Chapter 43 The Immune System

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Figure 43.28 Human papillomavirus Figure 43.27 The progress of an untreated HIV infection.

1) In the muscular disease myasthenia gravis, antibodies bind to and block certain receptors on muscle cells, preventing muscle contraction. Is this disease best classified as an immunodeficiency disease, an autoimmune disease, or an allergic reaction? Explain. Myasthenia gravis is considered an autoimmune disease because the immune system produces antibodies against self molecules (certain receptors on muscle cells).

Figure 43.7 Major events in a local inflammatory response. 1)At the injury site, mast cells release histamines, which cause nearby capillaries to dilate. Macrophages release other signaling molecules that attract neutrophils.

2)Capillaries widen and become more permeable, allowing neutrophils and fluid containing antimicrobial peptides to enter the tissue. 3)Neutrophils digest pathogens and cell debris at the site of injury, and the tissue heals.

Treatment of antibodies with a particular protease clips the heavy chains in half, releasing the two arms of the Y-shaped molecule. How might the antibodies continue to function? Since the antigen-binding site is intact, the antibody fragments could neutralize viruses and opsonize bacteria.

3) WHAT IF? Suppose that a snake handler bitten by a particular venomous snake species was treated with antivenin. Why might the same treatment for a second such bite have a harmful side effect? If the handler developed immunity to proteins in the antivenin, another injection could provoke a severe immune response.

Figure 43.6 1)Interstitial fluid bathing the tissues, along with the white blood cells in it, continually enters lymphatic vessels. 2)Fluid inside the lymphatic system, called lymph, flows through lymphatic vessels throughout the body.

3) Within lymph nodes, pathogens and foreign particles in the circulating lymph encounter and activate macrophages and other cells that carry out defensive actions. 4) Lymphatic vessels return lymph to the blood via two large ducts that drain into veins near the shoulders.

2)The bacteriophages are combined with serum from a drop of a person's blood. The serum contains antibodies, some of which were produced in response to exposure to viruses. Any antibody that is specific for a viral peptide binds to a bacteriophage displaying that peptide. Bacteriophages displaying peptides from viruses never encountered are not recognized.

3)DNA sequencing of bacteriophages to which antibodies are bound identifies the complete set of viruses to which a person has been exposed.

Like immune cells, infected cells can display antigens on their surface. What then distinguishes an antigen-presenting cell? The answer lies in the existence of two classes of MHC molecules. Most body cells have only the class I MHC molecules, but antigen-presenting cells have class I and class II MHC molecules. Class II molecules provide a molecular signature by which an antigen-presenting cell is recognized.

A helper T cell and the antigen-presenting cell displaying its specific epitope have a complex interaction (Figure 43.16). The antigen receptors on the surface of the helper T cell bind to the antigen fragment and to the class II MHC molecule displaying that fragment on the antigen-presenting cell. At the same time, an accessory protein called CD4 on the helper T cell surface binds to the class II MHC molecule, helping keep the cells joined. As the two cells interact, signals in the form of cytokines are exchanged. For example, the cytokines secreted from a dendritic cell act in combination with the antigen to stimulate the helper T cell, causing it to produce its own set of cytokines. Also, extensive contact between the cell surfaces enables further information exchange.

1)Pus is both a sign of infection and an indicator of immune defenses in action. Explain.

Because pus contains white blood cells, fluid, and cell debris, it indicates an active and at least partially successful inflammatory response against invading pathogens.

Figure 43.20 Activation of complement system and pore formation.

Binding of antibodies to antigens on the surface of a foreign cell activates the complement system. After activation of the complement system, the membrane attack complex forms pores in the cell's membrane, allowing water and ions to rush in. The cell swells and lyses.

Beyond their physical role in inhibiting microbial entry, body secretions create an environment that is hostile to many pathogens. Lysozyme in tears, saliva, and mucous secretions destroys the cell walls of susceptible bacteria as they enter the openings around the eyes or the upper respiratory tract. Pathogens in food or water and those in swallowed mucus must also contend with the acidic environment of the stomach (pH 2), which kills most of them before they can enter the intestines. Similarly, secretions from oil and sweat glands give human skin a pH ranging from 3 to 5, acidic enough to prevent the growth of many bacteria.

Cellular Innate Defenses: In mammals, as in insects, there are innate immune cells dedicated to detecting, devouring, and destroying invading pathogens. In doing so, these cells often rely on a Toll-like receptor (TLR), a mammalian recognition protein similar to the Toll protein of insects. Upon recognizing pathogens, TLR proteins produce signals that initiate responses tuned to the invading microorganism.

For a pathogen—a bacterium, fungus, virus, or other disease-causing agent—the internal environment of an animal offers a ready source of nutrients, a protected setting, and a means of transport to new environments. From the perspective of a cold or flu virus, we are in many ways wonderful hosts. From our vantage point, the situation is not so ideal. Fortunately, adaptations have arisen over the course of evolution that protect animals against many pathogens.

Dedicated immune cells in the body fluids and tissues of most animals specifically interact with and destroy pathogens. In Figure 43.1, for example, an immune cell called a macrophage (brown) is engulfing rod-shaped bacteria (green). Some immune cells are types of white blood cells called lymphocytes (such as the one shown below with bacteria). Most lymphocytes recognize and respond to specific types of pathogens.

Figure 43.9 The structure of a B cell antigen receptor.

Each light chain or heavy chain has a constant (C) region, where amino acid sequences vary little among the receptors on different B cells. The constant region of heavy chains contains a transmembrane region, which anchors the receptor in the cell's plasma membrane. As shown in Figure 43.9, each light or heavy chain also has a variable (V) region, so named because its amino acid sequence varies extensively from one B cell to another. Together, parts of a heavy-chain V region and a light-chain V region form an asymmetric binding site for an antigen. Therefore, each B cell antigen receptor has two identical antigen-binding sites.

Disruptions in immune system function can elicit or exacerbate disease: Although adaptive immunity offers significant protection against a wide range of pathogens, it is not fail-safe. Here we'll first examine the disorders and diseases that arise when adaptive immunity is blocked or misregulated. We'll then turn to some of the evolutionary adaptations of pathogens that diminish the effectiveness of adaptive immune responses in the host.

Exaggerated, Self-Directed, and Diminished Immune Responses: The highly regulated interplay among lymphocytes, other body cells, and foreign substances generates an immune response that provides extraordinary protection against many pathogens. When allergic, autoimmune, or immunodeficiency disorders disrupt this delicate balance, the effects are frequently severe.

B cell antigen receptors and antibodies bind to intact antigens in the blood and lymph. As illustrated in Figure 43.10b for antibodies, they can bind to antigens on the surface of pathogens or free in body fluids.

Figure 43.10 Antigen recognition by B cells and antibodies. (a) B cell antigen receptors and antibodies. An antigen receptor of a B cell binds to an epitope, a particular part of an antigen. Following binding, the B cell gives rise to cells that secrete a soluble form of the antigen receptor. This soluble receptor, called an antibody, is specific for the same epitope as the original B cell. (b) Antigen receptor specificity. Different antibodies can recognize distinct epitopes on the same antigen. Furthermore, antibodies can recognize free antigens as well as antigens on a pathogen's surface.

B cell activation leads to a robust humoral immune response: A single activated B cell gives rise to thousands of identical plasma cells. These plasma cells stop expressing a membrane-bound antigen receptor and begin producing and secreting antibodies (see step 3 in Figure 43.17). Each plasma cell secretes approximately 2,000 antibodies every second during its four- to five-day life span, nearly a trillion antibody molecules in total. Furthermore, most antigens recognized by B cells contain multiple epitopes. An exposure to a single antigen therefore normally activates a variety of B cells, which give rise to different plasma cells producing antibodies directed against different epitopes on the common antigen.

Figure 43.17 Activation of a B cell in the humoral immune response. Most protein antigens require activated helper T cells to trigger a humoral response. A macrophage (shown here) or a dendritic cell can activate a helper T cell, which in turn can activate a B cell to give rise to antibody-secreting plasma cells. 1)After an antigen-presenting cell engulfs and degrades a pathogen, it displays an antigen fragment complexed with a class II MHC molecule. A helper T cell that recognizes the complex is activated with the aid of cytokines secreted from the antigenpresenting cell. 2)When a B cell with receptors for the same epitope internalizes the antigen, it displays an antigen fragment on the cell surface in a complex with a class II MHC molecule. An activated helper T cell bearing receptors specific for the displayed fragment binds to and activates the B cell. 3) The activated B cell proliferates and differentiates into memory B cells and antibody-secreting plasma cells. The secreted antibodies are specific for the same antigen that initiated the response.

B cells can express five types, or classes, of immunoglobulin (IgA, IgD, IgE, IgG, and IgM). For a given B cell, each class has an identical antigen-binding specificity but a distinct heavy-chain C region. The B cell antigen receptor, known as IgD, is exclusively membrane bound. The other four classes have soluble forms, such as the antibodies found in blood, tears, saliva, and breast milk.

Figure 43.21 The killing action of cytotoxic T cells on an infected host cell. An activated cytotoxic T cell releases molecules that make pores in an infected cell's membrane and enzymes that break down proteins, promoting the cell's death. 1) An activated cytotoxic T cell binds to a class I MHC-antigen fragment complex on an infected cell via its antigen receptor and an accessory protein called CD8. 2) The T cell releases perforin molecules, which form pores in the infected cell membrane, and granzymes, enzymes that break down proteins. Granzymes enter the infected cell by endocytosis. 3) The granzymes initiate apoptosis within the infected cell, leading to fragmentation of the nucleus and cytoplasm and eventual cell death. The released cytotoxic T cell can attack other infected cells.

Summary of the Humoral and Cell-Mediated Immune Responses: As noted earlier, both humoral and cell-mediated immunity can include primary and secondary immune responses. Memory cells of each type—helper T cell, B cell, and cytotoxic T cell—enable the secondary response. For example, when body fluids are reinfected by a pathogen encountered previously, memory B cells and memory helper T cells initiate a secondary humoral response. Figure 43.22 summarizes adaptive immunity, reviews the events that initiate humoral and cell-mediated immune responses, highlights the difference in response to pathogens in body fluids versus in body cells, and emphasizes the central role of the helper T cell.

Figure 43.22 An overview of the adaptive immune response. HUMORAL IMMUNE RESPONSE: Defend against extracellular pathogens in blood and lymph by binding to antigens, thereby neutralizing pathogens or making them better targets for phagocytic cells and complement proteins. CELL-MEDIATED IMMUNE RESPONSE: Defend against intracellular pathogens and certain cancers by binding to and lysing the infected cells.

Insects also have specific defenses that protect against infection by viruses. Many viruses that infect insects have a genome consisting of a single strand of RNA. When the virus replicates in the host cell, this RNA strand is the template for synthesis of double-stranded RNA. Because animals do not produce doublestranded RNA, its presence can trigger a specific defense against the invading virus, as illustrated in Figure 43.4.

Figure 43.3 Phagocytosis. This diagram depicts events in the ingestion and destruction of pathogens by a typical phagocytic cell. 1) Pseudopodia surround pathogens. 2) Pathogens are engulfed by endocytosis. 3) Vacuole forms, enclosing pathogens. 4) Vacuole and lysosome fuse 5)Toxic compounds and lysosomal enzymes destroy pathogens. 6) Debris from pathogens is released by exocytosis.

Figure 43.4 Antiviral defence in insects. In defending against an infecting RNA virus, an insect cell turns the viral genome against itself, cutting the viral genome into small fragments that it then uses as guide molecules to find and destroy viral messenger RNAs (mRNAs). Viral infection: During infection, the single-stranded viral RNA genome is replicated. A double strand of viral RNA forms briefly during replication.

Host defence: 1)The host enzyme Dicer-2 recognises the double stranded RNA structure formed during the replicative cycle of an RNA virus. Dicer-2 cuts the viral RNA into fragments, each 21 nucleotides long. 2) A protein complex containing the host enzyme Argo binds to an RNA fragment, displacing one of the two strands. 3) The Argo complex uses the bound single-stranded fragment as a guide, matching it to the complementary sequence in a viral mRNA. Argo then cuts the viral mRNA, inactivating it and thus blocking synthesis of viral proteins.

Concept 43.1: In innate immunity, recognition and response rely on traits common to groups of pathogens

Innate immunity is found in all animals (as well as in plants). In exploring innate immunity, we'll begin with invertebrates, which repel and fight infection with only this type of immunity. We'll then turn to vertebrates, in which innate immunity serves both as an immediate defence against infection and as the foundation for adaptive immune defences.

Antimicrobial Peptides and Proteins: In mammals, pathogen recognition triggers the production and release of a variety of peptides and proteins that attack pathogens or impede their reproduction. As in insects, some of these defense molecules function as antimicrobial peptides, damaging broad groups of pathogens by disrupting membrane integrity. Others, including the interferons and complement proteins, are unique to vertebrate immune systems.

Interferons are proteins that provide innate defense by interfering with viral infections. Virus-infected body cells secrete interferon proteins that induce nearby uninfected cells to produce substances that inhibit viral replication. In this way, these interferons limit the cell-to-cell spread of viruses in the body, helping control viral infections such as colds and influenza. Some white blood cells secrete a different type of interferon that helps activate macrophages, enhancing their phagocytic ability. Pharmaceutical companies now use recombinant DNA technology to mass-produce interferons to help treat certain viral infections, such as hepatitis C

Cellular innate defenses in vertebrates also involve natural killer cells. These cells circulate through the body and detect the abnormal array of surface proteins characteristic of some virus-infected and cancerous cells. Natural killer cells do not engulf stricken cells. Instead, they release chemicals that lead to cell death, inhibiting further spread of the virus or cancer.

Many cellular innate defenses in vertebrates involve the lymphatic system, a network that distributes the fluid called lymph throughout the body (Figure 43.6). Some macrophages reside in lymph nodes, where they engulf pathogens that have entered the lymph from the interstitial fluid. Dendritic cells reside outside the lymphatic system but migrate to the lymph nodes after interacting with pathogens. Within the lymph nodes, dendritic cells interact with other immune cells, stimulating adaptive immunity.

Antigens are usually large foreign molecules, either proteins or polysaccharides. Many antigens protrude from the surface of foreign cells or viruses. Other antigens, such as toxins secreted by bacteria, are released into the extracellular fluid.

The small, accessible portion of an antigen that binds to an antigen receptor is called an epitope. An example is a group of amino acids in a particular protein. A single antigen usually has several epitopes, each binding a receptor with a different specificity. Because all antigen receptors produced by a single B cell or T cell are identical, they bind to the same epitope. Each B or T cell thus displays specificity for a particular epitope, enabling it to respond to any pathogen that produces molecules containing that epitope.

Concept 43.2: In adaptive immunity, receptors provide pathogen-specific recognition Figure 43.8 B and T lymphocytes.

Vertebrates are unique in having both adaptive and innate immunity. The adaptive response relies on T cells and B cells, which are types of white blood cells called lymphocytes (Figure 43.8). Like all blood cells, lymphocytes originate from stem cells in the bone marrow. Some migrate from the bone marrow to the thymus, an organ in the thoracic cavity above the heart (see Figure 43.6). These lymphocytes mature into T cells. Lymphocytes that remain and mature in the bone marrow develop as B cells. (Lymphocytes of a third type remain in the blood and become the natural killer cells active in innate immunity.)

Figure 43.24 A comprehensive test for past viral encounters. By combining the power of DNA sequencing with the specificity of antigen recognition by antibodies, researchers can identify every virus that an immune system has encountered during the person's lifetime.

Viruses that infect humans have unique peptides on their surface (insets). By introducing short DNA sequences from all known human viruses into copies of a bacteriophage genome, researchers generated a collection of 100,000 bacteriophages, each displaying many copies of one viral peptide.

Antigen Recognition by T Cells: For a T cell, the antigen receptor consists of two different polypeptide chains, an a chain and a b chain, linked by a disulfide bridge (Figure 43.11). Near the base of the T cell antigen receptor (often called simply a T cell receptor) is a transmembrane region that anchors the molecule in the cell's plasma membrane. At the outer tip of the molecule, the variable (V) regions of the α and β chains together form a single antigen-binding site. The remainder of the molecule is made up of the constant (C) regions.

Whereas the antigen receptors of B cells bind to epitopes of intact antigens protruding from pathogens or circulating free in body fluids, antigen receptors of T cells bind only to fragments of antigens that are displayed, or presented, on the surface of host cells. The host protein that displays the antigen fragment on the cell surface is called a major histocompatibility complex (MHC) molecule. By displaying antigen fragments, MHC molecules are essential for antigen recognition by T cells.

2) MAKE CONNECTIONS How do the molecules that activate the vertebrate TLR signal transduction pathway differ from the ligands in most other signaling pathways (see Concept 11.2)?

Whereas the ligand for the TLR receptor is a foreign molecule, the ligand for many signal transduction pathways is a molecule produced by the organism itself.

The secondary immune response relies on the reservoir of T and B memory cells generated upon initial exposure to an antigen. Because these cells are long-lived, they provide the basis for immunological memory, which can span many decades. (Most effector cells have much shorter life spans.) If an antigen is encountered again, memory cells specific for that antigen enable the rapid formation of clones of thousands of effector cells also specific for that antigen, thus generating a greatly enhanced immune defense.

Although the processes for antigen recognition, clonal selection, and immunological memory are similar for B cells and T cells, these two classes of lymphocytes fight infection in different ways and in different settings, as we'll explore in Concept 43.3.

To understand how ABO blood groups affect transfusions, let's consider further the example of a person with type A blood receiving a transfusion of type B blood. The person's anti-B antibodies would cause the transfused red blood cells to undergo lysis, triggering chills, fever, shock, and perhaps kidney malfunction. At the same time, anti-A antibodies in the donated type B blood would act against the recipient's red blood cells. Applying the same logic to a type O person, we can see that such interactions would cause a problem upon transfusion of any other blood type. Fortunately, the discovery of enzymes that can cleave the A and B carbohydrates from red blood cells may eliminate this problem in the future.

. If a child were born without a thymus gland, what cells and functions of the immune system would be deficient? Explain. . A child lacking a thymus would have no functional T cells. Without helper T cells to help activate B cells, the child would be unable to produce antibodies against extracellular bacteria. Furthermore, without cytotoxic T cells or helper T cells, the child's immune system would be unable to kill virus-infected cells.

2)Explain two advantages of having memory cells when a pathogen is encountered for a second time.

Generating memory cells ensures both that a receptor specific for a particular epitope will be present and that there will be more lymphocytes with this specificity than in a host that had never encountered the antigen.

2)People with herpes simplex type 1 viruses often get mouth sores when they have a cold or similar infection. How might this location benefit the virus? . A person with a cold is likely to produce oral and nasal secretions that facilitate viral transfer. In addition, since sickness can cause incapacitation or death, a virus that is programmed to exit the host when there is a physiological stress has the opportunity to find a new host at a time when the current host may cease to function.

3) WHAT IF? How would a macrophage deficiency likely affect a person's innate and adaptive defenses? A person with a macrophage deficiency would have frequent infections. The causes would be poor innate responses, due to diminished phagocytosis and inflammation, and poor adaptive responses, due to the lack of macrophages to present antigens to helper T cells.

A minor injury or infection causes a local inflammatory response, but more extensive tissue damage or infection may lead to a response that is systemic (throughout the body). Cells in injured or infected tissue often secrete molecules that stimulate the release of additional neutrophils from the bone marrow. In the case of a severe infection, such as meningitis or appendicitis, the number of white blood cells in the bloodstream may increase several-fold within only a few hours.

A systemic inflammatory response sometimes involves fever. In response to certain pathogens, substances released by activated macrophages cause the body's thermostat to reset to a higher temperature (see Concept 40.3). There is good evidence that fever can be beneficial in fighting certain infections, although the underlying mechanism is still a subject of debate. One hypothesis is that an elevated body temperature may enhance phagocytosis and, by speeding up chemical reactions, accelerate tissue repair.

Antibodies sometimes work together with the proteins of the complement system (Figure 43.20). (The name complement reflects the fact that these proteins add to the effectiveness of antibody-directed attacks on bacteria.) Binding of a complement protein to an antigen-antibody complex on a foreign cell triggers the generation of a membrane attack complex that forms a pore in the membrane of the cell. Ions and water rush into the cell, causing it to swell and lyse. Whether activated as part of innate or adaptive defenses, this cascade of complement protein activity results in the lysis of foreign cells and produces factors that promote inflammation or stimulate phagocytosis.

Although antibodies are the cornerstones of the response in body fluids, there is also a mechanism by which they can bring about the death of infected body cells. When a virus uses a cell's biosynthetic machinery to produce viral proteins, these viral products can appear on the cell surface. If antibodies specific for epitopes on these viral proteins bind to the exposed proteins, the presence of bound antibody at the cell surface can recruit a natural killer cell. The natural killer cell then releases proteins that cause the infected cell to undergo apoptosis. Thus the activities of the innate and adaptive immune systems are once again closely linked.

Such attachment cross-links adjacent IgE molecules, inducing the mast cell to release histamine and other inflammatory chemicals. Acting on a variety of cell types, these chemicals bring about the typical allergy symptoms: sneezing, runny nose, teary eyes, and smooth muscle contractions in the lungs that can inhibit effective breathing. Drugs known as antihistamines block receptors for histamine, diminishing allergy symptoms (and inflammation).

An acute allergic response sometimes leads to a lifethreatening reaction called anaphylactic shock. Inflammatory chemicals released from immune cells trigger constriction of bronchioles and sudden dilation of peripheral blood vessels, which causes a precipitous drop in blood pressure. Death may occur within minutes due to the inability to breathe and lack of blood flow. Substances that can cause anaphylactic shock in allergic individuals include bee venom, penicillin, peanuts, and shellfish. People with severe hypersensitivities often carry an autoinjector containing the hormone epinephrine. An injection of epinephrine rapidly counteracts this allergic response, constricting peripheral blood vessels, reducing swelling in the throat, and relaxing muscles in the lungs to help breathing (see Figure 45.20b).

The antigen receptors of B cells and T cells have similar components, but they encounter antigens in different ways. We'll consider the two processes in turn.

Antigen Recognition by B Cells and Antibodies: Each B cell antigen receptor is a Y-shaped protein consisting of four polypeptide chains: two identical heavy chains and two identical light chains. Disulfide bridges link the chains together (Figure 43.9).

Evolutionary Adaptations of Pathogens That Underlie Immune System Avoidance: Just as immune systems that ward off pathogens have evolved in animals, mechanisms that thwart immune responses have evolved in pathogens. Using human pathogens as examples, we'll examine some common mechanisms: antigenic variation, latency, and direct attack on the immune system.

Antigenic Variation: One mechanism for escaping the body's defenses is for a pathogen to alter how it appears to the immune system. Immunological memory is a record of the foreign epitopes an animal has encountered. If the pathogen that expressed those epitopes no longer does so, it can reinfect or remain in a host without triggering the rapid and robust response that memory cells provide. Such changes in epitope expression are called antigenic variation. The parasite that causes sleeping sickness (trypanosomiasis) provides an extreme example, periodically switching at random among 1,000 versions of the protein found over its entire surface. In the Scientific Skills Exercise, you'll interpret data on this form of antigenic variation and the body's response.

Innate Immunity of Invertebrates: The great success of insects in terrestrial and freshwater habitats teeming with diverse pathogens highlights the effectiveness of invertebrate innate immunity. In any environment, insects rely on their exoskeleton as a physical barrier against infection. Composed largely of the polysaccharide chitin, the exoskeleton provides an effective barrier defense against most pathogens. Chitin also lines the insect intestine, where it blocks infection by many pathogens ingested with food. Lysozyme, an enzyme that breaks down bacterial cell walls, further protects the insect digestive system.

Any pathogen that breaches an insect's barrier defenses encounters internal immune defenses. Insect immune cells produce a set of recognition proteins, each of which binds to a molecule common to a broad class of pathogens. Many of these molecules are components of fungal or bacterial cell walls. Because such molecules are not normally found in animal cells, they function as "identity tags" for pathogen recognition. Once bound to a pathogen molecule, a recognition protein triggers an innate immune response.

The capacity to generate diversity is built into the structure of Ig genes. A receptor light chain is encoded by three gene segments: a variable (V) segment, a joining (J) segment, and a constant (C) segment. The V and J segments together encode the variable region of the receptor chain, while the C segment encodes the constant region. The light-chain gene contains a single C segment, 40 different V segments, and 5 different J segments. The alternative copies of the V and J segments are arrayed along the gene in a series (Figure 43.13). Because a functional gene is built from one copy of each type of segment, the pieces can be combined in 200 different ways (40 V * 5 J * 1 C). The number of different heavy-chain combinations is even greater, resulting in even more diversity.

Assembling a functional Ig gene requires rearranging the DNA. Early in B cell development, an enzyme complex called recombinase links one light-chain V gene segment to one J gene segment. This recombination event eliminates the long stretch of DNA between the segments, forming a single exon that is part V and part J.

Herpes simplex viruses, which establish themselves in human sensory neurons, provide a good example of latency. The type 1 virus causes most oral herpes infections, whereas the type 2 virus is responsible for most cases of genital herpes. Because sensory neurons express relatively few MHC I molecules, the infected cells are inefficient at presenting viral antigens to circulating lymphocytes. Stimuli such as fever, emotional stress, or menstruation reactivate the virus to replicate and infect surrounding epithelial tissues. Activation of the type 1 virus can result in blisters around the mouth that are called "cold" sores. The type 2 virus can cause genital sores, but people infected with either the type 1 or type 2 virus often have no symptoms. Infections of the type 2 virus, which is sexually transmitted, pose a serious threat to the babies of infected mothers and can increase transmission of the virus that causes AIDS.

Attack on the Immune System: HIV The human immunodeficiency virus (HIV), the pathogen that causes AIDS, both escapes and attacks the adaptive immune response. Once introduced into the body, HIV infects helper T cells with high efficiency by binding specifically to the CD4 accessory protein (see Figure 43.17). HIV also infects some cell types that have low levels of CD4, such as macrophages and brain cells. Inside cells, the HIV RNA genome is reverse-transcribed, and the product DNA is integrated into the host cell's genome (see Figure 19.8). In this form, the viral genome can direct the production of new viruses.

Figure 43.12b shows a close-up view of antigen presentation, a process advertising the fact that a host cell contains a foreign substance. If the cell displaying an antigen fragment encounters a T cell with the right specificity, the antigen receptor on the T cell can bind to both the antigen fragment and the MHC molecule. This interaction of an MHC molecule, an antigen fragment, and an antigen receptor triggers an adaptive immune response, as we'll explore in Concept 43.3.

B Cell and T Cell Development: Now that you know how B cells and T cells recognize antigens, let's consider four major characteristics of adaptive immunity. First, the immense repertoire of lymphocytes and receptors enables detection of antigens and pathogens never before encountered. Second, adaptive immunity normally has self-tolerance, the lack of reactivity against an animal's own molecules and cells. Third, cell proliferation triggered by activation greatly increases the number of B and T cells specific for an antigen. Fourth, there is a stronger and more rapid response to an antigen encountered previously, due to a feature known as immunological memory, which we'll explore later in the chapter.

Innate Immunity of Vertebrates: In jawed vertebrates, innate immune defenses coexist with the more recently evolved system of adaptive immunity. Because most discoveries regarding vertebrate innate immunity have come from studies of mice and humans, we'll focus here on mammals. In this section, we'll consider first the innate defenses that are similar to those found among invertebrates: barrier defenses, phagocytosis, and antimicrobial peptides. We'll then examine some unique aspects of vertebrate innate immunity, such as natural killer cells, interferons, and the inflammatory response.

Barrier Defenses: The barrier defenses of mammals, which block the entry of many pathogens, include the mucous membranes and skin. The mucous membranes that line the digestive, respiratory, urinary, and reproductive tracts produce mucus, a viscous fluid that traps pathogens and other particles. In the airway, ciliated epithelial cells sweep mucus and any entrapped material upward, helping prevent infection of the lungs. Saliva, tears, and mucous secretions that bathe various exposed epithelia provide a washing action that also inhibits colonization by fungi and bacteria.

Transmission of HIV requires the transfer of virus particles or infected cells from person to person via body fluids such as semen, blood, or breast milk. Unprotected sex (that is, without using a condom) and transmission via HIV-contaminated needles (typically among intravenous drug users) cause the vast majority of HIV infections. The virus can enter the body through mucosal linings of the vagina, vulva, penis, or rectum during intercourse or via the mouth during oral sex. People infected with HIV can transmit the disease in the first few weeks of infection, before they produce HIV-specific antibodies that can be detected in a blood test. Currently, 10-50% of all new HIV infections appear to be caused by recently infected individuals. Although no cure has been found for HIV infection, drugs that can significantly slow HIV replication and the progression to AIDS have been developed.

Cancer and Immunity: When adaptive immunity is inactivated, the frequency of certain cancers increases dramatically. For example, the risk of developing Kaposi's sarcoma is 20,000 times greater for untreated AIDS patients than for healthy people. This observation was at first puzzling. If the immune system recognizes only nonself, it should fail to recognize the uncontrolled growth of self cells that is the hallmark of cancer. It turns out, however, that viruses are involved in about 15-20% of all human cancers. Because the immune system can recognize viral proteins as foreign, it can act as a defense against viruses that can cause cancer and against cancer cells that harbor viruses. A vaccine introduced in 1986 for hepatitis B virus helps prevent liver cancer, the first cancer for which a human vaccine became available.

In the 1970s, Harald zur Hausen, working in Heidelberg, Germany, proposed that human papillomavirus (HPV) causes cervical cancer. Many scientists were skeptical that cancer could result from infection by HPV, the most common sexually transmitted pathogen. However, after more than a decade of work, zur Hausen isolated two particular types of HPV from patients with cervical cancer. He quickly made samples available to other scientists, leading in 2006 to the development of highly effective vaccines against HPV. The computer graphic image of an HPV particle in Figure 43.28 illustrates the abundant copies of the capsid protein (yellow) that is used as the antigen in vaccination.

Cervical cancer kills more than 4,000 women annually in the United States and is the fifth-most common cause of cancer deaths among women worldwide. Administering an HPV vaccine, either Gardasil or Cervarix, to young adults greatly reduces their chance of being infected with the HPV viruses that cause cervical and oral cancers, as well as genital warts. In 2008, zur Hausen shared the Nobel Prize in Physiology or Medicine for his discovery.

Certain bacterial infections can induce an overwhelming systemic inflammatory response, leading to a life-threatening condition known as septic shock. Characterized by very high fever, low blood pressure, and poor blood flow through capillaries, septic shock occurs most often in the very old and the very young. It is fatal in roughly one-third of cases and contributes to the death of more than 200,000 people each year in the United States alone.

Chronic (ongoing) inflammation can also threaten human health. For example, millions of individuals worldwide suffer from Crohn's disease and ulcerative colitis, often debilitating disorders in which an unregulated inflammatory response disrupts intestinal function

Inflammatory Response: When a splinter lodges under your skin, the surrounding area becomes swollen and warm to the touch. Both changes reflect a local inflammatory response, a set of events triggered by signaling molecules released upon injury or infection (Figure 43.7). Activated macrophages discharge cytokines, signaling molecules that recruit neutrophils to the site of injury or infection. In addition, mast cells, immune cells found in connective tissue, release the signaling molecule histamine at sites of damage. Histamine triggers nearby blood vessels to dilate and become more permeable. The resulting increase in local blood supply produces the redness and increased skin temperature typical of the inflammatory response (from the Latin inflammare, to set on fire).

During inflammation, cycles of signaling and response transform the site of injury and infection. Activated complement proteins promote further release of histamine, attracting more phagocytic cells (see Figure 43.7) that carry out additional phagocytosis. At the same time, enhanced blood flow to the site helps deliver antimicrobial peptides. The result is an accumulation of pus, a fluid rich in white blood cells, dead pathogens, and debris from damaged tissue.

Receptor diversity and self-tolerance arise as a lymphocyte matures. Proliferation of cells and the formation of immunological memory occur later, after a mature lymphocyte encounters and binds to a specific antigen. We'll consider these four characteristics in the order in which they develop.

Figure 43.12 Antigen recognition by T cells. (a) Antigen recognition by a T cell. Inside the host cell, an antigen fragment from a pathogen binds to an MHC molecule and is brought up to the cell surface, where it is displayed. The combination of MHC molecule and antigen fragment is recognized by a T cell. (b) A closer look at antigen presentation. As shown in this ribbon model, the top of the MHC molecule cradles an antigen fragment, like a bun holding a hot dog. An MHC molecule can display many different antigen fragments, but the antigen receptor of a T cell is specific for a single antigen fragment.

Antigen-presenting cells interact with helper T cells in several contexts. Antigen presentation by a dendritic cell or macrophage activates a helper T cell, which proliferates, forming a clone of activated cells. In contrast, B cells present antigens to already activated helper T cells, which in turn activate the B cells themselves. Activated helper T cells also help stimulate cytotoxic T cells, as you'll see shortly.

Figure 43.16 The central role of helper T cells in humoral and cell-mediated immune responses. Here, a helper T cell responds to a dendritic cell displaying an antigen. 1)An antigen-presenting cell engulfs a pathogen, degrades it, and displays antigen fragments complexed with class II MHC molecules on the cell surface. A specific helper T cell binds to this complex via its antigen receptor and an accessory protein called CD4. 2) Binding of the helper T cell promotes secretion of cytokines by the antigen presenting cell. These cytokines, along with cytokines from the helper T cell itself, activate the helper T cell and stimulate its proliferation. 3) Cell proliferation produces a clone of activated helper T cells. All cells in the clone have receptors for the same antigen fragment complex with the same antigen specificity. These cells secrete other cytokines, which help activate B cells and cytotoxic T cells.

When antibodies facilitate phagocytosis, as in opsonization, they also help fine-tune the humoral immune response. Recall that phagocytosis enables macrophages and dendritic cells to present antigens to and stimulate helper T cells, which in turn stimulate the very B cells whose antibodies contribute to phagocytosis. This positive feedback between innate and adaptive immunity contributes to a coordinated, effective response to infection.

Figure 43.18 Neutralization: Antibodies bound to antigens on the surface of a virus neutralize it by blocking its ability to bind to a host cell. Figure 43.19 Opsonization: Binding of antibodies to antigens on the surface of bacteria promotes phagocytosis by macrophages and neutrophils.

In this chapter, we'll examine how each type of immunity protects animals from disease. We'll also investigate how pathogens can avoid or overwhelm the immune system and how defects in the immune system can imperil health.

Figure 43.2 Overview of animal immunity. Innate immunity offers a primary defence in all animals and sets the stage for adaptive immunity in vertebrates. INNATE IMMUNITY: (all animals) Recognition of traits shared by broad ranges of pathogens, using a small set of receptors &Rapid response Barrier defenses: Skin, Mucous membranes, Secretions Internal defenses: Phagocytic cells, Natural killer cells, Antimicrobial proteins, Inflammatory response

Misinformation about vaccine safety and disease risk has led to a growing public health problem. Consider measles as just one example. Side effects of immunization are remarkably rare, with fewer than one in a million children suffering a significant allergic reaction to the measles vaccine. The disease remains quite dangerous to this day, however, killing more than 200,000 people worldwide each year. Declines in vaccination rates in parts of the United Kingdom, Russia, and the United States have resulted in a number of recent measles outbreaks and many preventable deaths. In 2014-2015, a measles outbreak triggered by a visitor to a Disney theme park in Southern California spread to multiple states and affected people ranging in age from 6 weeks to 70 years.

Figure 43.23 Vaccine-based protection against two life-threatening communicable diseases. The graphs show deaths by year in the United States caused by polio and measles. The maps show examples of the global progress against these two diseases.

Allergies: Allergies are exaggerated (hypersensitive) responses to certain antigens called allergens. The most common allergies involve antibodies of the IgE class. Hay fever, for instance, occurs when plasma cells secrete IgE antibodies specific for antigens on the surface of pollen grains (Figure 43.25). Some IgE antibodies attach by their base to mast cells in connective tissues. Pollen grains that enter the body later attach to the antigen-binding sites of these IgE antibodies.

Figure 43.25 Mast cells, IgE, and the allergic response. In this example, pollen grains act as the allergen. 1) IgE antibodies 1 produced in response to initial exposure to an allergen bind to receptors on mast cells. 2) On subsequent exposure to the same allergen, IgE molecules attached to a mast cell recognize and bind the allergen. 3)Cross-linking of adjacent IgE molecules triggers release of histamine and other chemicals, leading to allergy symptoms.

Two other types of cells—dendritic cells and eosinophils— also have roles in innate defense. Dendritic cells mainly populate tissues, such as skin, that contact the environment. They stimulate adaptive immunity against pathogens that they encounter and engulf, as we'll explore shortly. Eosinophils, often found in tissues underlying an epithelium, are important in defending against multicellular invaders, such as parasitic worms. Upon encountering such parasites, eosinophils discharge destructive enzymes.

Figure 43.5: TLR signaling. Each mammalian Toll-like receptor (TLR) recognizes a molecular pattern characteristic of a group of pathogens. Lipopolysaccharide, flagellin, CpG DNA (DNA containing unmethylated CG sequences), and double-stranded (ds) RNA are all found in bacteria, fungi, or viruses but not in animal cells. Together with other recognition and response factors, TLR proteins trigger internal innate immune defenses, including production of cytokines and antimicrobial peptides.

The infection-fighting complement system consists of roughly 30 proteins in blood plasma. These proteins circulate in an inactive state and are activated by substances on the surface of many pathogens. Activation results in a cascade of biochemical reactions that can lead to lysis (bursting) of invading cells. The complement system also functions in the inflammatory response, our next topic, as well as in the adaptive defenses discussed later in the chapter.

Figure 43.6 The human lymphatic system. The lymphatic system consists of lymphatic vessels (shown in green), through which lymph travels, and structures that trap foreign substances. These structures include lymph nodes (orange) and lymphoid organs (yellow): the adenoids, tonsils, thymus, spleen, Peyer's patches, and appendix. Steps 1-4 trace the flow of lymph and illustrate the role of lymph nodes in activating adaptive immunity. (Concept 42.3 describes the relationship between the lymphatic and circulatory systems.)

Adaptive immunity defends against infection of body fluids and body cells: Having considered how clones of lymphocytes arise, we now explore how these cells help fight infections and minimize damage by pathogens. The defenses provided by B and T lymphocytes can be divided into humoral and cell-mediated immune responses. The humoral immune response occurs in the blood and lymph (once called body humors, or fluids). In this response, antibodies help neutralize or eliminate toxins and pathogens in body fluids. In the cell-mediated immune response, specialized T cells destroy infected host cells. Both humoral and cellular immunity can include a primary immune response and a secondary immune response, with memory cells enabling the secondary response.

Helper T Cells: Activating Adaptive Immunity A type of T cell called a helper T cell activates humoral and cell-mediated immune responses. Before this can happen, however, two conditions must be met. First, a foreign molecule must be present that can bind specifically to the antigen receptor of the helper T cell. Second, this antigen must be displayed on the surface of an antigen-presenting cell. An antigen-presenting cell can be a dendritic cell, macrophage, or B cell.

Autoimmune Diseases: In some people, the immune system is active against particular molecules of the body, causing an autoimmune disease. Such a loss of self-tolerance has many forms. In systemic lupus erythematosus, commonly called lupus, the immune system generates antibodies against histones and DNA released by the normal breakdown of body cells. These self-reactive antibodies cause skin rashes, fever, arthritis, and kidney dysfunction. Other targets of autoimmunity include the insulin-producing beta cells of the pancreas (in type 1 diabetes) and the myelin sheaths that encase many neurons (in multiple sclerosis).

Heredity, gender, and environment all influence susceptibility to autoimmune disorders. For example, members of certain families show an increased susceptibility to particular autoimmune disorders. In addition, many autoimmune diseases afflict females more often than males. Women are nine times as likely as men to suffer from lupus and two to three times as likely to develop rheumatoid arthritis, a damaging and painful inflammation of the cartilage and bone in joints (Figure 43.26). The causes of this sex bias, as well as the rise in autoimmune disease frequency in industrialized countries, are areas of active research and debate. An additional focus of current research on autoimmune disorders is the activity of regulatory T cells, nicknamed Tregs. These specialized T cells help modulate immune system activity and prevent response to self-antigens.

Figure 43.2 ADAPTIVE IMMUNITY: (only vertebrates) Recognition of traits specific to particular pathogens, using a vast array of receptors & Slower response

Humoral response: Antibodies defend against infection in body fluids. Cell-mediated response: Cytotoxic cells defend against infection in body cells

3)WHAT IF? If both copies of a light-chain gene and a heavy-chain gene recombined in each (diploid) B cell, how would this affect B cell development and function?

If each B cell produced two different light and heavy chains for its antigen receptor, different combinations would make four different receptors. If any one were self-reactive, the lymphocyte would be eliminated in the generation of self-tolerance. For this reason, many more B cells would be eliminated, and those that could respond to a foreign antigen would be less effective at doing so due to the variety of receptors (and antibodies) they express.

One of the most recently developed antibody tools uses a single drop of blood to identify every virus that a person has encountered through infection or vaccination. To detect the antibodies formed against these viruses, researchers generate a set of nearly 100,000 bacteriophages, each of which displays a different peptide from one of the roughly 200 species of viruses that infect humans. Figure 43.24 provides an overview of how this technique works.

Immune Rejection: Like pathogens, cells from another person can be recognized as foreign and attacked by immune defenses. For example, skin transplanted from one person to a genetically nonidentical person will look healthy for a week or so but will then be destroyed (rejected) by the recipient's immune response. It turns out that MHC molecules are a primary cause of rejection. Why? Each of us expresses MHC proteins from more than a dozen different MHC genes. Furthermore, there are more than 100 different versions, or alleles, of human MHC genes. As a consequence, the sets of MHC proteins on cell surfaces are likely to differ between any two people, except identical twins. Such differences can stimulate an immune response in the recipient of a graft or transplant, causing rejection. To minimize rejection of a transplant or graft, surgeons use donor tissue bearing MHC molecules that match those of the recipient as closely as possible. In addition, the recipient takes medicines that suppress immune responses (but as a result leave the recipient more susceptible to infections).

If a pathogen breaches barrier defenses and enters the body, the problem of how to fend off attack changes substantially. Housed within body fluids and tissues, the invader is no longer an outsider. To fight infections, an animal's immune system must detect foreign particles and cells within the body. In other words, a properly functioning immune system distinguishes nonself from self. How is this accomplished?

Immune cells produce receptor molecules that bind specifically to molecules from foreign cells or viruses and activate defense responses. The specific binding of immune receptors to foreign molecules is a type of molecular recognition and is the central event in identifying nonself molecules, particles, and cells.

Figure 43.26 X-ray of hands that are deformed by rheumatoid arthritis.

Immunodeficiency Diseases: A disorder in which an immune system response to antigens is defective or absent is called an immunodeficiency. Whatever its cause and nature, an immunodeficiency can lead to frequent and recurrent infections and increased susceptibility to certain cancers.

Active and Passive Immunity: The discussion of adaptive immunity has to this point focused on active immunity, the defenses that arise when a pathogen infection or immunization prompts an immune response. A different type of immunity results when the IgG antibodies in the blood of a pregnant female cross the placenta to her fetus. This protection is called passive immunity because the antibodies in the recipient (in this case, the fetus) are produced by another individual (the mother). IgA antibodies present in breast milk provide additional passive immunity to the infant's digestive tract while the infant's immune system develops. Because passive immunity does not involve the recipient's B and T cells, it persists only as long as the transferred antibodies last (a few weeks to a few months).

In artificial passive immunization, antibodies from an immune animal are injected into a nonimmune animal. For example, humans bitten by venomous snakes are sometimes treated with antivenin, serum from sheep or horses that have been immunized against a snake venom. When injected immediately after a snakebite, the antibodies in antivenin can neutralize toxins in the venom before the toxins do massive damage.

Two types of molecular recognition provide the basis for the two types of immune defense found among animals: innate immunity, which is common to all animals, and adaptive immunity, which is found only in vertebrates. Figure 43.2 summarizes these two types of immunity, highlighting fundamental similarities and differences.

In innate immunity, which includes barrier defenses, molecular recognition relies on a small set of receptor proteins that bind to molecules or structures that are absent from animal bodies but common to a group of viruses, bacteria, or other pathogens. Binding of an innate immune receptor to a foreign molecule activates internal defenses, enabling responses to a very broad range of pathogens.

Antibody Function: Antibodies do not directly kill pathogens, but by binding to antigens, they interfere with pathogen activity or mark pathogens in various ways for inactivation or destruction. Consider, for example, neutralization, a process in which antibodies bind to proteins on the surface of a virus (Figure 43.18). The bound antibodies prevent infection of a host cell, thus neutralizing the virus. Similarly, antibodies sometimes bind to toxins released in body fluids, preventing the toxins from entering body cells.

In opsonization, antibodies that are bound to antigens on bacteria do not block infection, but instead present a readily recognized structure for macrophages or neutrophils, thereby promoting phagocytosis (Figure 43.19). Because each antibody has two antigen-binding sites, antibodies can also facilitate phagocytosis by linking bacterial cells, viruses, or other foreign substances into aggregates.

3) WHAT IF? Parasitic wasps inject their eggs into host larvae of other insects. If the host immune system doesn't kill the wasp egg, the egg hatches and the wasp larva devours the host larva as food. Why can some insect species initiate an innate immune response to a wasp egg, but others cannot?

Mounting an immune response would require recognition of some molecular feature of the wasp egg not found in the host. It might be that only some potential hosts have a receptor with the necessary specificity.

Antigenic variation is the main reason the influenza, or "flu," virus remains a major public health problem. As it replicates in one human host after another, the virus undergoes frequent mutations. Because any change that lessens recognition by the immune system provides a selective advantage, the virus steadily accumulates mutations that change its surface proteins, reducing the effectiveness of the host immune response. As a result, a new flu vaccine must be developed, produced, and distributed each year. In addition, the human influenza virus occasionally forms new strains by exchanging genes with influenza viruses that infect domesticated animals, such as pigs or chickens. When this exchange of genes occurs, the new strain may not be recognized by any of the memory cells in the human population. The resulting outbreak can be deadly: The 1918-1919 influenza outbreak killed more than 20 million people.

Latency:Some viruses avoid an immune response by infecting cells and then entering a largely inactive state called latency. In latency, the production of most viral proteins and free viruses ceases; as a result, latent viruses do not trigger an adaptive immune response. Nevertheless, the viral genome persists in the nuclei of infected cells, either as a separate DNA molecule or as a copy integrated into the host genome. Latency typically persists until conditions arise that are favorable for viral transmission or unfavorable for host survival, such as when the host is infected by another pathogen. Such circumstances trigger the synthesis and release of free viruses that can infect new hosts.

An inborn immunodeficiency results from a genetic or developmental defect in the production of immune system cells or of specific proteins, such as antibodies or the proteins of the complement system. Depending on the specific defect, either innate or adaptive defenses—or both—may be impaired. In severe combined immunodeficiency (SCID), functional lymphocytes are rare or absent. Lacking an adaptive immune response, SCID patients are susceptible to infections that can cause death in infancy, such as pneumonia and meningitis. Treatments include bone marrow and stem cell transplantation.

Later in life, exposure to chemicals or biological agents can cause an acquired immunodeficiency. Drugs used to fight autoimmune diseases or prevent transplant rejection suppress the immune system, leading to an immunodeficient state. Certain cancers also suppress the immune system, especially Hodgkin's disease, which damages the lymphatic system. Acquired immunodeficiencies range from temporary states that may arise from physiological stress to the devastating disease AIDS (acquired immune deficiency syndrome), which we'll explore in the next section.

Antibodies as Tools: Antibodies that an animal produces after exposure to an antigen are the products of many different clones of plasma cells, each specific for a different epitope. However, antibodies can also be prepared from a single clone of B cells grown in culture. The monoclonal antibodies produced by such a culture are identical and specific for the same epitope on an antigen.

Monoclonal antibodies have provided the basis for many recent advances in medical diagnosis and treatment. For example, home pregnancy test kits use monoclonal antibodies to detect human chorionic gonadotropin (hCG). Because hCG is produced as soon as an embryo implants in the uterus (see Concept 46.5), the presence of this hormone in a woman's urine is a reliable indicator for a very early stage of pregnancy. Monoclonal antibodies are injected as a therapy for a number of human diseases, including certain cancers.

Exertion, Stress, and the Immune System: Many forms of exertion and stress influence immune system function. For example, moderate exercise improves immune system function and significantly reduces susceptibility to the common cold and other infections of the upper respiratory tract. In contrast, exercise to the point of exhaustion leads to more frequent infections and more severe symptoms. Studies of marathon runners support the conclusion that exercise intensity is the critical variable.

On average, such runners get sick less often than their more sedentary peers during training, a time of moderate exertion, but markedly more often in the period immediately following the grueling race itself. Similarly, psychological stress has been shown to disrupt immune system regulation by altering the interplay of the hormonal, nervous, and immune systems (see Figure 45.20). Research also confirms that rest is important for immunity: Adults who averaged fewer than 7 hours of sleep got sick three times as often when exposed to a cold virus as those who averaged at least 8 hours.

Proliferation of B Cells and T Cells: Despite the enormous variety of antigen receptors, only a tiny fraction are specific for a given epitope. How then does an effective adaptive response develop? To begin with, an antigen is presented to a steady stream of lymphocytes in the lymph nodes (see Figure 43.6) until a match is made. A successful match between an antigen receptor and an epitope initiates events that activate the lymphocyte bearing the receptor.

Once activated, a B cell or T cell undergoes multiple cell divisions. For each activated cell, the result of this proliferation is a clone, a population of cells that are identical to the original cell. Some cells from this clone become effector cells, mostly short-lived cells that take effect immediately against the antigen and any pathogens producing that antigen. For B cells, the effector forms are plasma cells, which secrete antibodies.

Although the body responds to HIV with an immune response sufficient to eliminate most viral infections, some HIV invariably escapes. One reason HIV persists is that it has a very high mutation rate. Altered proteins on the surface of some mutated viruses reduce interaction with antibodies and cytotoxic T cells. Such viruses replicate and mutate further. HIV thus evolves within the body. The continued presence of HIV is also helped by latency while the viral DNA is integrated in the host cell's genome. This latent DNA is shielded from the immune system as well as from antiviral agents currently used against HIV, which attack only actively replicating viruses.

Over time, an untreated HIV infection not only avoids the adaptive immune response but also abolishes it (Figure 43.27). Viral replication and cell death triggered by the virus lead to loss of helper T cells, impairing both humoral and cell-mediated immune responses. The eventual result is acquired immunodeficiency syndrome (AIDS), an impairment in immune responses that leaves the body susceptible to infections and cancers that a healthy immune system would usually defeat. For example, Pneumocystis jirovecii, a common fungus that does not cause disease in healthy individuals, can result in severe pneumonia in people with AIDS. Such opportunistic diseases, as well as nerve damage and body wasting, are the primary causes of death in AIDS patients, rather than HIV itself.

Figure 43.15 The specificity of immunological memory. Long-lived memory cells that are generated in the primary response to antigen A give rise to a heightened secondary response to the same antigen but don't affect the primary response to another antigen (B).

Primary immune response to antigen A produces antibodies to A. Secondary immune response to antigen A produces antibodies to A; primary immune response to antigen B produces antibodies to B.

Immunological Memory: Immunological memory is responsible for the long-term protection that a prior infection provides against many diseases, such as chicken pox. This type of protection was noted almost 2,400 years ago by the Greek historian Thucydides. He observed that individuals who had recovered from the plague could safely care for those who were sick or dying, "for the same man was never attacked twice—never at least fatally."

Prior exposure to an antigen alters the speed, strength, and duration of the immune response. The effector cells formed by clones of lymphocytes after an initial exposure to an antigen produce a primary immune response. The primary response peaks about 10-17 days after the initial exposure. If the same antigen is encountered again later, there is a secondary immune response, a response that is faster (typically peaking only 2-7 days after exposure), of greater magnitude, and more prolonged. These differences between primary and secondary immune responses are readily apparent in a graph of the concentrations of specific antibodies in blood over time (Figure 43.15).

1)1. DRAW IT Sketch a B cell antigen receptor. Label the V and C regions of the light and heavy chains. Label the antigen-binding sites, disulfide bridges, and transmembrane region. Where are these features located relative to the V and C regions?

See Figure 43.9. The transmembrane regions lie within the C regions, which also form the disulfide bridges. In contrast, the antigen-binding sites are in the V regions.

Origin of Self-Tolerance: In adaptive immunity, how does the body distinguish self from nonself? Because antigen receptor genes are randomly rearranged, some immature lymphocytes produce receptors specific for epitopes on the organism's own molecules. If these self-reactive lymphocytes were not eliminated or inactivated, the immune system could not distinguish self from nonself and would attack body proteins, cells, and tissues. Instead, as lymphocytes mature in the bone marrow or thymus, their antigen receptors are tested for self-reactivity.

Some B and T cells with receptors specific for the body's own molecules are destroyed by apoptosis, which is a programmed cell death (see Concept 11.5). The remaining self-reactive lymphocytes are typically rendered nonfunctional, leaving only those that react to foreign molecules. Since the body normally lacks mature lymphocytes that can react against its own components, the immune system is said to exhibit self-tolerance.

Evasion of Innate Immunity by Pathogens: Adaptations have evolved in some pathogens that enable them to avoid destruction by phagocytic cells. For example, the outer capsule that surrounds certain bacteria interferes with molecular recognition and phagocytosis. One such bacterium, Streptococcus pneumoniae, is a major cause of pneumonia and meningitis in humans (see Concept 16.1).

Some bacteria are recognized but resist breakdown after being engulfed by a host cell. One example is Mycobacterium tuberculosis, the bacterium shown in Figure 43.1. Rather than being destroyed, this bacterium grows and reproduces within host cells, effectively hidden from the body's immune defenses. The result of this infection is tuberculosis (TB), a disease that attacks the lungs and other tissues. Worldwide, TB kills more than 1 million people a year.

Binding of a B cell antigen receptor to an antigen is an early step in B cell activation, leading to formation of cells that secrete a soluble form of the receptor (Figure 43.10a). This secreted protein is called an antibody, also known as an immunoglobulin (Ig). Antibodies have the same Y-shaped structure as B cell antigen receptors but lack a membrane anchor. As you'll see later, antibodies provide a direct defense against pathogens in body fluids.

The antigen-binding site of a membrane-bound receptor or antibody has a unique shape that provides a lock-and-key fit for a particular epitope. This stable interaction involves any noncovalent bonds between an epitope and the surface of the binding site. Differences in the amino acid sequences of variable regions provide the variation in binding surfaces that enables binding to be highly specific.

In adaptive immunity, molecular recognition relies on a vast arsenal of receptors, each of which recognizes a feature typically found only on a particular part of a particular molecule in a particular pathogen. As a result, recognition and response in adaptive immunity occur with remarkable specificity.

The adaptive immune response, also known as the acquired immune response, is activated after the innate immune response and develops more slowly. As reflected by the names adaptive and acquired, this immune response is enhanced by previous exposure to the infecting pathogen. Examples of adaptive responses include the synthesis of proteins that inactivate a bacterial toxin and the targeted killing of a virus-infected body cell.

Any substance that elicits a B or T cell response is called an antigen. In adaptive immunity, recognition occurs when a B cell or T cell binds to an antigen, such as a bacterial or viral protein, via a protein called an antigen receptor. Each antigen receptor binds to just one part of one molecule from a particular pathogen, such as a species of bacteria or strain of virus.

The cells of the immune system produce millions of different antigen receptors. A given lymphocyte, however, produces just one variety; all of the antigen receptors made by a single B or T cell are identical. Infection by a virus, bacterium, or other pathogen triggers activation of B and T cells with antigen receptors specific for parts of that pathogen. Although drawings of B and T cells typically include just a few antigen receptors, a single B or T cell actually has about 100,000 antigen receptors on its surface.

Figure 43.11 The structure of a T cell antigen receptor.

The display and recognition of protein antigens begin when a pathogen infects a cell of the animal host or parts of a pathogen are taken in by an immune cell (Figure 43.12a). Inside the animal cell, enzymes cleave each antigen into antigen fragments, which are smaller peptides. Each antigen fragment binds to an MHC molecule, which transports the bound peptide to the cell surface. The result is antigen presentation, the display of the antigen fragment in an exposed groove of the MHC protein.

Together, the body's defenses make up the immune system, which enables an animal to avoid or limit many infections. A foreign molecule or cell doesn't have to be pathogenic to elicit an immune response, but we'll focus in this chapter on the immune system's role in defending against pathogens.

The first lines of defense offered by immune systems help prevent pathogens from gaining entrance to the body. For example, an outer covering, such as a skin or shell, blocks entry by many pathogens. Sealing off the entire body surface is impossible, however, because gas exchange, nutrition, and reproduction require opening to the environment. Secretions that trap or kill pathogens guard the body's entrances and exits, while the linings of the digestive tract, airway, and other exchange surfaces provide additional barriers to infection.

The major immune cells of insects are called hemocytes. Like amoebas, some hemocytes ingest and break down microorganisms, a process known as phagocytosis (Figure 43.3). One class of hemocytes produces a defense molecule that helps entrap large pathogens, such as Plasmodium, the single-celled parasite of mosquitoes that causes malaria in humans. Many other hemocytes release antimicrobial peptides, which circulate throughout the body of the insect and inactivate or kill fungi and bacteria by disrupting their plasma membranes.

The innate immune response of insects is specific for particular classes of pathogens. For example, if a fungus infects an insect, binding of recognition proteins to fungal cell wall molecules activates a transmembrane receptor called Toll. Toll in turn activates production and secretion of antimicrobial peptides that specifically kill fungal cells. Remarkably, phagocytic mammalian cells use receptor proteins very similar to the Toll receptor to recognize viral, fungal, and bacterial components, a discovery that was recognized with the Nobel Prize in Physiology or Medicine in 2011.

Figure 43.13 Immunoglobulin (antibody) gene rearrangement.

The joining of randomly selected V and J gene segments (V39 and J5 in the example shown) results in a functional gene that encodes the light-chain polypeptide of a B cell antigen receptor. Transcription, splicing, and translation result in a light chain that combines with a polypeptide produced from an independently rearranged heavy-chain gene to form a functional receptor. Mature B cells (and T cells) are exceptions to the generalization that all nucleated cells in the body have exactly the same DNA.

B Cells and Antibodies: A Response to Extracellular Pathogens: Secretion of antibodies is the hallmark of the humoral immune response. It begins with activation of the B cells. Activation of B Cells: As illustrated in Figure 43.17, activation of B cells involves both helper T cells and proteins on the surface of pathogens. Stimulated by both an antigen and cytokines, the B cell proliferates and differentiates into memory B cells and antibody secreting plasma cells.

The pathway for antigen processing and display in B cells differs from that in other antigen-presenting cells. A macrophage or dendritic cell can present fragments from a wide variety of protein antigens, whereas a B cell presents only the antigen to which it specifically binds. When an antigen first binds to receptors on the surface of a B cell, the cell takes in a few foreign molecules by receptor-mediated endocytosis (see Figure 7.19). The class II MHC protein of the B cell then presents an antigen fragment to a helper T cell. This direct cell-to-cell contact is usually critical to B cell activation (see step 2 in Figure 43.17).

For T cells, the effector forms are helper T cells and cytotoxic T cells, whose roles we'll explore in Concept 43.3. The remaining cells in the clone become memory cells, long-lived cells that can give rise to effector cells if the same antigen is encountered later in the animal's life.

The proliferation of a B cell or T cell into a clone of cells occurs in response to a specific antigen and to immune cell signals. The process is called clonal selection because an encounter with an antigen selects which lymphocyte will divide to produce a clonal population of thousands of cells specific for a particular epitope. Cells that have antigen receptors specific for other antigens do not respond. Figure 43.14 summarizes the process of clonal selection, using the example of B cells, which generate memory cells and plasma cells. When T cells undergo clonal selection, they generate memory T cells and effector T cells (cytotoxic T cells and helper T cells).

Recombinase acts randomly, linking any one of the 40 V gene segments to any one of the 5 J gene segments. Heavychain genes undergo a similar rearrangement. In any given cell, however, only one allele of a light-chain gene and one allele of a heavy-chain gene are rearranged. Furthermore, the rearrangements are permanent and are passed on to the daughter cells when the lymphocyte divides. After both a light-chain and a heavy-chain gene have been rearranged, antigen receptors can be synthesized.

The rearranged genes are transcribed, and the transcripts are processed for translation. Following translation, the light chain and heavy chain assemble together, forming an antigen receptor (see Figure 43.13). Each pair of randomly rearranged heavy and light chains results in a different antigen-binding site. For the total population of B cells in a human body, the number of such combinations has been calculated as 3.5 * 106 . Furthermore, mutations introduced during VJ recombination add additional variation, making the number of antigen-binding specificities even greater.

Cytotoxic T Cells: A Response to Infected Host Cells In the absence of an immune response, pathogens can reproduce in and kill infected cells (Figure 43.21). In the cell-mediated immune response, cytotoxic T cells use toxic proteins to kill cells infected by viruses or other intracellular pathogens before pathogens fully mature. To become active, cytotoxic T cells require signals from helper T cells and interaction with an antigen-presenting cell. Fragments of foreign proteins produced in infected host cells associate with class I MHC molecules and are displayed on the cell surface, where they can be recognized by cytotoxic T cells. As with helper T cells, cytotoxic T cells have an accessory protein that binds to the MHC molecule. This accessory protein, called CD8, helps keep the two cells in contact while the cytotoxic T cell is activated.

The targeted destruction of an infected host cell by a cytotoxic T cell involves the secretion of proteins that disrupt membrane integrity and trigger cell death (apoptosis; see Figure 43.21). The death of the infected cell not only deprives the pathogen of a place to multiply but also exposes cell contents to circulating antibodies, which mark released antigens for disposal.

Each TLR protein binds to fragments of molecules characteristic of a set of pathogens (Figure 43.5). For example, TLR3, on the inner surface of vesicles formed by endocytosis, binds to double-stranded RNA, a form of nucleic acid produced by certain viruses. Similarly, TLR4, located on immune cell plasma membranes, recognizes lipopolysaccharide, a type of molecule found on the surface of many bacteria, and TLR5 recognizes flagellin, the main protein of bacterial flagella.

The two main types of phagocytic cells in the mammalian body are neutrophils and macrophages. Neutrophils, which circulate in the blood, are attracted by signals from infected tissues and then engulf and destroy the infecting pathogens. Macrophages ("big eaters"), like the one shown in Figure 43.1, are larger phagocytic cells. Some migrate throughout the body, whereas others reside permanently in organs and tissues where they are likely to encounter pathogens. For example, some macrophages are located in the spleen, where pathogens in the blood are often trapped.

Generation of B Cell and T Cell Diversity: Each person makes more than 1 million different B cell antigen receptors and 10 million different T cell antigen receptors. Yet there are only about 20,000 protein-coding genes in the human genome. How, then, do we generate so many different antigen receptors? The answer lies in combinations. Think of selecting a cell phone that comes in three sizes and six colors. There are 18 (3 * 6) combinations to consider. Similarly, by combining variable elements, the immune system assembles millions of different receptors from a very small collection of parts.

To understand the origin of receptor diversity, let's consider an immunoglobulin (Ig) gene that encodes the light chain of both membrane-bound B cell antigen receptors and secreted antibodies (immunoglobulins). Although we'll analyze only a single Ig light-chain gene, all B and T cell antigen receptor genes undergo very similar transformations.

Immunization: The protection provided by a second immune response provides the basis for immunization, the use of antigens artificially introduced into the body to generate an adaptive immune response and memory cell formation. In 1796, Edward Jenner noted that milkmaids who had cowpox, a mild disease usually seen only in cows, did not contract smallpox, a far more dangerous disease. In the first documented immunization (or vaccination, from the Latin vacca, cow), Jenner used the cowpox virus to induce adaptive immunity against the closely related smallpox virus. Today, immunizations are carried out with vaccines—preparations of antigen—obtained from many sources, including inactivated bacterial toxins, killed or weakened pathogens, and even genes encoding microbial proteins. Because all of these agents induce a primary immune response and immunological memory, an encounter with the pathogen from which the vaccine was derived triggers a rapid and strong secondary immune response (see Figure 43.15).

Vaccination programs have been successful against many infectious diseases that once killed or incapacitated large numbers of people. A worldwide vaccination campaign led to eradication of smallpox in the late 1970s. In industrialized nations, routine immunization of infants and children has dramatically reduced the incidence of sometimes devastating diseases, such as polio and measles (Figure 43.23). Unfortunately, not all pathogens are easily managed by vaccination. Furthermore, some vaccines are not readily available in impoverished areas of the globe.

Blood Groups: In the case of blood transfusions, the recipient's immune system can recognize carbohydrates on the surface of blood cells as foreign, triggering an immediate and devastating reaction. To avoid this danger, the so-called ABO blood groups of the donor and recipient must be taken into account. Red blood cells are designated as type A if they have the A carbohydrate on their surface. Similarly, the B carbohydrate is found on the surface of type B red blood cells; both A and B carbohydrates are found on type AB red blood cells; and neither carbohydrate is found on type O red blood cells (see Figure 14.11).

Why does the immune system recognize particular sugars on red blood cells? It turns out that we are frequently exposed to certain bacteria that have epitopes very similar to the carbohydrates on blood cells. A person with type A blood will respond to the bacterial epitope similar to the B carbohydrate and make antibodies that will react with any B carbohydrate encountered upon a transfusion. However, that same person doesn't make antibodies against the bacterial epitope similar to the A carbohydrate because lymphocytes that would be reactive with the body's own cells and molecules were inactivated or eliminated during development.


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