11.2 Overview Page 436 The human body contains two systems of circulating fluids—the cardiovascular system and the lymphatic system. In the cardiovascular system chapters, you studied the circulation of blood. In this chapter, you will explore the lymphatic system, which involves the circulation of lymph, a fluid derived from blood. Your exploration of the lymphatic system will begin by examining the anatomy—the lymph, vessels, and lymphoid tissues—of lymph circulation. You will learn about the body’s three lines of defense against pathogens and see how specific immunity differs from nonspecific defenses. Then, as you did in all of the system chapters, you will explore the effects of aging and disorders of the system. Your first topic is the fluid of the system—lymph. Page 437 11.3 Anatomy of the Lymphatic System Lymph and Lymph Vessels Learning Outcomes 2. Explain the origin and composition of lymph. 3. Describe lymph vessels. 4. Explain the route of lymph from the blood and back again. Lymph is a fluid derived from plasma, but it has fewer dissolved proteins. This fluid from plasma leaves the capillaries to become interstitial fluid (extracellular fluid out in the tissues), which washes over the tissues delivering nutrients to the cells and washing away wastes, cellular debris, viruses, bacteria, and loose (possibly cancerous) cells. Lymph reaches cells that are not immediately adjacent to blood capillaries, so it helps these cells meet their nutrient and waste-removal needs. Unlike the circulation of blood through a closed system of blood vessels, this fluid leaves the system of blood vessels through the capillaries due to blood pressure and must then return to the cardiovascular system through a network of open lymph capillaries and vessels that drain the tissues of what is now called lymph. As you can see in Figure 11.2, gaps between the endothelial cells of the lymph capillaries allow lymph, bacteria, and even loose cells to enter the vessel. Valves inside the lymph vessels (shown in Figure 11.3) direct the flow of lymph to larger and larger lymph vessels. These vessels eventually drain into one of two collecting ducts—the thoracic duct and the right lymphatic duct. FIGURE 11.2 Lymphatic capillaries: (a) interspersed with a blood capillary bed, (b) lymph entering a lymph capillary. FIGURE 11.3 Valves in lymphatic vessels: (a) micrograph, (b) diagram showing one-way direction of flow. (a) Dennis Strete/McGraw Hill The thoracic and right lymphatic ducts deliver lymph to the subclavian veins, where it rejoins the circulating blood. As you can see in Figure 11.4, the right lymphatic duct drains lymph from the right side of the head, the right arm, and the right side of the thorax to the right subclavian vein. The thoracic duct delivers lymph from the rest of the body to the left subclavian vein. FIGURE 11.4 Lymph drainage to the subclavian veins: (a) in the thoracic region, (b) of the whole body. The pressure from the buildup of interstitial fluid in the tissues causes this fluid to enter lymph capillaries as lymph. Once lymph is in the capillaries, the skeletal muscle pump moves lymph through the lymph vessels to the collecting ducts and back into blood circulation at the subclavian veins. This is the same skeletal muscle pump that is partially responsible for venous return in the cardiovascular system. Page 438 Page 439 In summary, the cardiovascular and lymphatic systems are interconnected by this shared fluid—called plasma while in blood, interstitial fluid when it leaves the capillaries with fewer proteins to go to the tissues, and lymph when it is drained into lymph capillaries. It must be returned to the bloodstream to make up for the lost volume at the blood capillaries. See Figure 11.5. FIGURE 11.5 Fluid exchange between the cardiovascular and lymphatic systems. Arrows within the blood vessels show the path of blood. Arrows outside the blood vessels show the path of lymph leaving the blood capillaries and rejoining the circulatory system at the subclavian veins. Spot Check 1 Where specifically will lymph in the tissues of the left leg reenter the bloodstream? Spot Check 2 Which collecting duct delivers the lymph from the left leg to that location? Disease Pint Page 440 The lymphatic drainage process is an important part of a healthy, functioning lymphatic system. However, certain conditions may block drainage. For example, elephantiasis is a tropical disease caused by a roundworm that blocks lymphatic drainage. The roundworm gets into the system through a mosquito bite and infects a lymph node (to be discussed shortly), which blocks the flow of lymph, causing edema in the area before the blockage. Typical areas include the legs, arms, breasts, and scrotum. R. Umesh Chandran, TDR, WHO/Science Source You now understand how a common fluid links the cardiovascular and lymphatic systems and you are aware of the blood vessels they share for this fluid’s delivery to the tissues. Next, you will examine the lymphatic system’s cells. Cells of the Lymphatic System Learning Outcome 5. Describe cells of the lymphatic system and list their functions. The primary cells of this system are leukocytes—particularly, lymphocytes. As you may recall from the cardiovascular system chapter on blood, all of the formed elements are produced in the red bone marrow. The cells of this system fall into the following five categories: Natural kiler cels (NK cels). These large lymphocytes are important in nonspecific defense, which is covered in detail later in this chapter. NK cells destroy bacteria, fight against transplanted tissues, attack cells infected by viruses, and destroy cancer cells. T lymphocytes (T cels). These lymphocytes migrate from the red bone marrow to the thymus gland, where they mature. Several classes of T cells, based on their function, include the following: 1. Thelper cels are important for nonspecific defense and specific immunity by recognizing foreign pathogens and activating the cells to fight them. 2. Tcytotoxic cels directly kill cells infected by viruses and cancer cells in specific immunity. 3. Tmemory cels are also used in specific immunity. They remember pathogens that have been introduced to the body so that repeat exposure can be fought more swiftly. 4. Tregulatory cels suppress an immune response by inhibiting multiplication and chemical secretions from other T cells. Tregulatory cells are important in limiting and preventing autoimmune responses. B lymphocytes (B cels). These lymphocytes migrate from the red bone marrow to lymphoid tissues, such as lymph nodes, tonsils, and the spleen (covered in the next section). B cells also function as antigen presenting cells (APCs) by constantly sampling material from their environment, processing it, and then displaying it for other cells to see. You will learn how this works when you review the physiology of this system. There are two basic types of B cells: 1. Bplasma cels are important in specific immunity because they produce antibodies, which are dissolved proteins in plasma that seek out specific foreign antigens for their destruction. 2. Bmemory cels, like Tmemory cells, remember pathogens that have been introduced to the body so that repeat exposure can be fought more swiftly. You will learn more about this when we discuss humoral immunity later in this chapter. Macrophages. These cells are not lymphocytes. They are monocytes that were produced in the red bone marrow and have migrated to the tissues to become macrophages. Their purpose, in the nonspecific defense of the body, is to phagocytize bacteria, debris, and dead neutrophils. Like B cells, macrophages are APCs. Dendritic ce ls. These are immune system cells of the epidermis that stand guard to alert the body of pathogens entering through the skin. They also function as APCs. You were introduced to these cells in the integumentary system chapter. Page 441 Lymphoid tissues were mentioned as the location for several of the preceding cells. These tissues and organs are discussed in the next section. Spot Check 3 What important functions of the immune system might be affected by a disease that decreases a person’s number of viable T cells? Lymphoid Tissues and Organs Learning Outcome 6. Identify lymphoid tissues and organs and explain their functions. Lymphoid tissues and organs may be as small as a scattering of lymphocytes in mucous membranes or may be full-size organs, such as the spleen. Many of the tissues are shown in Figure 11.6. FIGURE 11.6 Lymphoid tissues and organs. Spot Check 4 Red bone marrow is shown in Figure 11.6. Why is red bone marrow relevant to this system? Mucosa-Associated Lymphatic Tissue Mucosa-associated lymphatic tissue (MALT) is a scattering of lymphocytes located throughout the mucous membranes lining tracts to the outside environment, such as the tracts for the digestive, respiratory, urinary, and reproductive systems. The purpose of MALT is to stand guard against and fight any pathogens trying to enter the body. Peyer’s Patches These patches of lymphatic tissue are located at the distal end of the small intestine, just before the opening to the large intestine. Peyer’s patches are an example of more densely packed pockets of lymphocytes called nodules. These particular nodules fight any bacteria moving into the small intestine from the colon, where they naturally reside. Lymph Nodes These lymphatic structures act as filters along lymph vessels. Lymph nodes remove anything that may be potentially harmful in lymph, much like a water-purification filter may remove impurities in the drinking water arriving at your kitchen faucet. Each lymph node has many nodules packed with lymphocytes and macrophages. As you can see in Figure 11.7, several lymph vessels direct lymph flow into the lymph node. There, fibers trap debris, cells, and bacteria picked up by the lymph in the tissues. Macrophages phagocytize the debris, while lymphocytes mount an attack on the pathogens. If an infection is present, germinal centers (sites for cloning lymphocytes) in the lymph nodes produce more B lymphocytes. Meanwhile, the lymph circulates through the lymph node on its way to larger lymph vessels. FIGURE 11.7 Lymph node: (a) lymph node showing direction of lymph flow, (b) micrograph of a lymph node, (c) dissection of lymph node and lymph vessels. (b) Alvin Telser/McGraw Hill; (c) Dr. Kent M. Van De Graaff Lymph nodes are located in specific areas, as outlined in the following list, to filter lymph as it is drained from different regions. See Figure 11.6. Page 442 Page 443 Cervical lymph nodes are located in groups in the neck. They filter lymph from the head and neck. Axillary lymph nodes are located in the axillary region and the lateral margin of the breast. They filter lymph from the breasts and arms. Thoracic lymph nodes are located in the mediastinum surrounding the trachea and bronchi. They filter lymph from organs in the thoracic cavity. Abdominal lymph nodes are located in the posterior wall of the abdominopelvic cavity. They filter lymph from the urinary and reproductive systems. Pelvic lymph nodes are deep in the pelvic region and surround the iliac arteries and veins. They also filter lymph from the urinary and reproductive systems. Intestinal and mesenteric lymph nodes are located in the mesenteries and surround the mesenteric arteries and veins. They filter lymph from the digestive organs. Lymph from the digestive system appears milky because it carries the products of lipid digestion. Popliteal lymph nodes are located in the popliteal region (behind the knee). They filter lymph from the leg. Inguinal lymph nodes are superficial in the groin. They filter lymph from the lower limbs. See Figure 11.8. FIGURE 11.8 Inguinal lymph nodes of a cadaver. Rebecca Gray, photographer/McGraw Hill Education Page 444 When a pathogen is under attack by the lymph node’s lymphocytes, the lymph node may become swollen and painful to the touch. This condition is called lymphadenitis (lim-FAD-eh-neye-tis). Understanding lymph drainage is helpful in locating the primary site of the cause of the attack. Clinical Pint For example, look at Figure 11.9, which shows the lymph drainage for the right breast. Swollen, painful lymph nodes in the right axillary region may indicate the presence of cancer cells that have metastasized from the right breast and have been trapped in the right axillary lymph nodes. Likewise, if breast cancer in the right breast has been found through other means (self-exam, mammography, or needle biopsy), a biopsy of the right axillary lymph nodes may give a good indication of whether the tumor has metastasized. If it has, the lymph should have carried any loose, metastatic cancer cells to the right axillary lymph nodes. FIGURE 11.9 Lymph drainage of the right breast. Spot Check 5 Which lymph nodes may be tender to the touch if Satya has a strep throat infection? Tonsils Page 445 Like lymph nodes, tonsils are lymphoid tissue with high concentrations of lymphocytes. As you can see in Figure 11.10, three types of tonsils— one pharyngeal, two palatine, and numerous lingual tonsils—ring the pharynx (throat) to guard against pathogens entering the body through the nose or mouth. Each tonsil has pits (crypts) to give the lymph nodules (small, localized collections of lymphoid tissue) more exposure to whatever may be passing by. The locations of the tonsils are as follows: FIGURE 11.10 Tonsils: (a) location of tonsils, (b) histology of a pharyngeal tonsil showing crypts. (b) Biophoto Associates/Science Source The pharyngeal tonsil (adenoids) is located on the roof of the nasopharynx (section of throat at the back of the nasal cavity). The palatine tonsils, located laterally in the oropharynx (section of the throat at the back of the mouth) are commonly recognized as the tonsils. These tonsils often swell and become inflamed during a throat infection and can be seen by looking in the mouth. The lingual tonsils have many nodules filled with lymphocytes at the root of the tongue. Page 446 Thymus Gland Another important lymphoid tissue is the thymus gland, which is located in the superior mediastinum between the sternum and the aortic arch. It is well developed at birth and continues to develop during childhood, but it starts to shrink around the age of 14. See Figure 11.11 for a relative size comparison between a fetal thymus and that of an adult. FIGURE 11.11 Thymus gland: (a) of a fetus, (b) of an adult. T cells migrate from the red bone marrow to the thymus gland, where they mature. In the maturation process, the thymus introduces self antigens to the developing T cells. If the T cell reacts to the self-antigen, the T cell is destroyed. Only those T cells that do not react to self antigens are stimulated to further develop by chemicals secreted by the thymus. These T cells are an important part of the immune system because they react only to foreign (not self-) antigens. Spleen You have already studied the spleen in relation to its role in the life cycle of a red blood cell and as a reservoir for blood, but it also has functions in the lymphatic system. The spleen is located in the upper left quadrant (ULQ), posterior and lateral to the stomach. See Figure 11.12. Tissues in the spleen consist of two types—red pulp and white pulp. Red pulp serves as a reservoir for RBCs and destroys old, worn-out red blood cells. White pulp is a reservoir for lymphocytes and macrophages, and it functions similarly to lymph nodes as a site of battle between lymphatic cells and pathogens. The spleen also maintains homeostasis by regulating blood volume by transferring excess fluid in the blood to the lymphatic system as lymph. FIGURE 11.12 The spleen: (a) spleen in a cadaver with the stomach removed, (b) medial surface of the spleen, (c) white and red pulp. (a) Dennis Strete/McGraw Hill; (c) Al Telser/McGraw Hill Clinical Pint Trauma to the spleen can be dangerous because it is such a highly vascular organ. In cases of trauma, surgical removal of the spleen is often easier than trying to deal with a repair and possible fatal hemorrhaging. It is possible to live a normal life without a spleen. Without a spleen, there is no reservoir for blood. However, the other functions of the spleen can be accomplished by the liver (breakdown of erythrocytes) and other lymphoid tissues (storage of lymphocytes and site to fight pathogens). Page 447 11.4 Physiology of the Lymphatic System You are already familiar with the circulation of lymph. It is forced out of capillaries due to blood pressure and washes over tissues to deliver nutrients and remove wastes. The pressure of the lymph in the tissues forces lymph back into lymph capillaries so that the lymph vessels can return it to the bloodstream at the subclavian veins. But how does this system fight pathogens? To understand the answer to this question, you need to study the physiology of defense. Three Lines of Defense Learning Outcome 7. Summarize three lines of defense against pathogens. Page 448 The three basic lines of defense against pathogens are the following: 1. External barriers 2. Inflammation, antimicrobial proteins, fever, and other active attacks 3. Specific immunity Nonspecific Resistance versus Specific Immunity Learning Outcome 8. Contrast nonspecific resistance and specific immunity. The first two lines of defense are considered to be nonspecific resistance, while the third is specific immunity. The lines of defense are not mutually exclusive, as more than one line of defense is likely to be at work at the same time to eliminate the same pathogen. What is the difference between nonspecific resistance and specific immunity? Nonspecific defenses are widespread, meaning they work to fight many pathogens without prior exposure. These defenses work to fend off any pathogen in the same way every time the pathogen comes along in the body. Specific immunity is just that—specific. It requires a prior exposure to a pathogen so that the system can recognize the pathogen, react to the pathogen to fight it off, and then remember the specific pathogen so that it can be fought off faster and stronger if it ever occurs in the body again. Now that you are familiar with the differences of the two types of defenses, you are ready to explore the three lines of defense, starting with the two lines of nonspecific defenses. Nonspecific Defenses Learning Outcome 9. Describe the body’s nonspecific defenses. The two lines of nonspecific defense are 1. external barriers; and 2. inflammation, antimicrobial proteins, fever, and other active attacks. Most of these have been mentioned in chapters you have already covered, but it will be helpful to refresh your memory in regard to how they relate to this system. External Barriers This first line of defense protects body tissues from pathogens in the outside environment. Skin Skin acts as an external barrier to pathogens for several reasons: Keratin is a tough protein that bacteria cannot easily break through. Skin is dry, with few nutrients for bacteria and other pathogens. The skin has an acid mantle, which makes it inhospitable for bacteria and other pathogens. Mucous membranes Mucous membranes (lining all the tracts through the body for the respiratory, digestive, urinary, and reproductive systems) also serve as an external barrier for the following reasons: Mucus traps microbes. Page 449 Mucus, tears, and saliva contain lysozymes to destroy pathogens. Deep to the mucous membranes is loose areolar connective tissue with fibers to hamper the progress of pathogens. We turn now to the body’s second line of nonspecific defense. Inflammation, Antimicrobial Proteins, Fever, and Other Active Attacks Like external barriers, each of these non-specific defenses works against a variety of pathogens in the same way regardless of the number of exposures to the pathogen. You will investigate each of them individually. Inflammation The functions of inflammation are threefold. See if you can picture how the steps in the inflammatory process meet the following functions of inflammation: To limit the spread of pathogens To remove debris and damaged tissue To initiate tissue repair As you will recall from “Chapter 1, The Basics,” the signs of inflammation are redness, heat, pain, and swelling. (Follow along with Figure 11.13 as you read more about inflammation.) The steps in the inflammatory process are as follows (in order of occurrence): FIGURE 11.13 The inflammatory response, illustrating margination, diapedesis, chemotaxis, and phagocytosis. 1. Chemicals (vasodilators) are released by damaged tissues and basophils. The chemicals diffuse across the surrounding tissues and affect any blood vessels in the area. The dilation of these vessels causes increased blood flow to the area and increased vessel permeability. The increased blood flow accounts for the signs of redness and heat (blood from the core transports heat), while the increased permeability accounts for the swelling and pain (more fluid to tissues causes the swelling, which puts pressure on nerve endings, causing the pain). The heat increases the local metabolic rate to increase cell division and healing. The increased blood flow dilutes possible toxins produced by pathogens, provides cells with more oxygen and nutrients, and removes more wastes. The increased permeability facilitates the movement of leukocytes to the tissues. 2. WBCs stick to the walls of the dilated vessels in the inflamed area (margination). See Figure 11.13. Neutrophils will be the first on the scene. 3. WBCs crawl through the vessel walls (diapedesis). 4. WBCs move to where the concentration of chemicals from damaged tissues is the greatest (chemotaxis). Since the chemicals move by diffusion, the greatest concentration will be at the source of the damage. 5. WBCs phagocytize foreign material, debris, and pathogens along the way (phagocytosis). The accumulation of WBCs, debris, bacteria, and interstitial fluid is called pus. Page 450 Spot Check 6 How does inflammation help with tissue repair? Spot Check 7 How does inflammation help remove debris and damaged tissue? Spot Check 8 How does inflammation limit the spread of pathogens? Inflammation works this way for all sorts of pathogens to limit their spread, to remove debris and damaged tissue, and to initiate tissue repair. If another splinter (like the one in Figure 11.13) damages tissue a week from Tuesday, the response will be the same because this is a nonspecific line of defense. Antimicrobial proteins There are two types of antimicrobial proteins that provide the body with nonspecific resistance to pathogens. These antimicrobial proteins— interferons and the 20 inactive proteins that make up the complement system—are explained as follows: Interferons are chemicals released by virally infected cells. They do not help the cell that produced them. Instead, interferons encourage surrounding healthy cells to make antiviral proteins so that the virus will not invade them. Interferons also activate macrophages and NK cells to fight cancer cells. The complement system includes 20 inactive proteins (always present in the blood) that may be activated by the presence of a pathogen. Once activated, the proteins initiate one of several different pathways to ensure pathogen destruction through increased inflammation, breaking apart of the pathogen (cytolysis), or coating a pathogenic cell to make it easier for a macrophage to phagocytize it (opsonization). Fever Most people view a fever as a bad thing, but it is another method of nonspecific defense. A fever is initiated by the production of chemicals (pyrogens) from activated macrophages. These pyrogens travel to the hypothalamus, which then raises the set point for body temperature. The body responds by shivering to produce more heat, while the blood vessels in the skin constrict to preserve the heat being generated. Once the new set point is reached (a stage called stadium), the liver and spleen hoard zinc and iron, which are necessary for bacteria growth. This gives time for other defenses to work to defeat the pathogen and increase cellular metabolism needed to heal damaged tissue. Once the pathogen is defeated, the hypothalamus resets the temperature to normal and the brain may initiate sweating to cool the body to homeostasis (defervescence). See the graph of body temperature in Figure 11.14. FIGURE 11.14 Graph of a fever. Normal body temperature approximates the temperature set by the hypothalamus. (1) The onset of a fever begins when the hypothalamus raises the set point. (2) The body temperature then approximates the new set point; this is called stadium. (3) Once the infection ends, the hypothalamus resets the body temperature to normal. (4) The body temperature decreases in a process called defervescence. Other active attacks This line of defense refers to the functions of leukocytes other than lymphocytes. You have already studied them in the cardiovascular system chapter on blood. As a means of nonspecific resistance, these cells make their attacks with the same speed and strength each time any pathogen enters the body. Here is how each of these cell types works: Neutrophils fight bacteria. Basophils release histamine to promote inflammation. Eosinophils attack worm parasites. Monocytes become macrophages to phagocytize bacteria. Specific Immunity Page 451 Learning Outcome 10. Explain the role of an APC in specific immunity. As mentioned earlier, specific immunity differs from nonspecific resistance because it requires a prior exposure to a pathogen in order to work. During the first exposure, the immune system recognizes the specific pathogen as being foreign, reacts to it, and then remembers it. The process starts with an antigen-presenting cell. How does an APC work? Figure 11.15 shows an APC in the process of presenting an antigen. In this case, the APC is a macrophage, but the process is the same for B cells and other APCs. Imagine that the APC is in an axillary lymph node. Its job is to sample antigens in the surrounding environment by phagocytosis (1). It may sample a foreign antigen or a self-antigen. Next, a lysosome fuses with the vesicle carrying the phagocytized antigen (2). The antigens and the enzymes of the lysosome mix (3). The antigen is broken down to fragments, or degraded (4). Most of the antigen residue is expelled from the cell by exocytosis (5). Some of the antigen fragments (epitopes) are displayed on an MHC protein on the surface of the APC (6). FIGURE 11.15 Antigen-presenting cell in the process of antigen presentation. An MHC protein is like a billboard posting what the APC has sampled. MHC stands for major histocompatibility complex. Other cells in the body have MHC proteins too. Unlike APC cells that sample their surrounding environment and post what they find, these other body cells present what is inside themselves on their MHC protein. In that case, the MHC protein is posting, “This is me.” Therefore, an MHC protein displays what is self and what is foreign. Specific immunity hinges on being able to tell the difference. If the MHC protein displays self-antigens, nothing happens. However, if the epitope in the MHC is foreign, a specific immune response is initiated. In the next section, we explain how that is accomplished in humoral immunity, one form of specific immunity. Page 452 Spot Check 9 Explain the relationship between an APC and MHC proteins and the role they play in specific immunity. Humoral (Antibody-Mediated) Immunity Learning Outcome 11. Explain the process of humoral immunity. This form of specific immunity involves B cells making antibodies to attack a foreign antigen. It begins when a B cell (APC) in lymphoid tissue displays an epitope from its environment on an MHC protein. A Thelper cell passing by either does nothing because the epitope is self or reacts to it by binding to the B cell because it recognizes the epitope as foreign. (Remember: All T cells that react to self are destroyed in the thymus.) The Thelper cell then communicates to the B cell by releasing a chemical (interleukin-2) that tells the B cell that the epitope is foreign and that the B cell should clone itself. The steps up to this point have been the recognize stage of specific immunity. See Figure 11.16. FIGURE 11.16 Humoral immunity: (1) antigen presentation and Thelper cell recognition, (2) cloning and differentiation, (3) antibody production for the attack. Under the direction of the Thelper cell, the B cell (still in the lymphoid tissue) begins to clone itself in the germinal centers in the lymphatic nodules. This clone develops (differentiates) into two types of B cells— plasma B cells that start to produce specific antibodies (to attack the specific antigen that was displayed previously) and memory B cells (that do nothing now). The antibodies produced by the plasma B cells leave the lymphoid tissue with the lymph and enter the blood at the subclavian veins. From there, they travel throughout the body seeking out the specific antigen from the specific pathogen wherever it may be. The antibodies may cover up the binding sites of the foreign invader (rendering the invader harmless), activate the complement system, or agglutinate the antigen so that macrophages can phagocytize it. Note that the B cell does not need to be present at the attack site because antibodies, which act as guided missiles, are sent from bunkers in the lymphoid tissues where the B cells reside. This paragraph describes the react stage of humoral immunity. Again, see Figure 11.16. Page 453 Spot Check 10 What method of attack do antibodies to blood-typing antigens (A, B, Rh) use? (Hint: See the cardiovascular system chapter on blood.) It takes 3 to 6 days for humoral immunity to accomplish antibody production in the first exposure to the pathogen. It will take another 10 days before the amount of antibody production reaches its peak. Once the pathogen is defeated, the amount of antibody in the system decreases, but it never totally drops to zero. If the pathogen enters the body again, Bmemory cells will recognize it immediately. The Bmemory cells will then increase antibody production to reach a peak in approximately 2 to 5 days, instead of 13 to 16. See Figure 11.17. In this way, the pathogen will likely be defeated before any signs of its presence are even noticed. With a repeated exposure like this, antibody production will stay high because the immune system has learned that this pathogen reoccurs. Specific immunity does not prevent a pathogen from entering the body. Instead, it fights it so much faster and stronger with repeated exposure that the pathogen is defeated before it can make you sick. This paragraph describes the remember stage of specific immunity. FIGURE 11.17 Graph of primary and secondary response in humoral immunity. Page 454 Cellular (Cell-Mediated) Immunity Learning Outcome 12. Explain the process of cellular immunity. This is another form of specific immunity, and, as such, it works on the principles of recognize, react, and remember. However, cellular immunity is a little more complicated. Like humoral immunity, cellular immunity starts with an antigen presenting cell, or any other cell presenting something on an MHC molecule. The epitope can be an antigen the cell sampled from its external environment (such as an APC) or a fragment of something in the cytoplasm of the cell itself (such as other body cells). The epitope may even be a part of an unusual (foreign) protein formed inside a cancer cell. In this form of immunity, a Thelper or Tcytotoxic cell reacts by binding to the APC because it recognizes the epitope as being foreign. It verifies that the epitope is foreign by binding to a costimulation protein on the APC, if there is one. Then either T cell releases interleukin-1 to cause the T cell to clone itself to become many Tcytotoxic cells (TC), Thelper cells (TH), and Tmemory cells (TM) that all recognize this antigen as foreign (recognize stage). See Figure 11.18. FIGURE 11.18 Cellular immunity: (1) antigen recognition, (2) costimulation to verify the epitope is foreign, (3) cloning and differentiation, (4) lethal hit or interleukin secretion to initiate other outcomes. An activated Tcytotoxic cell then travels throughout the body seeking cells with this specific foreign antigen. If it finds the foreign antigen, it docks to the cell and delivers a lethal hit to the cell. Unlike the antibodies released from B cells safe and secure in lymphoid tissue, Tcytotoxic cells mount a direct cell-to-cell attack. The Thelper cells of the clone secrete interleukins to attract neutrophils and NK cells to the area, attract and activate macrophages to clean up any debris, and further activate more Tcytotoxic and B cells. Of the T cells, only Tcytotoxic cells directly attack a pathogen or cancer cell (react stage) in this form of specific immunity. See Figure 11.19. FIGURE 11.19 Tcytotoxic cell attacking a cancer cell. (a) Tcytotoxic cell docks to a cancer cell. (b) Tcytotoxic cell delivers a lethal hit to the cancer cell. (a, b) Dr. Andrejs Liepins/Science Source Cellular immunity is effective against virally infected cells. Viruses are basically pieces of nucleic acids surrounded by a protein coat. They penetrate a cell of choice (specific to each virus) and insert their viral (foreign) nucleic acid into the DNA of the cell. The cell then drops its normal function to become a viral factory, producing more and more virus until the cell bursts with all of the virus it has produced. The free virus (enclosed in its protein coat) then seeks out other cells to invade. Tcytotoxic cells destroy the self cell that has been turned into a viral factory. See Figure 11.20. FIGURE 11.20 Virus action on a cell: (a) The virus enters the body, (b) the virus binds to cell of choice, (c) the virus inserts its RNA into the cell’s nucleus, (d) the cell’s function is turned off and it becomes a virus factory, (e) the virus-filled cell bursts to release new virus to infect other cells. Tmemory cells stand by until the pathogen reoccurs in the body. If it does reoccur, these cells mount a cellular immunity response that is faster and stronger than the initial response (remember stage). Clinical Pint In some instances, organ transplantation is a viable treatment option for thousands of patients with dysfunctional organs damaged by disease or trauma. Organ transplantation in the United States exceeded 30,000 for the first time annually in 2015.1 But transplanted organs are considered foreign tissue, so the body’s immune system naturally attacks this foreign tissue. Important breakthroughs in tissue typing and the development of immunosuppressant (anti rejection) drugs allow for more organ transplants and increased survival rates. For example, the first human heart transplant occurred in 1967 but the patient survived just 18 days.2 In 2016, 88% of patients were expected to survive the first year after surgery and the 5-year survival rate expectation was 75%.3 Advancements in scientific research and the improved development of these drugs over time have made successful organ transplantation possible. Spot Check Page 455 Page 456 11 How do the locations of the lymphocytes involved in humoral and cellular immunity differ during the attack on the pathogen? Forms of Acquired Immunity Learning Outcome 13. Compare the different forms of acquired immunity. Another way of looking at specific immunity is to consider how it is acquired. The four terms that become relevant in this discussion of acquired immunity are explained in the following list: Passive is used to indicate that the immunity was acquired through someone or something else (an animal such as a horse or pig). Active is used to indicate that the body actively created its own immunity. Natural is used to indicate that the immunity was accomplished through naturally occurring means. Artificial is used to indicate that the immunity was not acquired through naturally occurring means. These terms are used to classify the four types of acquired immunity: Natural active immunity is what has been described in the previous explanations of humoral and cellular immunity. A pathogen invades the body through everyday activities; the body responds by recognizing the specific pathogen as foreign and reacting to it by producing antibodies or activating Tcytotoxic cells to destroy the pathogen. The body then remembers the specific pathogen so that it can fight the pathogen faster and stronger if it reappears. An example of this is catching a cold from someone in your class. Your body recognizes the cold virus as foreign, activates Tcytotoxic cells to destroy your virally infected cells, and then remembers that specific cold virus so you do not get that cold again. The fact that you may get a cold every year does not mean your immune system is faulty. It just means that there are many different cold viruses. Specific immunity is specific to each cold virus. Natural passive immunity means that the body has acquired specific immunity through natural means from someone else. Some antibodies can pass from mother to child through breast milk. The child has specific immunity to some pathogens because the child has acquired its mother’s antibodies. This is one of many reasons some mothers choose to nurse their infants. Artificial active immunity occurs when the body acquires a pathogen in an artificial way and then develops its own humoral or cellular immunity. Examples of this are the smallpox, polio, and chicken pox vaccinations mentioned at the beginning of this chapter. Deborah was vaccinated on her arm with weakened antigens from the smallpox virus. So she did not come in contact with the antigens through normal, everyday activities—a health care worker scratched the skin of Deborah’s arm with a substance prepared in a laboratory that was designed to expose Deborah to a harmless smallpox virus antigen without causing her to get smallpox. Deborah’s body recognized the antigen as foreign, reacted to it by making antibodies, and now remembers that antigen, so it will attack it faster and stronger if it should ever enter Deborah’s body again. Artificial passive immunity is acquired when an individual receives an injection of serum containing antibodies from another person or an animal such as a horse or pig. Antibodies can also be synthetically made or produced by bacteria. The effect is temporary because the body has not actively developed the mechanism to replace the injected antibodies that will eventually be used up. This type of immunity is used for the emergency treatment of tetanus, rabies, and snakebites. Page 457 Spot Check 12 Which of the four types of acquired immunity listed in the preceding paragraphs is provided by an injection of Rhogam for Rh- mothers? Clinical P int Vaccines are preparations of pathogenic particles that have been killed or weakened so that they do not cause disease. These harmless particles provide cells of the lymphatic system a first exposure to a specific, potentially lethal pathogen. As a result of the clinical administration of a vaccine, APCs present epitopes of the killed or weakened pathogen and Thelper cells respond by starting the recognize, react, and remember steps of humoral and cellular immunity to that particular pathogen. In this way, the body develops specific immunity to mount a faster and stronger attack on a live, stronger version of the pathogen in future exposures. Some vaccines require more than one dose to induce specific immunity to a pathogen. The immunity induced by the vaccine may be time-limited, in which case, booster shots of the vaccine may be required. You have now become familiar with the three lines of defense in the body. Note that T cells are important in more than one line of defense. We summarize their role in the following section. Importance of Thelper Cells in Nonspecific Resistance and Specific Immunity Learning Outcome 14. Explain the importance of Thelper cells to specific and nonspecific defense. As you can see in Figure 11.21, Thelper cells provide a vital role in nonspecific defense and specific immunity. Thelper cells activate macrophages for nonspecific defenses such as inflammation and fever. Thelper cells are also important for both forms of specific immunity. In humoral immunity, these cells first recognize what is foreign and then release interleukin-2 to have B cells react by cloning themselves and producing antibodies. In cellular immunity, Thelper cells recognize what is foreign and release interleukin-1 to get Tcytotoxic cells to clone themselves and attack. Keep in mind the importance of these cells when you read about disorders and HIV later in the chapter. FIGURE 11.21 Importance of Thelper cells. Page 458 You can now combine all of this information concerning anatomy and physiology to clearly understand the functions of this system. Spot Check 13 Describe the role of Thelper cells in both nonspecific and specific immunity. Functions of the Lymphatic System Learning Outcome 15. Explain the functions of the lymphatic system. Remember Andre from the cardiovascular system chapter on blood? See Figure 11.22. In the following list, we explain the different functions of Andre’s lymphatic system as a general example of how a healthy lymphatic system works. FIGURE 11.22 Andre is bleeding through the bandage on his knee. Bellurget Jean Louis/Jupiterimages/Getty Images Page 459 Fluid balance. Every minute of every day, Andre loses fluid (lymph) from his cardiovascular system. In order to maintain homeostasis, the interstitial fluid washes over his tissues, delivering nutrients and removing wastes. It is collected by open-ended lymph vessels, which return it back to his bloodstream at his subclavian veins as lymph. Lipid absorption. The lymph drained from Andre’s digestive system organs carries the products of lipid digestion from the glass of milk he had for breakfast this morning. You will learn more about this in the digestive system chapter. Defense against disease. Although the skin as an external barrier has been broken with the scrape on his knee, Andre’s other nonspecific defenses are at work to destroy any pathogens that may have entered the damaged tissue. Dendritic cells in the skin are serving as APCs to present foreign antigens to Thelper cells so that macrophages can be activated. These Thelper cells may also activate the complement system. The inflammatory process has started, too, and will bring neutrophils to the area. The neutrophils will crawl out of the dilated blood vessels and move to the damaged tissue, consuming bacteria along the way. Immunity. Andre is still very young. His thymus gland is still growing and maturing the T cells that detect foreign antigens and destroying those that react to his own cells. His T cells will be vital for his lymphatic system to accomplish the third line of defense, whether it be humoral or cellular immunity. Andre’s immune system is capable of making at least 10 billion different antibodies, each specific to a particular pathogen. Hopefully, Andre will never be exposed to that many different pathogens, but his capacity for developing specific immunity is there as he needs it. What will happen to this system as Andre ages? We focus next on the effects of aging on the lymphatic system. Page 460 11.5 Effects of Aging on the Lymphatic System Learning Outcome 16. Summarize the effects of aging on the lymphatic system. Andre’s ability to move fluid between his cardiovascular system and the lymphatic system does not decrease with age. Lymph will continue to leave his blood vessels to nourish cells far from his blood capillaries and remove their wastes. Lymph will also continue to carry the products of lipid digestion in his old age. The number of B cells in Andre’s lymphoid tissues will remain relatively stable. What will be affected is his number of new T cells because his thymus will have shrunk and much of the tissue will have been replaced with connective tissue. His T cells in other lymphoid tissues will still be able to clone themselves, but not as many will be made with each clone. The decrease in Thelper cells could mean that his recognition of pathogens will be slower. This slowdown may be a reason that cancer is more prevalent in older people. Vaccinations might not offer as much protection as they did when Andre was younger. A good example of this is Deborah, who had chicken pox as a child and developed natural active immunity to the virus. The virus remained latent in her nerves while her immune system kept it from becoming active. But as Deborah ages, her immune system slows down, and the same virus may reemerge to cause painful lesions called shingles. The age-related changes to the immune system may have a positive effect if the older individual has allergies because this hyperimmune response may be slowed as well. Allergies and other lymphatic system disorders are discussed in the final section of this chapter. Page 461 11.6 Diagnostic Tests for Lymphatic System Disorders Learning Outcome 17. Describe common diagnostic tests used for lymphatic system disorders. Like the tables for other systems, Table 11.1 presents common diagnostic tests used for lymphatic system disorders. A lot of the tests may be familiar to you as they have been mentioned in previous chapters, but their specific relation to the lymphatic system is explained in Table 11.1. TABLE 11.1 Diagnostic Tests for Lymphatic System Disorders Diagnostic Test Function and Normal Values Bone marrow aspiration and biopsy A procedure used to collect and examine bone marrow for the presence of abnormal cells Computed tomography (CT) An imaging technique used to visualize internal structures. The scan produces images in “slices” of areas throughout the body. In regard to lymphatic system disorders, CT can be used to determine changes in lymphatic organs. Lumbar puncture A procedure used to collect and look at cerebrospinal fluid (CSF) surrounding the brain and spinal cord for the presence of abnormal WBCs Lymph node biopsy A procedure used to collect and examine part of a lymph node for the presence of abnormal cells Diagnostic Test Function and Normal Values Magnetic resonance imaging (MRI) or nuclear magnetic resonance imaging (NMRI) An imaging technique used to visualize internal structures. This test provides great contrast between various soft tissues in the body. In regard to disorders of the lymphatic system, MRI can be used to detect changes in lymphatic organs. White blood cell (WBC) count A blood test that determines the number of leukocytes. The normal number of all the leukocytes is 3,540–9,060/mm3 of blood. White blood cell (WBC) differential: Neutrophils Basophils Eosinophils Lymphocytes Monocytes A blood test that gives the percentage of each type of leukocyte in the total number of leukocytes. Normal values: Neutrophils: 40%–70% Basophils: 0%–2% Eosinophils: 0%–6% Lymphocytes: 20%–50% Monocytes: 4%–8% X-ray Electromagnetic radiation that sends photons through the body, allowing the visualization of dense structures. In regard to lymphatic system disorders, X-rays can be used to view the spleen for diagnosis of splenomegaly. Spot Check 14 How can imaging tests such as X-rays, MRIs, and CT scans be used to help diagnose lymphatic system disorders? 11.7 Lymphatic System Disorders Learning Outcome 18. Describe lymphatic system disorders and relate abnormal function to pathology. Lymphoma Page 462 Lymphoma is a type of cancer that affects white blood cells and can develop in the organs of the lymphatic system. There are two types of lymphoma: Hodgkin lymphoma and non Hodgkin lymphoma. Both types of lymphoma are characterized by abnormal B-cell or T-cell lymphocytes. Hodgkin lymphoma is characterized by the presence of abnormal B cells called Reed Sternberg cells. These cells are large, multinucleated macrophages that do not function as normal lymphocytes. They also proliferate and grow into tumors. Similar to Hodgkin lymphoma, non-Hodgkin lymphoma is characterized by abnormal B cells and T cells; however, these abnormal cells are not considered to be the Reed-Sternberg cells distinctive of Hodgkin lymphoma. Hodgkin lymphoma is less common than non-Hodgkin lymphoma. The symptoms of both Hodgkin and non-Hodgkin lymphomas are similar. Individuals may suffer from lymph node swelling, fever, weight loss, fatigue, and night sweats. Diagnosis is accomplished by physical examination, blood tests to determine the presence of abnormal WBCs or the presence of Reed-Sternberg cells (in the case of Hodgkin lymphoma), and bone marrow and lymph node biopsies. Treatment options for these cancers are also similar and include chemotherapy, radiation, medications, and bone marrow transplants. Multiple Myeloma Multiple myeloma is cancer of the plasma cells in the bone marrow. See Figure 11.23. As you may recall, B cells differentiate into two types of cells, memory cells and plasma cells. Plasma cells are responsible for secreting antibodies to fight infections. In multiple myeloma, plasma cell growth is accelerated and eventually forms tumors in bone tissue. Symptoms include abnormal bleeding and infection resulting from anemia, fatigue, fever, and bone fractures. Multiple myeloma is diagnosed using a variety of blood tests, including CBC, bone X-rays, bone density testing, and bone marrow biopsy. Treatment involves a combination of therapies such as chemotherapy, radiation, bone marrow transplant, and medications used to reduce pain and prevent fractures. FIGURE 11.23 Multiple myeloma in plasma cells from a bone marrow aspiration. David A Litman/Shutterstock Splenomegaly Splenomegaly is an enlargement of the spleen that can be caused by any number of pathological conditions, including anemia, cancers, and certain infections. Symptoms include tenderness or pain in the upper left abdomen or back, hiccups, and the inability to eat a large meal. Doctors can diagnose splenomegaly by physical examination, X-ray, CT scan, or MRI. The danger of an enlarged spleen is its effect on circulating blood cells. The enlarged spleen will trap blood cells, therefore reducing the number of circulating blood cells in the body. Trapped red blood cells are eventually destroyed in the spleen along with abnormal red blood cells. The excess cells can clog the organ, preventing it from functioning properly. Treatment of splenomegaly involves treating the cause of the condition. A splenectomy (surgical removal of the spleen) may also be performed. Allergies As you discovered in the “Chapter 1, The Basics,” allergies are hypersensitivities to a foreign antigen (allergen). The process in an allergy is the same as an immune response—the immune system recognizes the foreign antigen, reacts to it, and then remembers it so that it can mount a faster and stronger attack if it should ever occur in the body again. The difference between an allergic reaction and a normal immune response is that the allergic response produces undesirable side effects such as increased inflammation. The effect may even be lethal. Asthma is an example of an immediate hypersensitivity in which the allergen is inhaled. The allergen triggers the release of histamines in the bronchioles of the lungs, and this causes the bronchioles to constrict, making breathing difficult. You will learn more about asthma in the respiratory system chapter. Disease Pint Anaphylaxis (AN-ah-fih-LAK-sis) is an example of an immediate allergic reaction that can be life-threatening. An immune response to penicillin or bee stings is the most common cause. In anaphylaxis, systemic vasodilation (systemwide dilation of blood vessels) within a few minutes of exposure to the allergen can cause a drop in blood pressure and even cardiac failure. An EpiPen® can be used in emergencies to deliver a dose of epinephrine. This counteracts anaphylaxis by causing vasoconstriction, thus raising blood pressure. systemic Marco Uliana/Shutterstock Other allergies, called delayed hypersensitivities, may take hours or even days to develop side effects. Examples of these allergies include contact hypersensitivities to poison ivy, poison oak, soaps, or cosmetics. The allergen in this type of allergy comes in contact with epithelial cells (skin, mucous membranes). Next, T cells initiate inflammation, which causes excessive itching. Scratching the affected area further damages tissue. Allergies are hypersensitivities to foreign antigens, but some disorders of the lymphatic system do not involve foreign antigens at all. These disorders are autoimmune disorders, in which the body’s immune system attacks the body’s own tissues. Autoimmune Disorders Rheumatoid arthritis, Graves’ disease, and myasthenia gravis are examples of some of the autoimmune disorders you have already studied in previous chapters. Why does the immune system attack its own tissues? One explanation is molecular mimicry (in which one molecule is so similar in structure to another molecule that it is mistaken for the other molecule). To understand this, picture an action movie with a highly paid star. The movie studio protects its investment in the star by replacing the star with a stunt double during dangerous action scenes. Since the stunt double’s appearance is so similar to the star, the viewer never notices the difference. The same mistaken identity happens in molecular mimicry. An APC presents an epitope for a newly acquired foreign pathogen on its MHC protein. This epitope is unique but is very similar in shape to a self-antigen in the body. A Thelper cell recognizes the epitope as foreign and continues the process for humoral immunity, cellular immunity, or both forms of specific immunity. After the pathogen is defeated, the immune system continues to act against the self-antigen that is so similar. Here, the immune system is mistaking self-tissue as foreign tissue. The immune system is designed to fight the pathogen for life, which makes this mistake a lifelong problem that is very difficult to treat. Immunosuppressant drugs may help manage the progression of the disease. Page 463 You have seen how the immune system can overreact in the case of allergies and mistakenly react in autoimmune disorders. The immune system can also fail to react whatsoever in immunodeficiency disorders, which you will explore next. Clinical Pint A treatment option for rheumatoid arthritis and other autoimmune system disorders is a class of drugs called biologic disease-modifying antirheumatic drugs (biologic DMARDs). These drugs are genetically engineered to mimic the immune system proteins we naturally produce. With rheumatoid arthritis, the immune system is attacking the joints, causing damage and inflammation. Biologic DMARDs function by altering the specific signals used by the immune system to cause the inflammation associated with rheumatoid arthritis. This alteration in the immune system results in a decrease in joint inflammation and a decrease in the progression of rheumatoid arthritis. Immunodeficiency Disorders As you recall from “Chapter 1, The Basics,” immunodeficiency disorders are disorders that affect a part of the immune system, resulting in the inability of the immune system to adequately defend the body from pathogens. This usually involves lymphocytes not working properly or an inadequate production of antibodies. Immunodeficiency disorders can fit into two categories based on what caused the immunodeficiency: Congenital immunodeficiency disorders are those present at birth. These disorders are usually inherited and are very rare. Acquired immunodeficiency disorders are those that develop from a disease or disorder acquired during one’s lifetime. Use of certain prescribed drugs can also cause an individual to develop an acquired immunodeficiency. An example of an acquired immunodeficiency disorder is AIDS. AIDS is an acronym for acquired immune deficiency syndrome. Acquired means that it is not inherited. Immune deficiency means that the immune system fails to provide protection against pathogens. Syndrome refers to the collection of symptoms and signs of disease. Acquired immune deficiency syndrome is the final stage of an HIV (human immunodeficiency virus) infection. Page 464 How does this virus render the immune system deficient? The answer lies in the cells HIV invades—Thelper cells. By invading these T cells and turning them into viral factories, HIV prevents the processes of specific immunity and nonspecific resistance from even starting (explained earlier in the chapter, in the section on the importance of Thelper cells). As soon as an infected T cell has produced its fill of new HIV particles, it bursts and is destroyed. With the loss of Thelper cells, the immune system loses its ability to recognize what is foreign. See Figure 11.24. FIGURE 11.24 Infected T cell: (a) HIV virus, (b) dying T cell with emerging HIV. (b) NIBSC/SPL/Science Source An HIV test is used to determine whether a person is infected with the virus. The test detects the presence of HIV antibodies, but confirming an actual HIV infection is complicated by HIV’s invasion of Thelper cells. Antibodies should normally peak in 13 to 16 days, but in the case of HIV infections, antibodies may take 2 to 8 weeks to reach detectable levels. In some rare cases, it may take 6 months before there are sufficient antibodies to produce an HIV-positive result. A T-cell count is a good indicator of an HIV infection’s progression. Note that a normal T-cell count is 600 to 1,200 cells/mm3. AIDS is indicated if the T-cell count is less than 200 cells/mm3. Without enough Thelper cells to recognize a foreign pathogen, the body loses its ability to fight opportunistic infections (infections normally fought off by healthy immune systems). One common opportunistic infection is Kaposi sarcoma—a cancer of the epithelial cells lining blood vessels that is characterized by bruiselike lesions on the skin. See Figure 11.25. Other opportunistic infections include pathogens such as Pneumocystis (a group of respiratory fungi), herpes simplex virus, tuberculosis bacteria, and cytomegalovirus. Death from infection is inevitable once AIDS has been diagnosed. However, it may take a few months to several years from the time of an AIDS diagnosis. FIGURE 11.25 Kaposi sarcoma. National Cancer Institute (NCI) Page 465 Currently, there is no cure for AIDS. However, many people have been able to live decades with an HIV infection before it develops into AIDS because of the availability of effective combinations of drugs introduced in the 1990s. Table 11.2 summarizes all of the diseases and disorders described throughout the chapter. TABLE 11.2 Summary of Diseases and Disorders of the Lymphatic System Disease/Disorder Description Allergies Autoimmune disorders Elephantiasis Immunodeficiency disorders Hypersensitivities to a foreign antigen Disorders that result from the immune system attacking self-antigens A tropical disease caused by a roundworm that blocks lymphatic drainage Disorders that affect a part of the immune system, resulting in the inability of the immune system to adequately defend the body from pathogens. Congenital immunodeficiency disorders are those present at birth. Acquired immunodeficiency disorders are those that develop from a disease or disorder acquired during one’s lifetime. Disease/Disorder Description Lymphoma A type of cancer that affects white blood cells and can develop in the organs of the lymphatic system. There are two types of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Multiple myeloma Cancer of the plasma cells in the bone marrow Splenomegaly Spot Check 15 An enlargement of the spleen that can be caused by any number of pathological conditions, including anemia, cancers, and certain infections Explain the difference in the following types of lymphatic system disorders: hypersensitivities, autoimmune disorders, and immunodeficiency disorders. Putting the Pieces Together The Lymphatic System Page 466 FIGURE 11.26 Putting the Pieces Together—The Lymphatic System: connections between the lymphati