Image summary: This is a photograph. The image depicts a medical professional in a white coat reviewing a radiographic film while simultaneously using a laptop computer. The professional is focused on the medical imaging and the digital interface. The scene suggests a clinical environment where diagnostic tools and digital records are used together to analyze patient data. It can be inferred that the individual is performing a medical diagnosis or consultation, highlighting the integration of traditional imaging and modern computing in healthcare.

The Lymphoid (Lymphatic) System and Immunity

The Lymphoid System, Disease Resistance, and Homeostasis The lymphoid system contributes to homeostasis by draining interstitial fluid as well as providing the mechanisms for defense against disease.

The environment in which we live is filled with microbes that have the ability to cause disease if given the right opportunity. If we did not resist these microbes, we would be ill constantly or even die. Fortunately, we have a number of defenses that keep microbes from either entering our bodies or combat them. if they do gain entrance. The lymphoid system is one of the principal body systems that helps to defend us against disease-producing microbes. In this chapter you will learn about the organization and components of the lymphoid system and its role in keeping us healthy.

22.1 The Concept of Immunity

Objectives

• Define immunity.

• Compare the two basic types of immunity.

Maintaining homeostasis in the body requires continual combat against harmful agents in our internal and external environments. Despite constant exposure to a variety of pathogens pathojens microbes such as bacteria and viruses—most people remain healthy. The body's surface is also subjected to cuts and bumps, exposure to ultraviolet rays, chemical toxins, and minor burns. However, it protects itself with an array of defensive mechanisms.

Immunity (i-Mü-ni-të) or resistance is the ability to ward off damage or disease through our defenses. Vulnerability or lack of resistance is termed susceptibility. The two general types of immunity are (1) innate and (2) adaptive. Innate (non-specific) immunity refers to defenses that are present at birth. Innate immunity does not involve specific recognition of a microbe and acts against all microbes in the same way.

Among the components of innate immunity are the first line of defense (the physical and chemical barriers of the skin and mucous membranes) and the second line of defense (antimicrobial substances, natural killer cells, phagocytes, inflammation, and fever). Innate immune responses represent immunity's early warning system and are designed to prevent microbes from entering the body and to help eliminate those that do gain access.

Adaptive (specific) immunity refers to defenses that involve specific recognition of a microbe once it has breached the innate immunity defenses. Adaptive immunity is based on a specific response to a specific microbe; that is, it adapts or adjusts to handle a specific microbe. Adaptive immunity involves lymphocytes (a type of white blood cell) called T lymphocytes (T cells) and B lymphocytes (B cells).

The body system responsible for adaptive immunity (and some aspects of innate immunity) is the lymphoid system. This system is closely allied with the cardiovascular system, and it also functions with the digestive system in the absorption of fatty foods. In this chapter, we explore the mechanisms that provide defenses against intruders and promote the repair of damaged body tissues.

1. What is a pathogen?

2. How are innate and adaptive immunity different?

22.2 Overview of the Lymphoid System

• List the components of the lymphoid system.

• Describe the functions of the lymphoid system.

Components of the Lymphoid System

The lymphoid limfoyd or lymphatic system consists of a fluid called lymph plasma, vessels called lymphatic vessels that transport the lymph plasma, a number of structures and organs containing lymphoid tissue (lymphocytes within a filtering tissue), and red bone marrow (Figure 22.1). The lymphoid system assists in circulating body fluids and helps defend the body against disease-causing agents. As you will see shortly, most components of blood plasma filter through blood capillary walls to form interstitial fluid. After interstitial fluid passes into lymphatic vessels, it is called lymph plasma limf = clear fluid) or lymph. The major difference between interstitial fluid and lymph plasma is location: Interstitial fluid is found between cells, and lymph plasma is located within lymphatic vessels and lymphoid tissue.

Figure 22.1 summary: This figure is an anatomical diagram. It illustrates the human lymphatic system, depicting the distribution of lymphatic vessels, nodes, and organs such as the spleen, thymus, and tonsils throughout the body. The diagram shows how the network of vessels collects fluid from various regions and channels it toward the thoracic duct and right lymphatic duct for return to the circulatory system. This indicates that the lymphatic system is an extensive, body-wide network designed to maintain fluid balance and provide immune surveillance by filtering lymph through various nodes located in strategic areas like the neck, armpits, and groin.

Interstitial fluid and lymph plasma contain less protein than blood plasma because most blood plasma protein molecules are too large to filter through the capillary wall. Each day, about 20 liters of fluid filter from blood into tissue spaces. This fluid must be returned to the cardiovascular system to maintain normal blood volume.

About 17 liters of the fluid filtered daily from the arterial end of blood capillaries return to the blood directly by reabsorption at the venous end of the capillaries. The remaining 3 liters per day pass first into lymphatic vessels and are then returned to the blood.

Lymphoid tissue is a specialized form of reticular connective tissue (see Table 4.4) that contains large numbers of lymphocytes. Recall from Chapter 19 that lymphocytes are agranular white blood cells (see Section 19.4). Two types of lymphocytes participate in adaptive immune responses: B cells and T cells (described shortly).

Functions of the Lymphoid System

The lymphoid system has three primary functions:

1. Drains excess interstitial fluid. Lymphatic vessels drain excess interstitial fluid from tissue spaces and return it to the blood. This function closely links it with the cardiovascular system. In fact, without this function, the maintenance of circulating blood volume would not be possible.

Figure 22.1 Components of the Lymphoid System.

The lymphoid system consists of lymph plasma, lymphatic vessels, lymphoid tissues, and red bone marrow.

Functions

1. Drains excess interstitial fluid.

2. Transports dietary lipids from the digestive canal to the blood.

3. Protects against invasion through immune responses.

(b) Areas drained by right lymphatic and thoracic ducts Area drained by right lymphatic duct Area drained by thoracic duct 2. Transports dietary lipids. Lymphatic vessels transport lipids and lipid-soluble vitamins (A, D, E, and K) absorbed by the digestive canal.

3. Carries out immune responses. Lymphoid tissue initiates highly specific responses directed against particular microbes or abnormal cells.

Checkpoint

3. What are the components and functions of the lymphoid system?

22.3 Lymphatic Vessels and Lymph Circulation

Objectives • Describe the organization of lymphatic vessels.

• Explain the formation and flow of lymph plasma.

Lymphatic vessels begin as lymphatic capillaries. These capillaries, which are located in the spaces between cells, are closed at one end (Figure 22.2). Just as blood capillaries converge to form venules and then veins, lymphatic capillaries unite to form larger lymphatic vessels (see Figure 22.1), which resemble small veins in structure but have thinner walls and more valves. At intervals along the lymphatic vessels, lymph plasma flows through lymph nodes, encapsulated bean-shaped organs consisting of masses of B cells and T cells. In the skin, lymphatic vessels lie in the subcutaneous tissue and generally follow the same route as veins; lymphatic vessels of the viscera generally follow arteries, forming plexuses (networks) around them. Tissues that lack lymphatic capillaries include avascular tissues (such as cartilage, the epidermis, and the cornea of the eye), portions of the spleen, and red bone marrow.

Lymphatic Capillaries

Lymphatic capillaries have greater permeability than blood capillaries and thus can absorb large molecules such as proteins and lipids. Lymphatic capillaries are also slightly larger in diameter than blood capillaries and have a unique one-way structure that permits interstitial fluid to flow into them but not out. The ends of endothelial cells that make up the wall of a lymphatic capillary overlap (Figure 22.2b). When pressure is greater in the interstitial fluid than in lymph plasma, the cells separate slightly, like the opening of a one-way swinging door, and interstitial fluid enters the lymphatic capillary. When pressure is greater inside the lymphatic capillary, the cells adhere more

Figure 22.2 Lymphatic Capillaries.

Lymphatic capillaries are found throughout the body except in avascular tissues, the central nervous system, portions of the spleen, and bone marrow. closely, and lymph plasma cannot escape back into interstitial fluid. The pressure is relieved as lymph plasma moves further down the lymphatic capillary. Attached to the lymphatic capillaries are anchoring filaments, which contain elastic fibers.

They extend out from the lymphatic capillary, attaching lymphatic endothelial cells to surrounding tissues. When excess interstitial fluid accumulates and causes tissue swelling, the anchoring filaments are pulled, making the openings between cells even larger so that more fluid can flow into the lymphatic capillary.

In the small intestine, specialized lymphatic capillaries called lacteals lakteals; lact-= milky) carry dietary lipids into lymphatic vessels and ultimately into the blood (see Figure 24.20). The presence of these lipids causes the lymph plasma draining from the small intestine to appear creamy white; such lymph plasma is referred to as chyle kil = juice). Elsewhere, lymph is a clear, pale-yellow fluid.

Lymphatic Trunks and Ducts

As you have already learned, lymph plasma passes from lymphatic capillaries into lymphatic vessels and then through lymph nodes. As lymphatic vessels exit lymph nodes in a particular region of the body, they unite to form lymphatic trunks. The principal lymphatic trunks are the lumbar, intestinal, broncho-mediastinal, subclavian, and jugular trunks (see Figure 22.3). The lumbar trunks drain lymph plasma from the lower limbs, the wall and viscera of the pelvis, the kidneys, the suprarenal glands, and the abdominal wall.

Figure 22.3 summary: This figure is an anatomical illustration consisting of a full-body anterior view and a detailed close-up inset. The content depicts the lymphatic system's drainage pathways, specifically highlighting the lymphatic trunks and their convergence into the thoracic duct and the right lymphatic duct, as well as their relationship to major veins such as the subclavian and internal jugular veins. The illustration shows that lymph plasma from the majority of the body is collected by the thoracic duct, while a smaller portion from the upper right quadrant is handled by the right lymphatic duct. It can be inferred that the lymphatic system operates as a one-way drainage network that eventually returns fluid to the venous circulation at the junction of the internal jugular and subclavian veins.

The intestinal trunk drains lymph plasma from the stomach, intestines, pancreas, spleen, and part of the liver. The broncho-mediastinal trunks (brongko-me-de-as-Ti-nal) drain lymph plasma from the thoracic wall, lung, and heart. The subclavian trunks drain the upper limbs. The jugular trunks drain the head and neck.

The lymph plasma passage from the lymphatic trunks to the venous system differs on the right and left sides of the body. On the right side the three lymphatic trunks (right jugular trunk, right subclavian trunk, and right bronchodialastinal trunk) usually open independently into the venous system on the anterior surface of the junction of the internal jugular and subclavian veins (Figure 22.3). Rarely, the three trunks will join to form a short right lymphatic duct that forms a single junction with the venous system. On the left side of the body, the largest lymph vessel, the thoracic duct forms the main duct for return of lymph plasma to the blood.

This long duct, approximately 38 to 45 centimeters (15 to 18 in.), begins as a dilation called the cisterna chyli (sisterna-na Kl-le; cisterna = cavity or reservoir) anterior to the second lumbar vertebra. The cisterna chyli receives lymph plasma from the right and left lumbar trunks and from the intestinal trunk. In the neck, the thoracic duct also receives lymph plasma from the left jugular and left subclavian trunks before opening into the anterior surface of the junction of the left internal jugular and subclavian veins.

The left bronchodialastinal trunk joins the anterior surface of the subclavian vein independently and does not join the thoracic duct. As a result of these pathways, lymph plasma from the upper right quadrant of the body returns to the superior vena cava from the right brachiocephalic vein, while all the lymph plasma from the left upper side of the body and the entire body below the diaphragm returns to the superior vena cava via the left brachiocephalic vein.

Formation and Flow of Lymph Plasma

Most components of blood plasma, such as nutrients, gases, and hormones, filter freely through the capillary walls to form interstitial fluid, but more fluid filters out of blood capillaries than returns to them by reabsorption (see Figure 21.7). The excess filtered fluid—about 3 liters per day—drains into lymphatic vessels and becomes lymph plasma. Because most blood plasma proteins are too large to leave blood vessels, interstitial fluid contains only a small amount of protein. Proteins that do leave blood plasma cannot return to the blood by diffusion because the concentration gradient (high level of blood plasma proteins inside blood capillaries, low level outside) opposes such movement. The proteins can, however, move readily through the more permeable lymphatic capillaries into lymph plasma. Thus, an important function of lymphatic vessels is to return the lost blood plasma proteins and lymph plasma to the bloodstream.

Like some veins, lymphatic vessels contain valves, which ensure the one-way movement of lymph plasma. As noted previously, lymph plasma drains into venous blood through the right lymphatic duct and the thoracic duct at the junction of the internal jugular and subclavian veins (Figure 22.3). Thus, the sequence of fluid flow is blood capillaries (blood) to interstitial spaces (interstitial fluid) to lymphatic capillaries (lymph plasma) to lymphatic vessels (lymph plasma) to lymphatic trunks or ducts (lymph plasma) to junction of the internal jugular and subclavian veins (blood). Figure 22.4 illustrates this sequence, along with the relationship of the lymphoid and cardiovascular systems. Both systems form a very efficient circulatory system.

Figure 22.4 summary: This figure is a biological diagram illustrating the lymphatic system and its relationship with the systemic and pulmonary circulation. The diagram depicts the flow of interstitial fluid as it is collected by lymphatic capillaries, passed through afferent lymphatic vessels into lymph nodes for filtration, and then transported via efferent lymphatic vessels and lymphatic ducts back into the cardiovascular system through the subclavian veins. It highlights key components such as the heart, arteries, veins, and various types of capillaries. The content indicates that the lymphatic system serves as a drainage and filtration network that returns leaked plasma from the tissues back to the bloodstream. It can be inferred that the lymphatic system acts as a critical bridge between the interstitial spaces and the circulatory system, ensuring fluid balance and providing an immune defense mechanism through the filtration of lymph in the nodes.

The same two “pumps” that aid the return of venous blood to the heart maintain the flow of lymph plasma.

1. Respiratory pump. Lymph plasma flow is also maintained by pressure changes that occur during inhalation (breathing in). Lymph flows from the abdominal region, where the pressure is higher, toward the thoracic region, where it is lower. When the pressures reverse during exhalation (breathing out), the valves in lymphatic vessels prevent backflow of lymph. In addition, when a lymphatic vessel distends, the smooth muscle in its wall contracts, which helps move lymph plasma from one segment of the vessel to the next.

2. Skeletal muscle pump. The “milking action” of skeletal muscle contractions (see Figure 21.9) compresses lymphatic vessels (as well as veins) and forces lymph plasma toward the junction of the internal jugular and subclavian veins.

Checkpoint

4. How do lymphatic vessels differ in structure form veins?

5. Diagram the route of lymph circulation.

22.4 Lymphoid Organs and Tissues

Objective

• Distinguish between primary and secondary lymphoid organs.

The widely distributed lymphoid organs and tissues are classified into two groups based on their functions. Primary lymphoid organs are the sites where stem cells divide and become Figure 22.4 Schematic diagram showing the relationship of the lymphoid system to the cardiovascular system. Arrows indicate the direction of flow of lymph plasma and blood.

The sequence of fluid flow is blood capillaries (blood) flows to interstitial spaces (interstitial fluid) flows to lymphatic capillaries (lymph plasma) flows to lymphatic vessels (lymph plasma) flows to lymphatic trunks or ducts (lymph plasma) flows to junction of the internal jugular and subclavian veins (blood). immunocompetent immunocompetent, that is, capable of mounting an immune response. The primary lymphoid organs are the red bone marrow (in flat bones and the epiphyses of long bones of adults) and the thymus. Multipotent stem cells in red bone marrow give rise to mature, immunocompetent B cells and to pre-T cells. The pre-T cells in turn migrate to the thymus, where they become immunocompetent T cells. The secondary lymphoid organs and tissues are the sites where most immune responses occur.

They include lymph nodes, the spleen, and lymphoid nodules. The thymus, lymph nodes, and spleen are considered organs because each is surrounded by a connective tissue capsule; lymphoid nodules, in contrast, are not considered organs because they lack a capsule.

Thymus

The thymus is a bilobed organ located in the mediastinum between the sternum and the ay-or-tuh. It extends from the top of the sternum or the inferior cervical region to the level of the fourth costal cartilages, anterior to the top of the heart. and its great vessels (Figure 22.5a). An enveloping layer of connective tissue holds the two lobes closely together, but a connective tissue capsule encloses each lobe separately. Extensions of the capsule, called trabeculae trabekule = little beams), penetrate inward and divide each lobe into lobules (Figure 22.5b).

Each thymic lobule consists of a deeply staining outer cortex and a lighter-staining central medulla (Figure 22.5b). The cortex is composed of large numbers of T cells and scattered nodular dendritic cells, epithelial cells, and macrophages. Immature T cells (pre-T cells) migrate from red bone marrow to the cortex of the thymus, where they proliferate and begin to mature. Nodular dendritic cells dendritik; dendr-= a tree), which are derived from monocytes (and so named because they have long, branched projections that resemble the dendrites of a neuron), assist the maturation process. As you will see shortly, nodular dendritic cells in other parts of the body, such as lymph nodes, play another key role in immune responses. Each of the specialized epithelial cells in the cortex has several long processes that surround and serve as a framework for as many as 50 T cells. These epithelial cells help “educate” the pre-T cells in a process known as positive selection (see Figure 22.22). Additionally, they produce thymic hormones that are thought to aid in the maturation of T cells. Only about 2% of developing T cells survive in the cortex. The remaining cells die via apoptosis (programmed cell death). Thymic macrophages makrofajez help clear out the debris of dead and dying cells. The surviving T cells enter the medulla.

Figure 22.22 summary: This figure consists of three flowcharts illustrating biological selection processes. The first section depicts the positive and negative selection of immature T cells in the thymus, showing the paths toward survival, deletion, or anergy based on the recognition of self-MHC proteins and self-peptides. The second section describes the fate of mature T cells in lymphatic tissue, where outcomes such as activation, anergy, or death are determined by antigen recognition and the presence of costimulation. The third section outlines the selection of immature B cells in the bone marrow, detailing how negative selection leads to either the development of mature B cells or cell deletion, and how subsequent costimulation determines whether the B cell activates or becomes anergic. Overall, the figure concludes that the immune system employs rigorous screening mechanisms to ensure that only functional cells capable of recognizing foreign antigens while remaining tolerant to self-antigens survive and activate.

The medulla consists of widely scattered, more mature T cells, epithelial cells, nodular dendritic cells, and macrophages (Figure 22.5c). Some of the epithelial cells become arranged into concentric layers of flat cells that degenerate and become

Figure 22.5 Thymus.

filled with keratohyalin granules and keratin. These clusters are called thymic (Hassall's) corpuscles. Although their role is uncertain, they may serve as sites of T cell death in the medulla. T cells that leave the thymus via the blood migrate to lymph nodes, the spleen, and other lymphatic tissues, where they colonize parts of these organs and tissues.

Because of its high content of lymphoid tissue and a rich blood supply, the thymus has a reddish appearance in a living body. With age, however, fatty infiltrations replace the lymphoid tissue and the thymus takes on more of the yellowish color of the invading fat, giving the false impression of reduced The bilobed thymus is largest at puberty and then the functional portion atrophies with age. size. However, the actual size of the thymus, defined by its connective tissue capsule, does not change. In infants, the thymus has a mass of about 70 g (2.3 ounces). It is after puberty that adipose and areolar connective tissue begin to replace the thymic tissue. By the time a person reaches maturity, the functional portion of the gland is reduced considerably, and in old age the functional portion may weigh only 3 g (0.1 ounces). Before the thymus atrophies, it populates the secondary lymphoid organs and tissues with T cells. However, some T cells continue to proliferate in the thymus throughout an individual's lifetime, but this number decreases with age.

Figure 22.5 summary: This figure consists of an anatomical illustration and two light microscopy images. The first panel shows the gross anatomical position of the thymus in an adolescent, situated in the upper chest between the lungs and anterior to the heart, trachea, and major blood vessels. The second panel provides a lower magnification view of the thymic tissue, highlighting the structural organization into lobules separated by trabeculae, with a distinct outer cortex and a central medulla. The third panel presents a high magnification view of the thymic medulla, revealing cellular details including T cells, epithelial cells, and characteristic thymic corpuscles. Together, these images demonstrate that the thymus is a specialized organ with a hierarchical structure, moving from its systemic location to its lobulated histology and finally to its specific cellular composition within the medulla.

Lymph Nodes

Located along lymphatic vessels are about 600 bean-shaped lymph nodes. They are scattered throughout the body, both superficially and deep, and usually occur in groups (see Figure 22.1). Large groups of lymph nodes are present near the mammary glands and in the axillae and groin.

Lymph nodes are 1 to 25 millimeters (0.04 to 1 in.) long and, like the thymus, are covered by a capsule of dense connective tissue that extends into the node (Figure 22.6). The capsular extensions, called trabeculae, divide the node into compartments, provide support, and provide a route for blood vessels into the interior of a node. Internal to the capsule is a supporting network of reticular fibers and fibroblasts. The capsule, trabeculae, reticular fibers, and fibroblasts constitute the stroma (supporting framework of connective tissue) of a lymph node.

Figure 22.6 summary: This figure is a composite anatomical illustration and microscopy set. It features a detailed diagram of a partially sectioned lymph node, a light microscope image of a lymph node section, and a scanning electron microscope image of a medullary sinus. The content illustrates the internal organization of the lymph node, including the capsule, outer and inner cortex, and medulla, while identifying specific cell types such as T cells, B cells, macrophages, and dendritic cells located within these regions. It also maps the flow of lymph plasma from afferent lymphatic vessels through various sinuses to the efferent lymphatic vessels. The figure demonstrates that lymph nodes are highly organized structures where lymph is filtered through a series of sinuses and processed by a diverse population of immune cells distributed across distinct histological zones.

The parenchyma (functioning part) of a lymph node is divided into a superficial cortex and a deep medulla. The cortex consists of an outer cortex and an inner cortex. Within the outer cortex are egg-shaped aggregates of B cells called lymphoid nodules.

A lymphoid nodule consisting chiefly of B cells is called a primary lymphoid nodule. Most lymphoid nodules in the outer cortex are secondary lymphoid nodules (Figure 22.6), which form in response to an antigen (a foreign

Clinical Connection

Breast Cancer Metastasis Through the Lymphoid System

In Chapter 28, we will consider the pathology, detection, and treatment of breast cancer in detail. Very simply, breast cancer is the development of a malignant tumor within the breast. At this point, we will concentrate on how breast cancer may spread to other parts of the body via the lymphatic system.

An understanding of the lymphatic drainage of the breasts is clinically important because knowledge of the direction of lymph plasma flow can help predict the spread of breast cancer to other sites in the body. When considering the lymphatic drainage of the breasts, it is convenient to divide the breasts into quadrants: upper lateral, lower lateral, upper medial, and lower medial. About 75% of the lymph plasma of the breasts drains into lymphatics located in the lateral breast quadrants.

These lymphatics drain into the 20 to 40 axillary lymph nodes. The majority of breast cancers occur in the (substance) and are sites of plasmocyte and memory B cell formation. After B cells in a primary lymphoid nodule recognize an antigen, the primary lymphoid nodule develops into a secondary lymphoid nodule. The center of a secondary lymphoid nodule contains a region of light-staining cells called a germinal center.

In the germinal center are B cells, nodular dendritic cells, and macrophages. When nodular dendritic cells "present" an antigen (described later in the chapter), B cells proliferate and develop into antibody-producing plasmicocytes or develop into memory B cells. Memory B cells persist after an initial immune response and "remember" having encountered a specific antigen. B cells that do not develop properly undergo apoptosis (programmed cell death) and are destroyed by macrophages. The region of a secondary lymphoid nodule surrounding the germinal center is composed of dense accumulations of B cells that have migrated away from their site of origin within the nodule.

The inner cortex does not contain lymphoid nodules. It consists mainly of T cells and nodular dendritic cells that enter a lymph node from other tissues. The nodular dendritic cells present antigens to T cells, causing their proliferation. The newly formed T cells then migrate from the lymph node to areas of the body where there is antigenic activity.

The medulla of a lymph node contains B cells, antibody-producing plasmocytes that have migrated out of the cortex into the medulla, and macrophages. The various cells are embedded in a network of reticular fibers and reticular cells.

As you have already learned, lymph plasma flows through a node in one direction only (Figure 22.6a). It enters through several afferent lymphatic vessels aferent; afferent = carrying toward), which penetrate the convex surface of the node at several points. The afferent vessels contain valves that open toward the center of the node, directing the lymph plasma inward. Within the node, lymph plasma enters sinuses, a series of irregular channels that contain branching reticular fibers, lymphocytes, and macrophages. From the afferent lymphatic vessels, lymph plasma flows into the subcapsular sinus. upper lateral quadrant, and the lymphatic vessels from this quadrant provide routes for the cancer to spread to the axillary lymph nodes. The spread of cancer from the organ of origin to another part of the body is called metastasis metastasis; meta-= beyond; stasi-= to stand), and it is referred to as lymphogenic metastasis when it occurs through lymphatic vessels. Abundant communications among lymphatic vessels and among axillary, cervical, and sternal lymph nodes (see Figure 22.1a) may also cause metastasis from the breast to develop in the opposite breast and abdomen.

If a breast cancer spreads beyond the axillary nodes, it is called a distant metastasis. The most common sites for metastasis include the lungs, liver, and bones. In general, cancerous lymph nodes feel enlarged, firm, nontender, and fixed to underlying structures.

By contrast, most lymph nodes that are enlarged due to an infection are softer, tender, and movable. It is ironic that the role of the lymphoid system in filtering lymph plasma and returning it to the cardiovascular system is also unfortunately the pathway for metastasis.

Figure 22.6 Structure of a lymph node. Green arrows indicate the direction of lymph plasma flow through a lymph node.

Lymph nodes are present throughout the body, usually clustered in groups.

Figure 22.6 Continued

subkapsoolar, immediately beneath the capsule. From here the lymph plasma flows through trabecular sinuses trabekular, which extend through the cortex parallel to the trabeculae, and into medullary sinuses, which extend through the medulla. The medullary sinuses drain into one or two efferent lymphatic vessels eferent; efferent = carrying away), which are wider and fewer in number than afferent vessels.

They contain valves that open away from the center of the lymph node to convey lymph plasma, antibodies secreted by plasmocytes, and activated T cells out of the node. Efferent lymphatic vessels emerge from one side of the lymph node at a slight depression called a hilum hilum. Blood vessels also enter and leave the node at the hilum.

Lymph nodes function as a type of filter. As lymph plasma enters one end of a lymph node, foreign substances are trapped by the reticular fibers within the sinuses of the node. Then macrophages destroy some foreign substances by phagocytosis, while lymphocytes destroy others by immune responses. The filtered lymph plasma then leaves the other end of the lymph node. Since there are many afferent lymphatic vessels that bring lymph into a lymph node and only one or two efferent lymphatic vessels that transport lymph plasma out of a lymph node, the slow flow of lymph plasma within the lymph nodes allows additional time for lymph plasma to be filtered. Additionally, all lymph plasma flows through multiple lymph nodes on its path through the lymph vessels. This exposes the lymph plasma to multiple filtering events before returning to the blood.

Spleen The oval spleen is the largest single mass of lymphoid tissue in the body. It is a soft, encapsulated organ of variable size, but on average it fits in a person's open hand and measures about 12 centimeters (5 in.) in length (Figure 22.7a). It is located in the left hypochondriac region between the stomach and diaphragm. The superior surface of the spleen is smooth and convex and conforms to the concave surface of the diaphragm.

Neighboring organs make indentations in the visceral surface of the spleen—the gastric impression (stomach), the renal impression (left kidney), and the colic impression (left colic flexure of large intestine). Like lymph nodes, the spleen has a hilum. Through it pass the splenic artery, splenic vein, and efferent lymphatic vessels.

A capsule of dense connective tissue surrounds the spleen and is covered in turn by a serous membrane, the visceral peritoneum. Trabeculae extend inward from the capsule. The capsule plus trabeculae, reticular fibers, and fibroblasts constitute

Figure 22.7 summary: This figure consists of anatomical diagrams and a light micrograph. The content illustrates the external visceral surface of the spleen, its internal structural organization, and a histological view of the splenic tissue. The diagrams identify key features such as the splenic artery and vein, the hilum, various organ impressions, and the internal distribution of white pulp, red pulp, and trabeculae. The histological image provides a detailed view of the red pulp and white pulp surrounding a central artery. From this figure, it can be inferred that the spleen possesses a complex vascular network and a specialized internal architecture designed to filter blood, characterized by the distinct separation and interaction between the white pulp and red pulp within a protective capsule.

Clinical Connection

Ruptured Spleen

The spleen is the organ most often damaged in cases of abdominal trauma. Severe blows over the inferior left chest or superior abdomen can fracture the protecting ribs. Such crushing injury may result in a ruptured spleen, which causes significant hemorrhage and shock. Prompt removal of the spleen, called a splenectomy splenektome, is needed to prevent death due to

Q After birth, what are the main functions of the spleen?

the stroma of the spleen; the parenchyma of the spleen consists of two different kinds of tissue called white pulp and red pulp (Figure 22.7b, c). White pulp is lymphoid tissue, consisting mostly of lymphocytes and macrophages arranged around branches of the splenic artery called central arteries. The red pulp consists of blood-filled venous sinuses and cords of splenic tissue called splenic (Billroth's) cords. Splenic cords bleeding. Other structures, particularly red bone marrow and the liver, can take over some functions normally carried out by the spleen. Immune functions, however, decrease in the absence of a spleen. The spleen's absence also places the patient at higher risk for sepsis (a blood infection) due to loss of the filtering and phagocytic functions of the spleen. To reduce the risk of sepsis, patients who have undergone a splenectomy take prophylactic (preventive) antibiotics before any invasive procedures. consist of red blood cells, macrophages, lymphocytes, plasmacytes, and granulocytes. Veins are closely associated with the red pulp.

Blood flowing into the spleen through the splenic artery enters the central arteries of the white pulp. Within the white pulp, B cells and T cells carry out immune functions, similarly to lymph nodes, while spleen macrophages destroy blood-borne pathogens by phagocytosis. Within the red pulp, the spleen performs three functions related to blood cells: (1) removal by macrophages of ruptured, worn out, or defective blood cells and platelets; (2) storage of platelets, up to one-third of the body's supply; and (3) production of blood cells (hemopoiesis) during fetal life.

Lymphoid Nodules Lymphoid nodules are egg-shaped masses of lymphoid tissue that are not surrounded by a capsule. Because they are scattered throughout the lamina propria (connective tissue) of mucous membranes lining the digestive canal, urinary and genital tracts, and the respiratory airways, lymphoid nodules in these areas are also referred to as mucosa-associated lymphoid tissue (malt).

Although many lymphatic nodules are small and solitary, some occur in multiple large aggregations in specific parts of the body. Among these are the tonsils in the pharyngeal region and the aggregated lymphoid follicles (Peyer's patches) in the ileum of the small intestine. Aggregations of lymphoid nodules also occur in the appendix.

Usually there are five tonsils. Tonsils are masses of lymphoid tissue covered with a mucous membrane. They form a ring at the junction of the oral cavity and oropharynx and at the junction of the nasal cavity and nasopharynx (see Figure 23.2b). The tonsils are strategically positioned to participate in immune responses against inhaled or ingested foreign substances.

The single pharyngeal tonsil faringjeal or adenoid is embedded in the posterior wall of the nasopharynx. The two palatine tonsils palatin lie at the posterior region of the oral cavity, one on either side; these are the tonsils commonly removed in a tonsillectomy. The paired lingual tonsils lingwal, located at the base of the tongue, may also require removal during a tonsillectomy.

Clinical Connection

Tonsillitis

Tonsillitis is an infection or inflammation of the tonsils. Most often, it is caused by a virus, but it may also be caused by the same bacteria that cause strep throat. The principal symptom of tonsillitis is a sore throat.

Additionally, fever, swollen lymph nodes, nasal congestion, difficulty in swallowing, and headache may also occur. Tonsillitis is the original usually resolves on its own. Bacterial tonsillitis is typically treated with antibiotics.

Tonsillectomy tonsilektome; ectomy = cutting out), the removal of a tonsil, may be indicated for individuals who do not respond to other treatments. Such individuals usually have tonsillitis lasting for more than 3 months (despite medication), obstructed air pathways, and difficulty in swallowing and talking. It appears that tonsillectomy does not interfere with a person's response to subsequent infections.

6. What is the role of the thymus in immunity?

7. What functions do lymph nodes, the spleen, and the tonsils serve?

Image summary: This figure is a medical illustration. It depicts a human fetus positioned within a womb, connected to the uterine wall via an umbilical cord. The illustration demonstrates the fetal position and the anatomical relationship between the developing embryo and the gestational environment.

22.5 Development of Lymphoid Tissues

• Describe the development of lymphoid tissues.

Lymphoid tissues begin to develop by the end of the fifth week of embryonic life. Lymphatic vessels develop from lymph sacs that arise from developing veins, which are derived from mesoderm.

The first lymph sacs to appear are the paired jugular lymph sacs at the junction of the internal jugular and subclavian veins (Figure 22.8). From the jugular lymph sacs, lymphatic capillary plexuses spread to the thorax, upper limbs, neck, and head. Some of the plexuses enlarge and form lymphatic vessels in their respective regions. Each jugular lymph sac retains at least one connection with its jugular vein, the left one developing into the superior portion of the thoracic duct.

Figure 22.8 summary: This is an anatomical diagram. The figure illustrates the early development of the lymphatic system within a human embryo, labeling key structures such as the jugular, retroperitoneal, and posterior lymph sacs, along with the thoracic duct, cisterna chyli, and major veins including the internal jugular, subclavian, and inferior vena cava. The diagram shows that the lymphatic system originates from several distinct lymph sacs that are interconnected by ducts and eventually drain into the venous system, indicating a coordinated developmental pattern where lymphatic vessels form a network to transport lymph from the lower and upper body toward the heart.

The next lymph sac to appear is the unpaired retroperitoneal lymph sac (re'-tro-per'-i-to-Ne-al) at the root of the mesentery of the intestine. It develops from the primitive vena cava and mesonephric (primitive kidney) veins. Capillary plexuses and lymphatic vessels spread from the retroperitoneal lymph sac to the abdominal viscera and diaphragm. The sac establishes connections with the cisterna chyli but loses its connections with neighboring veins.

At about the time the retroperitoneal lymph sac is developing, another lymph sac, the cisterna chyli, develops inferior to the diaphragm on the posterior abdominal wall. It gives rise to the inferior portion of the thoracic duct and the cisterna chyli of the thoracic duct. Like the retroperitoneal lymph sac, the cisterna chyli also loses its connections with surrounding veins.

Figure 22.8 Development of Lymphoid Tissues.

Lymphoid tissues are derived from mesoderm.

The last of the lymph sacs, the paired posterior lymph sacs, develop from the iliac veins. The posterior lymph sacs produce capillary plexuses and lymphatic vessels of the abdominal wall, pelvic region, and lower limbs. The posterior lymph sacs join the cisterna chyl and lose their connections with adjacent veins.

With the exception of the anterior part of the sac from which the cisterna chyli develops, all lymph sacs become invaded by mesenchymal cells mesengkimal and are converted into groups of lymph nodes.

The spleen develops from mesenchymal cells between layers of the dorsal mesentery of the stomach. The thymus arises as an outgrowth of the third pharyngeal pouch (see Figure 18.20a).

Checkpoint

8. What are the names of the four lymph sacs from which lymphatic vessels develop?

22.6 Innate Immunity

Objective

• Describe the components of innate immunity.

Innate (nonspecific) immunity includes the external physical and chemical barriers provided by the skin and mucous membranes. It also includes various internal defenses, such as antimicrobial substances, natural killer cells, phagocytes, inflammation, and fever.

First Line of Defense: Skin and Mucous Membranes

The skin and mucous membranes of the body are the first line of defense against pathogens. These structures provide both physical and chemical barriers that discourage pathogens and foreign substances from penetrating the body and causing disease.

With its many layers of closely packed, keratinized cells, the outer epithelial layer of the skin—the epidermis—provides a formidable physical barrier to the entrance of microbes (see Figure 5.1). In addition, periodic shedding of epidermal cells helps remove microbes at the skin surface. Bacteria rarely penetrate the intact surface of healthy epidermis. If this surface is broken by cuts, burns, or punctures, however, pathogens can penetrate the epidermis and invade adjacent tissues or circulate in the blood to other parts of the body.

The epithelial layer of mucous membranes, which line body cavities, secretes a fluid called mucus that lubricates and moistens the cavity surface. Because mucus is slightly viscous, it traps many microbes and foreign substances. The mucous membrane of the nose has mucus-coated hairs that trap and filter microbes, dust, and pollutants from inhaled air.

The mucous membrane of the upper respiratory tract contains cilia, microscopic hairlike projections on the surface of the epithelial cells. The waving action of cilia propels inhaled dust and microbes that have become trapped in mucus toward the throat. Coughing and sneezing accelerate movement of mucus and its entrapped pathogens out of the body.

Swallowing mucus sends pathogens to the stomach, where gastric juice destroys them.

Other fluids produced by various organs also help protect epithelial surfaces of the skin and mucous membranes. The lacrimal apparatus lakrimal of the eyes (see Figure 17.6) manufactures and drains away tears in response to irritants. Blinking spreads tears over the surface of the eyeball, and the continual washing action of tears helps to dilute microbes and keep them from settling on the surface of the eye. Tears also contain lysozyme (Lî-sô-zîm), an enzyme capable of breaking down the cell walls of certain bacteria.

Besides tears, lysozyme is present in saliva, perspiration, nasal secretions, and tissue fluids. Saliva, produced by the salivary glands, washes microbes from the surfaces of the teeth and from the mucous membrane of the mouth, much as tears wash the eyes. The flow of saliva reduces colonization of the mouth by microbes.

The cleansing of the urethra by the flow of urine retards microbial colonization of the urinary system. Vaginal secretions likewise move microbes out of the body in females. Defecation and vomiting also expel microbes. For example, in response to some microbial toxins, the smooth muscle of the lower digestive canal contracts vigorously; the resulting diarrhea rapidly expels many of the microbes.

Certain chemicals also contribute to the high degree of resistance of the skin and mucous membranes to microbial invasion. Sebaceous glands of the skin secrete an oily substance called sebum that forms a protective film over the surface of the skin. The unsaturated fatty acids in sebum inhibit the growth of certain pathogenic bacteria and fungi.

The acidity of the skin (pH 3 to 5) is caused in part by the secretion of fatty acids and lactic acid. Perspiration helps flush microbes from the surface of the skin. Gastric juice, produced by the glands of the stomach, is a mixture of hydrochloric acid, enzymes, and mucus.

The strong acidity of gastric juice (pH 1.2 to 3.0) destroys many bacteria and most bacterial toxins. Vaginal secretions also are slightly acidic, which discourages bacterial growth.

Second Line of Defense: Internal Defenses

When pathogens penetrate the physical and chemical barriers of the skin and mucous membranes, they encounter a second line of defense: internal antimicrobial substances, phagocytes, natural killer cells, inflammation, and fever.

Antimicrobial Substances There are four main types of antimicrobial substances that discourage microbial growth: interferons, complement, iron-binding proteins, and antimicrobial proteins.

1. Lymphocytes, macrophages, and fibroblasts infected with viruses produce proteins called interferons I.F.N's (in'ter-FÉ-R-ons). Once released by virus-infected cells, I.F.N's diffuse to uninfected neighboring cells, where they induce synthesis of antiviral proteins that interfere with viral replication. Although I.F.N's do not prevent viruses from attaching to and penetrating host cells, they do stop replication. Viruses can cause disease only if they can replicate within body cells. I.F.N's are an important defense against infection by many different viruses. The three types of interferons are alpha-, beta-, and gamma-I.F.N.

2. A group of normally inactive proteins in blood plasma and on plasma membranes makes up the complement system. When activated, these proteins “complement” or enhance certain immune reactions (see Section 22.9). The complement system causes cytolysis (bursting) of microbes, promotes phagocytosis, and contributes to inflammation.

3. Iron-binding proteins inhibit the growth of certain bacteria by reducing the amount of available iron. Examples include transferrin (found in blood and tissue fluids), lactoferrin (found in milk, saliva, and mucus), ferritin (found in the liver, spleen, and red bone marrow), and hemoglobin (found in red blood cells).

4. Antimicrobial proteins A.M.P's are short peptides that have a broad spectrum of antimicrobial activity. Examples of A.M.P's are dermicidin (der-ma-Si-din) (produced by sweat glands), defensins and cathelicidins (cath-el-i-Si-dins) (produced by neutrophils, macrophages, and epithelia), and thrombocidin (throm'-bo-Si-din) (produced by platelets). In addition to killing a wide range of microbes, A.M.P's can attract dendritic cells and mast cells, which participate in immune responses. Interestingly enough, microbes exposed to A.M.P's do not appear to develop resistance, as often happens with antibiotics.

Natural Killer Cells and Phagocytes When microbes penetrate the skin and mucous membranes or bypass the antimicrobial substances in blood, the next nonspecific defense consists of natural killer cells and phagocytes. About 5 to 10% of lymphocytes in the blood are natural killer (N.K) cells. They are also present in the spleen, lymph nodes, and red bone marrow. N.K cells lack the membrane molecules that identify B and T cells, but they have the ability to kill a wide variety of infected body cells and certain tumor cells. N.K cells attack any body cells that display abnormal or unusual plasma membrane proteins.

The binding of N.K cells to a target cell, such as an infected human cell, causes the release of granules containing toxic substances from N.K cells. Some granules contain a protein called perforin perforin that inserts into the plasma membrane of the target cell and creates channels (perforations) in the membrane. As a result, extracellular fluid flows into the target cell and the cell bursts, a process called cytolysis.

sitolisiss; cyto-= cell; -lysis = loosening). Other granules of N.K cells release granzymes granzims, which are protein-digesting enzymes that induce the target cell to undergo apoptosis, or self-destruction. This type of attack kills infected cells, but not the microbes inside the cells; the released microbes, which may or may not be intact, can be destroyed by phagocytes.

Phagocytes fagosits; phago-= eat; -cytes = cells) are specialized cells that perform phagocytosis (fag-o-si-To-sis; -osis = process), the ingestion of microbes or other particles such as cellular debris (see Figure 3.13). The two major types of phagocytes are neutrophils and macrophages. When an infection occurs, neutrophils and monocytes migrate to the infected area. During this migration, the monocytes enlarge and develop into actively phagocytic macrophages called wandering macrophages.

Other macrophages, called resting (fixed) macrophages, stand guard in specific tissues. Among the resting macrophages are histiocytes histosits (connective tissue macrophages), stellate reticuloendothelial cells stelat retikuloendotheleal or Kupffer cells koopfer in the liver, alveolar macrophages in the lungs, microglial cells in the nervous system, and tissue macrophages in the spleen, lymph nodes, and red bone marrow. In addition to being an innate defense mechanism, phagocytosis plays a vital role in adaptive immunity, as discussed later in the chapter.

Clinical Connection

Microbial Evasion of Phagocytosis

Some microbes, such as the bacteria that cause pneumonia, have extracellular structures called capsules that prevent adherence. This makes it physically difficult for phagocytes to engulf the microbes. Other microbes, such as the toxin-producing bacteria that cause one kind of food poisoning, may be ingested but not killed; instead, the toxins they produce (leukocidins) may kill the phagocytes by causing the release of the phagocyte's own lysosomal enzymes into its cytoplasm.

Still other microbes—such as the bacteria that cause tuberculosis—inhibit fusion of phagosomes and lysosomes and thus prevent exposure of the microbes to lysosomal enzymes. These bacteria apparently can also use chemicals in their cell walls to counter the effects of lethal oxidants produced by phagocytes. Subsequent multiplication of the microbes within phagosomes may eventually destroy the phagocyte.

Phagocytosis occurs in five phases: chemotaxis, adherence, ingestion, digestion, and killing (Figure 22.9):

Figure 22.9 summary: This figure consists of a schematic diagram and a scanning electron micrograph. The first part illustrates the sequential stages of phagocytosis, detailing the process from chemotaxis and adherence to ingestion, digestion, and killing. It labels key cellular components such as pseudopods, phagosomes, lysosomes, and residual bodies. The second part provides a high-magnification image of a white blood cell actively engulfing a microbe. Together, these images demonstrate that phagocytes identify and surround foreign microbes using cytoplasmic extensions, internalize them into vesicles, and use digestive enzymes to break down the pathogen, eventually leaving behind indigestible material.

1 Chemotaxis. Phagocytosis begins with chemotaxis kemotaksis, a chemically stimulated movement of phagocytes to a site of damage. Chemicals that attract phagocytes might come from invading microbes, white blood cells, damaged tissue cells, or activated complement proteins.

2 Adherence. Attachment of the phagocyte to the microbe or other foreign material is termed adherence adherents.

Figure 22.9 Phagocytosis of a Microbe.

The major types of phagocytes are neutrophils and macrophages.

The binding of complement proteins to the invading pathogen enhances adherence.

③ Ingestion. The plasma membrane of the phagocyte extends projections, called pseudopods soodopods, that engulf the microbe in a process called ingestion. When the pseudopods meet they fuse, surrounding the microorganism with a sac called a phagosome fagosom.

4 Digestion. The phagosome enters the cytoplasm and merges with lysosomes to form a single, larger structure called a phagolysosome (fag-delta-L-s-delta-s-delta-m). The lysosome contributes lysozyme, which breaks down microbial cell walls, and other digestive enzymes that degrade carbohydrates, proteins, lipids, and nucleic acids. The phagocyte also forms lethal oxidants, such as superoxide anion (O 2 superscript minus), hypochlorite anion (O C l superscript minus), and hydrogen peroxide (H 2 O 2), in a process called an oxidative burst.

5 Killing. The chemical onslaught provided by lysozyme, digestive enzymes, and oxidants within a phagolysosome quickly kills many types of microbes. Any materials that cannot be degraded further remain in structures called residual bodies.

Inflammation Inflammation is a nonspecific defensive response of the body to tissue damage. Among the conditions that may produce inflammation are pathogens, abrasions, chemical irritations, distortion or disturbances of cells, and extreme temperatures. Inflammation is an attempt to dispose of microbes, toxins, or foreign material at the site of injury, to prevent their spread to other tissues, and to prepare the site for tissue repair in an attempt to restore tissue homeostasis. There are certain signs and symptoms associated with inflammation and these can be recalled by using the acronym Prish.

- P is for pain due to the release of certain chemicals.

- R is for redness because more blood is rushed to the affected area.

- I is for immobility that results from some loss of function in severe inflammations.

- S is for swelling caused by an accumulation of fluids.

- H is for heat which is also due to more blood rushing to the affected area.

Because inflammation is one of the body's nonspecific defense mechanisms, the response of a tissue to a cut is similar to the response to damage caused by burns, radiation, or bacterial or viral invasion. In each case, the inflammatory response has three basic stages: (1) vasodilation and increased permeability of blood vessels, (2) emigration (movement) of phagocytes from the blood into interstitial fluid, and, ultimately, (3) tissue repair.

Vasodilation and Increased Blood Vessel Permeability Two immediate changes occur in the blood vessels in a region of tissue injury: vasodilation (increase in diameter) of arterioles and increased permeability of capillaries (Figure 22.10). Increased permeability means that substances normally retained in blood are permitted to pass from the blood vessels. Vasodilation allows more blood to flow through the damaged area, and increased permeability permits defensive proteins such as antibodies and clotting factors to enter

Figure 22.10 summary: This figure is a biological diagram illustrating a physiological process. It depicts the sequence of events following a tissue injury where microbes enter the body, triggering a response from the circulatory system. The diagram shows the process of vasodilation and increased permeability in a blood vessel, followed by the emigration of phagocytes from the vessel into the surrounding tissue. These phagocytes then move toward the site of infection via chemotaxis to target the microbes. The figure demonstrates that the body responds to localized tissue damage and microbial invasion by recruiting immune cells from the bloodstream to the site of injury to neutralize the threat.

Figure 22.10 Inflammation.

The three stages of inflammation are: (1) vasodilation and increased permeability of blood vessels, (2) phagocyte emigration, and (3) tissue repair.

Q What causes each of the following signs and symptoms of inflammation: redness, pain, heat, and swelling? the injured area from the blood. The increased blood flow also helps remove microbial toxins and dead cells.

Among the substances that contribute to vasodilation, increased permeability, and other aspects of the inflammatory response are:

• Histamine. In response to injury, mast cells in connective tissue and basophils and platelets in blood release histamine. Neutrophils and macrophages attracted to the site of injury also stimulate the release of histamine, which causes vasodilation and increased permeability of blood vessels.

• Kinins. Polypeptides formed in blood from inactive precursors called kininogens (kinins) induce vasodilation and increased permeability and serve as chemotactic agents for phagocytes. An example of a kinin is bradykinin.

• Prostaglandins. Prostaglandins P.G's prostaglandins, especially those of the E series, are released by damaged cells and intensify the effects of histamine and kinins. P.G's also may stimulate the emigration of phagocytes through capillary walls.

• Leukotrienes. Produced by basophils and mast cells, leukotrienes L.T's lukotriens cause increased permeability; they also function in adherence of phagocytes to pathogens and as chemotactic agents that attract phagocytes.

• Complement. Different components of the complement system stimulate histamine release, attract neutrophils by chemotaxis, and promote phagocytosis; some components can also destroy bacteria.

Dilation of arterioles and increased permeability of capillaries produce three of the signs and symptoms of inflammation: heat, redness (erythema), and swelling (edema). Heat and redness result from the large amount of blood that accumulates in the damaged area. As the local temperature rises slightly, metabolic reactions proceed more rapidly and release additional heat. Edema results from increased permeability of blood vessels, which permits more fluid to move from blood plasma into tissue spaces.

Pain is a prime symptom of inflammation. It results from injury to neurons and from toxic chemicals released by microbes. Kinins affect some nerve endings, causing much of the pain associated with inflammation. Prostaglandins intensify and prolong the pain associated with inflammation. Pain may also be due to increased pressure from edema.

The increased permeability of capillaries allows leakage of blood-clotting factors into tissues. The clotting sequence is set into motion, and fibrinogen is ultimately converted to an insoluble, thick mesh of fibrin threads that localizes and traps invading microbes and blocks their spread.

Emigration of Phagocytes Within an hour after the inflammatory process starts, phagocytes appear on the scene. As large amounts of blood accumulate, neutrophils begin to stick to the inner surface of the endothelium (lining) of blood vessels (Figure 22.10). Then the neutrophils begin to squeeze through the wall of the blood vessel to reach the damaged area. This process, called emigration emigrashun, depends on chemotaxis. Neutrophils attempt to destroy the invading microbes by phagocytosis. A steady stream of neutrophils is ensured by the production and release of additional cells from red bone marrow. Such an increase in white blood cells in the blood is termed leukocytosis (loo-kô-sî-TÔ-sis).

Although neutrophils predominate in the early stages of infection, they die off rapidly. As the inflammatory response continues, monocytes follow the neutrophils into the infected area. Once in the tissue, monocytes transform into wandering macrophages that add to the phagocytic activity of the resting macrophages already present.

True to their name, macrophages are much more potent phagocytes than neutrophils. They are large enough to engulf damaged tissue, worn-out neutrophils, and invading microbes.

Eventually, macrophages also die. Within a few days, a pocket of dead phagocytes and damaged tissue forms; this collection of dead cells and fluid is called pus. Pus formation occurs in most inflammatory responses and usually continues until the infection subsides. At times, pus reaches the surface of the body or drains into an internal cavity and is dispersed; on other occasions the pus remains even after the infection is terminated. In this case, the pus is gradually destroyed over a period of days and is absorbed.

Clinical Connection

Abscesses and Ulcers

If pus cannot drain out of an inflamed region, the result is an abscess—an excessive accumulation of pus in a confined space. Common examples are pimples and boils. When superficial inflamed tissue sloughs off the surface of an organ or tissue, the resulting open sore is called an ulcer. People with poor circulation—for instance, diabetics with advanced atherosclerosis—are susceptible to ulcers in the tissues of their legs. These ulcers, which are called stasis ulcers, develop because of poor oxygen and nutrient supply to tissues that then become very susceptible to a very mild injury or infection.

Inflammation can be classified as acute or chronic depending on a number of factors. In acute inflammation the signs and symptoms develop rapidly and usually last for a few days or even a few weeks. It is usually mild and self-limiting and the principal defensive cells are neutrophils. Examples of acute inflammation are a sore throat, appendicitis, cold or flu, bacterial pneumonia, and a scratch on the skin.

In chronic inflammation the signs and symptoms develop more slowly and can last for up to several months or years. It is often severe and progressive and the principal defensive cells are monocytes and macrophages. Examples of chronic inflammation are mononucleosis, peptic ulcer disease, tuberculosis, rheumatoid arthritis, and ulcerative colitis.

Fever Fever is an abnormally high body temperature that occurs because the hypothalamic thermostat is reset. It commonly occurs during infection and inflammation. Many bacterial toxins elevate body temperature, sometimes by triggering release of fever-causing cytokines such as interleukin-1 from macrophages. Elevated body temperature intensifies the effects of interferons, inhibits the growth of some microbes, and speeds up body reactions that aid repair.

Table 22.1 summarizes the components of innate immunity.

Table 22.1 summary: This table outlines the components of the innate immune system, categorizing them into two primary lines of defense. The first line consists of physical barriers, such as the skin and various secretions that block or expel microbes, and chemical factors that inhibit microbial growth through acidity or antimicrobial substances. The second line comprises internal defenses, including a variety of antimicrobial proteins, specialized cells like phagocytes and natural killer cells, and systemic responses such as inflammation and fever that work together to destroy pathogens and repair tissues.

Adaptive Immunity

- Describe how T cells and B cells arise and function in adaptive immunity.

• Explain the relationship between an antigen and an antibody.

• Compare the functions of cell-mediated immunity and antibody-mediated immunity.

The ability of the body to defend itself against specific invading agents such as bacteria, toxins, viruses, and foreign tissues is called adaptive (specific) immunity. Substances that are recognized as foreign and provoke immune responses are called antigens (Ags) antijens, meaning antibody generators. Two properties distinguish adaptive immunity from innate immunity: (1) specificity for particular foreign molecules (antigens), which also involves distinguishing self from nonself molecules, and (2) memory for most previously encountered antigens so that a second encounter prompts an even more rapid and vigorous response.

The branch of science that deals with the responses of the body when challenged by antigens is called immunology immunolöje; immuno-= free from service or exempt; -logy = study of). The immune system includes the cells and tissues that carry out immune responses.

Maturation of T Cells and B Cells

Adaptive immunity involves lymphocytes called B cells and T cells. Both develop in primary lymphoid organs (red bone marrow and the thymus) from multipotent stem cells that originate in red bone marrow (see Figure 19.3). B cells complete their development in red bone marrow, a process that continues throughout life. T cells develop from pre-T cells that migrate from red bone marrow into the thymus, where they mature (Figure 22.11). Most T cells arise before puberty, but they continue to mature and leave the thymus throughout life. B cells and T cells are named based on where they mature.

In birds, B cells mature in an organ called the bursa of Fabricius. Although this organ is not present in humans, the term B cell is still used, but the letter B stands for bursa equivalent, which is the red bone marrow since that is the location in humans where B cells mature. T cells are so named because they mature in the thymus gland.

Before T cells leave the thymus or B cells leave red bone marrow, they develop immunocompetence immunokompens, the ability to carry out adaptive immune responses. This means that B cells and T cells begin to make several distinctive proteins that are inserted into their plasma membranes. Some of these proteins function as antigen receptors—molecules capable of recognizing specific antigens (Figure 22.11).

There are two major types of mature T cells that exit the thymus: helper T cells and cytotoxic T cells sitotoksik

(Figure 22.11). Helper T cells are also known as C.D.4 T cells, which means that, in addition to antigen receptors, their plasma membranes include a protein called C.D.4. Cytotoxic T cells are also referred to as C.D.8 T cells because their plasma membranes contain not only antigen receptors but also a protein known as C.D.8. As we will see later in this chapter, these two types of T cells have very different functions.

Types of Adaptive Immunity

There are two types of adaptive immunity: cell-mediated immunity and antibody-mediated immunity. Both types of adaptive immunity are triggered by antigens. In cell-mediated immunity, cytotoxic T cells directly attack invading antigens. In antibody-mediated immunity, B cells transform into plasmocytes, which synthesize and secrete specific proteins called antibodies (Abs) or immunoglobulins (Igs) immunoglobulins. A given antibody can bind to and inactivate a specific antigen. Helper T cells aid the immune responses of both cell-mediated and antibody-mediated immunity.

Cell-mediated immunity is particularly effective against (1) intracellular pathogens, which include any viruses, bacteria, or fungi that are inside cells; (2) some cancer cells; and (3) foreign tissue transplants. Thus, cell-mediated immunity always involves cells attacking cells. Antibody-mediated immunity works mainly against extracellular pathogens, which include any viruses, bacteria, or fungi that are in body fluids outside cells. Since antibody-mediated immunity involves antibodies that bind to antigens in body humors or fluids (such as blood plasma and lymph plasma), it is also referred to as humoral immunity.

In most cases, when a particular antigen initially enters the body, there is only a small group of lymphocytes with the correct antigen receptors to respond to that antigen; this small group of cells includes a few helper T cells, cytotoxic T cells, and B cells. Depending on its location, a given antigen can provoke both types of adaptive immune responses. This is due to the fact that when a specific antigen invades the body, there are usually many copies of that antigen spread throughout the body's tissues and fluids. Some copies of the antigen may be present inside body cells (which provokes a cell-mediated immune response by cytotoxic T cells), while other copies of the antigen may be present in extracellular fluid (which provokes an antibody-mediated immune response by B cells). Thus, cell-mediated and antibody-mediated immune responses often work together to eliminate the large number of copies of a particular antigen from the body.

Clonal Selection: The Principle

As you just learned, when a specific antigen is present in the body, there are usually many copies of that antigen located throughout the body's tissues and fluids. The numerous copies of the antigen initially outnumber the small group of helper T cells, cytotoxic T cells, and B cells with the correct antigen receptors to respond to that antigen. Therefore, once each of these lymphocytes encounters a copy of the antigen and

Figure 22.11 B cells and pre-T cells arise from pluripotent stem cells in red bone marrow.

B cells and T cells develop in primary lymphoid tissues (red bone marrow and the thymus) and are activated in secondary lymphoid organs and tissues (lymph nodes, spleen, and lymphoid nodules). Once activated, each type of lymphocyte forms a clone of cells that can recognize a specific antigen. For simplicity, antigen receptors, C.D.4 proteins, and C.D.8 proteins are not shown in the plasma membranes of the cells of the lymphocyte clones.

The two types of adaptive immunity are cell-mediated immunity and antibody-mediated immunity. receives stimulatory cues, it subsequently undergoes clonal selection. Clonal selection is the process by which a lymphocyte proliferates (divides) and differentiates (forms more highly specialized cells) in response to a specific antigen. The result of clonal selection is the formation of a population of identical cells, called a clone, that can recognize the same specific antigen as the original lymphocyte (Figure 22.11). Before the first exposure to a given antigen, only a few lymphocytes are able to recognize it, but once clonal selection occurs, there are thousands of lymphocytes that can respond to that antigen. Clonal selection of lymphocytes occurs in the secondary lymphoid organs and tissues. The swollen tonsils or lymph nodes in your neck you experienced the last time you were sick were probably caused by clonal selection of lymphocytes participating in an immune response.

A lymphocyte that undergoes clonal selection gives rise to two major types of cells in the clone: effector cells and memory cells. The thousands of effector cells of a lymphocyte clone carry out immune responses that ultimately result in the destruction or inactivation of the antigen. Effector cells include active helper T cells, which are part of a helper T cell clone; active cytotoxic T cells, which are part of a cytotoxic T cell clone; and plasmocytes, which are part of a B cell clone. Most effector cells eventually die after the immune response has been completed.

Memory cells do not actively participate in the initial immune response to the antigen. However, if the same antigen enters the body again in the future, the thousands of memory cells of a lymphocyte clone are available to initiate a far swifter reaction than occurred during the first invasion. The memory cells respond to the antigen by proliferating and differentiating into more effector cells and more memory cells.

Consequently, the second response to the antigen is usually so fast and so vigorous that the antigen is destroyed before any signs or symptoms of disease can occur. Memory cells include memory helper T cells, which are part of a helper T cell clone; memory cytotoxic T cells, which are part of a cytotoxic T cell clone; and memory B cells, which are part of a B cell clone. Most memory cells do not die at the end of an immune response.

Instead, they have long life spans (often lasting for decades). The functions of effector cells and memory cells are described in more detail later in this chapter.

Antigens and Antigen Receptors

Antigens have two important characteristics: immunogenicity and reactivity. Immunogenicity immunogenisite; -genic = producing) is the ability to provoke an immune response by stimulating the production of specific antibodies, the prolifer-ation of specific T cells, or both. The term antigen derives from its function as an antibody generator. Reactivity is the ability of the antigen to react specifically with the antibodies or cells it provoked. Strictly speaking, immunologists define antigens as substances that have reactivity; substances with both immunogenicity and reactivity are considered complete antigens. Commonly, however, the term antigen implies both immunogenicity and reactivity, and we use the word in this way.

Entire microbes or parts of microbes may act as antigens. Chemical components of bacterial structures such as flagella, capsules, and cell walls are antigenic, as are bacterial toxins. Nonmicrobial examples of antigens include chemical components of pollen, egg white, incompatible blood cells, and transplanted tissues and organs. The huge variety of antigens in the environment provides myriad opportunities for provoking immune responses.

Typically, just certain small parts of a large antigen molecule act as the triggers for immune responses. These small parts are called epitopes epitops, or antigenic determinants (Figure 22.12). Most antigens have many epitopes, each of which induces production of a specific antibody or activates a specific T cell.

Figure 22.12 summary: This is a schematic diagram. The figure illustrates an antigen, represented as a large oval structure, with various smaller shapes called epitopes protruding from its surface. These epitopes are distributed around the perimeter of the antigen. The diagram demonstrates that a single antigen can possess multiple distinct epitopes, suggesting that an antigen can be recognized by several different types of antibodies or immune receptors simultaneously.

Figure 22.12 Epitopes (Antigenic Determinants).

Most antigens have several epitopes that induce the production of different antibodies or activate different T cells.

Antigens that get past the innate defenses generally follow one of three routes into lymphatic tissue: (1) Most antigens that enter the bloodstream (for example, through an injured blood vessel) are trapped as they flow through the spleen. (2) Antigens that penetrate the skin enter lymphatic vessels and lodge in lymph nodes. (3) Antigens that penetrate mucous membranes are entrapped by mucosa-associated lymphoid tissue (malt).

Chemical Nature of Antigens Antigens are large, complex molecules. Most often, they are proteins. However, nucleic acids, lipoproteins, glycoproteins, and certain large polysaccharides may also act as antigens. Complete antigens usually have large molecular weights of 10,000 daltons or more, but large molecules that have simple, repeating subunits—for example, cellulose and most plastics—are not usually antigenic. This is why plastic materials can be used in artificial heart valves or joints.

A smaller substance that has reactivity but lacks immunogenicity is called a hapten hapten = to grasp). A hapten can stimulate an immune response only if it is attached to a larger carrier molecule. An example is the small lipid toxin in poison ivy, which triggers an immune response after combining with a body protein. Likewise, some drugs, such as penicillin, may combine with proteins in the body to form immunogenic complexes. Such hapten-stimulated immune responses are responsible for some allergic reactions to drugs and other substances in the environment (see Disorders: Homeostatic Imbalances at the end of the chapter).

As a rule, antigens are foreign substances; they are not usually part of body tissues. However, sometimes the immune system fails to distinguish “friend” (self) from “foe” (nonself). The result is an autoimmune disease (see Disorders: Homeostatic Imbalances at the end of the chapter) in which self-molecules or cells are attacked as though they were foreign.

Diversity of Antigen Receptors An amazing feature of the human immune system is its ability to recognize and bind to at least a billion (10⁹) different epitopes. Before a Figure 22.13 Processing and presenting of exogenous antigen by an antigen-presenting cell (A.P.C).

Figure 22.13 summary: This is a process diagram illustrating a biological sequence. The figure depicts the step-by-step mechanism of antigen processing and presentation by an antigen-presenting cell, beginning with the intake of an exogenous antigen and ending with the display of an antigen-MHC-II complex on the cell surface. The process involves phagocytosis, digestion of the antigen into fragments, the synthesis and packaging of MHC-II molecules in the endoplasmic reticulum, the fusion of vesicles, and the binding of peptide fragments to these molecules before exocytosis. It can be concluded that the antigen-presenting cell acts as a mediator that converts foreign external proteins into a format that can be recognized by the immune system by utilizing intracellular vesicle transport and molecular binding.

Fragments of exogenous antigens are processed and then presented with M.H.C-II molecules on the surface of an antigen-presenting cell (A.P.C). response. The presentation of exogenous antigen together with M.H.C-II molecules by antigen-presenting cells informs T cells that intruders are present in the body and that combative action should begin.

Processing of Endogenous Antigens Foreign

Foreign antigens that are present inside body cells are termed endoge- us antigens endogenous. Such antigens may be viral pro- ns produced after a virus infects the cell and takes over the all's metabolic machinery, toxins produced from intracellular acteria, or abnormal proteins synthesized by a cancerous cell.

The steps in the processing and presenting of an endogenous antigen by an infected body cell occur as follows (Figure 22.14): ① Digestion of antigen into peptide fragments. Within the infected cell, protein-digesting enzymes split the endogenous antigen into short peptide fragments. ② Synthesis of M.H.C-I molecules. At the same time, the infected cell synthesizes M.H.C-I molecules at the endoplasmic reticulum.

Figure 22.14 summary: This figure is a biological process diagram. It illustrates the sequential steps of antigen processing and presentation by an infected body cell, starting from the presence of an endogenous antigen. The process involves the digestion of the antigen into peptide fragments, the synthesis of MHC-I molecules within the endoplasmic reticulum, the binding of these fragments to the MHC-I molecules, the packaging of the resulting complexes into vesicles, and finally the transport of these vesicles to the plasma membrane via exocytosis. The diagram demonstrates that infected cells utilize a specific intracellular pathway to display internal antigens on their surface, allowing the immune system to recognize and target the compromised cell.

3 Binding of peptide fragments to M.H.C-I molecules. The antigen peptide fragments enter the Er and then bind to M.H.C-I molecules.

4 Packaging of antigen-M.H.C-I molecules. From the Er, antigen-M.H.C-I molecules are packaged into vesicles.

5 Insertion of antigen-M.H.C-I complexes into the plasma membrane. The vesicles that contain antigen-M.H.C-I complexes undergo exocytosis. As a result, the antigen-M.H.C-I complexes are inserted into the plasma membrane.

Most cells of the body can process and present endogenous antigens. The display of an endogenous antigen bound to an M.H.C-I molecule signals that a cell has been infected and needs help.

Cytokines

Cytokines (S ^{T} -to-kins) are small protein hormones that stimulate or inhibit many normal cell functions, such as cell growth and differentiation. Lymphocytes and antigen-presenting cells secrete cytokines, as do fibroblasts, endothelial cells, monocytes, hepatocytes, and kidney cells. Some cytokines stimulate proliferation of progenitor blood cells in red bone marrow. Others regulate activities of cells involved in innate defenses or adaptive immune responses, as described in Table 22.2.

Table 22.2 summary: This table outlines various cytokines involved in immune responses, detailing their cellular origins and primary biological functions. It highlights how different interleukins, tumor necrosis factor, interferons, and macrophage migration inhibiting factor coordinate the activity of helper T cells, B cells, macrophages, and natural killer cells to manage inflammation, viral replication, and antibody production.

Figure 22.14 Processing and Presenting of Endogenous Antigen by an Infected Body Cell.

Fragments of endogenous antigens are processed and then presented with M.H.C-I proteins on the surface of an infected body cell.

Clinical Connection

Cytokine Therapy

Cytokine therapy is the use of cytokines to treat medical conditions. Interferons were the first cytokines shown to have limited effects against some human cancers. Alpha-interferon (Intron A ^{} ) is approved in the United States for treating Kaposi sarcoma kap-delta-se, a cancer that often occurs in patients infected with H.I.V, the virus that causes AIDS. Other approved uses for alpha-interferon include treating genital herpes caused by the herpes virus; treating hepatitis B and C, caused by the hepatitis B and C viruses; and treating hairy cell leukemia. A form of beta-interferon (Betaseron ^{} ) slows the progression of multiple sclerosis and lessens the frequency and severity of M.S attacks. Of the interleukin, the one most widely used to fight cancer is interleukin-2. Although this treatment is effective in causing tumor regression in some patients, it also can be very toxic. Among the adverse effects are high fever, severe weakness, difficulty breathing due to pulmonary edema, and hypotension leading to shock.

Checkpoint

22.8 Cell-Mediated Immunity

Objectives

• Outline the steps in a cell-mediated immune response.

• Distinguish between the action of natural killer cells and cytotoxic T cells.

• Define immunological surveillance.

A cell-mediated immune response begins with activation of a small number of T cells by a specific antigen. Once a T cell has been activated, it undergoes clonal selection. Recall that clonal selection is the process by which a lymphocyte proliferates (divides several times) and differentiates (forms more highly specialized cells) in response to a specific antigen. The result of clonal selection is the formation of a clone of cells that can recognize the same antigen as the original lymphocyte (see Figure 22.11). Some of the cells of a T cell clone become effector cells, while other cells of the clone become memory cells. The effector cells of a T cell clone carry out immune responses that ultimately result in elimination of the intruder.

Activation of T Cells

At any given time, most T cells are inactive. Antigen receptors on the surface of T cells, called T-cell receptors T.C.R's, recognize and bind to specific foreign antigen fragments that are presented in antigen-M.H.C complexes. There are millions of different T cells; each has its own unique T.C.R's that can recognize a specific antigen-M.H.C complex. When an antigen enters the body, only a few T cells have T.C.R's that can recognize and bind to the antigen. Antigen recognition also involves other surface proteins on T cells, the C.D.4 or C.D.8 proteins. These proteins interact with the M.H.C antigens and help maintain the T.C.R-M.H.C coupling. For this reason, they are referred to as coreceptors. Antigen recognition by a T.C.R with C.D.4 or C.D.8 proteins is the first signal in activation of a T cell.

A T cell becomes activated only if it binds to the foreign antigen and at the same time receives a second signal, a process known as costimulation. Of the more than 20 known costimulators, some are cytokines, such as interleukin-2 I.L-2. Other costimulators include pairs of plasma membrane molecules, one on the surface of the T cell and a second on the surface of an antigen-presenting cell, that enable the two cells to adhere to one another for a period of time.

The need for two signals to activate a T cell is a little like starting and driving a car: When you insert the correct key (antigen) in the ignition (T.C.R) and turn it, the car starts (recognition of specific antigen), but it cannot move forward until you move the gearshift into drive (costimulation). The need for costimulation may prevent immune responses from occurring accidentally. Different costimulators affect the activated T cell in different ways, just as shifting a car into reverse has a different effect than shifting it into drive. Moreover, recognition (antigen binding to a receptor) without costimulation leads to a prolonged state of inactivity called anergy anergy in both T cells and B cells. Anergy is rather like leaving a car in neutral gear with its engine running until it's out of gas!

Once a T cell has received these two signals (antigen recognition and costimulation), it is activated. An activated T cell subsequently undergoes clonal selection.

Activation and Clonal Selection of Helper T Cells

Most T cells that display C.D.4 develop into helper T cells, also known as C.D.4 T cells. Inactive (resting) helper T cells recognize exogenous antigen fragments associated with major histocompatibility complex class 2 (M.H.C-II) molecules at the surface of an A.P.C (Figure 22.15). With the aid of the C.D.4 protein, the helper T cell and A.P.C interact with each other (antigenic recognition), costimulation occurs, and the helper T cell becomes activated.

Once activated, the helper T cell undergoes clonal selection (Figure 22.15). The result is the formation of a clone of helper T cells that consists of active helper T cells and memory helper T cells. Within hours after costimulation, active helper T cells start secreting a variety of cytokines (see Table 22.2). One very important cytokine produced by helper T cells is interleukin-2 I.L-2, which is needed for virtually all immune responses and is the prime trigger of T cell proliferation. I.L-2 can act as a costimulator for resting helper T cells or cytotoxic T cells, and it enhances activation and proliferation of T cells, B cells, and natural killer cells. Some actions of interleukin-2 provide a good example of a beneficial positive feedback system. As noted earlier, activation of a helper T cell stimulates it to start secreting I.L-2, which then acts in an autocrine manner by binding to I.L-2 receptors on the plasma membrane of the cell that secreted it. One effect is stimulation of cell division.

As the helper T cells proliferate, a positive feedback effect occurs because they secrete more I.L-2, which causes further cell division. I.L-2 may also act in a paracrine manner by binding to I.L-2 receptors on neighboring helper T cells, cytotoxic T cells, or B cells. If any of these neighboring cells have already become bound to a copy of the same antigen, I.L-2 serves as a costimulator.

The memory helper T cells of a helper T cell clone are not active cells. However, if the same antigen enters the body again in the future, memory helper T cells can quickly proliferate and differentiate into more active helper T cells and more memory helper T cells.

Activation and Clonal Selection of Cytotoxic T Cells

Most T cells that display C.D 8 develop into cytotoxic T cells, also termed C.D 8 T cells. Cytotoxic T cells recognize foreign antigens combined with major histocompatibility complex class I (M.H.C-I) molecules on the surface of (1) body cells infected by microbes, (2) some tumor cells, and (3) cells of a tissue transplant (Figure 22.16). Recognition requires the T.C.R and C.D 8 protein to maintain the coupling with M.H.C-I. Following antigenic recognition, costimulation occurs. In order to become activated, cytotoxic T cells require costimulation by interleukin-2 or other cytokines produced by active helper T cells that have already become bound to copies of the same antigen. (Recall that helper T cells are activated by antigen associated with M.H.C-II molecules.) Thus, maximal activation of cytotoxic T cells requires presentation of antigen associated with both M.H.C-I and M.H.C-II molecules.

Figure 22.16 summary: This figure is a biological process diagram. It illustrates the activation process of a cytotoxic T cell, starting from the interaction between an inactive cytotoxic T cell and an infected body cell. The process involves antigen recognition through the T cell receptor and MHC-I complex, along with costimulation provided by helper T cells via interleukin-2. This sequence leads to the transformation of the inactive cell into an activated cytotoxic T cell, which then undergoes clonal selection through proliferation and differentiation. The final outcome is the formation of a cytotoxic T cell clone consisting of active cytotoxic T cells that target infected body cells and long-lived memory cytotoxic T cells for future immune responses.

Once activated, the cytotoxic T cell undergoes clonal selection. The result is the formation of a clone of cytotoxic T cells that consists of active cytotoxic T cells and memory cytotoxic T cells. Active cytotoxic T cells attack other body cells that have been infected with the antigen. Memory cytotoxic T cells do not attack infected body cells. Instead, they can quickly proliferate and differentiate into more active cytotoxic T cells and more memory cytotoxic T cells if the same antigen enters the body at a future time.

Elimination of Invaders

Cytotoxic T cells are the soldiers that march forth to do battle with foreign invaders in cell-mediated immune responses. They

Figure 22.16 Activation and Clonal Selection of a Cytotoxic T Cell.

leave secondary lymphoid organs and tissues and migrate to seek out and destroy infected target cells, cancer cells, and transplanted cells (Figure 22.17). Cytotoxic T cells recognize and attach to target cells. Then, the cytotoxic T cells deliver a “lethal hit” that kills the target cells.

Figure 22.17 summary: This figure consists of two biological process diagrams. The diagrams illustrate the mechanisms by which an activated cytotoxic T cell targets and destroys an infected body cell. The first sequence shows the T cell recognizing and attaching to the infected cell, releasing granzymes that trigger apoptosis, leading to the breakdown of the cell and the subsequent engulfment of released microbes by a phagocyte. The second sequence shows the T cell releasing granulysin and perforin, which create channels in the target cell membrane, resulting in cytolysis. It can be concluded that cytotoxic T cells employ multiple pathways, including programmed cell death and direct membrane rupture, to eliminate intracellular pathogens and infected host cells.

Cytotoxic T cells kill infected target body cells much as natural killer cells do. The major difference is that cytotoxic T cells have receptors specific for a particular microbe and thus kill only target body cells infected with one particular type of microbe; natural killer cells can destroy a wide variety of microbe-infected body cells. Cytotoxic T cells have two principal mechanisms for killing infected target cells.

1. Cytotoxic T cells, using receptors on their surfaces, recognize and bind to infected target cells that have microbial antigens displayed on their surface. The cytotoxic T cell then releases granzymes, protein-digesting enzymes that trigger apoptosis (Figure 22.17a). Once the infected cell is destroyed, the released microbes are killed by phagocytes.

2. Alternatively, cytotoxic T cells bind to infected body cells and release two proteins from their granules: perforin and granulysin. Perforin inserts into the plasma membrane of the target cell and creates channels in the membrane (Figure 22.17b). As a result, extracellular fluid flows into the target cell and cytolysis (cell bursting) occurs. Other granules in cytotoxic T cells release granulysin (gran'-ü-Ll-sin), which enters through the channels and destroys the microbes by creating holes in their plasma membranes. Cytotoxic T cells may also destroy target cells by releasing a toxic molecule called lymphotoxin lymphotoxin, which activates enzymes in the target cell. These enzymes cause the target cell's D.N.A to fragment, and the cell dies. In addition, cytotoxic T cells secrete gamma-interferon, which attracts and activates phagocytic cells, and macrophage migration inhibition factor, which prevents migration of phagocytes from the infection site. After detaching from a target cell, a cytotoxic T cell can seek out and destroy another target cell.

Immunological Surveillance

When a normal cell transforms into a cancerous cell, it often displays novel cell surface components called tumor antigens. These molecules are rarely, if ever, displayed on the surface of normal cells. If the immune system recognizes a tumor antigen as nonself, it can destroy any cancer cells carrying that antigen.

Such immune responses, called immunological surveillance immunological sur-VÄ-lants), are carried out by cytotoxic T cells, macrophages, and natural killer cells. Immunological surveillance is most effective in eliminating tumor cells due to cancer-causing viruses. For this reason, transplant recipients who are taking immunosuppressive drugs to prevent transplant rejection have an increased incidence of virus-associated cancers. Their risk for other types of cancer is not increased.

Figure 22.17 Activity of cytotoxic T cells. After delivering a “lethal hit,” a cytotoxic T cell can detach and attack another infected target cell displaying the same antigen.

Cytotoxic T cells release granzymes that trigger apoptosis and perforin that triggers cytolysis of infected target cells.

Clinical Connection

Graft Rejection and Tissue Typing

Organ transplantation involves the replacement of an injured or diseased organ, such as the heart, liver, kidney, lungs, or pancreas, with an organ donated by another individual. Usually, the immune system recognizes the proteins in the transplanted organ as foreign and mounts both cell-mediated and antibody-mediated immune responses against them. This phenomenon is known as graft rejection.

The success of an organ or tissue transplant depends on histocompatibility (his'-to-kom-pat-i-BlL-i-te)—that is, the tissue compatibility between the donor and the recipient. The more similar the M.H.C antigens, the greater the histocompatibility, and thus the greater the probability that the transplant will not be rejected.

Figure 22.21 summary: This figure is a schematic diagram providing a key for biological components. The content identifies three specific molecular structures: the T cell receptor, the CD8 protein, and the antigen-MHC-I complex. The figure indicates that these components are the primary elements involved in the recognition process between a cytotoxic T cell and an antigen-presenting cell.

Tissue typing (histocompatibility testing) is done before any organ transplant. In the United States, a nationwide computerized registry helps physicians select the most histocompatible and needy organ transplant recipients whenever donor organs become available. The closer the match between the major histocompatibility complex proteins of the donor and recipient, the weaker is the graft rejection response.

To reduce the risk of graft rejection, organ transplant recipients receive immunosuppressive drugs. One such drug is cyclosporine, derived from a fungus, which inhibits secretion of interleukin-2 by helper T cells but has only a minimal effect on B cells. Thus, the risk of rejection is diminished while resistance to some diseases is maintained.

22.9 Antibody-Mediated Immunity

Objectives

• Describe the steps in an antibody-mediated immune response.

- List the chemical characteristics and actions of antibodies.

• Explain how the complement system operates.

• Distinguish between a primary response and a secondary response to infection.

The body contains not only millions of different T cells but also millions of different B cells, each capable of responding to a specific antigen. Cytotoxic T cells leave lymphoid tissues to seek out and destroy a foreign antigen, but B cells stay put. In the presence of a foreign antigen, a specific B cell in a lymph node, the spleen, or mucosa-associated lymphoid tissue becomes activated.

Then it undergoes clonal selection, forming a clone of plasmocytes and memory cells. Plasmocytes are the effector cells of a B cell clone; they secrete specific antibodies, which in turn circulate in the lymph and blood to reach the site of invasion.

Activation and Clonal Selection of B Cells

During activation of a B cell, an antigen binds to B-cell receptors B.C.R's (Figure 22.18). These integral transmembrane proteins are chemically similar to the antibodies that eventually are secreted by plasmocytes. Although B cells can respond to an unprocessed antigen present in lymph plasma or interstitial fluid, their response is much more intense when they process the antigen. Antigen processing in a B cell occurs in the following way: The antigen is taken into the B cell, broken down into peptide fragments and combined with M.H.C-II self-antigens, and moved to the B cell plasma membrane. Helper T cells recognize the antigen–M.H.C-II complex and deliver the costimulation needed for B cell proliferation and differentiation. The helper T cell produces interleukin-2 and other cytokines that function as costimulators to activate B cells.

Figure 22.18 summary: This figure is a biological process diagram. It illustrates the activation and differentiation of B cells during an immune response, starting from an inactive B cell with surface receptors. The process shows B cells becoming activated upon recognizing microbes, with one pathway involving direct recognition of unprocessed antigens and another requiring costimulation from helper T cells through the recognition of processed antigens and the release of interleukins. This leads to clonal selection, resulting in the formation of a B cell clone that differentiates into antibody-secreting plasmocytes and long-lived memory B cells. The figure concludes that the immune system employs both direct activation and T-cell mediated support to generate a specialized population of cells capable of producing antibodies and providing long-term immunity.

Once activated, a B cell undergoes clonal selection (Figure 22.18). The result is the formation of a clone of B cells that consists of plasmocytes and memory B cells. Plasma cells secrete antibodies. A few days after exposure to an antigen, a plasmocytes secretes hundreds of millions of antibodies each day for about 4 or 5 days, until the plasmocyte dies. Most antibodies travel in lymph plasma and blood plasma to the invasion site. Interleukin-4 and interleukin-6, also produced by helper T cells, enhance B cell proliferation, B cell Figure 22.18 Activation and clonal selection of B cells. Plasmocytes are actually much larger than B cells.

Plasmocytes secrete antibodies. differentiation into plasmocytes, and secretion of antibodies by plasmocytes. Memory B cells do not secrete antibodies. Instead, they can quickly proliferate and differentiate into more plasmocytes and more memory B cells should the same antigen reappear at a future time.

Different antigens stimulate different B cells to develop into plasmocytes and their accompanying memory B cells. All of the B cells of a particular clone are capable of secreting only one type of antibody, which is identical to the antigen receptor displayed by the B cell that first responded. Each specific antigen activates only those B cells that are predestined (by the combination of gene segments they carry) to secrete antibody specific to that antigen. Antibodies produced by a clone of plas-mocytes enter the circulation and form antigen–antibody complexes with the antigen that initiated their production.

Antibodies

An antibody (Ab) can combine specifically with the epitope on the antigen that triggered its production. The antibody's structure matches its antigen much as a lock accepts a specific key. In theory, plasmocytes could secrete as many different antibodies as there are different B-cell receptors because the same recombined gene segments code for both the B.C.R and the antibodies eventually secreted by plasma cells.

Antibody Structure Antibodies belong to a group of glycoproteins called globulins, and for this reason they are also known as immunoglobulins (Igs). Most antibodies contain four polypeptide chains (Figure 22.19). Two of the chains are identical to each other and are called heavy (H) chains; each consists of about 450 amino acids. Short carbohydrate chains are attached to each heavy polypeptide chain. The two other polypeptide chains, also identical to each other, are called light (50) chains, and each consists of about 220 amino acids.

Figure 22.19 summary: This figure consists of a three-dimensional molecular model and a corresponding schematic diagram. The figure illustrates the structure of an IgG molecule, detailing the arrangement of heavy and light polypeptide chains. It identifies specific structural components including the antigen-binding sites at the tips of the Y-shaped molecule, the hinge region, the stem region, and an attached carbohydrate chain. The schematic further breaks down the chains into variable and constant domains. Based on the structural layout, it can be inferred that the IgG molecule is symmetrical, with two identical arms that provide multiple binding sites for antigens. The variable regions at the ends of the arms are specialized for antigen recognition, while the constant regions and the stem provide structural stability and facilitate interactions with other immune system components.

A disulfide bond (S—S) holds each light chain to a heavy chain. Two disulfide bonds also link the midregion of the two heavy chains; this part of the antibody displays considerable flexibility and is called the hinge region. Because the antibody “arms” can move somewhat as the hinge region bends, an antibody can assume either a T shape or a Y shape (Figure 22.19a, b). Beyond the hinge region, parts of the two heavy chains form the stem region.

Within each H and L chain are two distinct regions. The tips of the H and L chains, called the variable (5) regions, constitute the antigen-binding site. The variable region, which is different for each kind of antibody, is the part of the antibody that recognizes and attaches specifically to a particular antigen. Because most antibodies have two antigen-binding sites, they are said to be bivalent. Flexibility at the hinge allows the antibody to simultaneously bind to two epitopes that are some distance apart—for example, on the surface of a microbe.

The remainder of each H and L chain, called the constant (C) region, is nearly the same in all antibodies of the same class and is responsible for the type of antigen-antibody reaction that occurs. However, the constant region of the H chain differs from one class of antibody to another, and its structure serves as a basis for distinguishing five different classes, designated IgG, IgA, IgM, IgG, and IgE. Each class has a distinct chemical structure and a specific biological role. Because they appear first and are relatively short-lived, IgM antibodies indicate a recent invasion.

In a sick patient, the responsible pathogen may be suggested by the presence of high levels of IgM specific to a particular organism. Resistance of the fetus and newborn baby to infection stems mainly from maternal IgG antibodies that cross the placenta before birth and IgA antibodies in breast milk after birth. Table 22.3 summarizes the structures and functions of the five classes of antibodies.

Table 22.3 summary: This table outlines the different classes of immunoglobulins, detailing their structural forms, relative abundance in the blood, and primary biological roles. IgG is the most prevalent and is unique in its ability to cross the placenta, while IgA provides localized protection in secretions. IgM is characterized as the first antibody secreted upon antigen exposure and often exists as a pentamer. IgD and IgE are present in very small quantities, with IgD primarily acting as a B cell receptor and IgE mediating allergic responses and defense against parasites.

Antibody Actions The actions of the five classes of immunoglobulins differ somewhat, but all of them act to disable antigens in some way. Actions of antibodies include the following:

• Neutralizing antigen. The reaction of antibody with antigen blocks or neutralizes some bacterial toxins and prevents attachment of some viruses to body cells.

Figure 22.19 Chemical structure of the immunoglobulin G (IgG) class of antibody. Each molecule is composed of four polypeptide chains (two heavy and two light) plus a short carbohydrate chain attached to each heavy chain. In (a), each circle represents one amino acid. In (b), V L = variable regions of light chain, C L = constant region of light chain, V H = variable region of heavy chain, and C H = constant region of heavy chain.

An antibody combines only with the epitope on the antigen that triggered its production.

• Immobilizing bacteria. If antibodies form against antigens on the cilia or flagella of motile bacteria, the antigen-antibody reaction may cause the bacteria to lose their motility, which limits their spread into nearby tissues.

• Agglutinating and precipitating antigen. Because antibodies have two or more sites for binding to antigen, the antigen–antibody reaction may cross-link pathogens to one another, causing agglutination (clumping together). Phagocytic cells ingest agglutinated microbes more readily. Likewise, soluble antigens may come out of solution and form a more easily phagocytized precipitate when cross-linked by antibodies.

• Activating complement. Antigen–antibody complexes initiate the classical pathway of the complement system (discussed shortly).

• Enhancing phagocytosis. The stem region of an antibody acts as a flag that attracts phagocytes once antigens have bound to the antibody's variable region. Antibodies enhance the activity of phagocytes by causing agglutination and precipitation, by activating complement, and by coating microbes so that they are more susceptible to phagocytosis.

Role of the Complement System in Immunity

The complement system complement is a defensive system made up of over 30 proteins produced by the liver and found circulating in blood plasma and within tissues throughout the

Clinical Connection

Monoclonal Antibodies

The antibodies produced against a given antigen by plasmocytes can be harvested from an individual's blood. However, because an antigen typically has many epitopes, several different clones of plasmocytes produce different antibodies against the antigen. If a single plasmocyte could be isolated and induced to proliferate into a clone of identical plasmocytes, then a large quantity of identical antibodies could be produced. Unfortunately, lymphocytes and plasmocytes are difficult to grow in culture, so scientists sidestepped this difficulty by fusing B cells with tumor cells that grow easily and proliferate endlessly.

The resulting hybrid cell is called a hybridoma (hi-bri-DÖ-ma). Hybridomas are long-term sources of large quantities of pure, identical antibodies, called monoclonal antibodies M.A.B's monoclonal because they come from a single clone of identical cells. One clinical use of monoclonal antibodies is for measuring levels of a drug in a patient's blood. Other uses include the diagnosis of strep throat, pregnancy, allergies, and diseases such as hepatitis, rabies, and some sexually transmitted infections.

M.A.B's have also been used to detect cancer at an early stage and to ascertain the extent of metastasis. They may also be useful in preparing vaccines to counteract the rejection associated with transplants, to treat autoimmune diseases, and perhaps to treat AIDS. body. Collectively, the complement proteins destroy microbes by causing phagocytosis, cytolysis, and inflammation; they also prevent excessive damage to body tissues.

Most complement proteins are designated by an uppercase letter C, numbered C.1 through C.9, named for the order in which they were discovered. The C.1–C.9 complement proteins are inactive and become activated only when split by enzymes into active fragments, which are indicated by lowercase letters a and b. For example, inactive complement protein C.3 is split into the activated fragments C.3a and C.3b. The active fragments carry out the destructive actions of the C.1–C.9 complement proteins. Other complement proteins are referred to as factors B, D, and P (properdin).

Complement proteins act in a cascade—one reaction triggers another reaction, which in turn triggers another reaction, and so on. With each succeeding reaction, more and more product is formed so that the net effect is amplified many times.

Complement activation may begin by three different pathways (described shortly), all of which activate C.3. Once activated, C.3 begins a cascade of reactions that brings about phagocytosis, cytolysis, and inflammation as follows (Figure 22.20):

Figure 22.20 summary: This figure is a biological process diagram. It illustrates the complement system activation pathway, showing the cascade of proteins starting from the cleavage of C3 and C5 into various fragments. The diagram tracks three primary outcomes: the coating of microbes with C3b to enhance phagocytosis, the release of C5a to trigger mast cells to release histamine for inflammation, and the sequential assembly of C5b through C9 to form a membrane attack complex. The process concludes that the complement system facilitates the destruction of microbes through opsonization, the recruitment of immune cells via increased blood vessel permeability, and direct cytolysis caused by the formation of channels in the microbial plasma membrane.

1 Inactivated C.3 splits into activated C.3a and C.3b.

② C.3b binds to the surface of a microbe and receptors on phagocytes attach to the C.3b. Thus C.3b enhances phagocytosis by coating a microbe, a process called opsonization (op-so-ni-ZÃ-shun). Opsonization promotes attachment of a phagocyte to a microbe.

3 C.3b also initiates a series of reactions that bring about cytolysis. First, C.3b splits C.5. The C.5b fragment then binds to C.6 and C.7, which attach to the plasma membrane of an invading microbe. Then C.8 and several C.9 molecules join the other complement proteins and together form a Figure 22.20 Complement activation and results of activation. (Adapted from Tortora, Funke, and Case, Microbiology: An Introduction, Eleventh Edition, Figure 16.9, Pearson Benjamin-Cummings, 2013.)

When activated, complement proteins enhance phagocytosis, cytolysis, and inflammation. cylinder-shaped membrane attack complex, which inserts into the plasma membrane.

④ The membrane attack complex creates channels in the plasma membrane that result in cytolysis, the bursting of the microbial cells due to the inflow of extracellular fluid through the channels.

5 C.3a and C.5a bind to mast cells and cause them to release histamine that increases blood vessel permeability during inflammation. C.5a also attracts phagocytes to the site of inflammation (chemotaxis).

C.3 can be activated in three ways: (1) The classical pathway starts when antibodies bind to antigens (microbes). The antigen–antibody complex binds and activates C.1. Eventually, C.3 is activated and the C.3 fragments initiate phagocytosis, cytolysis, and inflammation. (2) The alternative pathway does not involve antibodies. It is initiated by an interaction between lipid–carbohydrate complexes on the surface of microbes and complement protein factors B, D, and P. This interaction activates C.3. (3) In the lectin pathway, macrophages that digest microbes release chemicals that cause the liver to produce proteins called lectins. Lectins bind to the carbohydrates on the surface of microbes, ultimately causing the activation of C.3.

Once complement is activated, proteins in blood and on body cells such as blood cells break down activated C.3. In this way, its destructive capabilities cease very quickly so that damage to body cells is minimized.

Immunological Memory

A hallmark of immune responses is memory for specific antigens that have triggered immune responses in the past. Immunological memory is due to the presence of long-lasting antibodies and very long-lived lymphocytes that arise during clonal selection of antigen-stimulated B cells and T cells.

Immune responses, whether cell-mediated or antibody-mediated, are much quicker and more intense after a second or subsequent exposure to an antigen than after the first exposure. Initially, only a few cells have the correct specificity to respond, and the immune response may take several days to build to maximum intensity. Because thousands of memory cells exist after an initial encounter with an antigen, the next time the same antigen appears they can proliferate and differentiate into helper T cells, cytotoxic T cells, or plasmocytes within hours.

One measure of immunological memory is antibody titer (T {T} -ter), the amount of antibody in serum. After an initial contact with an antigen, no antibodies are present for a period of several days. Then, a slow rise in the antibody titer occurs, first IgM and then IgG, followed by a gradual decline in antibody titer (Figure 22.21). This is the primary response.

Memory cells may remain for decades. Every new encounter with the same antigen results in a rapid proliferation of memory cells. After subsequent encounters, the antibody titer is far greater than during a primary response and consists mainly of IgG antibodies. This accelerated, more intense response is Figure 22.21 Production of antibodies in the primary and secondary responses to a given antigen.

Immunological memory is the basis for successful immunization by vaccination. called the secondary response. Antibodies produced during a secondary response have an even higher affinity for the antigen than those produced during a primary response, and thus they are more successful in disposing of it.

Figure 22.21 summary: This figure is a line chart. It displays the antibody titers of IgM and IgG over time following an initial exposure and a subsequent second exposure to an antigen, dividing the timeline into a primary response and a secondary response. The data indicates that the primary response produces a modest amount of both IgM and IgG, with IgM appearing first. In contrast, the secondary response is characterized by a much more rapid and significantly higher production of IgG compared to the primary response, while the IgM response remains relatively low and similar in magnitude to the first exposure.

Primary and secondary responses occur during microbial infection. When you recover from an infection without taking antimicrobial drugs, it is usually because of the primary response. If the same microbe infects you later, the secondary response could be so swift that the microbes are destroyed before you exhibit any signs or symptoms of infection.

Immunological memory provides the basis for immunization by vaccination against certain diseases (for example, polio). When you receive the vaccine, which may contain attenuated (weakened) or killed whole microbes or portions of microbes, your B cells and T cells are activated. Should you subsequently encounter the living pathogen as an infecting microbe, your body initiates a secondary response.

Table 22.4 summarizes the various ways to acquire adaptive immunity.

Table 22.4 summary: This table outlines the different mechanisms for acquiring adaptive immunity, categorizing them by whether the process is natural or artificial and whether the resulting immunity is active or passive. Active immunity, whether naturally acquired through microbe exposure or artificially via vaccination, involves the body producing its own memory cells and antibodies. In contrast, passive immunity involves the transfer of pre-formed antibodies from an external source, such as from mother to child or through medical injection.

22.10 Self-Recognition and Self-Tolerance

Objective

• Describe how self-recognition and self-tolerance develop.

To function properly, your T cells must have two traits: (1) They must be able to recognize your own major histocompatibility complex (M.H.C) proteins, a process known as self-recognition, and (2) they must lack reactivity to peptide fragments from your own proteins, a condition known as self-tolerance (Figure 22.22). B cells also display self-tolerance. Loss of self-tolerance leads to the development of autoimmune diseases (see Disorders: Homeostatic Imbalances at the end of the chapter).

Pre-T cells in the thymus develop the capability for self-recognition via positive selection (Figure 22.22a). In this

Figure 22.22 Development of Self-Recognition and Self-Tolerance. M.H.C = major histocompatibility complex; T.C.R = T-cell receptor.

process, some pre-T cells express T-cell receptors T.C.R's that interact with self-M.H.C proteins on epithelial cells in the thymic cortex. Because of this interaction, the T cells can recognize the M.H.C part of an antigen–M.H.C complex. These T cells survive. Other immature T cells that fail to interact with thymic epithelial cells are not able to recognize self-M.H.C proteins. These cells undergo apoptosis.

The development of self-tolerance occurs by a weeding-out process called negative selection in which the T cells interact with nodular dendritic cells located at the junction of the cortex and medulla in the thymus. In this process, T cells with receptors that recognize self-peptide fragments or other self-antigens are eliminated or inactivated (Figure 22.22a). The T cells selected to survive do not respond to self-antigens, the fragments of molecules that are normally present in the body. Negative selection occurs via both deletion and anergy.

In deletion, self-reactive T cells undergo apoptosis and die; in anergy they remain alive but are unresponsive to antigenic stimulation. Only 1 to 5% of the immature T cells in the thymus receive the proper signals to survive apoptosis during both positive and negative selection and emerge as mature, immunocompetent T cells.

Once T cells have emerged from the thymus, they may still encounter an unfamiliar self-protein; in such cases they may also become anergic if there is no costimulator (Figure 22.22b). Deletion of self-reactive T cells may also occur after they leave the thymus.

B cells also develop tolerance through deletion and anergy (Figure 22.22c). While B cells are developing in bone marrow, those cells exhibiting antigen receptors that recognize common self-antigens (such as M.H.C proteins or blood group antigens)

Clinical Connection

Immunotherapy and Cancer

As you have learned, the immune system keeps track of all substances found in the body and any foreign substance triggers a response designed to attack and eliminate the foreign substance. This system can also target cancer cells. There are limitations on the ability of the immune system to fight cancer on its own and even individuals with healthy immune systems can develop cancer.

It appears that cancer cells may not be recognized by the immune system because they aren't different enough from normal cells. Sometimes the immune system recognizes cancer cells but cannot mount a strong enough attack to kill them. Also, cancer cells themselves can release substances that inhibit the immune system.

Immunotherapy immunotherapy is a treatment that uses certain components of a person's immune system to fight diseases such as cancer. This is accomplished by killing cancer cells directly or stimulating the immune system in a more general way. Several types of immunotherapy have been employed to fight cancer. Among them are the following:

Monoclonal antibodies (see the Clinical Connection on Monoclonal Antibodies in Section 22.9). Monoclonal antibodies attach to specific proteins on the surface of cancer cells that mark the cancer cells for destruction by the immune system or boost the ability of immune cells to mount a stronger response. are deleted. Once B cells are released into the blood, however, anergy appears to be the main mechanism for preventing responses to self-proteins. When B cells encounter an antigen not associated with an antigen-presenting cell, the necessary costimulation signal often is missing. In this case, the B cell is likely to become anergic (inactivated) rather than activated.

Table 22.5 summarizes the activities of cells involved in adaptive immune responses.

Table 22.5 summary: This table outlines the specialized roles of various cells involved in adaptive immune responses, categorizing them into antigen-presenting cells and lymphocytes. Antigen-presenting cells, including macrophages, dendritic cells, and B cells, focus on processing and presenting foreign antigens to T cells while secreting signaling molecules to stimulate other immune cells. Lymphocytes are further divided by function, with cytotoxic T cells directly destroying target cells via various toxins, helper T cells coordinating the response and amplifying antibody production, and memory cells providing long-term recognition of antigens. Additionally, B cells are shown to differentiate into antibody-secreting plasma cells or long-lived memory B cells.

Checkpoint

25. What do positive selection, negative selection, and anergy accomplish?

22.11 Stress and Immunity

Objective

• Describe the effects of stress on immunity.

The field of psychoneuroimmunology (P.N.I) deals with communication pathways that link the nervous, endocrine, and immune systems. P.N.I research appears to justify what people have long observed: Your thoughts, feelings, moods, and beliefs influence your level of health and the course of disease.

Immune checkpoint inhibitors. These are drugs that interfere with the ability of cancer cells to avoid immune system attack and help T cells to recognize and destroy cancer cells.

Adoptive cellular therapy. This treatment is designed to boost the natural ability of T cells to fight cancer. T cells that are most active against the cancer cells are removed from a tumor are grown in the laboratory. Then they are injected into the body.

Cancer vaccines. These help the body to recognize cancer cells and stimulate the immune system to destroy them. Some cancer vaccines are used to treat patients with a certain gene mutation. An example is Herceptin, which is used to treat breast cancer. Others vaccines are used to prevent the development of cancer. There is a vaccine for strains of the human papilloma virus H.P.V associated with cancer of the cervix, anus, and pharynx that is now part of the recommended childhood immunizations in the United States. A vaccine against the cancer-linked hepatitis B virus H.B.V is also available.

Cytokine therapy (see the Clinical Connection on Cytokine Therapy in Section 22.7). Cytokines not only play a role in the body's normal immune responses, they also combat specific types of cancer. For example, interleukin are used to treat kidney cancer and melanomas that have metastasized and interferons are used to treat Kaposi's sarcoma, genital herpes, hepatitis B and C, certain leukemias and lymphomas, and multiple sclerosis.

For example, cortisol, a hormone secreted by the suprarenal cortex in association with the stress response, inhibits immune system activity.

If you want to observe the relationship between lifestyle and immune function, visit a college campus. As the semester progresses and the workload accumulates, an increasing number of students can be found in the waiting rooms of student health services. When work and stress pile up, health habits can change.

Many people smoke or consume more alcohol when stressed, two habits detrimental to optimal immune function. Under stress, people are less likely to eat well or exercise regularly, two habits that enhance immunity.

People resistant to the negative health effects of stress are more likely to experience a sense of control over the future, a commitment to their work, expectations of generally positive outcomes for themselves, and feelings of social support. To increase your stress resistance, cultivate an optimistic outlook, get involved in your work, and build good relationships with others.

Adequate sleep and relaxation are especially important for a healthy immune system. But when there aren't enough hours in the day, you may be tempted to steal some from the night. While skipping sleep may give you a few more hours of productive time in the short run, in the long run you end up even farther behind, especially if getting sick keeps you out of commission for several days, blurs your concentration, and blocks your creativity.

Even if you make time to get 8 hours of sleep, stress can cause insomnia. If you find yourself tossing and turning at night, it's time to improve your stress management and relaxation skills! Be sure to unwind from the day before going to bed.

Checkpoint

22.12 Aging and the Lymphoid System

Objective

• Describe the effects of aging on the lymphoid system.

With advancing age, most people become more susceptible to all types of infections and malignancies. Their response to vaccines is decreased, and they tend to produce more autoantibodies (antibodies against their body's own molecules). In addition, the immune system exhibits lowered levels of function. For example, T cells become less responsive to antigens, and fewer T cells respond to infections. This may result from age-related atrophy of the thymus or decreased production of thymic hormones.

Because the T cell population decreases with age, B cells are also less responsive. Consequently, antibody levels do not increase as rapidly in response to a challenge by an antigen, resulting in increased susceptibility to various infections. It is for this key reason that elderly individuals are encouraged to get influenza (flu) vaccinations each year.

Checkpoint 27. How are T cells affected by aging?

To appreciate the many ways that the lymphatic system contributes to homeostasis of other body systems, examine Focus on Homeostasis: Contributions of the Lymphatic System and Immunity.

Next, in Chapter 23, we will explore the structure and function of the respiratory system and see how its operation is regulated by the nervous system. Most importantly, the respiratory system provides for gas exchange—taking in oxygen and blowing off carbon dioxide. The cardiovascular system aids gas exchange by transporting blood containing these gases between the lungs and tissue cells.

Disorders: Homeostatic Imbalances

AIDS: Acquired Immunodeficiency Syndrome

Acquired immunodeficiency syndrome aids is a condition in which a person experiences a telltale assortment of infections due to the progressive destruction of immune system cells by the human immunodeficiency virus (H.I.V). AIDS represents the end stage of infection by H.I.V. A person who is infected with H.I.V may be symptom-free for many years, even while the virus is actively attacking the immune system. In the two decades after the first five cases were reported in 1981, 22 million people died of AIDS. Worldwide, about 37 million people are currently infected with H.I.V.

H.I.V Transmission Because H.I.V is present in the blood and some body fluids, it is most effectively transmitted (spread from one person to another) by actions or practices that involve the exchange of blood or body fluids between people. H.I.V is transmitted in semen or vaginal fluid during unprotected (without a condom) anal, vaginal, or oral sex. H.I.V also is transmitted by direct blood-to-blood contact, such as occurs among intravenous drug users who share hypodermic needles or health-care professionals who may be accidentally stuck by H.I.V-contaminated hypodermic needles. In addition, H.I.V can be transmitted from an H.I.V-infected mother to her baby at birth or during breast-feeding.

The chance of transmitting or of being infected by H.I.V during vaginal or anal intercourse can be greatly reduced—although not entirely eliminated—by the use of latex condoms. Public health programs aimed at encouraging drug users not to share needles have proved effective at checking the increase in new H.I.V infections in this population. Also, giving certain drugs to pregnant H.I.V-infected women greatly reduces the risk of transmission of the virus to their babies.

H.I.V is a very fragile virus; it cannot survive for long outside the human body. The virus is not transmitted by insect bites. One cannot become infected by casual physical contact with an H.I.V-infected person, such as by hugging or sharing household items. The virus can be eliminated from personal care items and medical equipment by exposing them to heat 135 degrees Fahrenheit for 10 minutes) or by cleaning them with common disinfectants such as hydrogen peroxide, rubbing alcohol, household bleach, or germicidal cleansers such as Betadine or Hibiclens. Standard dishwashing and clothes washing also kill H.I.V.

H.I.V: Structure and Infection H.I.V consists of several components: R.N.A (two strands), viral enzymes (reverse transcriptase, integrase, and protease), a capsid (protein coat), and a membrane envelope that is penetrated by glycoproteins (Figure 22.23). H.I.V is classified as a retrovirus because its genetic information is carried in R.N.A instead of D.N.A.

Figure 22.23 summary: This figure is a detailed anatomical diagram of a virus. It illustrates the structural components of the Human immunodeficiency virus, showing an outer envelope composed of a lipid bilayer and glycoproteins. Inside the envelope, there is a protein coat known as a capsid that houses the viral genetic material in the form of RNA. The interior also contains essential enzymes, including protease, integrase, and reverse transcriptase. The diagram indicates that the virus is microscopic in size, with its overall diameter spanning a small range of nanometers.

Outside a living host cell, a virus is unable to replicate. However, when a virus infects and enters a host cell, it uses the host cell's enzymes and ribosomes to make thousands of copies of the virus. New viruses eventually leave and then infect other cells. H.I.V infection of a host cell begins with the binding of H.I.V glycoproteins to receptors in the host cell's plasma membrane.

This causes the cell to transport the virus into its cytoplasm via receptor-mediated endocytosis. Once inside the host cell, H.I.V sheds its protein coat, and a viral enzyme called reverse transcriptase converts the viral R.N.A into D.N.A. The viral D.N.A is then integrated into the host cell's D.N.A via the viral enzyme.

H.I.V is most effectively transmitted by practices that involve the exchange of body fluids.

Focus on Homeostasis

Contributions of the Lymphoid System and Immunity for all Body Systems

• B cells, T cells, and antibodies protect all body systems from attack by harmful foreign invaders (pathogens), foreign cells, and cancer cells

Image summary: This figure is an anatomical illustration. It depicts a full-body representation of a human female figure. The illustration serves as a schematic map of the human body, likely intended for marking specific locations or symptoms across the entire physical frame.

Image summary: This figure is a diagrammatic illustration. It depicts a stylized human figure composed of horizontal segments or layers, representing a full-body anatomical outline. The figure suggests a conceptual representation of a human body divided into systematic sections, implying a structural or layered analysis of human anatomy.

Image summary: This is an anatomical illustration. The figure depicts the muscular system of a human body in a frontal view, showing the distribution of muscles across the torso, arms, and legs. The illustration demonstrates that muscle mass is distributed symmetrically across the left and right sides of the body, with larger muscle groups concentrated in the thighs and chest compared to the extremities.

Image summary: This is an anatomical illustration. The figure depicts the human lymphatic system, showing a network of vessels and nodes distributed throughout the body, integrated with major organs such as the heart, lungs, and digestive tract. The illustration demonstrates that lymphatic vessels are present in almost every region of the body, with a higher concentration of nodes in the neck, armpits, and groin, indicating that the lymphatic system serves as a comprehensive drainage and immune surveillance network spanning the entire human anatomy.

Integumentary System

• Lymphatic vessels drain excess interstitial fluid and leaked plasma proteins from dermis of skin

• Immune system cells (intraepidermal macrophages) in skin help protect skin

• Lymphatic tissue provides IgA antibodies in sweat

Skeletal System

• Lymphatic vessels drain excess interstitial fluid and leaked blood plasma proteins from connective tissue around bones

Muscular System

• Lymphatic vessels drain excess interstitial fluid and leaked blood plasma proteins from muscles

Image summary: This figure is an anatomical diagram. It depicts a human figure from a posterior view, overlaid with a series of horizontal bands extending across the entire body from the head to the feet. The image illustrates a systematic mapping or segmentation of the human body into multiple horizontal levels, suggesting a method for regional analysis or data collection across different bodily heights.

Image summary: This figure is an anatomical illustration. It depicts a human figure with internal organs visible, specifically highlighting the digestive system including the liver and intestines. The illustration suggests a focus on the spatial arrangement and anatomical positioning of these organs within the human torso.

Image summary: This figure is an anatomical diagram. It depicts the human circulatory system, illustrating the network of blood vessels distributed throughout the entire body, including the torso, arms, and legs. The diagram demonstrates that blood vessels are pervasive across all extremities and central organs, indicating a comprehensive distribution system designed to transport blood to every part of the human anatomy.

Image summary: This figure consists of two anatomical diagrams. The illustrations depict human figures with highlighted internal organs, showing a comparison between different biological systems or states. The top figure emphasizes the respiratory system, specifically the lungs, while the bottom figure focuses on the digestive system, highlighting the liver and intestines. It can be inferred that the figure is intended to contrast the locations and structures of the pulmonary and gastrointestinal systems within the human body.

Image summary: This figure is an anatomical diagram. It depicts a human silhouette with highlighted internal organs, specifically focusing on the renal system. The image illustrates the positioning of the kidneys and the bladder within the body, showing their relative locations in the abdominal and pelvic regions.

Image summary: This figure is a diagrammatic illustration. It depicts a human figure overlaid with a series of horizontal parallel lines extending across the entire body from the head to the feet. The illustration suggests a systemic scanning or mapping process applied to the human anatomy, indicating a comprehensive analysis of the body's structure through a layered approach.

Nervous System

• Immune cells help protect the nervous system from pathogens and the brain helps regulate immune responses

• Lymphatic vessels drain excess interstitial fluid and leaked proteins from the nervous system

• Neuropeptides function as neurotransmitters

Endocrine System

• Flow of lymph plasma helps distribute some hormones and cytokines

• Lymphatic vessels drain excess interstitial fluid and leaked blood plasma proteins from endocrine glands

Cardiovascular System

• Lymph returns excess fluid filtered from blood capillaries and leaked blood plasma proteins to venous blood

• Macrophages in spleen destroy aged red blood cells and remove debris in blood

Respiratory System

• Tonsils, alveolar macrophages, and malt (mucosa-associated lymphoid tissue) help protect lungs from pathogens

• Lymphatic vessels drain excess interstitial fluid from lungs

Digestive System

• Tonsils and malt help defend against toxins and pathogens that penetrate the body from the digestive canal

• Digestive system provides IgA antibodies in saliva and gastrointestinal secretions

• Lymphatic vessels pick up absorbed dietary lipids and fat-soluble vitamins from the small intestine and transport them to the blood

• Lymphatic vessels drain excess interstitial fluid and leaked blood plasma proteins from organs of the digestive system

Urinary System

• Lymphatic vessels drain excess interstitial fluid and leaked blood plasma proteins from organs of the urinary system

• malt helps defend against toxins and pathogens that penetrate the body via the urethra

Genital (Reproductive) Systems

• Lymphatic vessels drain excess interstitial fluid and leaked blood plasma proteins from organs of the genital systems

• malt helps defend against toxins and pathogens that penetrate the body via the vagina and penis

• In females, sperm deposited in the vagina are not attacked as foreign invaders due to inhibition of immune responses

•IgG antibodies can cross the placenta to provide protection to a developing fetus

• Lymphoid tissue provides IgA antibodies in the milk of a nursing mother

Image summary: This figure is a medical illustration. It depicts a full-body human silhouette with horizontal lines across the torso and limbs, featuring a specific highlighted area in the pelvic region. The illustration indicates a localized area of interest or pathology within the lower abdomen, suggesting a concentrated medical condition or symptom in that specific anatomical zone compared to the rest of the body.

integrase. Thus, the viral D.N.A is duplicated along with the host cell's D.N.A during normal cell division. In addition, the viral D.N.A can cause the infected cell to begin producing millions of copies of viral R.N.A and to form a capsid for each copy. Capsid formation involves the viral enzyme protease, which cuts proteins into pieces to assemble the capsid. Once new copies of H.I.V are formed, they bud off from the cell's plasma membrane and circulate in the blood to infect other cells.

H.I.V mainly damages helper T cells, and it does so in various ways. At least 100 billion viral copies may be produced each day. The viruses bud so rapidly from an infected cell's plasma membrane that cell lysis eventually occurs.

In addition, the body's defenses attack the infected cells, killing them but not all the viruses they harbor. In most H.I.V-infected individuals, helper T cells are initially replaced as fast as they are destroyed. After several years, however, the body's ability to replace helper T cells is slowly exhausted, and the number of helper T cells in circulation progressively declines because of the daily net loss of helper T cells.

Signs, Symptoms, and Diagnosis of H.I.V Infec-

tion Soon after being infected with H.I.V, most people experience a brief flulike illness. Common signs and symptoms are fever, fatigue, rash, headache, joint pain, sore throat, and swollen lymph nodes. About 50% of infected people also experience night sweats. As early as 3 to 4 weeks after H.I.V infection, plasma cells begin secreting antibodies against H.I.V. These antibodies are detectable in blood plasma and form the basis for some of the screening tests for H.I.V. When people test "H.I.V-positive," it usually means they have antibodies to H.I.V antigens in their bloodstream.

Progression to AIDS After a period of 2 to 10 years, H.I.V destroys enough helper T cells that most infected people begin to experience symptoms of immunodeficiency. H.I.V-infected people commonly have enlarged lymph nodes and experience persistent fatigue, involuntary weight loss, night sweats, skin rashes, diarrhea, and various lesions of the mouth and gums. In addition, the virus may begin to infect neurons in the brain, affecting the person's memory and producing visual disturbances.

As the immune system slowly collapses, an H.I.V-infected person becomes susceptible to a host of opportunistic infections. These are infections caused by microorganisms that are normally held in check but now proliferate because of the defective immune system. AIDS is diagnosed when the helper T cell count drops below 200 cells per microliter (= cubic millimeter) of blood or when opportunistic infections arise, whichever occurs first. In time, opportunistic infections usually are the cause of death.

Among the opportunistic infections that are H.I.V/AIDS related are candidiasis, a fungal infection that may involve the mouth, esophagus, lungs, or vagina; fungal meningitis; persistent diarrhea; cytomegalovirus infections that can cause fever, encephalitis, and blindness; cold sores; fungal pneumonia; tuberculosis; cancer of the skin, blood vessels, vagina, and cervix; lymphoma; AIDS dementia; and wasting syndrome.

Treatment of H.I.V Infection At present, infection with H.I.V cannot be cured. Vaccines designed to block new H.I.V infections and to reduce the viral load (the number of copies of H.I.V R.N.A in a microliter of blood plasma) in those who are already infected are in clinical trials. Meanwhile, several classes of drugs have proved successful in extending the life of many H.I.V-infected people:

1. Nucleoside reverse transcriptase inhibitors N.R.T.I's interfere with the action of reverse transcriptase, preventing the enzyme from converting viral R.N.A into viral D.N.A. Recall that D.N.A and R.N.A are nucleic acids comprised of repeating units called nucleotides and that an individual nucleotide consists of a nitrogenous base, a pentose sugar, and a phosphate group (see Figure 2.24). Reverse transcriptase converts viral R.N.A into viral D.N.A by reading the viral R.N.A strand and forming a complementary D.N.A strand from D.N.A nucleotides in the host cell. Although a nucleotide is the repeating unit of a nucleic acid, an even smaller component is a nucleoside. A nucleoside is simply a nitrogenous base bound to a pentose sugar. In other words, a nucleoside is a nucleotide that does not include the phosphate group. Nucleoside reverse transcriptase inhibitors N.R.T.I's are nucleosides whose structures are slightly altered compared to the normal nucleosides or nucleotides of D.N.A. When N.R.T.I's are present in a cell infected with H.I.V, reverse transcriptase will mistakenly attempt to use N.R.T.I's instead of normal D.N.A nucleotides to form the viral D.N.A strand, but the enzyme shuts down prematurely because of the altered structure of the N.R.T.I's. Hence, N.R.T.I's block the action of reverse transcriptase by serving as faulty substrates for the enzyme, thereby blocking the enzyme's ability to function. Among the drugs in this category are emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, abacavir, didanosine, stavudine, lamivudine, and zidovudine Z.D.V, previously called A.Z.T.

2. Non-nucleoside reverse transcriptase inhibitors N.N.R.T.I's also block the action of reverse transcriptase. However, unlike N.R.T.I's, N.N.R.T.I's have chemical structures that are different from nucleosides and they directly bind to reverse transcriptase to inhibit the enzyme's activity. Examples of drugs in this category include delavirdine, doravirine, and efavirenz.

3. Integrase inhibitors interfere with the action of integrase. As a result, viral D.N.A is unable to insert into host cell D.N.A. The drugs raltegravir and dolutegravir are examples of integrase inhibitors.

4. Protease inhibitors interfere with the action of protease, thereby blocking the formation of the viral capsid. Drugs in this category include nelfinavir, saquinavir, ritonavir, and indinavir.

5. Entry or fusion inhibitors prevent the entry of H.I.V into helper T cells. Examples of drugs in this category are enfuvirtide and maraviroc.

The recommended treatment for H.I.V-infected patients is antiretroviral therapy (art)—a combination of three or more antiretroviral medications from at least two inhibitor drug classes. Most H.I.V-infected individuals receiving art experience a drastic reduction in viral load and an increase in the number of helper T cells in their blood. Not only does art delay the progression of H.I.V infection to AIDS, but many individuals with AIDS have seen the remission or disappearance of opportunistic infections and an apparent return to health. However, art can have a grueling dosing schedule, and not all people can tolerate the toxic side effects of the drugs. Although H.I.V may virtually disappear from the blood with drug treatment (and thus a blood test may be “negative” for H.I.V), the virus typically still lurks in various lymphoid tissues. In such cases, the infected person can still transmit the virus to another person.

There are also two additional methods of antiretroviral therapy: pre-exposure prophylaxis and post-exposure prophylaxis. People who are at high risk of contracting H.I.V (injection drug users or individuals with multiple sex partners) are recommended to take pre-exposure prophylaxis (PrEP). PrEP involves taking antiviral medication on a daily basis. The medication used for PrEP is Truvada® (emtricitabine plus tenofovir disoproxil fumarate) or Descovy® (emtricitabine plus tenofovir alafenamide).

Only people who are H.I.V negative can take PrEP, and, if they take the medication as prescribed, it helps to significantly reduce the ability of H.I.V to infect the body. For those individuals who think that they may have been exposed to H.I.V through unprotected sex, injection drug use, or accidental needle prick with contaminated blood, another type of antiretroviral therapy called post-exposure prophylaxis (P.E.P) is recommended. P.E.P involves taking antiretroviral medication after a possible exposure to H.I.V to help prevent an infection. P.E.P should be started within 72 hours of the possible exposure and continued for approximately one month. P.E.P significantly reduces the chance that the virus will be able to infect the individual.

The medication approved for P.E.P is Truvada® (emtricitabine plus tenofovir disoproxil fumarate) plus raltegravir.

Allergic Reactions

A person who is overly reactive to a substance that is tolerated by most other people is said to be allergic or hypersensitive. Whenever an allergic reaction takes place, some tissue injury occurs. The antigens that induce an allergic reaction are called allergens allergens. Common allergens include certain foods (milk, peanuts, shellfish, eggs), antibiotics (penicillin, tetracycline), vaccines (pertussis, typhoid), venoms (honeybee, wasp, snake), cosmetics, chemicals in plants such as poison ivy, pollens, dust, molds, iodine-containing dyes used in certain x-ray procedures, and even microbes.

There are four basic types of hypersensitivity reactions: type I (anaphylactic), type 2 (cytotoxic), type 3 (immune-complex), and type 4 (cell-mediated). The first three are antibody-mediated immune responses; the last is a cell-mediated immune response.

Type 1 (anaphylactic) reactions anaphylactic are the most common and occur within a few minutes after a person sensitized to an allergen is re-exposed to it. In response to the first exposure to certain allergens, some people produce IgE antibodies that bind to the surface of mast cells and basophils. The next time the same allergen enters the body, it attaches to the IgE antibodies already present. In response, the mast cells and basophils release histamine, prostaglandins, leukotrienes, and kinins.

Collectively, these mediators cause vasodilation, increased blood capillary permeability, increased smooth muscle contraction in the airways of the lungs, and increased mucus secretion. As a result, a person may experience inflammatory responses, difficulty in breathing through the constricted airways, and a runny nose from excess mucus secretion. In anaphylactic shock, which may occur in a susceptible individual who has just received a triggering drug or been stung by a wasp, wheezing and shortness of breath as airways constrict are usually accompanied by shock due to vasodilation and fluid loss from blood.

This life-threatening emergency is usually treated by injecting epinephrine to dilate the airways and strengthen the heartbeat.

Type 2 (cytotoxic) reactions are caused by antibodies (IgG or IgM) directed against antigens on a person's blood cells (red blood cells, lymphocytes, or platelets) or tissue cells. The reaction of antibodies and antigens usually leads to activation of complement. Type 2 reactions, which may occur in incompatible blood transfusion reactions, damage cells by causing lysis.

Type 3 (immune-complex) reactions involve antigens, antibodies (IgA or IgM), and complement. When certain ratios of antigen to antibody occur, the immune complexes are small enough to escape phagocytosis, but they become trapped in the basement membrane under the endothelium of blood vessels, where they activate complement and cause inflammation. Glomerulonephritis and rheumatoid arthritis R.A arise in this way.

Type 4 (cell-mediated) reactions or delayed hypersensitivity reactions usually appear 12 to 72 hours after exposure to an allergen. Type 4 reactions occur when allergens are taken up by antigen-presenting cells (such as intraepidermal macrophages in the skin) that migrate to lymph nodes and present the allergen to T cells, which then proliferate. Some of the new T cells return to the site of allergen entry into the body, where they produce gamma-interferon, which activates macrophages, and tumor necrosis factor, which stimulates an inflammatory response. Intracellular bacteria such as Mycobacterium tuberculosis mycobacterium too-ber'-ku-LŐ-sis) trigger this type of cell-mediated immune response, as do certain haptens, such as poison ivy toxin. The skin test for tuberculosis also is a delayed hypersensitivity reaction.

Autoimmune Diseases

In an autoimmune disease (aw-tô-i-MŨN) or autoimmunity, the immune system fails to display self-tolerance and attacks the person's own tissues. Autoimmune diseases usually arise in early adulthood and are common, afflicting an estimated 5% of adults in North America and Europe. Females suffer autoimmune diseases twice as often as males. Recall that self-reactive B cells and T cells normally are deleted or undergo anergy during negative selection (see Figure 22.22). Apparently, this process is not 100% effective. Under the influence of unknown environmental triggers and certain genes that make some people more susceptible, self-tolerance breaks down, leading to activation of self-reactive clones of T cells and B cells. These cells then generate cell-mediated or antibody-mediated immune responses against self-antigens.

A variety of mechanisms produce different autoimmune diseases. Some involve production of autoantibodies, antibodies that bind to and stimulate or block self-antigens. For example, autoantibodies that mimic T.S.H (thyroid-stimulating hormone) are present in Graves' disease and stimulate secretion of thyroid hormones (thus producing hyperthyroidism); autoantibodies that bind to and block acetylcholine receptors cause the muscle weakness characteristic of myasthenia gravis.

Other autoimmune diseases involve activation of cytotoxic T cells that destroy certain body cells. Examples include type 1 diabetes mellitus, in which T cells attack the insulin-producing pancreatic beta cells, and multiple sclerosis, in which T cells attack myelin sheaths around axons of neurons. Inappropriate activation of helper T cells or excessive production of gamma-interferon also occurs in certain autoimmune diseases. Other autoimmune disorders include rheumatoid arthritis, systemic lupus erythematosus, rheumatic fever, hemolytic and pernicious anemias, Addison's disease, Hashimoto's thyroiditis, and ulcerative colitis.

Therapies for various autoimmune diseases include removal of the thymus gland (thymectomy), injections of beta-interferon, immunosuppressive drugs, and plasmapheresis, in which the person's blood plasma is filtered to remove antibodies and antigen-antibody complexes.

Infectious Mononucleosis

Infectious mononucleosis (mon'-o-noo-kle-o-sis) or "mono" is a contagious disease caused by the Epstein-Barr virus (E.B.V). It occurs mainly in children and young adults, and more often in females than in males. The virus most commonly enters the body through intimate oral contact such as kissing, which accounts for its common name, the "kissing disease." E.B.V then multiplies in lymphoid tissues and filters into the blood, where it infects and multiplies in B cells, the primary host cells. Because of this infection, the B cells become so enlarged and abnormal in appearance that they resemble monocytes, the primary reason for the term mononucleosis.

In addition to an elevated white blood cell count with an abnormally high percentage of lymphocytes, signs and symptoms include fatigue, headache, dizziness, sore throat, enlarged and tender lymph nodes, and fever. There is no cure for infectious mononucleosis, but the disease usually runs its course in a few weeks.

Lymphomas

Lymphomas (lim-FÖ-mas; lymph-= clear water; -oma = tumor) are cancers of the lymphoid organs, especially the lymph nodes. Most have no known cause. The two main types of lymphomas are Hodgkin disease and non-Hodgkin lymphoma.

Hodgkin disease (H.D) Hodgkin is characterized by a painless, nontender enlargement of one or more lymph nodes, most commonly in the neck, chest, and axilla. If the disease has metastasized from these sites, fever, night sweats, weight loss, and bone pain also occur. H.D primarily affects individuals between ages 15 and 35 and those over 60, and it is more common in males. If diagnosed early, H.D has a 90 to 95% cure rate.

Non-Hodgkin lymphoma (N.H.L), which is more common than H.D, occurs in all age groups, the incidence increasing with age to a maximum between ages 45 and 70. N.H.L may start the same way as H.D but may also include an enlarged spleen, anemia, and general malaise. Up to half of all individuals with N.H.L are cured or survive for a lengthy period. Treatment options for both H.D and N.H.L include radiation therapy, chemotherapy, and bone marrow transplantation.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (S.L.E) (er'-e-thê'-ma-TÔ-sus), or simply lupus (= wolf), is a chronic autoimmune, inflammatory disease that affects multiple body systems. Lupus is characterized by periods of active disease and remission; symptoms range from mild to life-threatening. Lupus most often develops between ages 15 and 44 and is 10 to 15 times more common in females than males. It is also 2 to 3 times more common in African Americans, Hispanics, Asian Americans, and Native Americans than in European Americans. Although the cause of S.L.E is not known, both a genetic predisposition to the disease and environmental factors (infections, antibiotics, ultraviolet light, stress, and hormones) may trigger it. Sex hormones appear to influence the development of S.L.E. The disorder often occurs in females who exhibit extremely low levels of androgens.

Signs and symptoms of S.L.E include joint pain, muscle pain, chest pain with deep breaths, headaches, pale or purple fingers or toes, kidney dysfunction, low blood cell count, nerve or brain dysfunction, slight fever, fatigue, oral ulcers, weight loss, swelling in the legs or around the eyes, enlarged lymph nodes and spleen, photosensitivity, rapid loss of large amounts of scalp hair, and sometimes an eruption across the bridge of the nose and cheeks called a “butterfly rash.” The erosive nature of some of the S.L.E skin lesions was thought to resemble the damage inflicted by the bite of a wolf—thus the term lupus.

Two immunological features of S.L.E are excessive activation of B cells and inappropriate production of autoantibodies against D.N.A (anti-D.N.A antibodies) and other components of cellular nuclei such as histone proteins. Triggers of B cell activation are thought to include various chemicals and drugs, viral and bacterial antigens, and exposure to sunlight. Circulating complexes of abnormal autoantibodies and their “antigens” cause damage in tissues throughout the body. Kidney damage occurs as the complexes become trapped in the basement membrane of kidney capillaries, obstructing blood filtering. Renal failure is the most common cause of death.

There is no cure for lupus, but drug therapy can minimize symptoms, reduce inflammation, and forestall flare-ups. The most commonly used lupus medications are pain relievers (nonsteroidal anti-inflammatory drugs such as aspirin and

Severe Combined Immunodeficiency Disease

Severe combined immunodeficiency disease (S.C.I.D) immunodeficiency is a rare inherited disorder in which both B cells and T cells are missing or inactive. Scientists have now identified mutations in several genes that are responsible for some types of S.C.I.D. In some cases, an infusion of red bone marrow cells from a sibling having very similar M.H.C antigens can provide normal stem cells that give rise to normal B and T cells. The result can be a complete cure. Less than 30% of afflicted patients, however, have a compatible, sibling who can

Medical Terminology

- Adenitis (ad'-e-Ni-tis; aden-= gland; -itis = inflammation of) Enlarged, tender, and inflamed lymph nodes resulting from an infection.

- Allograft allograft; allo-= other) A transplant between genetically distinct individuals of the same species. Skin transplants from other people and blood transfusions are allografts.

- Autograft autograft; auto-= self) A transplant in which one's own tissue is grafted to another part of the body (such as skin grafts for burn treatment or plastic surgery).

- Chronic fatigue syndrome C.F.S A disorder, usually occurring in young adults and primarily in females, characterized by (1) extreme fatigue that impairs normal activities for at least 6 months and (2) the absence of other known diseases (cancer, infections, drug abuse, toxicity, or psychiatric disorders) that might produce similar symptoms.

- Gamma globulin globulin Suspension of immunoglobulins from blood consisting of antibodies that react with a specific pathogen. It is prepared by injecting the pathogen into animals, removing blood from the animals after antibodies have been produced,

Chapter Review

Review

22.1 The Concept of Immunity

1. The ability to ward off disease is called immunity (resistance). Lack of resistance is called susceptibility.

2. The two general types of immunity are (a) innate and (b) adaptive.

3. Innate immunity refers to a wide variety of body responses to a wide range of pathogens.

isolating the antibodies, and injecting them into a human to provide short-term immunity.

- Hypersplenism hypersplenism; hyper-= over) Abnormal splenic activity due to splenic enlargement and associated with an increased rate of destruction of normal blood cells.

- Lymphadenopathy lymphadenopathy; lymph-= clear fluid; -pathy = disease) Enlarged, sometimes tender lymph nodes as a response to infection; also called swollen glands.

- Lymphangitis (lim-fan-Ji-tis; -itis = inflammation of) Inflammation of lymphatic vessels.

- Lymphedema lymphedema; edema = swelling) Accumulation of lymph plasma in lymphatic vessels, causing painless swelling of a limb.

- Splenomegaly splenomegaly; mega-= large) Enlarged spleen. Xenograft xenograft; xeno-= strange or foreign) A transplant between animals of different species. Xenografts from porcine (pig) or bovine (cow) tissue may be used in humans as a physiological dressing for severe burns. Other xenografts include pig heart valves and baboon hearts.

22.2 Lymphoid System Structure and Function

1. The lymphoid system carries out immune responses and consists of lymph plasma, lymphatic vessels, and structures and organs that contain lymphoid tissue (specialized reticular tissue containing many lymphocytes).

2. The lymphoid system drains interstitial fluid, transports dietary lipids, and protects against invasion through immune responses.

2. The route of lymph plasma flow is from lymphatic capillaries to lymphatic vessels to lymph trunks to the thoracic duct and right lymphatic duct to the subclavian veins.

3. Lymph plasma flows because of skeletal muscle contractions and respiratory movements. Valves in lymphatic vessels also aid flow of lymph plasma.

22.4 Lymphoid Organs and Tissues

1. The primary lymphoid organs are red bone marrow and the thymus. Secondary lymphoid organs are lymph nodes, the spleen, and lymphatic nodules.

2. The thymus lies between the sternum and the large blood vessels above the heart. It is the site of T cell maturation.

3. Lymph nodes are encapsulated, egg-shaped structures located along lymphatic vessels. Lymph plasma enters lymph nodes through afferent lymphatic vessels, is filtered, and exits through efferent lymphatic vessels. Lymph nodes are the site of proliferation of B cells and T cells.

4. The spleen is the largest single mass of lymphoid tissue in the body. Within the spleen, B cells and T cells carry out immune functions and macrophages destroy blood-borne pathogens and worn-out red blood cells by phagocytosis.

5. Lymphoid nodules are scattered throughout the mucosa of the digestive canal and respiratory, urinary, and genital tracts. This lymphatic tissue is termed mucosa-associated lymphoid tissue (malt).

22.5 Development of Lymphoid Tissues

1. Lymphatic vessels develop from lymph sacs, which arise from developing veins. Thus, they are derived from mesoderm.

2. Lymph nodes develop from lymph sacs that become invaded by mesenchymal cells.

22.6 Innate Immunity

1. Innate immunity includes physical factors, chemical factors, antimicrobial proteins, natural killer cells, phagocytes, inflammation, and fever.

2. The skin and mucous membranes are the first line of defense against entry of pathogens.

3. Antimicrobial substances include interferons, the complement system, iron-binding proteins, and antimicrobial proteins.

4. Natural killer cells and phagocytes attack and kill pathogens and defective cells in the body.

5. Inflammation aids disposal of microbes, toxins, or foreign material at the site of an injury, and prepares the site for tissue repair.

6. Fever intensifies the antiviral effects of interferons, inhibits growth of some microbes, and speeds up body reactions that aid repair.

7. Table 22.1 summarizes the innate defenses.

22.7 Adaptive Immunity

1. Adaptive immunity involves lymphocytes called B cells and T cells. B cells and T cells arise from stem cells in red bone marrow. B cells mature in red bone marrow; T cells mature in the thymus gland.

5. Clonal selection is the process by which a lymphocyte proliferates and differentiates in response to a specific antigen. The result of clonal selection is the formation of a clone of cells that can recognize the same specific antigen as the original lymphocyte.

6. A lymphocyte that undergoes clonal selection gives rise to two major types of cells in the clone: effector cells and memory cells. The effector cells of a lymphocyte clone carry out immune responses that ultimately result in the destruction or inactivation of the antigen. Effector cells include active helper T cells, which are part of a helper T cell clone; active cytotoxic T cells, which are part of a cytotoxic T cell clone; and plasmocytes, which are part of a B cell clone. The memory cells of a lymphocyte clone do not actively participate in the initial immune response. However, if the antigen reappears in the body in the future, the memory cells can quickly respond to the antigen by proliferating and differentiating into more effector cells and more memory cells. Memory cells include memory helper T cells, which are part of a helper T cell clone; memory cytotoxic T cells, which are part of a cytotoxic T cell clone; and memory B cells, which are part of a B cell clone.

7. Antigens (Ags) are chemical substances that are recognized as foreign by the immune system. Antigen receptors exhibit great diversity due to genetic recombination.

8. “Self-antigens” called major histocompatibility complex (M.H.C) antigens are unique to each person's body cells. All cells except red blood cells display M.H.C-I molecules. Antigen-presenting cells A.P.C's display M.H.C-II molecules. A.P.C's include macrophages, B cells, and dendritic cells.

9. Exogenous antigens (formed outside body cells) are presented with M.H.C-II molecules; endogenous antigens (formed inside body cells) are presented with M.H.C-I molecules.

10. Cytokines are small protein hormones that may stimulate or inhibit many normal cell functions such as growth and differentiation. Other cytokines regulate immune responses (see Table 22.2).

22.8 Cell-Mediated Immunity

1. A cell-mediated immune response begins with activation of a small number of T cells by a specific antigen.

2. During the activation process, T-cell receptors T.C.R's recognize antigen fragments associated with M.H.C molecules on the surface of a body cell.

3. Activation of T cells also requires costimulation, either by cytokines such as interleukin-2 or by pairs of plasma membrane molecules.

4. Once a T cell has been activated, it undergoes clonal selection. The result of clonal selection is the formation of a clone of effector cells and memory cells. The effector cells of a T cell clone carry out immune responses that ultimately result in elimination of the antigen.

Severe Combined Immunodeficiency Disease

Severe combined immunodeficiency disease (S.C.I.D) immunodeficiency is a rare inherited disorder in which both B cells and T cells are missing or inactive. Scientists have now identified mutations in several genes that are responsible for some types of S.C.I.D. In some cases, an infusion of red bone marrow cells from a sibling having very similar M.H.C antigens can provide normal stem cells that give rise to normal B and T cells. The result can be a complete cure. Less than 30% of afflicted patients, however, have a compatible sibling who can

Medical Terminology

- Adenitis (ad'-e-Ni-tis; aden-= gland; -itis = inflammation of) Enlarged, tender, and inflamed lymph nodes resulting from an infection.

- Allograft allograft; allo-= other) A transplant between genetically distinct individuals of the same species. Skin transplants from other people and blood transfusions are allografts.

- Autograft autograft; auto-= self) A transplant in which one's own tissue is grafted to another part of the body (such as skin grafts for burn treatment or plastic surgery).

- Chronic fatigue syndrome C.F.S A disorder, usually occurring in young adults and primarily in females, characterized by (1) extreme fatigue that impairs normal activities for at least 6 months and (2) the absence of other known diseases (cancer, infections, drug abuse, toxicity, or psychiatric disorders) that might produce similar symptoms.

- Gamma globulin globulin Suspension of immunoglobulins from blood consisting of antibodies that react with a specific pathogen. It is prepared by injecting the pathogen into animals, removing blood from the animals after antibodies have been produced,

Chapter Review

Review

22.1 The Concept of Immunity

1. The ability to ward off disease is called immunity (resistance). Lack of resistance is called susceptibility.

2. The two general types of immunity are (a) innate and (b) adaptive.

3. Innate immunity refers to a wide variety of body responses to a wide range of pathogens.

isolating the antibodies, and injecting them into a human to provide short-term immunity.

- Hypersplenism hypersplenism; hyper-= over) Abnormal splenic activity due to splenic enlargement and associated with an increased rate of destruction of normal blood cells.

- Lymphadenopathy lymphadenopathy; lymph-= clear fluid; -pathy = disease) Enlarged, sometimes tender lymph nodes as a response to infection; also called swollen glands.

- Lymphangitis (lim-fan-Ji-tis; -itis = inflammation of) Inflammation of lymphatic vessels.

- Lymphedema lymphedema; edema = swelling) Accumulation of lymph plasma in lymphatic vessels, causing painless swelling of a limb.

- Splenomegaly splenomegaly; mega-= large) Enlarged spleen. Xenograft xenograft; xeno-= strange or foreign) A transplant between animals of different species. Xenografts from porcine (pig) or bovine (cow) tissue may be used in humans as a physiological dressing for severe burns. Other xenografts include pig heart valves and baboon hearts.

22.2 Lymphoid System Structure and Function

1. The lymphoid system carries out immune responses and consists of lymph plasma, lymphatic vessels, and structures and organs that contain lymphoid tissue (specialized reticular tissue containing many lymphocytes).

2. The lymphoid system drains interstitial fluid, transports dietary lipids, and protects against invasion through immune responses.

2. The route of lymph plasma flow is from lymphatic capillaries to lymphatic vessels to lymph trunks to the thoracic duct and right lymphatic duct to the subclavian veins.

3. Lymph plasma flows because of skeletal muscle contractions and respiratory movements. Valves in lymphatic vessels also aid flow of lymph plasma.

22.4 Lymphoid Organs and Tissues

1. The primary lymphoid organs are red bone marrow and the thymus. Secondary lymphoid organs are lymph nodes, the spleen, and lymphatic nodules.

2. The thymus lies between the sternum and the large blood vessels above the heart. It is the site of T cell maturation.

3. Lymph nodes are encapsulated, egg-shaped structures located along lymphatic vessels. Lymph plasma enters lymph nodes through afferent lymphatic vessels, is filtered, and exits through efferent lymphatic vessels. Lymph nodes are the site of proliferation of B cells and T cells.

4. The spleen is the largest single mass of lymphoid tissue in the body. Within the spleen, B cells and T cells carry out immune functions and macrophages destroy blood-borne pathogens and worn-out red blood cells by phagocytosis.

5. Lymphoid nodules are scattered throughout the mucosa of the digestive canal and respiratory, urinary, and genital tracts. This lymphatic tissue is termed mucosa-associated lymphoid tissue (malt).

22.5 Development of Lymphoid Tissues

1. Lymphatic vessels develop from lymph sacs, which arise from developing veins. Thus, they are derived from mesoderm.

2. Lymph nodes develop from lymph sacs that become invaded by mesenchymal cells.

22.6 Innate Immunity

1. Innate immunity includes physical factors, chemical factors, antimicrobial proteins, natural killer cells, phagocytes, inflammation, and fever.

2. The skin and mucous membranes are the first line of defense against entry of pathogens.

3. Antimicrobial substances include interferons, the complement system, iron-binding proteins, and antimicrobial proteins.

4. Natural killer cells and phagocytes attack and kill pathogens and defective cells in the body.

5. Inflammation aids disposal of microbes, toxins, or foreign material at the site of an injury, and prepares the site for tissue repair.

6. Fever intensifies the antiviral effects of interferons, inhibits growth of some microbes, and speeds up body reactions that aid repair.

7. Table 22.1 summarizes the innate defenses.

22.7 Adaptive Immunity

1. Adaptive immunity involves lymphocytes called B cells and T cells. B cells and T cells arise from stem cells in red bone marrow. B cells mature in red bone marrow; T cells mature in the thymus gland.

5. Clonal selection is the process by which a lymphocyte proliferates and differentiates in response to a specific antigen. The result of clonal selection is the formation of a clone of cells that can recognize the same specific antigen as the original lymphocyte.

6. A lymphocyte that undergoes clonal selection gives rise to two major types of cells in the clone: effector cells and memory cells. The effector cells of a lymphocyte clone carry out immune responses that ultimately result in the destruction or inactivation of the antigen. Effector cells include active helper T cells, which are part of a helper T cell clone; active cytotoxic T cells, which are part of a cytotoxic T cell clone; and plasmocytes, which are part of a B cell clone. The memory cells of a lymphocyte clone do not actively participate in the initial immune response. However, if the antigen reappears in the body in the future, the memory cells can quickly respond to the antigen by proliferating and differentiating into more effector cells and more memory cells. Memory cells include memory helper T cells, which are part of a helper T cell clone; memory cytotoxic T cells, which are part of a cytotoxic T cell clone; and memory B cells, which are part of a B cell clone.

7. Antigens (Ags) are chemical substances that are recognized as foreign by the immune system. Antigen receptors exhibit great diversity due to genetic recombination.

8. “Self-antigens” called major histocompatibility complex (M.H.C) antigens are unique to each person's body cells. All cells except red blood cells display M.H.C-I molecules. Antigen-presenting cells A.P.C's display M.H.C-II molecules. A.P.C's include macrophages, B cells, and dendritic cells.

9. Exogenous antigens (formed outside body cells) are presented with M.H.C-II molecules; endogenous antigens (formed inside body cells) are presented with M.H.C-I molecules.

10. Cytokines are small protein hormones that may stimulate or inhibit many normal cell functions such as growth and differentiation. Other cytokines regulate immune responses (see Table 22.2).

22.8 Cell-Mediated Immunity

1. A cell-mediated immune response begins with activation of a small number of T cells by a specific antigen.

2. During the activation process, T-cell receptors T.C.R's recognize antigen fragments associated with M.H.C molecules on the surface of a body cell.

3. Activation of T cells also requires costimulation, either by cytokines such as interleukin-2 or by pairs of plasma membrane molecules.

4. Once a T cell has been activated, it undergoes clonal selection. The result of clonal selection is the formation of a clone of effector cells and memory cells. The effector cells of a T cell clone carry out immune responses that ultimately result in elimination of the antigen.

7. Active cytotoxic T cells eliminate invaders by (1) releasing granzymes that cause target cell apoptosis (phagocytes then kill the microbes) and (2) releasing perforin, which causes cytolysis, and granulysin that destroys the microbes.

8. Cytotoxic T cells, macrophages, and natural killer cells carry out immunological surveillance, recognizing and destroying cancerous cells that display tumor antigens.

22.9 Antibody-Mediated Immunity

1. An antibody-mediated immune response begins with activation of a B cell by a specific antigen.

2. B cells can respond to unprocessed antigens, but their response is more intense when they process the antigen. Interleukin-2 and other cytokines secreted by helper T cells provide costimulation for activation of B cells.

3. Once activated, a B cell undergoes clonal selection, forming a clone of plasmocytes and memory cells. Plasmocytes are the effector cells of a B cell clone; they secrete antibodies.

4. An antibody (Ab) is a protein that combines specifically with the antigen that triggered its production.

5. Antibodies consist of heavy and light chains and variable and constant regions.

6. Based on chemistry and structure, antibodies are grouped into five principal classes (IgG, IgA, IgM, IgD, and IgE), each with specific biological roles.

7. Actions of antibodies include neutralization of antigen, immobilization of bacteria, agglutination and precipitation of antigen, activation of complement, and enhancement of phagocytosis.

Critical Thinking Questions

1. Esperanza watched as her mother got her flu shot. "Why do you need a shot if you're not sick?" she asked. "So I won't get sick," answered her mom. Explain how the influenza vaccination prevents illness.

2. Due to the presence of breast cancer, Mrs. Franco had a right radical mastectomy in which her right breast, underlying muscle, and right axillary lymph nodes and vessels were removed. Now she is experiencing

Answers to Figure Questions

22.1 Red bone marrow contains stem cells that develop into lymphocytes.

22.2 Lymph plasma is more similar to interstitial fluid than to blood plasma because the protein content of lymph plasma is low.

22.3 The left and right lumbar trunks and the intestinal trunk empty into the cisterna chyli, which then drains into the thoracic duct.

22.4 Inhalation promotes the movement of lymph plasma from abdominal lymphatic vessels toward the thoracic region because the 8. Complement is a group of proteins that complement immune responses and help clear antigens from the body.

9. Immunization against certain microbes is possible because memory B cells and memory T cells remain after a primary response to an antigen. The secondary response provides protection should the same microbe enter the body again.

22.10 Self-Recognition and Self-Tolerance

1. T cells undergo positive selection to ensure that they can recognize self-M.H.C proteins (self-recognition), and negative selection to ensure that they do not react to other self-proteins (self-tolerance). Negative selection involves both deletion and anergy.

2. B cells develop tolerance through deletion and anergy.

22.11 Stress and Immunity

1. Psychoneuroimmunology (P.N.I) deals with communication pathways that link the nervous, endocrine, and immune systems. Thoughts, feelings, moods, and beliefs influence health and the course of disease.

2. Under stress, people are less likely to eat well or exercise regularly, two habits that enhance immunity.

22.12 Aging and the Lymphoid System

1. With advancing age, individuals become more susceptible to infections and malignancies, respond less well to vaccines, and produce more autoantibodies.

2. Immune responses also diminish with age. severe swelling in her right arm. Why did the surgeon remove lymph tissue as well as the breast? Why is Mrs. Franco's right arm swollen?

3. Tariq's little sister has the mumps. Tariq can't remember if he has had mumps or not, but he is feeling slightly feverish. How could Tariq's doctor determine if he is getting sick with mumps or if he has previously had mumps? pressure in the vessels of the thoracic region is lower than the pressure in the abdominal region when a person inhales.

22.5 T cells mature in the thymus.

22.6 Foreign substances in lymph plasma that enter a lymph node may be phagocytized by macrophages or attacked by lymphocytes that mount immune responses.

22.7 White pulp of the spleen functions in immunity; red pulp of the spleen performs functions related to blood cells.

22.8 Lymphoid tissues begin to develop by the end of the fifth week of gestation.

22.9 Lysozyme, digestive enzymes, and oxidants can kill microbes ingested during phagocytosis.

22.10 Redness results from increased blood flow due to vasodilation; pain, from injury of nerve fibers, irritation by microbial toxins, kinins, and prostaglandins, and pressure due to edema; heat, from increased blood flow and heat released by locally increased metabolic reactions; swelling, from leakage of fluid from capillaries due to increased permeability.

22.11 Helper T cells participate in both cell-mediated and antibody-mediated immune responses.

22.12 Epitopes are small immunogenic parts of a larger antigen; haptens are small molecules that become immunogenic only when they attach to a body protein.

22.13 A.P.C's include macrophages in tissues throughout the body, B cells in blood and lymphoid tissue, and dendritic cells in mucous membranes and the skin.

22.14 Endogenous antigens include viral proteins, toxins from intracellular bacteria, and abnormal proteins synthesized by a cancerous cell.

22.15 The first signal in T cell activation is antigen binding to a T.C.R; the second signal is a costimulator, such as a cytokine or another pair of plasma membrane molecules.

22.16 The C.D.8 protein of a cytotoxic T cell binds to the M.H.C-I molecule of an infected body cell to help anchor the T-cell receptor (T.C.R)-antigen interaction so that antigen recognition can occur.

22.17 Cytotoxic T cells attack some tumor cells and transplanted tissue cells, as well as cells infected by microbes.

22.18 Since all of the plasmocytes in this figure are part of the same clone, they secrete just one kind of antibody.

22.19 The variable regions recognize and bind to a specific antigen.

22.20 The classical pathway for the activation of complement is linked to antibody-mediated immunity because Ag-Ab complexes activate C.1.

22.21 At peak secretion, approximately 1000 times more IgG is produced in the secondary response than in the primary response.

22.22 In deletion, self-reactive T cells or B cells die; in anergy, T cells or B cells are alive but are unresponsive to antigenic stimulation.

22.23 H.I.V attacks helper T cells.

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