Immunodeficiency Diseases

In the foregoing diseases, the immune system reacts too vigorously or directs its attack against the wrong targets. In immunodeficiency diseases, by contrast, the immune system fails to respond vigorously enough.

Severe Combined Immunodeficiency Disease (SCID)

Severe combined immunodeficiency disease is a group of disorders caused by recessive alleles that result in a scarcity or absence of both T and B cells. Children with SCID are highly vulnerable to opportunistic infections and must live in protective enclosures. Perhaps the most publicized case was David, who spent his life in sterile plastic chambers (fig. 21.28), finally succumbing at age 12 to cancer triggered by a viral infection. Children with SCID are sometimes helped by transplants of bone marrow or fetal thymus, but in some cases the transplanted cells fail to survive and multiply, or transplanted T cells attack the patient's tissues (the graft-versus-host response). David contracted a fatal virus from his sister through a bone marrow transplant.

Acquired Immunodeficiency Syndrome (AIDS)

Acquired immunodeficiency diseases are nonhereditary diseases contracted after birth. The best-known example is acquired immunodeficiency syndrome (AIDS), a group of conditions that involve a severely depressed immune response resulting from infection with the human immunodeficiency virus (HIV).

The structure of HIV is shown in figure 21.29a. Its inner core consists of a protein capsid enclosing two molecules of RNA, two molecules of an enzyme called reverse transcriptase, and a few other enzyme molecules. The cap-sid is enclosed in another layer of viral protein, the matrix. External to this is a viral envelope composed of phospho-lipids and glycoproteins derived from the host cell. Like other viruses, HIV can only be replicated by a living host cell. It invades helper T (CD4) cells, dendritic cells, and macrophages. HIV adheres to a target cell by means of one of its envelope glycoproteins and "tricks" the target cell into internalizing it by receptor-mediated endocytosis. Within the host cell, reverse transcriptase uses the viral RNA as a template to synthesize DNA—the opposite of the usual process of genetic transcription. Viruses that carry

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David Vetter Blood Scid

Figure 21.28 Severe Combined Immunodeficiency Disease.

David Vetter lived with SCID from ,97, to ,984. At the age of six, he received a portable sterile enclosure designed by NASA that allowed him to leave the hospital for the first time.

Figure 21.28 Severe Combined Immunodeficiency Disease.

David Vetter lived with SCID from ,97, to ,984. At the age of six, he received a portable sterile enclosure designed by NASA that allowed him to leave the hospital for the first time.

out this RNA^DNA reverse transcription are called retroviruses.24 The new DNA is inserted into the host cell's DNA, where it may lie dormant for months to years. When activated, however, it induces the host cell to produce new retr = an acronym from reverse transcription

Helper Cells Invaded Hiv

Figure 21.29 The Human Immunodeficiency Virus (HIV).

(a) Structure of the virus. (b) Viruses emerging from a dying helper T cell Each virus can now invade a new helper T cell and produce a similar number of descendents.

Which of the molecules in figure a is the target of the drug azidothymidine (AZT)? Why does AZT inhibit the spread of HIV?

Figure 21.29 The Human Immunodeficiency Virus (HIV).

(a) Structure of the virus. (b) Viruses emerging from a dying helper T cell Each virus can now invade a new helper T cell and produce a similar number of descendents.

Which of the molecules in figure a is the target of the drug azidothymidine (AZT)? Why does AZT inhibit the spread of HIV?

viral RNA, capsid proteins, and matrix proteins. As the new viruses emerge from the host cell (fig. 21.29b), they are coated with bits of the cell's plasma membrane, forming the new viral envelope. The new viruses then adhere to more host cells and repeat the process.

By destroying TH cells, HIV strikes at a central coordinating agent of nonspecific defense, humoral immunity, and cellular immunity (see fig. 21.21). The incubation period—from the time of infection to the time of the first symptoms—can range from a few months to 12 years. Flulike episodes of chills and fever occur as HIV attacks TH cells. At first, antibodies against HIV are produced and the TH count returns nearly to normal. As the virus destroys more and more cells, however, the signs and symptoms

Saladin: Anatomy & I 21. The Lymphatic and I Text I © The McGraw-Hill

Physiology: The Unity of Immune System Companies, 2003 Form and Function, Third Edition become more pronounced: night sweats, fatigue, headache, extreme weight loss, and lymphadenitis.

Normally, the TH count is 600 to 1,200 cells/^L of blood, but a criterion of AIDS is a TH count less than 200 cells/^L. With such severe depletion of TH cells, a person succumbs to opportunistic infections with Toxoplasma (a protozoan previously known mainly for causing birth defects), Pneumocystis (a group of respiratory fungi), herpes simplex virus, cytomegalovirus (which can cause blindness), or tuberculosis bacteria. White patches may appear in the mouth, caused by Candida (thrush) or Epstein-Barr25 virus (leukoplakia). A form of cancer called Kaposi26 sarcoma, common in AIDS patients, originates in the endothelial cells of the blood vessels and causes bruiselike purple lesions visible in the skin (fig. 21.30).

Patients with full-blown AIDS show no response to standard skin tests for delayed hypersensitivity. Slurred speech, loss of motor and cognitive functions, and dementia may occur as HIV invades the brain by way of infected macrophages and induces them to release toxins that destroy neurons and astrocytes. Death from cancer or infection is inevitable, usually within a few months but sometimes as long as 8 years after diagnosis. Some people, however, have been diagnosed as HIV-positive and yet have survived for 10 years or longer without developing AIDS.

HIV is transmitted through blood, semen, vaginal secretions, and breast milk. It can be transmitted from mother to fetus through the placenta or from mother to infant during childbirth or nursing. HIV occurs in saliva and tears, but is not believed to be transmitted by those fluids. The most common means of transmission are sexual intercourse (vaginal, anal, or oral), contaminated

25M. A. Epstein (1921- ), British physician; Y. M. Barr (1932- ), British virologist 26Moritz Kaposi (1837-1902), Austrian physician

25M. A. Epstein (1921- ), British physician; Y. M. Barr (1932- ), British virologist 26Moritz Kaposi (1837-1902), Austrian physician

Kaposi Sacoma The Arm

Figure 21.30 Kaposi Sarcoma. Typical lesions on the arm and chest of a patient with AIDS.

Figure 21.30 Kaposi Sarcoma. Typical lesions on the arm and chest of a patient with AIDS.

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blood products, and drug injections with contaminated needles. Worldwide, about 75% of HIV infections are acquired through heterosexual, predominantly vaginal intercourse. In the United States, most cases occur in men who have sex with other men, but adolescents are the fastest rising group of AIDS patients because of the increasing exchange of unprotected sexual intercourse for drugs. The sharing of needles for drug use remains the chief means of transmission in urban ghettos. Many hemophiliacs became infected with HIV through blood transfusions before preventive measures were implemented in 1984, but all donated blood is now tested for HIV and the risk of infection is less than 1%. HIV cannot be contracted by donating blood, but irrational fear has resulted in an alarming drop in blood donors.

AIDS is not known to be transmitted through casual contact—for example, to family members, friends, cowork-ers, classmates, or medical personnel in charge of AIDS patients. It is not transmitted by kissing. Despite some speculation and fear, it has not been found to be transmitted by mosquitoes or other blood-sucking arthropods.

HIV survives poorly outside the human body. It is destroyed by laundering, dishwashing, exposure to heat (50°C [135°F] for at least 10 minutes), chlorination of swimming pools and hot tubs, and disinfectants such as bleach, Lysol, hydrogen peroxide, rubbing alcohol, and germicidal skin cleansers (Betadine and Hibiclens, for example). A properly used, undamaged latex condom is an effective barrier to HIV, especially if augmented with the spermicide nonoxynol-9. Animal membrane condoms are not effective at blocking HIV transmission because the viruses are smaller than the gaps in the membrane.

The AIDS epidemic has triggered an effort of unprecedented intensity to find a vaccine or cure. The strategies against HIV include efforts to prevent its binding to the CD4 proteins of TH cells, disrupting the action of reverse transcriptase, or inhibiting the assembly of new viruses or their release from host cells. HIV is a difficult pathogen to attack. Since it "hides" within host cells, it usually escapes recognition by the immune system. In the brain, it is protected by the blood-brain barrier.

About 1% of HIV's genes mutate every year. This rapid rate of mutation is a barrier to both natural immunity and development of a vaccine. Even when immune cells do become sensitized to HIV, the virus soon mutates and produces new surface antigens that escape recognition. The high mutation rate also would quickly make today's vaccine ineffective against tomorrow's strain of the virus. Another obstacle to treatment and prevention is the lack of animal models for vaccine and drug research and development. Most animals are not susceptible to HIV. The chimpanzee is an exception, but chimpanzees are difficult to maintain, and there are economic barriers and ethical controversies surrounding their use.

Until recently, the only anti-HIV drug approved by the Food and Drug Administration (FDA) was azi-

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832 Part Four Regulation and Maintenance dothymidine (AZT, or Retrovir), which inhibits reverse transcriptase and prolongs the lives of some HIV-positive individuals. AZT is now recommended for any patient with a CD4 count below 500 cells/^L, but it has undesirable side effects including bone marrow toxicity and anemia. The FDA has approved other drugs, including dideoxyinosine (ddI) and dideoxycytidine (ddC) for patients who do not respond to AZT, but these drugs can also have severe side effects.

Another class of drugs—protease inhibitors—inhibit enzymes (proteases) that HIV needs in order to replicate. In 1995, a "triple cocktail" of two reverse transcriptase inhibitors and a protease inhibitor was proving to be highly effective at inhibiting viral replication, but by 1997, HIV had evolved a resistance to these drugs and this treatment was failing in more than half of all patients. Alpha interferon has shown some success in inhibiting HIV replication and slowing the progress of Kaposi sarcoma.

There remain not only these vexing clinical problems but also a number of unanswered questions about the basic biology of HIV. It remains unknown, for example, why there are such strikingly different patterns of heterosexual versus homosexual transmission in different countries and why some people succumb so rapidly to infection, while others can be HIV-positive for years without developing

AIDS. AIDS remains a stubborn problem sure to challenge virologists and epidemiologists for many years to come.

We have surveyed the major classes of immune system disorders and a few particularly notorious immune diseases. A few additional lymphatic and immune system disorders are described in table 21.8. The effects of aging on the lymphatic and immune systems are described on page 1111.

Before You Go On

Answer the following questions to test your understanding of the preceding section:

24. How does subacute hypersensitivity differ from acute hypersensitivity? Give an example of each.

25. Aside from the time required for a reaction to appear, how does delayed hypersensitivity differ from the acute and subacute types?

26. State some reasons why antibodies may begin attacking self-antigens that they did not previously respond to. What are these self-reactive antibodies called?

27. What is the distinction between a person who has an HIV infection and a person who has AIDS?

28. How does a reverse transcriptase inhibitor such as AZT slow the progress of AIDS?

Table 21.8 Some Disorders of the Lymphatic and Immune Systems

Contact dermatitis Hives (urticaria27) Hodgkin28 disease Splenomegaly29 Systemic lupus erythematosus

Disorders described elsewhere Acute glomerulonephritis 907 AIDS 829 Allergy 828 Anaphylaxis 828 Asthma 828

A form of delayed hypersensitivity that produces skin lesions limited to the site of contact with an allergen or hapten; includes responses to poison ivy, cosmetics, latex, detergents, industrial chemicals, and some topical medicines.

An allergic skin reaction characterized by a "wheal and flare" reaction: white blisters (wheals) surrounded by reddened areas (flares), usually with itching. Caused by local histamine release in response to allergens. Can be triggered by food or drugs, but sometimes by nonimmunological factors such as cold, friction, or emotional stress.

A lymph node malignancy, with early symptoms including enlarged painful lymph nodes, especially in the neck, and fever of unknown origin; often progresses to neighboring lymph nodes. Radiation and chemotherapy cure about three out of four patients.

Enlargement of the spleen, sometimes without underlying disease but often indicating infections, autoimmune diseases, heart failure, cirrhosis, Hodgkin disease, and other cancers. The enlarged spleen may "hoard" erythrocytes, causing anemia, and may become fragile and subject to rupture.

Formation of autoantibodies against DNA and other nuclear antigens, resulting in accumulation of antigen-antibody complexes in blood vessels and other organs, where they trigger widespread connective tissue inflammation. Named for skin lesions once likened to a wolf bite.30 Causes fever, fatigue, joint pain, weight loss, intolerance of bright light, and a "butterfly rash" across the nose and cheeks. Death may result from renal failure.

Diabetes mellitus 668 Elephantiasis 801 Lymphadenitis 806 Myasthenia gravis 437 Pemphigus vulgaris 179

Rheumatic fever 723 Rheumatoid arthritis 320 SCID 829 Toxic goiter 666

27urtica = nettle

28Thomas Hodgkin (1798-1866), British physician

29megaly = enlargement

30lupus = wolf + erythema = redness

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Insight 21.3 Clinical Application

Neuroimmunology— The Mind-Body Connection

Neuroimmunology is a relatively new branch of medicine concerned with the relationship between mind and body in health and disease. It is attempting especially to understand how a person's state of mind influences health and illness through a three-way communication between the nervous, endocrine, and immune systems.

The sympathetic nervous system issues nerve fibers to the spleen, thymus, lymph nodes, and Peyer patches, where nerve fibers contact thymocytes, B cells, and macrophages. These immune cells have adrenergic receptors for norepinephrine and many other neurotrans-mitters such as neuropeptide Y, substance P, and vasoactive intestinal peptide (VIP). These neurotransmitters have been shown to influence immune cell activity in various ways. Epinephrine, for example, reduces the lymphocyte count and inhibits NK cell activity, thus suppressing immunity. Cortisol, another stress hormone, inhibits T cell and macrophage activity, antibody production, and the secretion of inflammatory chemicals. It also promotes atrophy of the thymus, spleen, and lymph nodes and reduces the number of circulating lymphocytes, macrophages, and eosinophils. Thus, it is not surprising that prolonged stress increases susceptibility to illnesses such as infections and cancer.

The immune system also sends messages to the nervous and endocrine systems. Immune cells synthesize numerous hormones and neurotransmitters that we normally associate with endocrine and nerve cells. B lymphocytes produce adrenocorticotropic hormone (ACTH)

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and enkephalins; T lymphocytes produce growth hormone, thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone. Monocytes secrete prolactin, VIP, and somatostatin. The inter-leukins and tumor-necrosis factor (TNF) produced by immune cells produce feelings of fatigue and lethargy when we are sick, and stimulate the hypothalamus to secrete corticotropin-releasing hormone, thus leading to ACTH and cortisol secretion. It remains uncertain and controversial whether the quantities of some of these substances produced by immune cells are enough to have far-reaching effects on the body, but it seems increasingly possible that immune cells may have wideranging effects on nervous and endocrine functions that affect recovery from illness.

Although neuroimmunology has met with some skepticism among physicians, there is less and less room for doubt about the importance of a person's state of mind to immune function. People under stress, such as medical students during examination periods and people caring for relatives with Alzheimer disease, show more respiratory infections than other people and respond less effectively to hepatitis and flu vaccines. The attitudes, coping abilities, and social support systems of patients significantly influence survival time even in such serious diseases as AIDS and breast cancer. Women with breast cancer die at markedly higher rates if their husbands cope poorly with stress. Attitudes such as optimism, cheer, depression, resignation, or despair in the face of disease significantly affect immune function. Religious beliefs can also influence the prospect of recovery. Indeed, ardent believers in voodoo sometimes die just from the belief that someone has cast a spell on them. The stress of hospitalization can counteract the treatment one gives to a patient, and neuroimmunology has obvious implications for treating patients in ways that minimize their stress and thereby promote recovery.

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