Adaptive Immunity

Adaptive Immunity LE A R N I N G O U TC O M E S 16.1 Describe five distinctive characteristics of adaptive immunity. 16.2 List the two basic types of white blood cells involved in adaptive immunity. 16.3 List two basic divisions of adaptive immunity and describe their targets. ­ Adaptive immunity is a vertebrate’s ability to recognize and then mount a defense against distinct invaders and their products, whether they are protozoa, fungi, bacteria, viruses, or toxins. Only vertebrates have adaptive immunity (see Table 16.1). Immunologists—scientists who study the cells and ­ TABLE 16.1 A Comparison of Innate and Adaptive (Acquired) Branches of Immunity Innate Adaptive Distribution Almost all multicellular eukaryotes Only in vertebrates Targets Limited number of key structures present in many microbes (PAMPs), perhaps 20–50 Antigens, which are mostly proteins; different ones number in the billions Immune Receptors Pattern recognition receptors, such as Toll-like receptors (TLRs) T cell receptors and antibodies Cellular Presence Almost all cells Lymphocytes only Discrimination Host cells do not contain PAMPs Tolerance for self-antigens can break down, resulting in autoimmune disease M16_BAUM7206_05_SE_C16.indd 469 • Specificity. Any particular adaptive immune response acts against only one particular molecular shape, called an antigen, and not against others. Adaptive immune responses are precisely tailored reactions against specific attackers, whereas innate immunity involves more generalized responses to pathogen-associated molecular patterns (PAMPs)—molecular shapes common to many microbes. Thus, adaptive immunity can act against pathogenic Escherichia coli (esh-ĕ-rik’ē-ă kō’lī) strain O157:H7 without harming a beneficial member of the human microbiome such as E. coli strain MG1655. • Inducibility. The specific antigen-containing pathogen activates or induces cells of adaptive immunity. • Clonality. Once induced, cells of adaptive immunity proliferate to form many generations of nearly identical cells, which are collectively called clones. • Unresponsiveness to self. As a rule, adaptive immunity does not act against normal body cells; in other words, adaptive immune responses are self-tolerant. Several mechanisms help ensure that immune responses, when functioning properly, do not attack the body itself. • Memory. An adaptive immune response has immunological memory for specific pathogens; that is, it adapts to respond faster and more effectively in subsequent encounters with a particular type of pathogen or toxin. This memory distinguishes adaptive immunity from innate immunity (see Table 16.1). These aspects of adaptive immunity involve the activities of lymphocytes (lim’fō-sītz), which are a type of leukocyte (white blood cell) that acts against specific pathogens. Lymphocytes in their resting state are the smallest white blood cells, and each is characterized by a large, round, central nucleus surrounded by a thin rim of cytoplasm (FIGURE 16.1). Initially, lymphocytes of humans form in the red bone marrow, located in the ends of long bones in juveniles and in the centers of adult flat bones such as the ribs and hip bones. These sites contain blood stem cells (hematopoietic stem cells), which are cells that give rise to all types of blood cells, including lymphocytes (see Chapter 15, Figure 15.4). This is why a bone marrow transplant can restore a person’s entire adaptive immune system. Although lymphocytes appear identical when viewed with a microscope, scientists make distinctions between two main types—B lymphocytes and T lymphocytes—according to surface proteins that are part of each lymphocyte’s cytoplasmic membrane. These proteins allow lymphocytes to recognize specific pathogens and toxins by their molecular shapes, and the proteins play roles in intercellular communication among immune cells. Lymphocytes must undergo a maturation process. B lymphocytes, which are also called B cells, arise and mature in the red bone marrow of adults. T lymphocytes, also known Overview of Adaptive Immunity chemicals involved in immunity—are continually refining and revising our knowledge of adaptive immunity. In this chapter, we will examine some of what they have discovered. Adaptive immunity has five distinctive attributes: ­ ­ Innate, or native, immunity includes two lines of rapid defense against microbial pathogens (see Chapter 15). The first line includes intact skin and mucous membranes, and the second line includes phagocytosis, nonspecific chemical defenses (such as complement), inflammation, and fever. Innate defenses do not always offer enough protection in defending the body. Although the mechanisms of innate immunity are readily available and fast acting, they respond in the same ways to the great variety of pathogens confronting the body—they do not adapt to make their response more effective against specific pathogens. For example, a fever triggered by a flu virus is similar to a fever triggered by Ebola virus. Vertebrates have a third line of defense that augments the mechanisms of innate immunity by destroying and targeting specific invaders while adapting to be more effective in the process. This response is called adaptive immunity or acquired immunity. TABLE 16.1 compares innate and adaptive immunity. 11/23/16 3:34 AM e 16   Adaptive Immunity r hapt       C Lymphocyte Red blood cell and fatally attack the body’s own cells. Therefore, the body regulates adaptive immune responses to prevent damage; for example, an immune response requires multiple chemical signals before proceeding, thus reducing the possibility that an immune response will be randomly triggered against uninfected healthy tissue. Autoimmune disorders, hypersensitivities, or immunodeficiency diseases result when regulation is insufficient or overexcited. (Chapter 18 deals with such disorders.) TELL ME WHY Why are the activities of B and T cells called adaptive? Elements of Adaptive Immunity than a red blood cell. ­ as T cells, begin in bone marrow as well but do not mature there. Instead, T cells travel to and mature in the thymus, located in the chest near the heart in humans. T lymphocytes are so called because of the role the thymus plays in their maturation. Adaptive immunity consists of many different immune responses that can be considered under two broad categories: cell-mediated immune responses and antibody immune responses. Long-lived B and T lymphocytes in each of these categories retain the ability to fight specific pathogens as long as they live—the characteristic called immunological memory. Both cell-mediated and antibody immune responses stimulate and regulate innate immunity as well as act directly against the specific pathogen that initiated the adaptive response. Cell-mediated immune responses are controlled and carried out by T cells and often act against intracellular pathogens, such as viruses replicating inside a cell. B cells carry out antibody immune responses, though T cells also play roles in regulating and fulfilling antibody immune responses. Antibody immune responses are often directed against extracellular pathogens and toxins. An antibody is a protective protein secreted by descendants of a B cell that recognizes and strongly binds to the specific biochemical shape of the antigen. We will consider antibodies in more detail later. Scientists have also used another term for antibody immune responses—humoral immune responses1—because many antibody molecules circulate in the liquid portion of the blood. ▶ ANIMATIONS: Host Defenses: The Big Picture; Cell-Mediated Immunity: Overview; Humoral Immunity: Overview Both cell-mediated and antibody immune responses are powerful defensive reactions that have the potential to severely 1From Latin humor, meaning “liquid,” referring to bodily fluids, such as blood. M16_BAUM7206_05_SE_C16.indd 470 The Tissues and Organs of the Lymphatic System LE A R N I N G O UTC O M E S 16.4 Compare and contrast the flow of lymph with the flow of blood. 16.5 Describe the primary and secondary organs of the lymphatic system. ­ immunity. An inactive lymphocyte is the smallest leukocyte—slightly larger When you attend a theatrical performance, you are given a program that presents a synopsis of the play and introduces the actors and their roles. In that vein, the following sections present elements of adaptive immunity by describing the “stage” and introducing the “cast of characters” involved. We will examine the lymphatic system—the organs, tissues, and cells of adaptive immunity; then we consider the molecules, called antigens, that trigger adaptive immune responses; next, we take a look at antibodies; and finally, we examine special chemical sig­ nals and mediators involved in coordinating and controlling a specific immune response. First, we turn our attention to the “stage”—the lymphatic system, which plays an important role in the production, maturation, and housing of the cells that function in adaptive immunity. 16.6 Describe the importance to immunity of red bone marrow, the thymus, lymph nodes, spleen, tonsils, and mucosa-associated lymphoid tissue. ­ ▲ FIGURE 16.1 Lymphocytes play a central role in adaptive ­ 10 µm ­ LM The lymphatic system is composed of the lymphatic vessels, which conduct the flow of a liquid called lymph (pronounced “limf”); and lymphoid cells, tissues, and organs, which are directly involved in adaptive immunity (FIGURE 16.2a). Taken together, the components of the lymphatic system constitute a surveillance system that screens the tissues of the body—particularly possible places of entry such as the throat and intestinal tract—for foreign molecules. We begin by examining lymphatic vessels. 11/23/16 3:34 AM       E lements of Adaptive Immunity Blood capillary Tonsils From heart Tissue cell Cervical lymph node Intercellular fluid Lymphatic ducts Thymus Lymph to heart via lymphatic vessels Axillary lymph node Heart Gap in wall Breast lymphatics Spleen Valve Abdominal lymph node To heart Lymphatic capillary (b) Intestines Peyer’s patches in intestinal wall Appendix Mucosa-associated lymphoid tissue (MALT) (in part) Red bone marrow Afferent lymphatic vessel Inguinal lymph node Medulla Lymphatic vessel Cortex Vein Artery Valve (prevents backflow) Lymphatic nodule Primary follicle (a) Efferent lymphatic vessel; lymph flows toward heart Capsule (c) ­ ▲ FIGURE 16.2 The lymphatic system. (a) The system consists of primary lymphoid organs—bone marrow (not shown) and thymus—and secondary lymphoid organs, including lymphatic vessels, lymph nodes, tonsils, and other lymphoid tissue. (b) Lymphatic capillaries collect lymph from intercellular spaces. (c) Afferent lymphatic vessels carry lymph into lymph nodes; efferent vessels carry it away. The cortex contains primary follicles, where B lymphocytes proliferate; the lymphocytes in the medulla encounter foreign molecules. Why do lymph nodes enlarge during an infection? Figure 16.2 During an infection, lymphocytes multiply profusely in lymph nodes. This proliferation and swelling cause lymph nodes to enlarge. M16_BAUM7206_05_SE_C16.indd 471 11/23/16 3:34 AM e 16   Adaptive Immunity r hapt       C The Lymphatic Vessels and the Flow of Lymph Lymphatic vessels form a one-way system that conducts lymph from local tissues and returns it to the circulatory system. Most importantly for immune responses, lymph carries toxins and pathogens to areas where lymphocytes are concentrated. Lymph is a colorless, watery liquid similar in composition to blood plasma; indeed, lymph arises from fluid that has leaked out of blood vessels into the surrounding intercellular spaces. Lymph is first collected by remarkably permeable lym­ phatic capillaries (FIGURE 16.2b), which are located in most parts of the body (exceptions include the bone marrow, brain, and spinal cord). From the lymphatic capillaries, lymph passes into increasingly larger lymphatic vessels until it finally flows via two large lymphatic ducts into blood vessels near the heart. Unlike the cardiovascular system, the lymphatic system has no unique pump and is not circular; that is, lymph flows in only one direction—toward the heart. One-way valves ensure the direction of lymphatic flow as contractions of skeletal muscles squeeze the lymphatic vessels. Located at various points within the system of lymphatic vessels are hundreds of lymph nodes, which house numerous white blood cells, including B and T lymphocytes. These lymphocytes recognize and attack foreigners present in the lymph, allowing for immune system surveillance and interactions. Lymphoid Organs Once lymphocytes have arisen and matured in the primary lym­ phoid organs of the red bone marrow and thymus, they migrate to secondary lymphoid organs and tissues, including lymph nodes, spleen, and other less organized accumulations of lymphoid tissue, where they in effect lie in wait for foreign microbes. Lymph nodes are located throughout the body but are concentrated in the cervical (neck), inguinal (groin), axillary (armpit), and abdominal regions. Each lymph node receives lymph from numerous afferent (inbound) lymphatic vessels. Just one or two efferent (outbound) lymphatic vessels drain each lymph node (FIGURE 16.2c). Essentially, lymph nodes are sites to facilitate interactions among immune cells and between immune cells and material arriving at lymph nodes from throughout the body. A node has a medulla, or central region, consisting of a maze of passages that filter the lymph as it passes through. The medulla also houses numerous lymphocytes that survey the lymph for foreign molecules and mount specific immune responses against them. The cortex, or outer portion, of a lymph node consists of a tough capsule surrounding primary follicles, which is where clones of B cells replicate. The lymphatic system contains additional secondary lymphoid tissues and organs, including the spleen, the tonsils, and mucosa­associated lymphoid tissue (MALT). The spleen is similar in structure and function to lymph nodes, except that it filters blood instead of lymph. The spleen removes bacteria, viruses, toxins, and other foreign matter from the blood. It also cleanses the blood of old and damaged blood cells, stores blood platelets (which are required for the proper clotting of blood), and stores blood components, such as iron. M16_BAUM7206_05_SE_C16.indd 472 Tonsils are two mounds of tissue, one on each side of the tongue, similar to lymph nodes without afferent or efferent vessels. They sample microbes that enter the mouth or nose. MALT includes lymphoid tissue associated with the mucous membranes of the appendix; lymphoid tissue of the respiratory tract, vagina, urinary bladder, and mammary glands; and discrete bits of lymphoid tissue called Peyer’s patches in the wall of the small intestine. MALT contains most of the body’s lymphocytes. The tonsils and MALT lack the tough outer capsules of lymph nodes and the spleen, but they function in the same way by physically trapping foreign particles and microbes. We are considering adaptive immunity in terms of a “play” taking place on the stage of the lymphatic system. Now, let’s meet the “villains”—the foreign molecules that lymphocytes recognize. Antigens LE A R N I N G O UTC O M E S 16.7 Identify the characteristics of antigens that stimulate effective immune responses. 16.8 Distinguish among exogenous antigens, endogenous antigens, and autoantigens. Adaptive immune responses are directed not against whole bacteria, fungi, protozoa, or viruses but instead against portions of cells, viruses, and even parts of single molecules that the body recognizes as foreign and worthy of attack. Immunologists call these biochemical shapes antigens2 (an’ti-jenz). Lymphocytes bind to antigens and can then trigger adaptive immune responses. Antigens from pathogens and toxins are the “villains” of our story. Properties of Antigens Not every molecule is an effective antigen. Among the properties that make certain molecules more effective at provoking adaptive immunity are a molecule’s shape, size, and complexity. The body recognizes antigens by the three-dimensional shapes of regions called epitopes, which are also known as antigenic determinants because they are the actual part of an antigen that determines an immune response (FIGURE 16.3a). In general, larger molecules with molecular masses (sometimes misidentified as molecular weights) between 5000 and 100,000 daltons 3 are better antigens than smaller ones. The most effective antigens are large foreign macromolecules, such as proteins and glycoproteins, but carbohydrates and lipids can also be antigenic. Small molecules, especially those with a molecular mass under 5000 daltons, make poor antigens by themselves because they evade detection; however, they can antibody generator; antibodies are proteins secreted during an antibody immune response that bind to specific regions of antigens. 3Named for John Dalton, the British chemist who helped develop atomic theory around 1800. 2From 11/23/16 3:34 AM       E lements of Adaptive Immunity Epitopes Antigens Pathogen Antigen Epitope (a) Epitopes (antigenic determinants) Endogenous antigens Extracellular microbes Autoantigens (normal cell antigens) Intracellular virus Virally infected cell Exogenous antigens (b) Exogenous antigens Normal (uninfected) cell (d) Autoantigens (c) Endogenous antigens E E ▲ FIGURE 16.3 Antigens, molecules that provoke a specific immune response. (a) ach pathogen has hundreds to thousands of antigens. ach antigen E E contains one to dozens of epitopes (antigenic determinants). pitopes are three-dimensional regions of antigens whose shapes are recognized by immune receptors. (b–d) Categories of antigens are based on their relationship to the host cells. xogenous antigens originate from microbes located outside the body’s cells; endogenous antigens are produced by intracellular microbes and are typically incorporated into a host cell’s cytoplasmic membrane; autoantigens are components of normal body cells. become antigenic when bound to larger carrier molecules (often proteins). For example, the fungal product penicillin is too small by itself (molecular mass: 302 daltons) to trigger a specific immune response. However, bound to a carrier protein in the blood, penicillin can become antigenic and trigger an allergic response in some patients. Complex molecules make better antigens than simple ones because they have more epitopes, like a gemstone with its many facets. For example, starch, which is a very large polymer of repeating glucose subunits, is not a good antigen, despite its large size, because it lacks structural complexity. In contrast, complicated molecules, such as glycoproteins and phospholipids, have multiple distinctive shapes and novel combinations of subunits that cells of the immune system recognize as foreign. Examples of antigens include components of bacterial cell walls, capsules, pili, and flagella as well as the external and internal proteins of viruses, fungi, and protozoa. Many toxins and some nucleic acid molecules are also antigenic. Invading microorganisms are not the only source of antigens; for example, food may contain antigens called allergens that provoke allergic reactions, and inhaled dust contains mite feces, pollen grains, dander (flakes of skin), and other antigenic and allergenic particles. (Chapter 18 covers allergies in more detail.) M16_BAUM7206_05_SE_C16.indd 473 Types of Antigens Though immunologists categorize antigens in various ways, one especially important way is to group antigens according to their relationship to the body: • Exogenous4 antigens (FIGURE 16.3b). Exogenous (eks-oj’en-us) antigens come from outside the body’s cells and include toxins and other secretions and components of microbial cell walls, membranes, flagella, and pili. • Endogenous5 antigens (FIGURE 16.3c). Protozoa, fungi, bacteria, and viruses that reproduce inside a body’s cells produce endogenous antigens. The immune system cannot assess the internal health of the body’s cells; it responds to endogenous antigens only if the body’s cells incorporate such antigens into their cytoplasmic membranes, leading to their external display. • Autoantigens6 (FIGURE 16.3d). Antigenic molecules derived from normal cellular processes are autoantigens (or self­antigens). As we will discuss more fully in a later section, immune cells that treat autoantigens as if they Greek exo, meaning “without,” and genein, meaning “to produce.” Greek endon, meaning “within.” 6From Greek autos, meaning “self.” 4From 5From 11/23/16 3:34 AM were foreign are normally eliminated during the development of the immune system. This phenomenon, called self­tolerance, prevents the body from mounting an immune response against itself. Antigen-binding sites (grooves) MHC-I So far, we have examined two aspects of immune responses in terms of an analogy to a stage play—the lymphoid organs and tissues provide the stage, and antigens of pathogens are the villains that induce an immune response with their epitopes (antigenic determinants). Now, we will examine more important players in the drama—membrane proteins called major his­ tocompatibility complex (MHC) proteins. The body prepares for an adaptive immune response by making MHC proteins and processing antigens. Cells of adaptive immunity only recognize epitopes carried on MHC proteins. (b) Class II MHC on antigen-presenting cells (APCs) (in addition to MHC-I) Cytoplasm ▲ FIGURE 16.4 The two classes of major histocompatibility complex (MHC) proteins. ach is composed of two polypeptides H that form an antigen-binding groove. (a) M C class I glycoproteins are found on all cells except red blood cells. (b) In addition to M C-I, M C class II glycoproteins are expressed only by B cells and special antigen-presenting cells ( Cs). AP H LE A R N I N G O U TC O M E S (a) Class I MHC on every nucleated cell E Preparation for an Adaptive Immune Response Cytoplasmic membrane H       Chapter 16   Adaptive Immunity 16.9 Describe the two classes of major histocompatibility ­ M16_BAUM7206_05_SE_C16.indd 474 ­ ­ ­ When scientists first tried grafting skin tissue from one animal onto another to treat burn victims, they discovered that if the animals were not closely related, the recipients swiftly rejected the grafts. When they analyzed the reason for such rapid rejection, they found that a graft recipient mounted a very strong immune response against a specific protein found on the cells of unrelated grafts, resulting in rapid rejection. This helped scientists understand how the body is able to distinguish “self” from “nonself.” Immunologists named the cluster of genes that code for these proteins the major histocompatibility complex (MHC). (The prefix histo­ means “tissue,” so the name indicates the importance in determining tissue compatibility during transplantation.) In humans, an MHC is located on each copy of chromosome 6. The protein product of MHC genes is MHC protein, though scientists often use MHC to refer to both the genes and the protein products of the genes. This might be confusing at first, but context should make it clear whether MHC refers to the genes or their products. Because organ grafting is a modern surgical procedure with no counterpart in nature, scientists reasoned that MHC must have some natural function. Indeed, immunologists have determined that MHC proteins in cytoplasmic membranes function ­ The Roles of the Major Histocompatibility Complex and Antigen-Presenting Cells to hold and position epitopes for presentation to immune cells. Each MHC molecule has an antigen­binding groove that lies between two polypeptides that make up an MHC. Inherited variations in the amino acid sequences of the polypeptides modify the shapes of MHC binding sites and determine which epitopes can be bound and presented. Cells of adaptive immunity recognize epitopes that are bound to MHC molecules. There are two classes of MHC proteins (FIGURE 16.4). Class I MHC molecules are found on the cytoplasmic membranes of all human cells except red blood cells. Special cells called antigen-presenting cells (APCs) also have class II MHC proteins. Professional antigen-presenting cells regularly present antigens. They include macrophages, B cells, and most importantly, dendritic cells. Dendritic cells are so named because they have many long, thin cytoplasmic processes called dendrites7 (FIGURE 16.5). Phagocytic dendritic cells are found under the surface of the skin and mucous membranes. Some dendritic cells extend dendrites between skin cells or through a mucous surface to sample antigens, much like a submarine extends a periscope to get a view of surface activity. After acquiring antigens, dendritic cells migrate to lymph nodes to interact with cells of adaptive immunity. Certain other phagocytes, such as microglia in the brain and stellate macrophages (formerly called Kupffer cells) in the liver, may also present antigens under certain conditions. These cells are termed nonprofessional antigen­presenting cells. The cytoplasmic membrane of a professional APC has about 100,000 MHC II molecules. Both MHC I and MHC II are broad in their binding, so they can bind thousands of different epitopes (unlike enzymes, they are not specific). ­ ­  ­ complex (MHC) proteins with regard to their location and function. 16.10 Explain the roles of antigen-presenting cells (e.g., dendritic cells and macrophages) and MHC molecules in antigen processing and presentation. 16.11 Contrast endogenous antigen processing with exogenous antigen processing. Greek dendron, meaning “tree,” referring to long cellular extensions that look like branches of a tree. 7From 06/03/2018 07:49       E lements of Adaptive Immunity Dendrites Polypeptide Cytoplasm 1 Polypeptide is processed. MHC I protein in membrane of endoplasmic reticulum LM Epitopes Lumen of endoplasmic reticulum 10 µm 2 Epitopes are loaded onto complementary MHC I proteins in the ER. ▲ FIGURE 16.5 Dendritic cells. These important antigen-presenting cells in the body are found in the skin and mucous membranes. When active, they migrate to lymph nodes. They have numerous thin cytoplasmic processes called dendrites. Their binding diversity is dependent on an individual’s genes. Some epitopes won’t be bound to the MHC of a particular person, and such epitopes typically don’t trigger an immune response. Thus, MHC molecules determine which epitopes might trigger immune responses. This explains why some people are allergic to peanuts and others are not. MHC I protein– epitope complex Antigen Processing 3 Golgi bodies package MHC I protein–epitope complexes into vesicles. Before MHC proteins can display epitopes, antigens must be processed to isolate epitopes. Antigen processing occurs via somewhat different processes according to whether an antigen is endogenous or exogenous. Recall that endogenous antigens come from a cell’s cytoplasm or from pathogens living within the cell, whereas exogenous antigens have extracellular sources, such as from pathogens in the lymph. ▶ANIMATION: 4 Vesicles fuse with cytoplasmic membrane. Antigen Processing and Presentation: Overview MHC I protein– epitope complexes on cell surface Cytoplasmic membrane 5 MHC I protein–epitope complexes are displayed on cytoplasmic membranes of all nucleated cells. ­ M16_BAUM7206_05_SE_C16.indd 475 ▲ FIGURE 16.6 The processing of endogenous tor i V de Tu o E antigens. pitopes from all polypeptides synthesized within a nucleated cell load onto complementary MHC I proteins in the endoplasmic reticulum ( R), which are exported to the cytoplasmic membrane. E Processing Endogenous Antigens FIGURE 16.6 illustrates the processing of endogenous antigens. A few molecules of each polypeptide produced within nucleated cells—including polypeptides produced by intracellular bacteria or polypeptides coded by viruses—are cut by proteases into smaller pieces containing about 8 to 12 amino acids 1 . These pieces, which will include epitopes of the polypeptides, move into the endoplasmic reticulum (ER) and bind onto complementary antigenbinding grooves of MHC class I molecules that were previously inserted into the membrane of the ER 2 . The ER membrane, now loaded with MHC class I proteins and epitopes, is packaged by a Golgi body to form vesicles 3 . Each vesicle fuses with the cytoplasmic membrane in such a way that the vesicle’s 11/23/16 7:29 PM       Chapter 16   Adaptive Immunity membrane becomes part of the cytoplasmic membrane 4 . The result is that the cell displays the MHC I protein-epitope complex on the cell’s surface 5 . Since every nucleated cell in the body makes MHC class I, each cell displays epitopes from every endogenous antigen and every autoantigen inside that cell. This allows immune cells to detect all the antigens inside cells. Phagocytosis by APC Exogenous pathogen with antigens Processing Exogenous Antigens In contrast, only antigenpresenting cells (APCs)—usually dendritic cells—process exogenous antigens. Processing these antigens from outside the body’s cells differs from the processing done for antigens produced within cells (FIGURE 16.7). First, a dendritic cell phagocytizes an invading pathogen 1 . A lysosome, which contains MHC class II molecules in its membrane, fuses with the phagosome. MHC II molecules bind complementary epitopes 2 . The vesicle then fuses with the cytoplasmic membrane 3 , leaving MHC II–epitope complexes on the cell’s surface 4 . Empty MHC II molecules (those not bound to epitopes) are not stable on a cell’s surface; they degrade. ▶ ANIMATIONS: Antigen Processing and Presentation: 1 MHC II protein in membrane of vesicle Steps, MHC Having considered the “villains” and set the stage, it’s time to introduce the “stars,” or the “heroes,” of the play—the T and B lymphocytes. First, we consider various T lymphocytes that function in cell-mediated immune responses. Epitopes in phagolysosome MHC II protein– epitope complex T Lymphocytes (T Cells) LE A R N I N G O U TC O M E S 16.12 Describe the importance of the thymus in the develop- ment of T lymphocytes. 16.13 Describe basic structural characteristics common to T lymphocytes. 2 Vesicles fuse and epitopes bind to complementary MHC II molecules. 16.14 Compare and contrast three types of T cells. 16.15 Describe apoptosis, and explain its role in lymphocyte editing by clonal deletion. M16_BAUM7206_05_SE_C16.indd 476 3 Vesicle fuses with cytoplasmic membrane. MHC II protein– epitope complexes on cell surface Cytoplasmic membrane 4 MHC II protein–epitope complexes are displayed on cytoplasmic membranes of antigen-presenting cell. A ▲ FIGURE 16.7 The processing of exogenous antigens. nti- H AP T AP gens arising outside the body’s cells are phagocytized by an C and digested to release epitopes, which are loaded into complementary antigen-binding grooves of M C II molecules. he M C II–epitope complexes are then displayed on the outside of the C’s cytoplasmic membrane. H T lymphocytes often act against body cells that harbor intracellular pathogens, such as viruses, and against body cells that produce abnormal antigens (such as cancer cells). Because T cells act directly against antigens, T lymphocyte immune activities are called cell­mediated immune responses. A human adult’s red bone marrow produces T lymphocytes (T cells), which are released into the blood. Chemotactic molecules attract T lymphocytes from blood vessels to the thymus, where they adhere and mature under the influence of sticky, adhesive chemicals and molecular signals from the thymus. Following maturation, they circulate in the lymph and blood and migrate to the lymph nodes, spleen, and Peyer’s patches. T cells account for about 70% to 85% of all lymphocytes in the blood. T cell maturation involves production of about half a million copies of a protein called a T cell receptor (TCR) on each T cell’s cytoplasmic membrane. Every T cell randomly chooses and combines segments of DNA from TCR genes to create a new genetic combination specific to that cell, which codes for the cell’s unique and specific TCR. 06/03/2018 07:54       E lements of Adaptive Immunity intracellular pathogens. They also kill abnormal cells, such as cancer cells. Epitope-binding site Carbohydrate Variable regions ­ Constant regions Helper T Lymphocyte Immunologists distinguish helper T cells (Th cells) by the presence of CD4 glycoproteins in the cells’ cytoplasmic membranes, so Th cells are also called CD4 positive (CD4 + ) cells. These cells are called “helpers” because their function is to help regulate the activity of B cells and cytotoxic T cells during immune responses by providing necessary signals and growth factors. During an immune response, there are two main subpopulations of helper T cells: type 1 helper T cells (Th1 cells), which assist cytotoxic T cells and stimulate and regulate innate immunity, and type 2 helper T cells (Th2 cells), which function in conjunction with B cells. Immunologists distinguish Th1 from Th2 cells on the basis of their secretions and by characteristic cell-surface proteins. Helper T cells secrete various soluble protein messengers called cytokines that regulate the entire immune system, both adaptive and innate portions. We will consider the types and effects of cytokines shortly. ▶ ANIMATION: Cell-Mediated Cytoplasmic membrane of T cell T cell receptor (TCR) Cytoplasm ▲ FIGURE 16.8 A T cell receptor (TCR). A TCR is a surface ­ molecule composed of two polypeptides containing a single epitope-binding site between them. Immunity: Helper T Cells Specificity of the T Cell Receptor (TCR) 9 In your body, there are at least 10 different TCRs—each specific TCR type on a different T cell—enough to recognize every possible epitope. Each T cell expresses only one TCR, and so it displays one specific epitope-binding site, which recognizes and binds to a complementary shape (FIGURE 16.8). So, unlike the MHC, each TCR binds only one unique epitope. An analogy will serve to clarify this point. Imagine a locksmith who has a copy of every possible key to fit every possible lock. If a customer arrives at the shop with a lock needing a key, the locksmith can provide it (though it may take a while to find the correct key). Similarly, you have a TCR complementary to every possible epitope in the environment, though you will encounter only some of them. For example, you have lymphocytes with TCRs complementary to epitopes of stingray venom, though it is unlikely you will ever be stabbed by a stingray. Types of T Lymphocytes Immunologists recognize three main types of T cells based on surface molecules and characteristic functions. These are cyto­ toxic T cells, helper T cells, and regulatory T cells. Cytotoxic T Lymphocyte Every cytotoxic T cell (Tc cell) is distinguished by copies of its own unique TCR as well as the presence of CD8 cell-surface glycoproteins. 8 For this reason, cytotoxic T cells are also known as CD8 positive (CD8+) cells. As the name cytotoxic T cell implies, these lymphocytes directly kill other cells, such as those infected with viruses or other 8Scientists name molecules on cells’ surfaces with internationally accepted designations consisting of CD, which stands for cluster of differentiation, followed by a number that reflects the order in which the CD was discovered. M16_BAUM7206_05_SE_C16.indd 477 Regulatory T Lymphocyte Immunologists recognize regulatory T cells (Tr cells), previously known as suppressor T cells, by the presence of both CD4 and CD25 glycoproteins. Scientists have not fully characterized the manner in which Tr cells work, but it is known that they are activated by contact with other immune cells and that they secrete cytokines different from those secreted by helper T cells. Regulatory T cells generally suppress immune responses and promote tolerance of certain antigens. TABLE 16.2 on p. 478 compares and contrasts the features of various types of T lymphocytes. Now, we turn our attention to the way in which the body eliminates T cells that recognize the body’s normal autoantigens. Clonal Deletion of T Cells Given that T lymphocytes randomly generate the variable region shapes of their TCRs, a population of new lymphocytes will include numerous cells with receptors complementary to normal body components (the autoantigens mentioned earlier). It is vitally important that adaptive immune responses not be directed against autoantigens; in other words, the immune system must be tolerant of “self.” When self-tolerance is impaired, the result is an autoimmune disease (see Chapter 18). The body eliminates self-reactive lymphocytes via clonal deletion, so named because elimination of a self-reactive cell deletes its potential daughter cells (clones). In this process, lymphocytes are exposed to autoantigens, and those lymphocytes that react to autoantigens undergo apoptosis9 (programmed cell suicide) and are thereby deleted from the repertoire (collection) of lymphocytes. Apoptosis is the critical feature of clonal 9Greek, meaning “falling off.” 11/23/16 3:34 AM TABLE 16.2 r e 16   Adaptive Immunity hapt       C Characteristics of T Lymphocytes Site of Maturation Representative Cell-Surface Glycoproteins Notable Secretions Helper T cell type 1 (Th1) Thymus C 4 and distinctive TCR Interleukin 2, IFN@g D Lymphocyte Thymus C 4 and distinctive TCR Interleukin 4 and 5 Thymus C 8, C 95L, and distinctive TCR Perforin, granzyme Regulatory T cell (Tr) Thymus C 4, C 25, and distinctive TCR Interleukin 10 deletion and the development of self-tolerance. Clonal deletion ensures that surviving lymphocytes respond only to foreign antigens. In humans, clonal deletion for T lymphocytes occurs in the thymus. As we have seen, T cells recognize epitopes only when the epitopes are bound to MHC protein. Immature T lymphocytes spend about a week in the thymus being exposed to all of the body’s natural epitopes through a unique feature of thymus cells. As a group, these cells express all of the body’s normal proteins, including proteins that have no function in the thymus. For example, some thymus cells synthesize lysozyme, hemoglobin, and muscle cell proteins, though these proteins are not expressed externally to the cells. Rather, thymus cells process these autoantigens so as to express their epitopes in association with an MHC protein. Since the cells collectively synthesize polypeptides from all the body’s proteins, together they process and present all the body’s autoantigens to immature T cells. FIGURE 16.9 illustrates the development of T cells. Stem cells in the bone marrow produce T cells 1 that derive their unique TCRs in the thymus 2 . These T cells undergo several steps of selection: D Stem cell (in red bone marrow) 1 Thymus T cells 2 TCRs with differently shaped binding sites MHC Epitope 3 Bind MHC? Thymus Thymus cells cells No Yes Receive survival signal 4 Recognize autoantigen with MHC? Apoptosis No Yes Few Most 5 ­ ­ • Those T cells that do not have a functional TCR that binds the body’s MHC proteins will undergo apoptosis, in other words, clonal deletion. Because they do not bind the body’s own MHC protein, they will be of no use identifying foreign epitopes carried by the body’s MHC protein. T cells that do bind MHC protein receive a signal to survive 3 , so called positive selection. • Those T cells that subsequently recognize autoantigen in conjunction with MHC protein mostly die by apoptosis— further clonal deletion 4 . This negative selection prevents autoimmune disease and results in tolerance of autoantigens. • A few of these “self-recognizing” T cells remain alive to become regulatory T cells, to dampen immune responses to autoantigens 5 . • The remaining T cells are those that will bind the body’s own MHC protein in conjunction with foreign epitopes and not with autoantigens. These T lymphocytes become the repertoire of protective T cells, which leave the thymus to circulate in the blood and lymph 6 . D D D D Helper T cell type 2 (Th2) Cytotoxic T cell (Tc) M16_BAUM7206_05_SE_C16.indd 478 Repertoire of immature Tc cells Regulatory T cell (Tr) ▲ FIGURE 16.9 Development and clonal deletion of T cells. o tor i 1 Stem cells in the red bone marrow generate a host of lymphocytes that move to the thymus. 2 In the thymus, each lymphocyte randomly generates a TCR with one particular shape. V de Note that each cell’s TCR binding sites differ from those of other Tu cells. 3 T cells pass through a series of “decision questions” in the thymus: Are their TCRs complementary to the body’s MHC protein? If no, they undergo apoptosis—clonal deletion. If yes, they survive. 4 o the surviving cells recognize MHC protein bound to any autoantigen? If yes, then most undergo apoptosis (more clonal deletion); 5 a few survive as regulatory T cells (Tr). 6 If no, they survive and become the repertoire of immature T cells. D Now that we have considered major histocompatibility proteins, antigen-presenting cells, and T lymphocytes, we consider the other star player in adaptive immune responses— B lymphocytes. Apoptosis 6 11/23/16 7:29 PM       E lements of Adaptive Immunity B Lymphocytes (B Cells) and Antibodies LE A R N I N G O U TC O M E S 16.16 Describe the characteristic of B lymphocytes that gives them specificity. 16.17 Describe the basic structure of an immunoglobulin molecule. 16.18 Contrast the structure, function, and prevalence of the five classes of immunoglobulins. 16.19 Compare and contrast clonal deletion of B cells with clonal deletion of T cells. B lymphocytes are found in the spleen, in MALT, and in the primary follicles of lymph nodes. A small percentage of B cells circulates in the blood. The major function of B cells is the secretion of soluble antibodies, which we examine in more detail shortly. As we have established, B cells function in antibody immune responses, each of which is against only a particular epitope. As with T cells, such specificity comes from membrane proteins, in this case called B cell receptors. Specificity of the B Cell Receptor (BCR) The surface of each B lymphocyte is covered with about 500,000 identical copies of a B cell receptor (BCR) unique to that cell. A BCR is a type of immunoglobulin (im’yū-nō-glob’yū-lin; Ig) made of six polypeptide chains: Two identical longer chains called heavy chains and two identical shorter light chains are arranged in such a way that they form two arms that extend outside the cell and look like the letter Y (FIGURE 16.10). Two Epitope Antigenbinding sites Heavy chain Light chain S Lymphocyte Receptor Diversity S S S Variable regions S S S S Disulfide bond Cytoplasmic membrane of B lymphocyte Transmembrane portion of BCR Transmembrane polypeptides Cytoplasm ▲ FIGURE 16.10 B cell receptor (BCR). The B cell receptor is composed of a symmetrical, epitope-binding, Y-shaped protein composed of two heavy and two light polypeptide chains in association with two additional transmembrane polypeptides. M16_BAUM7206_05_SE_C16.indd 479 additional polypeptide chains attach to the stem of the “Y” and anchor the BCR into the membrane, forming a transmembrane portion of the BCR. The terms heavy and light refer to the relative molecular masses of the polypeptide chains that extend beyond the surface of the cell. Disulfide bonds, which are covalent bonds between sulfur atoms in adjoining amino acids, link the heavy and light chains together. The end of each arm is a variable region; that is, the ends of BCRs on any one B cell differ from the ends of any other B cell’s BCRs, because the ends of each heavy and each light chain vary in amino acid sequence among B cells. Together the two variable regions, one at the end of each arm of the “Y,” form antigen-binding sites (see Figure 16.10). Antigen-binding sites are complementary in shape to the three-dimensional shape of an epitope and bind precisely to it. Exact binding between antigen-binding site and epitope accounts for the specificity of an antibody immune response. Though all of the BCRs on a single B cell are the same, the BCRs of one cell differ from the BCRs of all other B cells, much as each snowflake is distinct from all others. Scientists estimate that each person forms no fewer than 109 and likely as many as 1013 B lymphocytes—each with its own unique BCR. Because an antigen (e.g., a bacterial protein) typically has numerous epitopes of various shapes, many different BCRs will recognize any particular antigen, though each BCR recognizes only one epitope of that antigen. When an antigenic epitope stimulates a specific B cell via the B cell’s unique BCR, the B cell responds by undergoing cell division, giving rise to nearly identical offspring that secrete immunoglobulins into the blood or lymph. The immunoglobulins act against the same epitope shape that stimulated the B cell. Activated, immunoglobulin-secreting B lymphocytes are called plasma cells. They no longer display BCRs and have extensive rough endoplasmic reticulum and many Golgi bodies involved in the synthesis, packaging, and secreting of the immunoglobulins (FIGURE 16.11). BCR genes are randomly generated in sufficient numbers to render the entire collection of BCRs capable of recognizing almost every one of the billions of different epitopes. In other words, at least one BCR is fortuitously complementary to any given specific epitope that the body may or may not encounter. Just as T cells recombine their TCR genes to generate a repertoire of TCRs complementary to every epitope, B cells also recombine their genes to make unique B cell receptors complementary to the same epitopes. Each of us has billions of different BCR proteins, yet we have only about 25,000 genes. Obviously, a person cannot have a separate gene for each of the different BCRs, so how does such variability among B cells develop? Basically, each B cell randomly generates its own BCR genes. Genes for the constant regions and for the variable regions of BCRs occur in discrete stretches of DNA called loci (singular: locus). The variable loci are where diversity is generated, and the variable regions code for the epitope-binding sites in the antibody proteins. 11/23/16 3:34 AM e 16   Adaptive Immunity r hapt       C Rough endoplasmic reticulum Nucleus Heavy chain locus Golgi body VH1 VH2 VH3 VH65 DH1 DH2 DH3 DH27 DJ JH1 JH2 JH3 JH6 1 RAG randomly combines one D segment with one J segment. V DJ 2 RAG randomly combines DJ with one V segment. 3 Transcription and translation result in a unique BCR for that B cell. BCR E ▲ FIGURE 16.12 Immunoglobulin heavy chain loci have three genetic segments, V, D, and J. ach B cell randomly TEM 1 µm ▲ FIGURE 16.11 A plasma cell. Plasma cells are almost twice as large as inactive B cells and are filled with rough endoplasmic reticulum and Golgi bodies for the synthesis and secretion of antibodies. ­ BCR variable region genes occur in three loci on each of two chromosomes—one locus for the heavy chain variable region and two loci (called kappa and lambda) for the light chain variable region. Each cell is diploid—having two of each type of chromosome—so there are six loci altogether, though an individual B cell uses only one chromosome’s loci for each of its heavy and light chains. Once a locus on a particular ­chromosome is chosen, the other chromosome’s corresponding locus is inhibited. Each locus is divided further into distinct genetic segments coding for portions of its respective chain. The heavy chain variable region locus (FIGURE 16.12) has segments called variable (VH), diversity (DH), and junction (JH) segments. In each developing B cell, there are 65 variable segments, 27 diversity segments, and 6 junction segments. Each light chain variable region locus has additional variable segments (VL) and junction segments (JL). For the kappa locus, there are 40 variable segments and 5 junction segments. The lambda locus is simpler, having only 30 V segments and a single J segments. A great variety of BCRs form during B cell maturation when each B cell uses an enzyme called RAG—the recombina­ tion activating gene protein—to randomly combine one of each kind of the various segments to form its BCR gene. First, RAG randomly combines one D segment with one J segment 1 , then RAG adds one randomly chosen V segment 2 to create that cell’s unique BCR gene. The cell transcribes and translates the BCR gene to give each B cell its own characteristic BCR protein protruding from its cytoplasmic membrane 3 . An analogy will help you understand of this concept. Imagine that you have a wardrobe consisting of 65 different M16_BAUM7206_05_SE_C16.indd 480 recombines an exon from each of the three segments to generate an antigenbinding site that is unique for immunoglobulins of each B cell. pairs of shoes, 27 different shirts, and 6 different pairs of pants that can be combined to create outfits. (These correspond to the V, D, and J segments of the heavy chain locus.) You can choose any one pair of shoes, any one shirt, and any one pair of pants each day, so with these 98 pieces of clothing, you will potentially have 10,530 different outfits (65 * 27 * 6). Your roommate, who happens to be the same size as you, might have the same numbers of items but in different colors and styles. With each of you having 10,530 potential outfits, which either of you could wear, there are 21,060 potential outfits! Similarly, each developing B cell has 10,530 possible combinations of VH, DH, and JH segments on each of its two chromosomes, for a total of 21,060 possible gene combinations for the heavy chain variable region. The developing B cell also uses RAG to recombine the segments of the light chain variable loci. Because there are 200 (40 * 5) possible kappa genetic combinations and 30 (30 * 1) possible lambda combinations on each chromosome, there is a total of 460 (230 + 230) possible light chain genes on the two chromosomes. Therefore, each B cell can make one of a possible 9,687,600 (21,060 * 460) different BCRs using only 348 genetic segments in the heavy and light chain loci on its two chromosomes. Still, these nearly 10 million different BCRs do not account for all the variability seen among BCRs. Each B cell creates additional diversity when RAG randomly removes portions of D and J segments before joining the two together. Another enzyme randomly adds nucleotides to each heavy chain VDJ combination, and B cells in the primary follicles of lymph nodes undergo random point mutations in their V regions. The result of RAG recombinations, random deletions, random insertions, and point mutations is tremendous potential variability. Scientists estimate that you may have about 1023 B cell receptor 11/23/16 3:34 AM       E lements of Adaptive Immunity possibilities. That’s one hundred billion trillion—a number 10 times greater than all the stars in the known universe! T cells generate their receptors in a similar way, so there are billions of possible TCRs as well. Light chain Variable region of heavy chain Variable region of light chain Arm (Fab) Next, we consider the structure and functions of secreted immunoglobulins—called antibodies. S Hinge Specificity and Antibody Structure S S S S S S S Constant region of light chain Constant region of heavy chain Stem (Fc) ­ Antibodies are free immunoglobulins—not attached to a membrane—and similar to BCRs in shape except they lack most of the transmembrane portions of a BCR. Thus, a basic antibody molecule is Y-shaped with two identical heavy chains and two identical light chains. The ends of the four chains form two identical antigen-binding sites (FIGURE 16.13). The antigen-binding sites of antibodies from a given plasma cell are identical to one another and to the antigen-binding sites of that cell’s BCR; thus, antibodies carry the same specificity for an epitope as the BCR of the activated B cell. Because the arms of an antibody molecule contain antigenbinding sites, they are also known as the Fab regions (fragment, antigen­binding region). The angle between the arms and the stem can change because the point at which they join is hingelike. Fab regions of all the antibodies produced by a single cell are nearly identical and unique to each B cell. An antibody stem, which is formed of the lower portions of the two heavy chains, is also called the Fc region (because it forms a fragment that is crystallizable). There are five basic types of stems (Fc regions), designated by the Greek letters mu, gamma, alpha, epsilon, and delta or by the corresponding English letters, M, G, A, E, and D. A plasma cell attaches DNA coding for its heavy chain variable region to one of five DNA sequences coding for the five types of stems to form one of five classes of antibodies known as IgM (immunoglobulin class mu), IgG, IgA, IgE, or IgD. The Fc regions of all antibodies of each class in a person’s body are identical; that is, the Fc regions of all IgM molecules are identical, the Fc regions of all IgA molecules are identical, and so on for each antibody class. Antigen-binding sites Heavy chains (a) Arm (Fab) Hinge Stem (Fc) Antibody Function Activation of Complement and Inflammation Stems of two or more IgM antibodies bind to complement protein 1 (C1), activating it to become enzymatic. This begins the classical complement M16_BAUM7206_05_SE_C16.indd 481 (b) ▲FIGURE 16.13 Basic antibody structure. (a) Artist’s rendition. E ach antibody molecule, which is shaped like the letter Y, consists of two identical heavy chains and two identical light chains held together by disulfide bonds. Five different kinds of heavy chains form an antibody’s stem (F c region). The arms (F ab regions) terminate in variable regions to form two antigenbinding sites. The hinge region is flexible, allowing the arms to bend in almost any direction. (b) Three-dimensional shape of an antibody based on X-ray crystallography. Why are the two antigen-binding sites on a typical antibody molecule identical? Figure 16.13 The amino acid sequences of the two light chains of an antibody molecule are identical, as are the sequences of the two heavy chains, so the binding sites—each composed of the ends of one light chain and one heavy chain—must be identical. As we have seen, antigen-binding sites of antibodies are complementary to epitopes; in fact, the shapes of the two can match so closely that most water molecules are excluded from the area of contact, producing a strong, highly specific, noncovalent interaction. Additionally, hydrogen bonds and other molecular attractions mediate antibody binding to epitope. The binding of antibody to epitope is the central functional feature of antibody adaptive immune responses. Once bound, antibodies function in several ways. These include activation of complement and inflammation, neutralization, opsonization, agglutination, and antibody-dependent cell-mediated cytotoxicity. 11/23/16 3:34 AM e 16   Adaptive Immunity r hapt       C pathway, which releases inflammatory mediators. In addition, IgE bound to antigen attaches via its stem to mast cells and eosinophils. Attachment triggers the release of inflammatory chemicals. This is what is seen in allergies. (Figures 15.8 and 15.13 more fully illustrate the defense reactions of complement activation and inflammation.) Neutralization Antibodies can neutralize a toxin by binding to a critical portion of the toxin so that it can no longer harm the body. Similarly, antibodies can block adhesion molecules on the surface of a bacterium or virus, neutralizing the pathogen’s virulence because it cannot adhere to its target cell (FIGURE 16.14a). Toxin Virus (a) Neutralization Pseudopod of phagocyte opsonins 10—molecules  ­ Agglutination Because each basic antibody has two antigenbinding sites, each can attach to two epitopes at once. Numerous antibodies can aggregate antigens together—a state called agglutination (ă-glū-ti-nā’shŭn; FIGURE 16.14c ). Agglutination of soluble molecules typically causes them to become insoluble and precipitate. Agglutination may hinder the activity of pathogenic organisms and increases the chance that they will be phagocytized or filtered out of the blood by the spleen. (Chapter 17 examines some uses scientists make of the agglutinating nature of antibodies.) Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Antibodies often coat a target cell by binding to epitopes all over the target’s surface. The antibodies’ stems can then bind to receptors on special lymphocytes called natural killer lymphocytes (NK cells), which are neither B nor T cells. NK lymphocytes destroy target cells with proteins called perforin (per’fōr-in) and granzyme (gran’zīm). Perforin molecules form into a tubular structure in the target cell’s membrane, forming a channel through which granzyme enters the cell and triggers apoptosis (FIGURE 16.14d). Antibody-dependent cell-mediated cytotoxicity (ADCC) is similar to opsonization in that antibodies cover the target cell; however, with ADCC the target dies by apoptosis, whereas with opsonization the target is phagocytized.▶ ANIMATION: Humoral Immunity: Antibody Function Classes of Antibodies Threats confronting the body can be extremely variable, so it is not surprising that there are several classes of antibody. The class involved in any given antibody immune response 10From Greek opsonein, meaning “to supply food,” and izein, meaning “to cause”; thus, loosely, “to prepare for dinner.” M16_BAUM7206_05_SE_C16.indd 482 Fc receptor protein (b) Opsonization (c) Agglutination NK lymphocyte Fc receptor protein Perforin allows granzyme to enter, triggers apoptosis and lysis (d) Antibody-dependent cellmediated cytotoxicity (ADCC) ▲FIGURE 16.14 Four functions of antibodies. rawings are D Opsonization Antibodies act as that stimulate phagocytosis. Neutrophils and macrophages have receptors for the stems of IgG molecules; therefore, these leukocytes bind to the stems of antibodies. Once antibodies are so bound, the leukocytes phagocytize them, along with the antigens they carry, at a faster rate compared to antigens lacking bound antibody. Changing the surface of an antigen so as to enhance phagocytosis is called opsonization (op’sŏ-nī-zā’shŭn; FIGURE 16.14b). Bacterium Adhesin proteins not to scale. (a) Neutralization of toxins and microbes. (b) Opsonization. (c) Agglutination. (d) Antibody-dependent cellular cytotoxicity. Antibodies have two other functions—activation of complement and participation in inflammation (illustrated in Chapter 15). depends on the type of invading foreign antigens, the portal of entry involved, and the antibody function required. Here, we consider the structure and functions of the five classes of antibodies. Every plasma cell (activated B lymphocyte) begins by attaching its variable region gene to the gene for the mu stem and thus begins by making immunoglobulin M (IgM). Most IgM is secreted during the initial stages of an immune response. A secreted IgM molecule is more than five times larger than the basic Y-shape because secreted IgM is a pentamer, consisting of five basic units linked together in a circular fashion via 11/23/16 3:34 AM M16_BAUM7206_05_SE_C16.indd 483 antigen receptors on B cells that are often seen during the initial phases of an antibody immune response. As mentioned previously, a BCR is composed of two transmembrane subunits bound to an immunoglobulin, which is either IgM or IgD (see Figure 16.10). Not all mammals have IgD, and animals that lack IgD show no observable ill effects; therefore, scientists are uncertain of all the functions or importance of the D class of antibody. TABLE 16.3 on p. 484 compares the different classes of immunoglobulins and adds some details of antibody structure. Clonal Deletion of B Cells Clonal deletion of B cells occurs in the bone marrow in a manner similar to deletion of T cells (FIGURE 16.15), though self-reactive B cells may become inactive or change their BCR rather than undergo apoptosis. In any case, self-reactive Stem cell (in red bone marrow) 1 B cells 2 3 Cell with autoantigens BCRs with differently shaped binding sites Cell with autoantigens 4 Apoptosis Blood vessel To spleen ­ ­ ­ E ▲FIGURE 16.15 Clonal deletion of B cells. 1 Stem cells in the red bone marrow generate a host of B lymphocytes. 2 ach newly formed B cell randomly generates a BCR with a particular shape. Note that each cell’s BCR binding sites differ from those of other cells. 3 Cells whose BCR is complementary to some autoantigen bind with that autoantigen, stimulating the cell to undergo apoptosis. Thus, an entire set of potential daughter B cells (a clone) that are reactive with the body’s own cells is eliminated—clonal deletion. 4 B cells with a BCR that is not complementary to any autoantigen are released from the bone marrow and into the blood. Of the B cells shown, which is likely to undergo apoptosis? ­ Figure 16.15 The second and third B lymphocytes from the left will undergo apoptosis; their active sites are complementary to the second and fourth autoantigens from the top, respectively. disulfide bonds and a short polypeptide joining (J) chain. Each IgM subunit has a conventional immunoglobulin structure, consisting of two light chains and two mu heavy chains. IgM is most efficient at complement activation, which also triggers inflammation, and IgM can be involved in agglutination and neutralization. In a process called class switching, a plasma cell then combines its variable region gene to the gene for a different stem and begins secreting a new class of antibodies; that is, the cell switches from synthesizing IgM to secreting IgA or IgE or, most commonly, IgG. Immunoglobulin G (IgG) molecules are the most common and longest-lasting class of antibodies, accounting for about 80% of serum antibodies, possibly because IgG has many functions. Each molecule of IgG has the basic Y-shaped antibody structure. IgG molecules play a major role in antibody-mediated defense mechanisms, including complement activation, opsonization, neutralization, and antibody-dependent cellular cytotoxicity (ADCC). IgG molecules can leave blood vessels to enter extracellular spaces more easily than can other types of immunoglobulins. This is especially important during inflammation because it enables IgG to bind to invading pathogens before they get into the circulatory systems. IgG molecules are also the only antibodies that cross a placenta to protect a developing child. Immunoglobulin A (IgA), which has alpha heavy chains, is the immunoglobulin most closely associated with various body secretions. Some of the body’s IgA is a monomer with the basic Y-shape that circulates in the blood, constituting about 12% of total serum antibody. However, plasma cells in the tear ducts, mammary glands, and mucous membranes synthesize secretory IgA, which is composed of two IgA molecules linked via a J chain and another short polypeptide (called a secretory component). Plasma cells add secretory component during the transport of secretory IgA across mucous membranes. Secretory component protects secretory IgA from digestion by intestinal enzymes. Secretory IgA agglutinates and neutralizes antigens and is of critical importance in protecting the body from infections arising in the gastrointestinal, respiratory, urinary, and reproductive tracts. IgA provides nursing newborns some protection against foreign antigens because mammary glands secrete IgA into milk. Thus, nursing babies receive antibodies directed against antigens that have infected their mothers and are likely to infect them as well. Immunoglobulin E (IgE) is a typical Y-shaped immunoglobulin with two epsilon heavy chains. Because it is found in extremely low concentrations in serum (less than 1% of total antibody), it is not critical for most antibody immune responses. Instead, IgE antibodies act as signal molecules—they attach to receptors on eosinophil cytoplasmic membranes to trigger the release of cell-damaging molecules onto the surface of parasites, particularly parasitic worms. IgE antibodies also trigger mast cells and basophils to release inflammatory chemicals, such as histamine. In more-developed countries, IgE is more likely associated with allergies than with parasitic worms. Immunoglobulin D (IgD) is characterized by delta heavy chains. IgD molecules are not secreted but are membrane-bound       E lements of Adaptive Immunity 11/23/16 3:34 AM TABLE 16.3 r e 16   Adaptive Immunity hapt       C Characteristics of the Five Classes of Antibodies IgM IgG IgA Antigen-binding site Disulfide bond i IgE c Carbohydrate IgD ( f Monomer o Secretory J Chain c component Secretory (dimer) J Chain Monomer, 2 Pentamer, 10 Monomer, 2 Monomer, 2 imer, 4 Type of Heavy Chain Mu (m) Gamma (g) Alpha (a) Functions Monomer can act as BCR; pentamer acts in complement activation, neutralization, agglutination Complement activation, neutralization, opsonization, production of hydrogen peroxide, agglutination, and antibody-dependent cell-mediated cytotoxicity (A CC); crosses placenta to protect fetus Neutralization and agglutination; dimer is secretory antibody Triggers release of antiparasitic molecules from eosinophils and of histamines from basophils and mast cells (allergic reactions) nknown, but perhaps acts as BCR Locations Monomer on B cell surface, pentamer in serum Serum, mast cell surfaces Monomer: serum imer: mucous membrane secretions (e.g., tears, saliva, mucus); milk Serum, mast cell surfaces B cell surface Approximate Half-Lifea in Blood 5 days 23 days 6 days 2 days 3 days Percentage of Serum Antibodies 5–10% 80% 10–15% <1% <0.05% Size (mass in kilodaltons) Monomer: 194 imer: 970 150 Monomer: 160 imer: 385 188 184 a(time D psilon (e) elta (d) U D Monomer, 2 E Monomer, 2 D D D D Structure, Number of Binding Sites it takes for concentration to reduce by half) ­ B cells are removed from the active B cell repertoire so that an antibody immune response does not act against autoantigens. Tolerant B cells leave the bone marrow and travel to the spleen, where they undergo further maturation before circulating in the blood and lymph. Surviving B and T lymphocytes move into the blood and lymph, where they collectively scan for antigens. They communicate among one another and with other body cells via chemical signals called cytokines. In terms of our analogy of a stage play, there is dialogue among the cast of characters—in the story of adaptive immunity, the dialogue consists of chemical signals. M16_BAUM7206_05_SE_C16.indd 484 Immune Response Cytokines LE A R N I N G O UTC O M E 16.20 Describe five types of cytokines. Cytokines (sī’tō-kīnz) are soluble regulatory proteins that act as intercellular messages when released by certain body cells, including those of the kidney, skin, and immune system. Here, we are concerned with cytokines that signal among various immune leukocytes. For example, cytotoxic T cells (Tc) 11/23/16 3:34 AM       Cell-Mediated Immune Responses do not respond to antigens unless they are first signaled by cytokines. Immune system cytokines are secreted by various leukocytes and affect diverse cells. Many cytokines are redundant; that is, their effects are almost identical to those of other cytokines. Such complexity has given rise to the concept of a cytokine network—a complex web of signals among all the cell types of the immune system. The nomenclature of cytokines is not based on a systematic relationship among them; instead, scientists named cytokines after their cells of origin, their function, and/or the order in which they were discovered. Cytokines of the immune system include the following substances: TELL ME WHY Why are exogenous epitopes processed in vesicles instead of in endoplasmic reticulum, as endogenous epitopes are? We have been considering adaptive immunit y as a stage play. To this point, we have examined the “stage” (the tissues and organs of the lymphatic system) and the “cast of characters” involved in adaptive immunity. The “villainous” characters are antigens with their epitopes; the “heroes” are T cells with their TCRs, B cells with their BCRs, and plasma cells and their antibodies. The dialogue consists of chemical signals—cytokines. We have set the stage for the immune system “play” by examining the preparatory steps of antigen processing and antigen presentation. We have seen that adaptive immunity is specific because of the precise and accurate fit of lymphocyte receptors with their complements; that adaptive immunity involves clones of T and B cells, which are unresponsive to self (because of clonal deletion); and that immune responses are inducible against foreign antigens. Now, we can examine cell-mediated and antibody immune responses in more detail. We begin with cell-mediated immunity. ­ • Interleukins (ILs)11 (in-ter-lū’kinz). As their name suggests, ILs signal among leukocytes, though cells other than leukocytes may also use interleukins. Immunologists named interleukins sequentially as they were discovered. Scientists have identified about 37 human interleukins. • Interferons (IFNs) (in-ter-fēr’onz). These proteins, which inhibit the spread of viral infections (as discussed in Chapter 15), may also act as cytokines. The most important interferon with such a dual function is gamma interferon (IFN@g), which is a potent phagocytic activator secreted by type 1 helper T cells. • Growth factors. These proteins stimulate leukocyte stem cells to divide, ensuring that the body is supplied with sufficient white blood cells of all types. The body can control the progression of an adaptive immune response by limiting the production of growth factors. • Tumor necrosis factor (TNF).12 Macrophages and T cells secrete TNF to kill tumor cells and to regulate immune responses and inflammation. • Chemokines (kē’mō-kīnz). Chemokines are chemotactic cytokines; that is, they signal leukocytes to move—for example, to rush to a site of inflammation or infection or to move within tissues. Cell-Mediated Immune Responses LE A R N I N G O UTC O M E S 16.21 Describe a cell-mediated immune response. 16.22 Compare and contrast the two pathways of cytotoxic T cell action. The body uses cell-mediated immune responses primarily to fight intracellular pathogens and abnormal body cells. Recall that inducibility and specificity are two hallmark characteristics of adaptive immunity. The body induces cell-mediated immune responses only against specific endogenous antigens. Given that many common intracellular invaders are viruses, our examination of cell-mediated immunity will focus on these pathogens. However, cell-mediated immune responses TABLE 16.4 summarizes some properties of selected cytokines. TABLE 16.4 Selected Immune Response Cytokines Representative Source Representative Target Representative Action Interleukin 2 (IL-2) Type 1 helper T (Th1) cell, cytotoxic T (Tc) cell Tc cell Cloning of Tc cell Interleukin 4 (IL-4) Type 2 helper T (Th2) cell B cell B cell differentiates into plasma cell Helper T (Th) cell Th cell differentiates into Th1 cell Interleukin 12 (IL-12) D Cytokine endritic cell Gamma interferon (IFN@l) Th1 cell Macrophage Increases phagocytosis Tumor necrosis factor (TNF) Macrophages, T cells Body tissues Triggers inflammation or apoptosis 11From 12From Latin inter, meaning “between,” and Greek leukos, meaning “white.” Latin necare, meaning “to kill.” M16_BAUM7206_05_SE_C16.indd 485 11/23/16 3:34 AM r e 16   Adaptive Immunity are also mounted against cancer cells, intracellular parasitic protozoa, and intracellular bacteria, such as the tuberculosis bacterium, Mycobacterium tuberculosis (mī’kō-bak-tēr’ē-ŭm too-ber-kyū-lō’sis). Tc cell, which specifically binds to MHC I protein, stabilizes the synapse. 2 Helper T cell differentiation. A nearby CD4-bearing helper T (Th) lymphocyte assists by binding to MHC II on the dendritic cell via the TCR of the helper cell. (Recall that dendritic cells present the same epitopes on MHC II and MHC I.) Association with a helper T cell induces the APC to more vigorously signal the Tc cell. Viruses and some intracellular bacteria induce dendritic cells to secrete interleukin 12 (IL-12), which stimulates the helper T cells to differentiate into many clones of type 1 helper T (Th1) cells. Th1 cells in turn secrete IL-2. Lacking the assistance of Th cells, an immunological synapse between the APC and the Tc cell fails to progress. This limits improper immune responses. 3 Clonal expansion. The dendritic cell imparts a second signal (not shown) in the immunological synapse. This signal, in conjunction with IL-2 from a Th1 cell, activates the cytotoxic T (Tc) cell to secrete its own IL-2. Interleukin 2 triggers cell division by Tc cells. Activated Tc cells reproduce to form memory T cells (discussed shortly) and more Tc progeny—a process known as clonal expansion. Activation of Cytotoxic T Cell Clones and Their Functions Adaptive immune responses do not initiate at the site of an infection but rather in lymphoid organs, usually lymph nodes, where antigen-presenting cells interact with lymphocytes. The initial event in cell-mediated immunity is the activation of a specific clone of cytotoxic T cells, as depicted for a dendritic cell infected by a virus in FIGURE 16.16: Antigen presentation. The infected dendritic cell migrates to a nearby lymph node, where it presents virus epitopes in conjunction with its MHC I protein. Because of the vast diversity of randomly generated T cell receptors (TCRs), at least one cytotoxic T (Tc) cell will have a TCR complementary to the presented MHC I protein–epitope complex. This Tc cell binds to the dendritic cell to form a cell-cell contact site called an immunological synapse. CD8 glycoprotein of the   1  hapt       C Dendritic cell 1 Antigen presentation CD8 DC MHC II Epitope MHC I Epitope MHC I TCR TCR Th cell Tc cell Inactive Tc cell IL-12 IL-2 receptor (IL-2R) 2 Th differentiation Immunological synapse IL-2 Th1 cell 3 Clonal expansion IL-2R IL-2 4 Self-stimulation ◀ FIGURE 16.16 Activation of a clone of cytotoxic T (Tc) cells. 1 Antigen-presenting cells (APCs), here a dendritic cell ( C), present epitopes in conjunction with MHC II protein to helper T (Th) cells and with MHC I to Tc cells. 2 Infected APCs secrete IL-12, which causes helper T cells to differentiate into Th1 cells. 3 Signaling from the APC and IL-2 from the Th1 cell activate Tc cells that recognize the MHC I protein–epitope complex. IL-2 triggers Tc cells to divide, forming a clone of active Tc cells as well as memory T cells. 4 Active Tc cells secrete IL-2, becoming self-stimulatory. D IL-2 Memory T cell Active Tc cells IL-2R Active Tc cells IL-2 M16_BAUM7206_05_SE_C16.indd 486 11/23/16 3:34 AM       Cell-Mediated Immune Responses As previously discussed, when any nucleated cell synthesizes proteins, it displays epitopes from them in the antigen-binding grooves of MHC class I molecules on its cytoplasmic membrane. Thus, when viruses are replicated inside cells, epitopes of viral proteins are displayed on the host cell’s surface. An active Tc cell binds to an infected cell via its TCR, which is complementary to the MHC I protein–epitope complex, and via its CD8 glycoprotein, which is complementary to the MHC class I protein of the infected cell (FIGURE 16.17a). Cytotoxic T cells kill their targets through one of two pathways: the perforin­granzyme pathway, which involves the synthesis of special killing proteins, or the CD95 pathway, which is mediated through a glycoprotein found on the body’s cells. ▶ ANIMATION: Cell-Mediated Immunity: Cytotoxic T Cells ­ cytotoxicity (discussed previously). When a cytotoxic T cell first attaches to its target, vesicles containing the cytotoxins release their contents. Perforin molecules associate into a channel in the membrane of the infected cell through which granzyme enters, activating apoptosis in the target cell (FIGURE 16.17b). Having forced its target to commit suicide, the cytotoxic T cell disengages and moves on to another infected cell. The CD95 Cytotoxic Pathway The CD95 pathway of cell-mediated cytotoxicity involves the integral glycoprotein CD95, also called Fas, that is present in the cytoplasmic membranes of many body cells. Activated Tc cells insert CD95L—the receptor for CD95—into their ­c ytoplasmic membranes. When an activated Tc cell comes into contact with its target via its TCR, CD95L binds to CD95 on the target, which then activates enzymes that trigger apoptosis, killing the target cells (FIGURE 16.17c). ­ Self-stimulation. Daughter Tc cells activate and produce both IL-2 receptors (IL-2R) and more IL-2, thereby becoming self-stimulating; they no longer require either an APC or a helper T cell. They leave the lymph node and are now ready to attack virally infected cells.  Memory T Cells The Perforin-Granzyme Cytotoxic Pathway LE A R N I N G O UTC O M E The cytoplasm of cytotoxic T cells has vesicles containing two key protein cytotoxins—perforin and granzyme, which are also used by NK cells in conjunction with antibody-dependent cellular 16.23 Some activated T cells become memory T cells, which may persist in a state of “suspended animation” for months or years in ◀ FIGURE 16.17 A cell-mediated immune response. Tc cell Perforin Granzyme Viral epitope MHC I protein Virally infected cell Intracellular virus (a) The binding of a virus-infected cell by an active cytotoxic T (Tc) cell. (b) The perforin-granzyme cytotoxic pathway. After perforins and granzymes have been released from Tc cell vesicles, granzymes enter the infected cell through the perforin complex pore and activate the enzymes of apoptosis. (c) The C 95 cytotoxic pathway. Binding of C 95L on the Tc cell activates the enzymatic portion of the infected cell’s C 95 such that apoptosis is induced. Perforin complex (pore) CD8 D D Active cytotoxic T (Tc) cell TCR Describe the establishment of memory T cells. D 4 Granzymes activate apoptotic enzymes Inactive apoptotic enzymes Active enzymes induce apoptosis Virally infected cell (b) Tc cell (a) CD95L CD95 Inactive apoptotic enzymes Enzymatic portion of CD95 becomes active Active enzymes induce apoptosis Virally infected cell (c) M16_BAUM7206_05_SE_C16.indd 487 11/23/16 3:34 AM e 16   Adaptive Immunity r Inducement of T-Dependent Antibody Immunity with Clonal Selection LE A R N I N G O UTC O M E S 16.25 Describe the formation and functions of plasma cells and memory B cells. 16.26 Describe the steps and effect of clonal selection. ­ Most antibody immune responses depend on interaction with helper T cells, so they are called T-dependent antibody immunity. (T­independent immune responses act against molecules with multiple repeating epitopes, such as polysaccharides. T-independent responses are beyond the scope of this introductory explanation.) A T-dependent response begins with the action of an antigenpresenting dendritic cell (APC). After endocytosis and processing of the antigen, the dendritic cell presents epitopes in conjunction with its MHC II proteins. This APC will induce the specific helper T (Th, CD4+ ) lymphocyte with a TCR complementary to the MHC II–epitope complex presented by the APC. The activated Th2 cell must in turn induce the specific B cell that recognizes the same antigen. Lymph nodes facilitate and cytokines mediate interactions among the antigen-presenting cells and lymphocytes, increasing the chance that the appropriate cells find each other. Thus, a T-dependent antibody immune response involves a series of interactions among antigen-presenting cells, helper T cells, and B cells, all of which are mediated and enhanced by cytokines. Now we will examine each step in more detail (FIGURE 16.18): 16.24 Explain the process and significance of the regulation of cell-mediated immunity. ­ The body carefully regulates cell-mediated immune responses so that T cells do not respond to autoantigens. As we have seen, T cells require several signals from an antigen-presenting cell to activate. If the T cells do not receive these signals in a specific sequence—like the sequence of numbers in a combination padlock—they will not respond. Thus, when a T cell and an antigen-presenting cell interact in an immunological synapse, the two cell types have a chemical dialogue that stimulates the T cell to fully respond to the antigen. If a T cell does not receive the signals required for its activation, it will “shut down” as a precaution against autoimmune responses. Regulatory T (Tr) cells also modulate cytotoxic T cells by mechanisms that are beyond the scope of our discussion. Suffice it to say that Tr cells provide one more level of control over potentially dangerous cell-mediated autoimmune responses. TELL ME WHY Why did scientists give the name perforin to a molecule secreted by Tc cells? Antibody Immune Responses As we have discussed, the body induces antibody immune responses against the antigens of exogenous pathogens and toxins. Recall that inducibility is one of the main characteristics of adaptive immunity: antibody immunity activates only in response to specific pathogens. The following sections examine the activity of B lymphocytes in antibody immune responses. 13Sometimes also called anamnestic responses, from Greek ana, meaning “again,” and mimneskein “to call to mind.” M16_BAUM7206_05_SE_C16.indd 488 1 Antigen presentation for Th activation and proliferation. A dendritic cell, after acquiring antigens in the skin or mucous membrane, moves via the lymph to a local lymph node. The trip takes about a day. As helper T (Th, CD4+ ) cells pass through the lymph node, they survey all the resident APCs for complementary epitopes in conjunction with MHC II proteins. Antigen presentation depends on chance encounters between Th cells and the dendritic cells, but immunologists estimate that every lymphocyte browses the dendritic cells in every lymph node every day; therefore, complementary cells eventually find each other. Once they have established an immunological synapse, CD4 molecules in membrane rafts of the Th cell’s cytoplasmic membrane recognize and bind to MHC II, stabilizing the synapse. As we saw in cell-mediated immune responses, helper T cells need further stimulation before they activate. The requirement for a second signal helps prevent accidental inducement of an immune response. As before, the APC imparts the second signal by displaying an integral membrane protein in the immunological synapse. This induces the Th cell to proliferate, producing clones.  LE A R N I N G O U TC O M E ­ T Cell Regulation ­ ­ ­ ­ ­ lymphoid tissues. If a memory T cell subsequently contacts an epitope–MHC I protein complex matching its TCR, it responds immediately (without a need for interaction with APCs) and produces cytotoxic T cell clones that recognize the offending epitope. These cells need fewer regulatory signals and become functional immediately. Further, because the number of memory T cells is greater than the number of T cells that recognized the antigen during the initial exposure, a subsequent cellmediated immune response to a previously encountered antigen is much more effective than a primary response. An enhanced cell-mediated immune response upon subsequent exposure to the same antigen is called a memory response.13 ­ hapt       C 11/23/16 3:34 AM       Antibody Immune Responses Repertoire of Th cells (CD4 cells) Th cell CD4 TCR CD4 CD28 Epitope CD80 (or CD86) MHC II TCRs APC 1 APC presents antigen to Th cells for Th activation and cloning. APC 2 Th cell differentiates into Th2 cell. Th cell clones IL-4 Th2 cell MHC II proteins Th2 cell Th2 cell CD4 TCR CD40L Epitope MHC II CD40 IL-4 B cell Repertoire of B cells 3 Th2 cell activates B cell. Clone of plasma cells 4 5 Antibodies Memory B cells D ▲ FIGURE 16.18 A T-dependent antibody immune response. 1 Antigen presentation, in which an APC, typically a dendritic cell, presents antigen to a complementary Th cell. 2 ifferentiation of the Th cell into a Th2 cell. 3 Activation of the B cell in response to secretion of IL-4 by the Th2 cell, which causes the B cell to differentiate into 4 antibody-secreting plasma cells and 5 long-lived memory cells. D ▶ To see a 3- animation on immunology, go to the MasteringMicrobiology Study Area and watch the MicroFlix. M16_BAUM7206_05_SE_C16.indd 489 11/23/16 3:34 AM r Activation of B cells. B cells and newly formed Th2 cells survey one another. A Th2 cell binds to the B cell with an MHC II protein–epitope complex that is complementary to the TCR of the Th2 cell. CD4 glycoprotein again stabilizes the immunological synapse. Th2 cells secrete more IL-4, which induces the selected B cell to move to the cortex of the lymph node. A Th2 cell in contact with an MHC II protein–epitope on the B cell is stimulated, expresses new gene products, and inserts a protein called CD40L into its cytoplasmic membrane. CD40L binds to CD40, which is found on B cells. This provides a second signal in the immunological synapse, triggering B cell activation. These processes are called clonal selection because in effect they select a particular B cell. 4 Proliferation and Differentiation of B Cells. The selected B cell proliferates rapidly to produce a population of cells (clones) that make up a primary follicle in the lymph node. The clones differentiate into two types of cells—memory B cells (discussed shortly) and antibody-secreting plasma cells. ▶ ANIMATION: Humoral Immunity: Clonal Selection and   3 Expansion Most differentiated B cells become plasma cells. The initial plasma cell descendants of any single activated B cell secrete antibodies with binding sites identical to one another and complementary to the specific antigen recognized by their parent cell. However, as the plasma cell clones replicate, each one slightly modifies its antigen-binding-site genes such that each descendant secretes antibodies with slightly different variable regions. Plasma cells that secrete antibodies with a higher affinity for the epitope have a selective survival advantage over plasma cells secreting antibodies with a less good fit; that is, active B cells with BCRs that bind the epitope more closely survive at a higher rate. Thus, as the antibody immune response progresses, there are more and more plasma cells, secreting antibodies whose affinity gets progressively better. Each plasma cell produces different classes of antibodies. They begin by secreting IgM and then, through class switching, secrete IgG or IgA or IgE. Class switching is primarily controlled by Th cells and is irreversible. Plasma cells are able to secrete their own weight in IgG every day. As discussed previously, antibodies activate complement, trigger inflammation, agglutinate and neutralize antigen, act as opsonins, and induce antibody-dependent cellular cytotoxicity. Individual plasma cells are short lived, at least in part because of their high metabolic rate; they die within a few days of activation, although their antibodies can remain in body fluids for several weeks. Providentially, their descendants persist for years to maintain long-term adaptive responses. M16_BAUM7206_05_SE_C16.indd 490 Memory Cells and the Establishment of Immunological Memory LE A R N I N G O UTC O M E 16.27 Contrast primary and secondary immune responses. A small percentage of the cells produced during B cell proliferation do not secrete antibodies but survive as memory B cells— that is, long-lived cells with BCRs complementary to the specific epitope that triggered their production (Figure 16.18 5 ). In contrast to plasma cells, memory cells retain their BCRs and persist in lymphoid tissues, surviving for more than 20 years, ready to initiate antibody production if the same epitope is encountered again. Let’s examine how memory cells provide the basis for immunization to prevent disease, using tetanus immunization as an example. Because the body produces an enormous variety of T and B cells (and therefore TCRs and BCRs), a few Th cells and B cells bind to and respond to epitopes of tetanus toxoid (deactivated tetanus toxin), which is used for tetanus immunization. In a primary response (FIGURE 16.19a), relatively small amounts of antibodies are produced, and it may take days before sufficient antibodies are made to completely eliminate the toxoid from the body. Though some antibody molecules may persist for three weeks, a primary immune response basically ends when the plasma cells have lived out their normal life spans. ▶ ANIMATION: Humoral Immunity: Primary Immune Response Memory B cells (and memory T cells), surviving in lymphoid tissue, constitute a reserve of antigen-sensitive cells that become active when there is another exposure to the antigen, in this case, toxin from infecting tetanus bacteria. Exposure may occur many years later. Thus, tetanus toxin produced during the course of a bacterial infection directly stimulates a population of memory cells, which proliferate and differentiate rapidly into plasma cells without having to be activated by antigen- presenting cells. Newly differentiated plasma cells produce large amounts of antibody within a few days (FIGURE 16.19b), and the tetanus toxin is neutralized before it can cause disease. Because many memory cells recognize and respond to the antigen, such a secondary immune response is much faster and more effective than the primary response. ­ Differentiation of helper T cells into Th2 cells. In antibody immune responses, the cytokine interleukin 4 (IL-4) acts as a signal to the Th cells to become type 2 helper T cells (Th2 cells). Immunologists do not know the source of IL-4, but it may be secreted initially by innate cells, such as mast cells, or secreted later in a response by the Th cells themselves. ▶ ANIMATION: Humoral Immunity: Secondary Immune Response As you might expect, a third exposure (whether to tetanus toxin or to toxoid in an immunization booster) results in an even more effective response. Enhanced immune responses triggered by subsequent exposure to antigens are memory responses, which are the basis of immunization. (Chapter 17 discusses immunization in more detail.) In summary, the body’s response to infectious agents seldom relies on one mechanism alone because this course of action would be far too risky. Therefore, the body typically uses several different mechanisms to combat infections. An initial response to intruders is inflammation (a nonspecific, innate response), but a specific immune response against the invading microorganisms is also sometimes necessary. APCs phagocytize some of the invaders, process their epitopes, and induce ­ hapt       e 16   Adaptive Immunity  2 C 11/23/16 3:34 AM Antibody concentration in serum       Types of Acquired Immunity responses are specific, are inducible, involve clones, are unresponsive to self, and give the body long-term memory against their antigenic triggers. ▶ ANIMATION: Host Defenses: The Big Primary response Picture TELL ME WHY IgG IgM Lag period Day 3 Day 15 Types of Acquired Immunity LE A R N I N G O UTC O M E Tetanus toxoid 16.28 Contrast active versus passive acquired immunity and (a) Antibody concentration in serum Plasma cells are vital for protection against infection, but memory B cells are not. Why not? naturally acquired versus artificially acquired immunity. Secondary response IgG IgM Day 3 Day 6 Exposure to tetanus toxin (b) ▲ FIGURE 16.19 The production of primary and secondary antibody immune responses. This example depicts some events U following the administration of a tetanus toxoid in immunization. (a) Primary response. After the tetanus toxoid is introduced into the body, the body slowly removes the toxoid while producing memory B cells. (b) Secondary response. pon exposure to active tetanus toxin during the course of an infection, memory B cells immediately differentiate into plasma cells and proliferate, producing a response that is faster and results in greater antibody production than occurs in the primary response. clones of lymphocytes in both antibody and cell-mediated immune responses. Key to enduring protection are the facts that adaptive immunity is unresponsive to self and involves immunological memory brought about by long-lived memory B and T cells. Cell-mediated adaptive immune responses involve the activity of cytotoxic T lymphocytes in killing cells infected with intracellular bacteria and viruses. Antibody adaptive immunity involves the secretion of specific antibodies that have a variety of functions. A T-dependent antibody immune response occurs when an APC binds to a specific Th cell and signals the Th cell to proliferate. The relative importance of each of these pathways depends on the type of pathogen involved and on the mechanisms by which it causes disease. In any case, adaptive immune M16_BAUM7206_05_SE_C16.indd 491 As we have seen, adaptive immunity is acquired during an individual’s life. Immunologists categorize immunity as either naturally or artificially acquired. Naturally acquired immunity occurs when the body mounts an immune response against antigens, such as influenza viruses or food antigens, encountered during the course of daily life. Artificial immunity is the body’s response to antigens introduced in vaccines, as occurs with immunization against tetanus and flu. Immunologists further distinguish acquired immune responses as either active or passive; that is, either the immune system responds actively to antigens via antibody or cell-mediated responses, or the body passively receives antibodies from another individual. Next, we consider each of four types of acquired immunity. Naturally Acquired Active Immunity Naturally acquired active immunity occurs when the body responds to exposure to pathogens and environmental antigens by mounting specific immune responses. The body is naturally and actively engaged in its own protection. As we have seen, once an immune response occurs, immunological memory persists—on subsequent exposure to the same antigen, the immune response will be rapid and powerful and often provides the body complete protection. Naturally Acquired Passive Immunity Although newborns possess the cells and tissues needed to mount an immune response, they respond slowly to antigens. If required to protect themselves solely via naturally acquired active immunity, they might die of infectious disease before their immune systems were mature enough to respond adequately. However, they are not on their own; in the womb, IgG molecules cross the placenta from the mother’s bloodstream to provide protection, and after birth, children receive secretory IgA in breast milk. Via these two processes, a mother provides her baby with antibodies that protect it during its early months. Because the baby is not actively producing its own antibodies, this type of protection is known as naturally acquired passive immunity. 11/23/16 3:34 AM r e 16   Adaptive Immunity Y UD E E E D M RGING IS AS CAS ST E E hapt       C Microsporidiosis D ­ D Artificially Acquired Active Immunity Physicians induce immunity in their patients by introducing antigens in the form of vaccines. The patients’ own immune systems then mount active responses against the foreign antigens, just as if the antigens were part of a naturally acquired pathogen. Such artificially acquired active immunity is the basis of immunization (see Chapter 17). Artificially Acquired Passive Immunotherapy Active immunity usually requires days to weeks to develop fully, and in some cases such a delay can prove detrimental or even fatal. For instance, an active immune response may be too slow to protect against infection with rabies or exposure to rattlesnake venom. Therefore, medical personnel routinely harvest antibodies specific for toxins and pathogens that are so deadly or so fast acting that an individual’s active immune response M16_BAUM7206_05_SE_C16.indd 492 D U D reveal that they are closer to zygomycete yeasts. Microsporidia appear to infect humans who engage in unprotected sexual activity, consume contaminated food or drink, or swim in contaminated water. People with active T cells rarely have symptoms, but people with suppressed immunity become easy targets for the fungus. Microsporidia attack by uncoiling a flexible, hollow filament that stabs a host cell and serves as a conduit for the microsporidium’s cytoplasm to invade. In this way, the pathogens become intracellular parasites. They can destroy the intestinal lining, causing diarrhea, and spread to the eyes, muscles, or lungs. Fortunately for arius, an antimicrobial drug, albendazole, kills the parasite, and the effects of the infection are reversed. nfortunately for arius, the loss of helper T cells in AI S means that another emerging, reemerging, or opportunistic infection is likely to follow. D D arius is sick, which is not surprising for an HIV-infected man. But he is sick in several new ways. Sick of having to stay within 20 feet of a toilet. Sick of the cramping, the gas, the pain, and the nausea. Sick with irregular but persistent, watery diarrhea. He is losing weight because food is passing through him undigested. Most days over the past seven months have been disgusting despite his use of over-the-counter remedies, which provide a few days of intermittent relief. His belief that these normal days signaled the end of the ordeal have kept him from the doctor. But now his eyes have begun to hurt, and his vision is blurry. Whatever it is, it’s attacking him at both ends. Time to get stronger drugs from his physician. Microscopic examination of arius’s stool sample reveals that he is being assaulted by Encephalitozoon intestinalis, a member of a group of opportunistic emerging pathogens called microsporidia. The single-celled pathogens are also seen on smears from arius’s nose and eyes. Microsporidia were long thought to be simple single-celled animals, but genetic analysis and comparison with other organisms 1. Why are microsporidia considered to be opportunistic pathogens? 2. How could the discovery that microsporidia are fungi rather than animals improve treatment of microsporidiosis? 3. Microsporidia are intracellular pathogens. Which immune cells likely fight off the infection in people with a normal immune system? is inadequate. They acquire these antibodies from the blood of immune humans or animals, typically a horse. Physicians then inject such antisera or antitoxins into infected patients to confer artificially acquired passive immunotherapy. (Chapter 17 discusses this type of treatment in greater detail.) Active immune responses, whether naturally or artificially induced, are advantageous because they result in immunological memory and protection against future infections. However, they are slow acting. Passive processes, in which individuals are provided fully formed antibodies, have the advantage of speed but do not confer immunological memory because B and T lymphocytes are not activated. TABLE 16.5 summarizes the four types of acquired immunity. TELL ME WHY Why is passive immunity effective more quickly than active immunity? 11/23/16 3:34 AM       Types of Acquired Immunity TABLE 16.5 A Comparison of the Types of Acquired Immunity Active Passive The body responds to antigens that enter naturally, such as during infections. Antibodies are transferred from mother to offspring, either across the placenta (IgG) or in breast milk (secretory IgA). Health care workers introduce antigens in vaccines; the body responds with antibody or cell-mediated immune responses, including the production of memory cells. Health care workers give patients antisera or antitoxins, which are preformed antibodies obtained from immune individuals or animals. Naturally Acquired Artificially Acquired More Than the Common Cold? street fair that Bill attended with Connie. None of the infected individuals had been vaccinated against measles. 1. The measles vaccine uses an attenuated (less virulent) virus to generate long-term protective immunity. Explain how an adaptive immune response is generated and how this response will lead to long-term protection. M16_BAUM7206_05_SE_C16.indd 493 D D D D Based on the initial physical examination and Bill’s medical history, it doesn’t take r. Knapp long to make a diagnosis. He informs Bill that he has measles. Given his travel history and lack of vaccination, Bill likely became infected while he was traveling. There isn’t any specific antiviral medication for measles, so r. Knapp tells Bill that he should stay at home, rest, and minimize his contact with other people for the next few days. r. avis reports the measles case to public health authorities. Measles is a highly contagious virus, and it is likely that Bill has infected other people. It will be important for health officials to track Bill’s movement and activities since he re-entered the country. Over the next week, Bill makes a full recovery. In the ten days since Bill was diagnosed, an additional 12 people in the town have been diagnosed with measles. Several of these people were at the 2. Vaccination of a high proportion of the population can provide a protective effect known as “herd immunity”; this may explain why only 12 additional cases of measles were identified after Bill’s diagnosis. How does a high level of acquired immunity within a population offer protection against contagious diseases such as measles? 11/23/16 3:34 AM e 16   Adaptive Immunity r hapt       C CHAPTER SUMMARY ­ 1. The lymphatic system is composed of lymphatic vessels, which conduct the flow of lymph, and lymphoid tissues and organs that are directly involved in specific immunity. The latter include lymph nodes, the thymus, the spleen, the tonsils, and mucosaassociated lymphoid tissue (MALT). Lymphocytes originate in the red bone marrow. They mature in the marrow or in the thymus. Mature lymphocytes express characteristic membrane proteins. They migrate to and persist in various lymphoid organs, where they are available to encounter foreign invaders in the blood and lymph. 2. Antigens are substances that trigger specific immune responses. Effective antigen molecules are large, usually complex, stable, degradable, and foreign to their host. An epitope (or antigenic determinant) is the three-dimensional shape of a region of an antigen that is recognized by the immune system. 3. Exogenous antigens are found on microorganisms that multiply outside the cells of the body; endogenous antigens are produced by pathogens multiplying inside the body’s cells. 4. Ideally, the body does not attack antigens on the surface of its normal cells, called autoantigens; this phenomenon is called self-tolerance. ­ ­ M16_BAUM7206_05_SE_C16.indd 494 ­ V de Tu 11. B lymphocytes (B cells), which mature in the red bone marrow, make immunoglobulins (Ig) of two types—B cell receptors (BCRs) and antibodies. Immunoglobulins are complementary to epitopes and consist of two light chains and two heavy chains joined via disulfide bonds to form Y-shaped molecules. BCRs are inserted into the cytoplasmic membranes of B cells via transmembrane polypeptides, whereas antibodies are secreted. 12. Together the variable regions of an immunoglobulin arm’s heavy chain and light chain form an antigen-binding site that is called an Fab region. Each B cell randomly selects (once in its life) genes for its Fab regions; therefore, the Fab regions are called variable regions because they differ from cell to cell. Each basic immunoglobulin molecule has two antigen-binding sites and can potentially bind two epitopes. 13. Antibodies function in complement activation, inflammation, neutralization (blocking the action of a toxin or attachment of a pathogen), as opsonins for opsonization (enhanced phagocytosis), agglutination, and antibody-dependent cellular cytotoxicity (ADCC). ▶ ANIMATION: Humoral Immunity: Antibody Function 5. Nucleated cells display epitopes of their own proteins and epitopes from intracellular pathogens, such as viruses, on major histocompatibility complex (MHC) class I proteins. i V de Tu o 14. Antibodies are of five basic classes based upon their stems (Fc regions), which differ in their type of heavy chain. tor 6. In the initial step in mounting an immune response, antigens are captured, ingested, and degraded into epitopes by antigen-presenting cells (APCs), such as B cells, macrophages, and dendritic cells. Epitopes are inserted into major histocompatibility complex (MHC) class II proteins. ▶ ANIMATIONS: Antigen Processing and Presentation: Overview, Steps, MHC 10. T cells that do not recognize MHC I protein and most T cells that recognize MHC I protein in conjunction with autoantigens are removed by apoptosis. This is clonal deletion. A few self-recognizing T cells are retained and become regulatory T cells (Tr cells). T cells that recognize MHC I protein but not autoantigens become the repertoire of immature T cells. o Elements of Adaptive Immunity (pp. 470–485) 9. Two types of helper T cells (Th cells)—Th1 and Th2—are characterized by a membrane protein, CD4, so they are CD4+. They direct cell-mediated and antibody immune responses, respectively. ▶ ANIMATION: Cell-Mediated Immunity: Helper T Cells i ­ 2. B lymphocytes (B cells) attack extracellular pathogens in antibody immune responses (also called humoral immune responses), involving soluble proteins called antibodies. T lymphocytes (T cells) carry out cell-mediated immune responses against intracellular pathogens. ▶ ANIMATIONS: Host Defenses: The Big Picture; Cell-Mediated Immunity: Overview; Humoral Immunity: Overview 8. In cell-mediated immunity, cytotoxic T cells (Tc cells) also called CD8 positive (CD8+) cells because they have membrane protein CD8, act against infected or abnormal body cells, including virus-infected cells, bacteria-infected cells, some fungus- or protozoan-infected cells, some cancer cells, and foreign cells that enter the body as a result of organ transplantation. tor 1. Adaptive immunity is the body’s ability to recognize and defend against distinct species or strains of invaders. Adaptive immunity, which is present only in vertebrates, is characterized by specificity, inducibility, clonality, unresponsiveness to self, and memory. Adaptive immunity involves the actions of lymphocytes. ­ Overview of Adaptive Immunity (pp. 469–470) 7. T cells have T cell receptors (TCRs), which have an antigenbinding site for a specific epitope. T cells mature under the influence of signals from the thymus, and they attack cells that harbor endogenous pathogens during cell-mediated immune responses. ­ ▶ This chapter has MicroFlix. Go to the MasteringMicrobiology Study Area for 3-D movie-quality animations on immunology. 15. Immunoglobulin M (IgM), a pentamer with 10 antigen-binding sites, is the predominant class of antibody produced first during a primary antibody response. Immunoglobulin G (IgG) is the predominant antibody found in the bloodstream and is largely responsible for defense against invading bacteria. IgG can cross a 11/23/16 3:34 AM       Questions for Review 16. Through a process called class switching, antibody-producing cells change the class of antibody they secrete, beginning with IgM and then producing IgG or IgA or IgE. 17. B cells with B cell receptors that respond to autoantigens are selectively killed via apoptosis—further clonal deletion. Only B cells that respond to foreign antigens survive to defend the body. 18. Cytokines are soluble regulatory proteins that act as intercellular signals to direct activities in immune responses. Cytokines include interleukins (ILs), interferons (IFNs), growth factors, tumor necrosis factors (TNFs), and chemokines. Cell-Mediated Immune Responses (pp. 485–488) 1. Once activated by dendritic cells, cytotoxic T cells (Tc cells) recognize abnormal molecules presented by MHC I protein on the surface of infected, cancerous, or foreign cells. Sometimes cytotoxic T cells require cytokines from Th1 cells. 2. Activated Tc cells reproduce to form memory T cells and more Tc progeny in a process called clonal expansion. 3. Cytotoxic T cells destroy their target cells via two pathways: the perforin-granzyme pathway, which kills the affected cells by secreting perforins and granzymes; or the CD95 pathway, in which CD95L binds to CD95 on the target cell, triggering target cell apoptosis. Cytotoxic T cells may also form memory T cells, which function in memory responses. ▶ ANIMATION: Cell-Mediated Immunity: Cytotoxic T Cells Antibody Immune Responses (pp. 488–491) 2. In clonal selection, an immunological synapse forms between the Th2 cell and a B cell bearing a complementary MHC II protein– epitope complex. The Th2 cell secretes IL-4, which induces the B cell to divide. Its offspring, collectively called a clone, become plasma cells or memory B cells. ▶ ANIMATION: Humoral Immunity: Clonal Selection and Expansion 3. Plasma cells live for only a short time but secrete large amounts of antibodies, beginning with IgM and class switching as they get older. Memory B cells migrate to lymphoid tissues to await a subsequent encounter with the same antigen. 4. The primary response to an antigen is slow to develop and of limited effectiveness. When that antigen is encountered a second time, the activation of memory cells ensures that the immune response is rapid and strong. This is a secondary immune response. Such enhanced antibody immune responses are memory responses. ▶ ANIMATIONS: Humoral Immunity: Primary Immune Response, Secondary Immune Response Types of Acquired Immunity (pp. 491–493) 1. When the body mounts a specific immune response against an infectious agent, the result is called naturally acquired active immunity. 2. The passing of maternal IgG to the fetus and the transmission of secretory IgA in milk to a baby are examples of naturally acquired passive immunity. 3. Artificially acquired active immunity is achieved by deliberately injecting someone with antigens in vaccines to provoke an active response, as in the process of immunization. 4. Artificially acquired passive immunotherapy involves the administration of preformed antibodies in antitoxins or antisera to a patient. E STIONS FOR R VI W E Q UE ­ 1. In T-dependent antibody immunity, an APC’s MHC II protein– epitope complex activates a helper T cell (Th cell) bearing a complementary TCR. CD4 stabilizes the connection between the cells, which is an example of an immunological synapse. Interleukin 4 (IL-4) then induces the Th cell to become a type 2 helper T cell (Th2). ­ placenta to protect the fetus. Two molecules of immunoglobulin A (IgA) are attached via J chains and a polypeptide secretory component to produce secretory IgA, which is found in milk, tears, and mucous membrane secretions. Immunoglobulin E (IgE) triggers inflammation and allergic reactions. It also functions during helminth infections. Immunoglobulin D (IgD) is found in cytoplasmic membranes of some animals. Answers to the Questions for Review (except Short Answer questions) begin on p. A-1. Multiple Choice 1. Antibodies function to __________________. a. directly destroy foreign organ grafts b. mark invading organisms for destruction c. kill intracellular viruses d. directly promote cytokine synthesis e. stimulate T cell growth 2. MHC class II molecules bind to __________________ and trigger __________________. a. endogenous antigens; cytotoxic T cells b. exogenous antigens; cytotoxic T cells M16_BAUM7206_05_SE_C16.indd 495 c. antibodies; B cells d. endogenous antigens; helper T cells e. exogenous antigens; helper T cells 3. Rejection of a foreign skin graft is an example of _______________ ______________________. a. destruction of virus-infected cells b. tolerance c. antibody-mediated immunity d. a secondary immune response e. a cell-mediated immune response 11/23/16 3:34 AM e 16   Adaptive Immunity r 8. Which cells express MHC class I molecules in a patient? a. red blood cells b. antigen-presenting cells only c. neutrophils only d. all nucleated cells e. dendritic cells only 9. In which of the following sites in the body can B cells be found? a. lymph nodes d. intestinal wall b. spleen e. all of the above c. red bone marrow 10. Tc cells recognize epitopes only when the latter are held by _____ ________________________________. a. MHC proteins c. interleukin 2 b. B cells d. granzyme A. MHC II molecule 2. ____ Cytotoxic T cell B. Interleukin 4 3. ____ Th2 cell C. Perforin and granzyme 4. ____ Dendritic cell D. Immunoglobulin Match each type of immunity in the left column with its associated example from the right column. A. Production of IgE in response to pollen 2. ____ Naturally acquired active immunity B. Acquisition of maternal antibodies in breast milk 3. ____ Naturally acquired passive immunity C. Administration of tetanus toxoid 4. ____ Artificially acquired active immunity D. Administration of antitoxin  VISUALIZE IT! 1. Label the parts of the immunoglobulin below. a. _______________ b. _______________ c. _______________ d. _______________ e. _______________ Modified True/False Mark each statement as either true or false. Rewrite false statements to make them true by changing the underlined words.  1. ____ Artificially acquired passive immunotherapy  7. The major class of immunoglobulin found on the surfaces of the walls of the intestines and airways is secretory _________________ ____________________. a. IgG d. IgE b. IgM e. IgD c. IgA 1. ____ Plasma cell  6. Which of the following lymphocytes predominates in blood? a. T cells d. memory cells b. B cells e. All are about equally c. plasma cells prevalent Match each cell in the left column with its associated protein from the right column.  5. Among the key molecules that control cell-mediated cytotoxicity are ___________________. a. perforin d. cytokines b. immunoglobulins e. interferons c. complement Matching  4. An autoantigen is _____________________________________. a. an antigen from normal microbiota b. a normal body component c. an artificial antigen d. any carbohydrate antigen e. nucleic acid  hapt       C g. _______________ h. _______________ f. _______________ 1. __________________ MHC class II molecules are found on T cells. ­ 2. __________________ Apoptosis is the term used to describe cellular suicide. 3. __________________ Lymphocytes with CD8 glycoprotein are helper T cells. 4. __________________ Cytotoxic T cells secrete immunoglobulin. 5. __________________ Secretion of antibodies by activated B cells is a form of cell-mediated immunity. M16_BAUM7206_05_SE_C16.indd 496 11/23/16 3:34 AM       Questions for Review 2. The nearby image is a transmission electron micrograph of a dendritic cell. Indicate where a scientist could find molecules of MHC I and MHC II. Label a pseudopod and a vesicle. 15. Short Answer 1. When is antigen processing an essential prerequisite for an immune response? 2. Why does the body have both antibody and cell-mediated immune responses? TEM 5 µm CRITICAL THINKING 1. Why is it advantageous for the lymphatic system to lack a pump? 2. Contrast innate defenses with adaptive immunity. 3. How does requiring the immune system to process antigen benefit the body? 4. Scientists can develop genetically deficient strains of mice. Describe the immunological impairments that would result in mice deficient in each of the following: class I MHC, class II MHC, TCR, BCR, IL-2 receptor, and IFN@g. 5. Human immunodeficiency virus (HIV) preferentially destroys CD4+ cells. Specifically, what effect does this have on antibody and cell-mediated immunity? 6. What would happen to a person who failed to make MHC molecules? 7. Why does the body make five different classes of immunoglobulins? 8. Some materials, such as metal bone pins and plastic heart valves, can be implanted into the body without fear of rejection by the patient’s immune system. Why is this? What are the ideal properties of any material that is to be implanted? M16_BAUM7206_05_SE_C16.indd 497 9. What nonmembranous organelle is prevalent in plasma cells? What membranous organelle is prevalent? 10. The cross-sectional area of the afferent lymphatic vessels arriving at a lymph node is greater than the cross-sectional area of the efferent lymphatics exiting the lymph node. The result is that lymph moves slowly through a lymph node. Why is this advantageous? 11. Two students are studying for an exam on the body’s defense systems. One of them insists that complement is part of the nonspecific second line of defense, but the partner insists that complement is part of an antibody immune response in the third line of defense. How would you explain to them that they are both correct? 12. In general, what sorts of pathogens might be able to more successfully attack a patient with an inability to synthesize B lymphocytes? 13. What sorts of pathogens could successfully attack a patient who is unable to produce T lymphocytes? 14. As part of the treatment for some cancers, physicians kill the cancer patients’ dividing cells, including the stem cells that produce leukocytes, and then give the patients a bone marrow transplant from a healthy donor. Which cell is the most important cell in such transplanted marrow? 11/23/16 3:34 AM M APP CONC EPT       Chapter 16   Adaptive Immunity ING Using the following terms, fill in the following concept map that describes antibodies. Antigen-stimulated B cells Complement activation IgA IgD Agglutination Antibody-dependent cell-mediated cytotoxicity (ADDC) Antigens Antibodies are secreted by Neutralization Phagocytosis Plasma cells Secreted immunoglobulins IgE IgG IgM Inflammation are also known as bind to 1 are grouped into 5 classes 2 11 12 4 derived from 13 3 15 causing 5 6 Toxins M16_BAUM7206_05_SE_C16.indd 498 8 10 enhancing resulting in enhancing 7 9 Opsonization of 14 Phagocytosis Viruses 3/6/18 4:55 PM