in 1981 among homosexual males in the United States to its emergence as a M18_BAUM7206_05_SE_C18.indd 537 6The normal value for CD4 + cells is 500–1200 cells/ml. 11/23/16 3:37 AM ter a       Ch p 18   Immune Disorders including meningitis, toxoplasmosis, and Cytomegalovirus (sī-tō-meg’ă-lō-vī’rŭs) disease; diseases of the respiratory system, such as tuberculosis, Pneumocystis (nū-mō-sis’tis) pneumonia, histoplasmosis, and coccidioidomycosis (koksid-ē-oy’dō-mī-kō-sis); and diseases of the digestive system, including chronic diarrhea, thrush, and oral hairy leukoplakia. A rare cancer of blood vessels called Kaposi’s sarcoma is also commonly seen in AIDS patients (FIGURE 18.13b). AIDS often results in dementia during the final stages. T 18.6 summarizes these and other diseases associated with AIDS. (Chapters 19–24 deal with the signs, symptoms, diagnosis, and treatment of these specific diseases in more detail.) ssRNA genome able ­ gp120 gp41 Protease Envelope AIDS Pathogen and Its Virulence Factors Integrase Reverse transcriptase Capsid ­ Hu ma n i m mu nodef ic ienc y v ir us (HIV) causes AIDS, though it should be noted that infection with HIV is not AIDS; HIV infection typically leads to AIDS in untreated patients. HIV is an enveloped, positive single-stranded RNA (+ssRNA) virus of the type called retroviruses because it uses reverse transcriptase to make a DNA copy of its genome. Luc Montagnier (1932–) and his colleagues at the Pasteur Institute discovered HIV in 1983. Note that the acronym HIV indicates that it is a virus. It is repetitive and incorrect to call this pathogen “HIV virus”; a more appropriate name is “AIDS virus,” or simply “HIV.” Taxonomists classify HIV in the genus Lentivirus, family Retroviridae. There are two major types of the virus. HIV-1 is more prevalent in the United States and Europe, and HIV-2 is more prevalent in West Africa. HIV-2, which shares about 50% of the nucleic acid sequence of HIV-1, reproduces more slowly than HIV-1. Researchers have studied HIV-1 more, so the following sections focus on this strain. 18.6 able T ▲ FIGURE 18.14 Artist’s conception of HIV. The virion is about 90 nm in diameter. Structure of HIV HIV-1 is a typical retrovirus in shape, components, and size (FIGURE 18.14). Two antigenic glycoproteins characterize its envelope. The larger glycoprotein, named gp120,7 is the primary attachment molecule of HIV. Its antigenicity changes during the course of prolonged infection, making it difficult for the body to make an effective antibody response against gp120. A smaller glycoprotein, gp41, promotes fusion of the viral envelope with the Opportunistic Infections Associated with AIDS Causative Agent Organ Primarily Affected (Chapter Where Covered) Coccidioidomycosis Coccidioides (fungus) Lung (22) Cytomegalovirus disease Cytomegalovirus Brain (20), liver (23) Diarrhea (severe and prolonged) Various bacteria, Cryptosporidium (protozoan) Intestines (23) erpes HerpesvirusSimplexvirus Skin (19) H Disease Histoplasma (fungus) Lung (22) Human herpesvirus 8 Blood vessels (21) Meningitis Cryptococcus (yeast), Listeria (bacterium) Brain and meninges (20) Oral hairy leukoplakia Lymphocryptovirus (Epstein-Barr virus) Tongue (23) Pneumocystis (fungus) Lung (22) Shingles Varicellovirus Skin (19) Thrush Candida (yeast) Mouth and tongue (23), vagina (24) Toxoplasmosis Toxoplasma (protozoan) Lungs, liver, heart (21) Tuberculosis Mycobacterium Lung (22) P H istoplasmosis Kaposi’s sarcoma neumonia 7gp120 M18_BAUM7206_05_SE_C18.indd 538 is short for “glycoprotein with a molecular weight of 120,000 daltons.” 11/23/16 3:37 AM       Immunodeficiency Diseases cytoplasmic membrane of a CD4 + cell. The effects of these structural characteristics—antigenic variability and the ability to fuse with host cells—interfere with clearance of HIV from a patient. Replication of HIV ­ We can consider replication as occurring in eight steps (FIGURE 18.15). We first look at the eight-step replication process and then examine details of various steps. Attachment. HIV primarily attaches to four kinds of cells: helper T cells; cells of the macrophage lineage, including monocytes, macrophages, and microglia (special phagocytic cells of the central nervous system); smooth muscle cells, such as those in arterial walls; and dendritic cells. HIV can also rarely infect nerve cells, liver cells, and some epithelial cells. 1 Additionally, B lymphocytes attach to HIV that has been covered with complement proteins. Though HIV does not infect these B cells, the B cells deliver HIV to helper T cells, which then become infected. Similarly, infected macrophages can pass HIV to helper T cells. 2 Entry. HIV triggers the cell to endocytize the virus; that is, the cell’s cytoplasmic membrane forms a pocket and folds in to surround the virus, forming a vesicle holding the virus.  1  Origin of HIV Evidence suggests that HIV arose from mutation of a similar virus—simian immunodeficiency virus (SIV)— found in African monkeys, chimpanzees, and other simians; the nucleotide sequence of SIV is similar to those of the two strains of HIV. Based on mutation rates and the rate of antigenic change in HIV, researchers estimate that HIV may have emerged in the human population in Africa about 1930. Scientists have identified antibodies against HIV in human blood stored since 1959, though they did not document the first case of AIDS until 1981. The historical relationships between the two types of HIV and SIV are not clear. HIV-1 and HIV-2 may be derived from different strains of SIV, or one type of HIV may be derived from the other. We may never know the exact evolutionary relationships among the immunodeficiency viruses. HIV 8 Assembly and maturation (protease function) Cytoplasmic membrane 1 Attachment CD4 2 Entry by endocytosis gp 41 7 Release gp 120 3 Uncoating Endosome gp41 Translation of mRNA into viral proteins Virus enters cytosol and capsid uncoats 6 Synthesis of RNA and polypeptides 4 Synthesis of DNA dsDNA is transcribed from ssRNA by reverse transcriptase 5 Integration dsDNA Nucleus Genome RNA mRNA Provirus Integrase Transcription Virus inserted into human DNA Human DNA P ▲ FIGURE 18.15 The replication cycle of HIV. The artist’s rendition depicts eight steps involved in the replication of the virus within a helper T cell. hotos show attachment and penetration ( 1 – 3 ) and budding, release, and maturation of a virion ( 4 – 6 ). How does the replication of HIV differ from the replication of bacteriophage T4? ­ Figure 18.15 Bacteriophage T4 is a DNA virus; therefore, it does not have reverse transcription. Further, T4 does not integrate into a bacterium’s chromosome; it assembles completely before being released from the cell; it has no envelope; and it does not carry enzymes. M18_BAUM7206_05_SE_C18.indd 539 11/23/16 3:37 AM 7 ter a       6  1 gp120 binds to CD4 receptor on target cell. Integration. The dsDNA made by reverse transcriptase enters the nucleus and becomes part of a human DNA molecule. There it remains as a part of the cell for life—a condition known as latency. gp41 gp120 CD4 Envelope Synthesis of RNA and polypeptides. An infected cell transcribes integrated HIV genes to produce messenger RNA and multiple copies of viral ssRNA that will act as genomes for new viruses. Ribosomes within the infected cell translate mRNA to make viral-encoded polypeptides. These include attachment proteins, integrase, and a large polypeptide composed of inactive reverse transcriptase and capsomeres. The attachment proteins are inserted in the host’s cytoplasmic membrane. Release. Two molecules of genomic RNA, molecules of tRNA, and several viral polypeptides bud from the host’s cytoplasmic membrane to form an immature virion. 2 CD4-gp120 complex attaches to fusin (CXCR4), which triggers endocytosis. RNA Capsid Endosome 3 The virus is now in an endosome. 4 Glycoprotein 41 facilitates fusion of the viral envelope with the endosome membrane. Details of Attachment, Entry, and Uncoating 5 The viral capsid is now in the cytosol.  Assembly and maturation. HIV that buds from a cell is nonvirulent because its capsid is not fully functional, and reverse transcriptase is inactive. Protease, a viral enzyme packaged in the virion, cleaves the large polypeptide to release reverse transcriptase and capsomeres. This action of protease, which occurs only after the virus has budded from the cell, allows final maturation of the viral capsid. HIV is now active. Now, let us examine some of the steps of HIV replication in more detail. 8 TARGET CELL Fusin (CXCR4)  Synthesis of DNA. Reverse transcriptase, which has been released from the capsid, synthesizes double-stranded DNA (dsDNA) using viral ssRNA as a template (look ahead to Figure 18.17). HIV  5 Uncoating. The viral envelope fuses with the vesicle’s membrane, and the intact capsid of HIV enters the cytosol. The virus then uncoats the capsid and releases its two ssRNA molecules from the capsid into the cell’s cytoplasm.  4 18   Immune Disorders  3 Ch p HIV uses gp120 and gp41 to attach to and enter target cells (FIGURE 18.16). CD4 8 on a target cell’s cytoplasmic membrane is the receptor for gp120 that is, gp120 attaches HIV to CD4 1 . The CD4-gp120 complex binds to another membrane receptor, called fusin (also known as CXCR4), which triggers the cell’s membrane to move out and surround the virus—a process called endocytosis 2 . Endocytosis forms a bubble of membrane with the virus inside. This structure is called an endosome 3 . 8Scientists commonly name membrane proteins with letter-number combinations; CD4 stands for the fourth cluster of differentiation to be discovered. M18_BAUM7206_05_SE_C18.indd 540 gp41 6 The capsid breaks down, realeasing viral RNA and proteins. ▲ FIGURE 18.16 The process by which HIV attaches to and enters a host cell. 11/23/16 3:37 AM       Immunodeficiency Diseases 1 2 ssRNA-ssDNA hybrid ssRNA RNA degrades 3 dsDNA tase, depicted here as three distinct steps. 1 The enzyme transcribes a complementary -s s DNA molecule to form a DNA-RNA hybrid. It uses tRNA brought from a previous host cell as a primer for transcription. 2 The RNA portion of the hybrid is degraded, leaving -s s DNA. 3 The enzyme synthesizes a complementary +s s DNA strand, forming dsDNA. tRNA primer Reverse transcriptase –ssDNA HIV remains intact within an endosome for about 30 minutes. Glycoprotein 41 on the viral envelope evidently then facilitates fusion of the envelope with the endosome membrane. The two fuse 4 , and the viral capsid is introduced intact into the cell’s cytosol 5 . The viral capsid uncoats, releasing viral RNA and proteins 6 . molecules as well as entire RNA copies of the whole HIV genome. Details of Release, Assembly, and Maturation HIV actively participates in its release from the cell. A viral protein selects a lipid raft—a region of regularly packed lipids— in the cytoplasmic membrane as the point of exit. As the virus blebs from the cell, components of the raft become the envelope of the virion. Once the virus is outside the cell, capsomeres organize to form an immature capsid, and viral protease cleaves a polypeptide within the capsid to release functional proteins. The proteins cause the virus to mature and become infective. Protease inhibitors—drugs that interfere with the function of protease—have become a standard therapeutic agent in the treatment of HIV infection and have significantly lengthened the life expectancy of patients. Details of Synthesis and Latency ­ ­ Reverse transcriptase, which was carried inside the capsid, becomes active in the cytosol. It uses tRNA as a primer to transcribe dsDNA from the ssRNA genome of the virus (see Figure 18.17). Reverse transcriptase is very error prone, making about five errors per genome. This generates multiple antigenic variations of HIV. Billions of variants may develop in a single patient over the course of the syndrome. HIV is a latent virus. The dsDNA made by reverse transcriptase is known as a provirus, and it enters the nucleus. A viral enzyme known as integrase inserts the dsDNA provirus into a human chromosome. Once integrated, the provirus permanently remains part of the cellular DNA. It may remain dormant for years or be activated immediately, depending on its location in the human genome and the availability of promoter DNA sequences (see Figure 7.9). Infected macrophages and monocytes are major reservoirs of integrated HIV, and they serve as a means of distributing the virus throughout the body. An infected cell replicates integrated DNA every time cellular DNA is replicated. In this way, HIV ends up infecting all progeny of infected cells. An infected cell may also transcribe integrated HIV to make viral messenger RNA TABLE 18.7 ◀ FIGURE 18.17 Action of reverse transcrip- Detail of DNA Synthesis Reverse transcriptase transcribes dsDNA in three nearly simultaneous steps, as shown in FIGURE 18.17. First, the enzyme synthesizes a negative single-stranded DNA (ssDNA) copy of the viral ssRNA, forming a ssDNA-ssRNA hybrid. Transfer RNA from the previous host cell serves as primer for this reaction. The enzyme then degrades the ssRNA of the hybrid to leave ssDNA and, finally, synthesizes a complementary positive strand of DNA, thereby completing the process of forming dsDNA. TABLE 18.7 summarizes some of the characteristics that make HIV particularly difficult to combat. Characteristics of HIV That Challenge the Immune System Effect(s) Retrovirus with a genome that consists of two copies of + s s RNA Reassortment of viral genes possible; reverse transcription produces much mutation and thus genetic variation; genome integrates into host’s chromosome Targets helper T cells especially, but also macrophages, dendritic cells, and muscle cells, and possibly liver, nerve, and epithelial cells P Characteristic ermanently infects key cells of host’s immune system Antigenic variability Numerous antigenic variations due to mutations help virus evade host’s immune response Induces fusion of infected cells with neighboring cells Increases routes of infection; intracellular site helps virus evade immune detection M18_BAUM7206_05_SE_C18.indd 541 11/23/16 3:37 AM 18   Immune Disorders CD4 T cells/mm3 blood 5 Clinical latency 106 105 4 500 0 2 0 3 104 3 6 9 12 Weeks 1 2 3 103 4 5 6 7 Years 8 9 10 11 HIV RNA copies/ml plasma 1 1000 Death Opportunistic diseases Primary infection 102 HIV in blood CD4 (helper) T cell count Antibody against HIV ▲ FIGURE 18.18 The course of untreated AIDS follows the course of helper T cell destruction. Pathogenesis of AIDS  ­ ­ Only human cells replicate HIV effectively, and, as its name indicates, the virus causes destruction of a human’s immune system. As FIGURE 18.18 illustrates, the destruction of helper T (CD4+) cells directly relates to the course of AIDS. Initially, there is a burst of virion production and release from infected cells 1 . Fever, fatigue, weight loss, diarrhea, and body aches accompany this primary infection. The immune system responds by producing antibodies, and the number of free virions (red line) plummets 2 . The body and HIV are waging an invisible war with few signs or symptoms. During this period, the body destroys almost a billion virions each day, but cytotoxic T cells kill about 100 million virally infected CD4 + cells in the same time period. No specific symptoms accompany this stage, and the patient is often unaware of the infection. Integrated viruses continue to replicate and virions are released into the blood to such an extent that the body cannot make enough helper T cells (green line) 3 . Over the course of 5 to 10 years, the number of helper T cells declines to a level that severely impairs the immune response. The rate of antibody formation (purple line) falls precipitously as helper T cell function is lost. HIV production climbs (red line) 4 , and eventually the patient dies 5 . Many of the diseases associated with the loss of immune function in AIDS (see Table 18.6 on p. 538) are nonlethal infections in other patients, but AIDS patients cannot effectively resist them. Diseases such as Kaposi’s sarcoma, disseminated herpes, toxoplasmosis, and Pneumocystis pneumonia occur rarely except in AIDS patients. Epidemiology of AIDS Epidemiologists first identified AIDS in young male homosexuals in the United States, but now AIDS is worldwide. WHO M18_BAUM7206_05_SE_C18.indd 542 estimated as of December 2013 AIDS had killed more than 39 million people and that another approximately 35 million people were infected with HIV worldwide. Approximately 240 new infections occur each hour worldwide, including over 130 new cases in the United States daily. About onethird of infected individuals have already developed AIDS; most of the rest will eventually develop the syndrome. The spread of AIDS in sub-Saharan Africa is particularly horrific (FIGURE 18.19). All body secretions of AIDS patients contain HIV; however, viruses typically exist in sufficient concentration to cause infection only in blood, semen, vaginal secretions, and breast milk. Virions may be free or inside infected leukocytes. Infected blood contains 1000 to 100,000 virions per milliliter, while semen has 10 to 50 virions per milliliter. Other secretions have lower concentrations and are less infective than blood or semen. Infected fluid must be injected into the body or encounter a tear or lesion in the skin or mucous membranes. Because HIV is only about 90 nm in diameter, a break in the protective membranes of the body allowing entry of HIV may be too small to bleed or to see or feel. Sufficient numbers of virions must be transmitted to target cells to establish an infection, though scientists do not know the exact number of virions required. The number probably varies with the strain of HIV and the overall health of the patient’s immune system. HIV is transmitted primarily via sexual contact (including vaginal, anal, and oral sex, either homosexual or heterosexual) and intravenous drug abuse (FIGURE 18.20). Blood transfusions, organ transplants, tattooing, and accidental medical needlesticks also transmit HIV, though rarely. For example, the risk of infection from a needlestick injury involving an HIV-infected patient is less than 1%. Mothers also transmit HIV to their babies across the placenta and in breast milk; HIV infects approximately one-third of babies born to HIV-positive women. ≥1 million 100,000 to 1 million 10,000 to 100,000 <10,000 No data available ▲ FIGURE 18.19 The global distribution of HIV/AIDS. Figures indicate the prevalence of 2013. H ter a       Ch p IV/AIDS among children and adults as of the end of 11/23/16 3:37 AM       Immunodeficiency Diseases Adult Males Adult Females Use of injected drugs 5.7% Male homosexual contact plus use of injected drugs 3.6% High-risk 11.8% heterosexual contact 78.7% Other 0.1% Use of injected drugs Other 0.15% Male homosexual contact 14% 86% High-risk heterosexual contact ▲ FIGURE 18.20 Modes of HIV transmission in people over H P 12 years of age in the United States during 2011. ercentages represent the estimated proportions of IV infections that result from each type of transmission. (Estimates are rounded to the nearest 1% and thus do not add up to 100%.) Behaviors that increase the risk of infection include the following: • Anal intercourse, especially receptive anal intercourse • Sexual promiscuity; that is, sex with more than one partner • Intravenous drug use • Sexual intercourse with anyone in the previous three categories The mode of infection is unknown for a small number of AIDS patients, who are often unable or unwilling to answer questions about their sexual and drug abuse history. The U.S. Centers for Disease Control and Prevention (CDC) has documented a few cases of casual spread of HIV, including infections from sharing razors and toothbrushes and from mouth-to-mouth kissing. In all cases of casual spread, researchers suspect that small amounts of the donor’s blood may have entered abrasions in the recipient’s skin or mouth. Diagnosis, Treatment, and Prevention Physicians diagnose AIDS on the basis of unexplained weight loss, fatigue, fever, fewer than 200 CD4+ lymphocytes per microliter (ml)9 of blood, and the demonstration of antibodies against HIV combined with other signs and symptoms, which vary according to the diseases involved. HIV itself is difficult to locate in a patient’s secretions and blood because it becomes a provirus inserted into chromosomes and because for years it can be kept in check by the immune system. Therefore, diagnosis involves detecting antibodies against HIV in the blood using enzyme-linked immunosorbent assay (ELISA) and immunoblot testing. Most 9The normal value for CD4 + cells is 500 to 1500 cells/ml. M18_BAUM7206_05_SE_C18.indd 543 individuals develop antibodies within six months of infection, though some remain without detectable antibodies for up to three years. A positive test for antibodies does not mean that HIV is currently present or that the patient has or will develop AIDS; it merely indicates that the patient has been exposed to HIV. Doctors use a PCR test for HIV RNA to make a definitive diagnosis. A small percentage of infected individuals, called long­term nonprogressors, do not develop AIDS even years or decades after infection. It appears that either these individuals are infected with defective virions, they have a mutated fusin receptor that does not bind effectively to HIV, or they have unusually well-developed immune systems. Discovering a treatment for AIDS is an area of intense research and development. Currently physicians prescribe antiretroviral therapy (ART), previously known as highly active antiretroviral therapy (HAART). ART is a “cocktail” of three or more antiviral drugs to reduce viral replication, including nucleotide analogs, integrase inhibitors, protease inhibitors (e.g., darunavir), and reverse transcriptase inhibitors (e.g., emtricitabine). ART is expensive and generally must be taken on a strict schedule. Studies indicate that the therapy stops the replication of HIV because strains of the virus are unlikely to develop resistance to all of the drugs simultaneously. As long as treatment continues, a patient can live a relatively normal life; however, treatment is not a cure because the infection remains. Some scientists estimate that it would take 60 years on ART for all HIV-infected cells to die. In addition to ART, physicians manage and treat individual diseases associated with AIDS on a case-by-case basis. Doctors can use a PCR test for the presence of HIV RNA to measure the effectiveness of ART. Recent studies show that treatment begun immediately after diagnosis of HIV infection significantly reduces the chance that a patient will develop AIDS. Researchers are working to develop methods that will prevent attachment of HIV to target cells, block the entry of HIV into cells, and halt HIV synthesis and release. Progress in developing a vaccine against HIV has been disappointing. Among the problems that must be overcome in developing an effective vaccine are the following: • A vaccine must generate both cell-mediated immunity (so that cytotoxic T lymphocytes would be able to eliminate infected cells) and antibody immunity (especially secretory antibody [IgA], whose presence in mucus would reduce sexual transmission of the virus). • Induction of synthesis of gamma class antibodies (IgG), a necessary function of a vaccine, can actually be detrimental to a patient. Because IgG-HIV complexes bind to B cells and also remain infective inside phagocytic cells, a vaccine must stimulate cell-mediated immune response more than antibody immune response so as to kill infected cells. • HIV is highly mutable, generating antigenic variants that enable it to evade the immune response. Scientists estimate 11/23/16 3:37 AM 18   Immune Disorders • HIV can spread directly from cell to cell because gp41 remains on an infected cell’s cytoplasmic membrane after HIV has entered. Glycoprotein 41 can fuse the HIVinfected cell to neighboring cells, allowing HIV access to the neighbor and enabling it to evade some immune surveillance. ­ the diversity of HIV sequences found in one person at any one time is greater than the diversity of flu viruses in everyone worldwide during a full year. CLINICAL CASE STUDY A Case of AIDS A 25-year-old man is admitted to the hospital with thrush, diarrhea, unexplained weight loss, and difficulty in breathing. Cultures of pulmonary fluid reveal the presence of Pneumocystis. The man admits to being a heroin addict and to sharing needles in a “shooting gallery.” ­ ter a       Ch p • HIV infects and inactivates macrophages, dendritic cells, and helper T cells—cells that combat infections. ­ ­ • Testing a vaccine presents ethical and medical problems because HIV is a pathogen of humans only. For example, researchers stopped a study in 1994 when HIV infected five volunteers despite their having received an experimental vaccine. 1. What laboratory tests could confirm a diagnosis of AIDS? 2. How did the man most likely acquire an IV infection? • Abstinence and mutually faithful monogamy between uninfected individuals are the only truly safe sexual behaviors. Studies have shown that whereas condoms reduce a heterosexual individual’s risk of acquiring HIV by about 69%, the benefit of condom usage to a population can be undone by an overall increase in sexual activity that may result from a false sense of security that condoms provide safe sex. • Use of new, clean needles and syringes for all injections, as well as caution in dealing with sharp, potentially contaminated objects, can reduce HIV infection rates. If clean supplies are not available, 10% household bleach deactivates HIV on surfaces uncontaminated by a large amount of organic material (blood, mucus). • Antiviral drugs given to pregnant women have reduced transfer of HIV across the placenta and in breast milk. Generally, HIV-infected mothers should not breast-feed their infants, though feeding with formula made with contaminated water is often more dangerous, triggering life-threatening diarrhea. WHO recommends formula only when it is “acceptable, feasible, affordable, sustainable, and safe.” • Screening blood, blood products, and organ transplants for HIV and anti-HIV antibodies has virtually eliminated the risk of HIV infection from these sources. 3. What changes to the man’s immune system allowed the opportunistic infection of neumocystis to arise? 4. What precautions should health care providers take in handling blood? M18_BAUM7206_05_SE_C18.indd 544 P H Scientists have developed a vaccine that protects monkeys from SIV disease but have not been able to translate this success into an effective vaccine for humans. In the meantime, individuals can slow the AIDS epidemic with personal decisions: • Proper use of gloves, protective eyewear, and masks can prevent contact with infected blood. • Researchers have determined that men who are circumcised reduce their risk of infection through sexual activity by at least 60%. Circumcision lowers their partner’s risk by 30%. • For many individuals, pre-exposure prophylaxis (PrEP), which involves taking a daily oral dose of an antiviral drug (tenofovir), prevents sexual acquisition of HIV. • Women who apply 1% tenofovir gel vaginally before and after sex significantly reduce the chance of infection from HIV-positive men. TELL ME WHY Why is it difficult for a medical treatment to rid the body’s cells of HIV? 11/23/16 3:37 AM       Chapter Summary the hives; they should clear up in a couple of days. The doctor also prescribes Tim a single-dose epinephrine autoinjector so that if he should have a similar reaction in the future, he can self-administer epinephrine as soon as necessary. ­ Danger in the Blackberry Patch? ­ 1. Explain how the hornet venom caused Tim’s hives and his difficulty in breathing. In other words, what physiological responses are causing his symptoms? 2. Why will an antihistamine help treat Tim’s hives? H By the time that Cassie and Tim arrive at the ER, Tim is having a hard time catching his breath. The doctor quickly assesses Tim’s condition and administers epinephrine. Within a minute, Tim is breathing much more easily. The doctor keeps Tim in the hospital for a few hours to monitor his condition and make sure that no additional respiratory complications occur. The doctor tells Tim and Cassie that Tim had a type I hypersensitivity reaction to the venom that the hornet stings injected. After a few hours with no further complications, the doctor releases Tim from the hospital. e instructs Tim to use an antihistamine (diphenhydramine hydrochloride) to relieve the symptoms of CHAPTER SUMMARY 1. Type I hypersensitivity gives rise to allergies. Antigens that trigger this response are called allergens. 2. Allergies result from a two-step process: (1) allergens trigger the production of IgE antibodies that bind to mast cells, basophils, and eosinophils, which are thereby sensitized to the allergen; and (2) the same kinds of allergens later bind to the antibodies, causing the sensitized cells to degranulate and release histamine, kinins, proteases, leukotrienes, and prostaglandins. 3. Depending on the amount of these molecules and the site at which they are released, the result can produce various diseases, including hay fever, asthma, urticaria (hives), or various other allergies. When the inflammatory mediators exceed the body’s coping mechanisms, acute anaphylaxis, or anaphylactic shock, may occur. The specific treatment for anaphylaxis is epinephrine. 4. Type I hypersensitivity can be diagnosed by skin testing and can be partially prevented by avoidance of allergens and by immunotherapy. Some type I hypersensitivities are treated with antihistamines. M18_BAUM7206_05_SE_C18.indd 545 6. Red blood cells have blood group antigens on their surface. If incompatible blood is transfused into a recipient, a severe transfusion reaction can result. 7. The most important of the blood group antigens is the ABO group, which is largely responsible for transfusion reactions. 8. Approximately 85% of the human population carries Rh antigen, which is also found in rhesus monkeys. If an Rh-negative pregnant woman is carrying an Rh-positive fetus, the fetus may be at risk of hemoV lytic disease of the newborn, in which antibodies T made by the mother against the Rh antigen may cross the placenta and destroy the fetus’s red blood cells. RhoGAM administered to pregnant Rh-negative women may prevent this disease. ideo Hypersensitivities (pp. 522–534) 5. Type II cytotoxic hypersensitivities, such as incompatible blood transfusions and hemolytic disease of the newborn, result when cells are destroyed by an immune response. utor 1. Immunological responses may give rise to inflammatory reactions called hypersensitivities. An immunological attack on normal tissues gives rise to autoimmune disorders. A failure of the immune system to function normally may give rise to immunodeficiency diseases. 9. In type III hypersensitivity, excessive amounts of small immune complexes, which are complexes of antigen bound to antibodies, are deposited in tissues, where they cause significant tissue damage. 10. Immune complexes deposited in the lung cause a hypersensitivity pneumonitis, of which the most common example is farmer’s lung. If large amounts of immune complexes form in the bloodstream, they may be filtered out by the glomeruli of the 11/23/16 3:37 AM 18   Immune Disorders ­ 13. Type IV hypersensitivity, also known as delayed hypersensitivity reaction (or cell-mediated hypersensitivity reaction, is a T cell– mediated inflammatory reaction that takes 24–72 hours to reach maximal intensity. 14. A good example of a delayed hypersensitivity reaction is the tuberculin response, generated when tuberculin, a protein extract of Mycobacterium tuberculosis, is injected into the skin of an individual who has been infected with or vaccinated against M. tuberculosis. 15. Another example of a type IV hypersensitivity reaction is allergic contact dermatitis, which is T cell–mediated damage to chemically modified skin cells. The best-known example is a reaction to poison ivy. 16. An organ or tissue graft can be made between different sites within a single individual (an autograft), between genetically identical individuals (an isograft), between genetically dissimilar individuals (an allograft), or between individuals of different species (a xenograft). Most surgical organ grafting involves allografts, which, if not treated with immunosuppressive drugs, lead to graft rejection. 17. In graft-versus-host disease, an organ donor’s cells attack the recipient’s body. 18. Commonly used immunosuppressive drugs include glucocorticoids, cytotoxic drugs, cyclosporine, and lymphocyte-depleting therapies, which involve treatment with antibodies against T cells or their receptors. Autoimmune Diseases (pp. 534–536) 1. Autoimmune diseases may result when an individual begins to make autoantibodies or cytotoxic T cells against normal body components. 2. There are at least eight hypotheses concerning the cause of autoimmune disease. One involves molecular mimicry, in which microorganisms with epitopes similar to self-antigens trigger autoimmune tissue damage. Others implicate estrogen, cell transfer from mother to fetus or from fetus to mother during pregnancy, environmental factors such as viral infection, genetic predisposition, movement of T cells into sequestered areas such as testes, or failure of normal immunological control mechanisms. ­ 3. One group of autoimmune diseases involves only a single organ or cell type. Examples of such diseases include autoimmune hemolytic anemia, type 1 diabetes mellitus, Graves’ disease, multiple sclerosis (MS), and rheumatoid arthritis. M18_BAUM7206_05_SE_C18.indd 546 1. Immunodeficiency diseases may be classified as primary immunodeficiency diseases, which result from mutations or developmental anomalies and occur in young children, or acquired (secondary) immunodeficiency diseases, which result from other known causes such as viral infections.  ­ 12. Systemic lupus erythematosus (SLE), or lupus, is a systemic, autoimmune, type III hypersensitivity in which autoantibodies bind to many autoantigens, especially the patient’s DNA. Immunodeficiency Diseases (pp. 536–544) 2. Examples of primary immunodeficiency diseases include chronic granulomatous disease, in which a child’s neutrophils are incapable of killing ingested bacteria. Inability to produce both T cells and B cells is called severe combined immunodeficiency disease. In DiGeorge syndrome, the thymus fails to develop. In Bruton-type agammaglobulinemia, B cells fail to function. ­ 11. Rheumatoid arthritis (RA) is an autoimmune, type III hypersensitivity in which immune complexes result in the growth of inflammatory tissue within joints. 4. A second group of autoimmune diseases, such as systemic lupus erythematosus, involves multiple organs or body systems. ­ kidney causing glomerulonephritis, which can result in kidney failure. ­ ter a       Ch p 3. Acquired immunodeficiency syndrome (AIDS) is a condition defined by the presence of antibodies against human immunodeficiency virus (HIV) in conjunction with certain opportunistic infections, or by HIV and a CD4 + count below 200 cells/ml of blood. A syndrome is a complex of signs and symptoms with a common cause. 4. Human immunodeficiency viruses (HIV-1 or HIV-2) destroy the immune system. HIV is characterized by glycoproteins such as gp120 and gp41, which enable attachment and have significant antigenic variability. The viruses also have a reverse transcriptase enzyme that synthesizes double-stranded DNA from a single-stranded RNA template. The destruction of the immune system results in vulnerability to any infection. 5. HIV converts its genome into double-stranded DNA, which is integrated permanently into the host DNA—a condition called latency. 6. HIV affects helper T cells, macrophages, and dendritic cells. Using gp120, HIV fuses to a cell, uncoats, enters the cell, and transcribes dsDNA to become a provirus. The viral enzyme integrase inserts the provirus into a human chromosome. After HIV is replicated and released, an internal viral enzyme, protease, cleaves a polypeptide, allowing HIV to assemble and become virulent. 7. HIV progressively kills infected cells. The body fights this onslaught but eventually succumbs, allowing opportunistic pathogens to proliferate. 8. Sexual activity and sharing needles are the main ways individuals spread HIV. 9. Antiretroviral therapy (ART) is a combination of antiviral drugs for the treatment of AIDS. 10. No effective vaccine against AIDS exists. Prevention of infection primarily depends on faithful mutual monogamy, proper condom use, use of sterile needles, and screening blood and donated organs for HIV. HIV-positive mothers should not breast-feed their children. 11/23/16 3:37 AM       Questions for Review QUESTIONS FOR REVIEW Answers to the Questions for Review (except Short Answer questions) begin on p. A-1. 9. Infection with HIV causes . a. primary immunodeficiency disease b. acquired hypersensitivity syndrome c. acquired immunodeficiency syndrome d. anaphylactic immunodeficiency diseases e. combined immunodeficiency diseases                    Multiple Choice                    2. The major inflammatory mediator released by degranulating mast cells in type I hypersensitivity is . a. immunoglobulin d. interleukin b. complement e. prostaglandin c. histamine 3. Hemolytic disease of the newborn is caused by antibodies against which major blood group antigen? a. MHC protein d. rhesus antigen b. MN antigen e. type II protein c. ABO antigen                    4. Farmer’s lung is a hypersensitivity pneumonitis resulting from . a. a type I hypersensitivity reaction to grass pollen b. a type II hypersensitivity to red cells in the lung c. a type III hypersensitivity to mold spores d. a type IV hypersensitivity to bacterial antigens e. none of the above 11. Which of the following is not typically part of an ART cocktail for treating AIDS? a. protease inhibitor b. corticosteroids c. reverse transcriptase inhibitor d. nucleotide analog 12. Which of these HIV proteins binds to CD4 on human cells? a. integrase c. gp41 b. protease d. gp120 13. A provirus is . a. a virus inserted into its host’s chromosome b. any effective virus c. a type of syncytium d. active only when housed in its capsid                    Modified True/False                    M18_BAUM7206_05_SE_C18.indd 547  1.                     Cyclosporine is released by degranulating mast cells.  2.                     Type III hypersensitivity reactions may lead to the development of glomerulonephritis. 3.                     ABO blood group antigens are found on nucleated cells.  8. A deficiency of both B cells and T cells is most likely a(n) . a. secondary immunodeficiency b. complex immunodeficiency c. acquired immunodeficiency d. primary immunodeficiency e. induced immunodeficiency Indicate whether each statement is true or false. If the statement is false, change the underlined word or phrase to make the statement true. 4.                     The tuberculin reaction is a type I hypersensitivity. 5.                     Graft-versus-host disease can follow a bone marrow isograft.                     ­ 7. When a surgeon conducts a cardiac bypass operation by transplanting a piece of vein from a patient’s leg to the same patient’s heart, this is a(n) . a. rejected graft b. autograft c. allograft d. type IV hypersensitivity e. cardiograft 15. Protease is an enzyme required by HIV to . a. integrate the viral genome into the host chromosome b. enter human cells c. replicate the viral genome d. cleave a polypeptide so as to release reverse transcriptase                    6. Which of the following is an autoimmune disease? a. a heart attack b. acute anaphylaxis c. farmer’s lung d. graft-versus-host disease e. systemic lupus erythematosus 14. Human immunodeficiency viruses most likely arose from . a. genetically engineered human virus b. reverse transcription c. mutation of protease d. simian immunodeficiency viruses                    ­ 5. A positive tuberculin skin test indicates that a patient not immunized against tuberculosis . a. is free of tuberculosis b. is shedding Mycobacterium c. has been exposed to tuberculosis antigens d. is susceptible to tuberculosis e. is resistant to tuberculosis 10. What do medical personnel administer to counteract various type I hypersensitivities? a. antihistamine d. epinephrine b. bronchodilator e. all of the above c. corticosteroid                                       1. The immunoglobulin class that mediates type I hypersensitivity is . a. IgA d. IgD b. IgM e. IgE c. IgG 11/23/16 3:37 AM 18   Immune Disorders ter a Short Answer Match the immune system complication in the first column with the types of hypersensitivities in the second column. Choices may be used more than once or not at all. 1.           Acute anaphylaxis A. Type I hypersensitivity 2.           Allergic contact dermatitis B. Type II hypersensitivity 3.           Systemic lupus erythematosus C. Type III hypersensitivity 4.           Allograft rejection 5.           AIDS D. Type IV hypersensitivity 6.           Graft-versus-host disease E. Not a hypersensitivity 1. Why is AIDS more accurately termed a syndrome rather than a mere disease? 2. Why is a child born to an Rh + mother not susceptible to Rh-related hemolytic disease of the newborn? ­ Matching ­       Ch p 3. Why is a person who produces a large amount of IgE more likely to experience anaphylactic shock than a person who instead produces a large amount of IgG? 4. Contrast autografts, isografts, allografts, and xenografts. 5. Compare and contrast the functions of four classes of immunosuppressive drugs. 7.           Milk allergy 8.           Farmer’s lung 9.           Asthma 10.           Hay fever VISUALIZE IT! 1. Label the four types of grafts on the figure below. 2. Label the replication cycle of HIV. a. ____________ b. ___________ c. _____________ _____________ a. b. ____________ Genetically identical sibling or clone c. ____________ ___________ d. d. ____________ Genetically different member of same species e. _______________ ________________ g. ______________ f. _____________ h. M18_BAUM7206_05_SE_C18.indd 548 11/23/16 3:37 AM Questions for Review      549 3. Identify the type of hypersensitivity reaction in each photo. a. _____________________________ b. _____________________________ c. _____________________________ d. _____________________________ CRITICAL THINKING 1. What possible advantages might an individual gain from making IgE? 8. Retroviruses such as HIV use RNA as a primer for DNA synthesis. Why is a primer necessary? 2. Why can’t physicians use skin tests similar to the tuberculin reaction to diagnose other bacterial diseases? 9. Recently scientists synthesized a chemical that inhibits fusin. What effect might this chemical have on infection with HIV? 3. In both Graves’ disease and type I diabetes mellitus, autoantibodies are directed against cytoplasmic membrane receptors. Speculate on the clinical consequences of an autoimmune response to estrogen receptors. 4. In general, people with B cell defects acquire numerous bacterial infections, whereas those with T cell defects get viral diseases. Explain why this is so. 5. What types of illnesses cause death in patients with combined immunodeficiencies or AIDS? 6. Because of the severe shortage of organ donors for transplants, many scientists are examining the possibility of using organs from nonhuman species such as pigs. What special clinical problems might be encountered when these xenografts are used? 7. Why do the blisters of positive tuberculin reactions resemble the blisters of poison ivy? M18_BAUM7206_05_SE_C18.indd 549 10. Reverse transcriptase is notoriously sloppy in making DNA copies from RNA templates. How do retroviruses survive when their genomes are subjected to such shoddy replication? 11. A patient arrives at the doctor’s office with a rash covering her legs. How could you determine whether the rash is a type I or a type IV hypersensitivity? 12. A 43-year-old woman has been diagnosed with rheumatoid arthritis. Unable to find relief from her symptoms, she seeks treatment from a doctor in another country, who injects antibodies and complement into her afflicted joints. Do you expect the treatment to improve her condition? Explain your reasoning. 13. Two boys have autoimmune diseases: One has Bruton-type agammaglobulinemia, and the other has DiGeorge syndrome. On a camping trip, each boy is stung by a bee, and each falls into poison ivy. What hypersensitivity reactions might each boy experience as a result of his camping mishaps? 11/23/16 3:37 AM 550     Chapter 18   Immune Disorders CONCEPT MAPPING Using the following terms, fill in the following concept map that describes immediate hypersensitivity. IgE Increased vascular permeability Mast cells Peanuts Pollen Basophils Bee venom Dust mites Epinephrine Hay fever Allergens Allergies Anaphylactic shock Antihistamine Asthma Smooth muscle contraction Type I hypersensitivity Urticaria Vasodilation 1 Immediate hypersensitivity also known as 2 stimulated by exposure to involves 3 may be treated with may be such as 8 10 9 18 19 4 release 5 Localized Systemic such as such as Histamine 6 causes 7 17 14 11 12 13 15 cause 16 Allergy symptoms M18_BAUM7206_05_SE_C18.indd 550 3/6/18 4:52 PM