Innate Immunity

         Innate Immunity A pathogen causes a disease only if it can (1) gain access, either by penetrating the surface of the skin or by entering through some other portal of entry; (2) attach itself to host cells; and (3) evade the body’s defensive mechanisms long enough to produce harmful changes. In this chapter, we examine the structures, processes, and chemicals that respond in a general way to protect the body from all types of pathogens. pathogens and alter the body’s defenses such that they act more effectively upon subsequent infection by that same specific strain. In other words, they are specific and have memory. For this reason, scientists call the third line of defense adaptive immunity (see Chapter 16). Now we turn our attention to the two lines of innate immunity. ▶ ANIMATION: Host Defenses: Overview TELL ME WHY An Overview of the Body’s Defenses LE A R N I N G O U TC O M E S 15.1 List and briefly describe the three lines of defense The Body’s First Line of Defense The body’s initial line of defense is made up of structures, chemicals, and processes that work together to prevent pathogens from entering the body in the first place. Here, we discuss the main components of the first line of defense: the skin and the mucous membranes of the respiratory, digestive, urinary, and reproductive systems. These structures provide a formidable barrier to the entrance of microorganisms. When these barriers are pierced, broken, or otherwise damaged, they become portals of entry for pathogens. In this section, we examine aspects of the first line of defense, including the role of the microbiome, which is all the microorganisms in a given location, in this case the human body. ­ ­ Because the cells and certain basic physiological processes of humans are incompatible with structures and physiology of most plant and animal pathogens, humans have what is termed species resistance to these pathogens. In many cases, the chemical receptors that these pathogens require for attachment to a host cell do not exist in the human body; in other cases, the pH or temperature of the human body is incompatible with the conditions under which these pathogens can survive. Thus, for example, all humans have species resistance to tobacco mosaic virus, which affects only tobacco plants, and to the virus that causes feline immunodeficiency syndrome, which attaches only to cellular receptors found on cats’ cells. Nevertheless, we are confronted every day with other pathogens that can and do cause disease in humans. Bacteria, viruses, fungi, protozoa, and parasitic worms come in contact with your body in the air you breathe, in the water you drink, in the food you eat, and during the contacts you have with other people. Your body must defend itself from these potential pathogens and, in some cases, from members of your normal microbiota, which may become opportunistic pathogens. It is convenient to cluster the structures, cells, and chemicals that act against pathogens into three so-called lines of defense, each of which overlaps and reinforces the other two. The first line of defense is composed chiefly of external physical barriers to pathogens, especially the skin and mucous membranes. The second line of defense is internal and composed of protective cells, bloodborne chemicals, and processes that inactivate or kill invaders. Together, the first two lines of defense are called innate immunity because they are present at birth. Innate immunity, which is also called natural or native immunity, is always active, nonspecific, and rapid, and it works against a wide variety of pathogens, including parasitic worms, protozoa, fungi, bacteria, and viruses. Lymphocytes are the main cells of the third line of defense; unlike the participants in the first and second lines of defense, lymphocytes respond against unique species and strains of M15_BAUM7206_05_SE_C15.indd 444 ­ ­ in the human body. 15.2 Explain the phrases species resistance and innate immunity. Why aren’t the body’s skin and mucous membrane barriers significant factors in your resistance to infection by hyperthermophiles? The Role of Skin in Innate Immunity LE A R N I N G O UTC O M E 15.3 Identify the physical and chemical aspects of skin that enable it to prevent the entry of pathogens. The skin—the organ of the body with the greatest surface area—is composed of two major layers: an outer epidermis and a deeper dermis, which contains hair follicles, glands, and nerve endings (see Chapter 14, Figure 14.4). Both the physical structure and the chemical components of skin enable it to act as an effective defense. The epidermis is composed of multiple layers of tightly packed cells that constitute a physical barrier to most bacteria, fungi, and viruses. Few pathogens can penetrate the layers of epidermal cells unless the skin has been burned, broken, or cut. The deepest cells of the epidermis continually divide, pushing their daughter cells toward the surface. As the daughter cells are pushed toward the surface, they flatten and die and are eventually shed in flakes (FIGURE 15.1). Microorganisms that attach to the skin’s surface are sloughed off with the flakes of dead cells. The skin illustrates two basic characteristics of the first line of defense in innate immunity: barriers and clearance. In this case, the tightly joined layer of epithelial cells acts as a barrier, and clearance comes as the outermost dead cells slough off. 11/23/16 3:32 AM       The Body’s First Line of Defense SEM 40 µm E ▲ FIGURE 15.1 A scanning electron micrograph of the surface of human skin. pidermal cells are dead and dry and slough off, subunits of the peptidoglycan walls. Bacteria without cell walls are more susceptible to osmotic shock and digestion by other enzymes within phagocytes (discussed later in the chapter as part of the second line of defense). The skin also contains sebaceous (oil) glands, which secrete sebum (sē’bŭm). This oily substance not only helps keep the skin pliable and less sensitive to breaking or tearing but also contains fatty acids that lower the pH of the skin’s surface to about pH 5, which is inhibitory to many bacteria. Although salt, antimicrobial peptides, lysozyme, and acidity make the surface of the skin an inhospitable environment for most microorganisms, some bacteria, such as Staphylococcus epidermidis (staf’i-lō-kok’ŭs ep-i-der-mid’is), find the skin a suitable environment for growth and reproduction. Bacteria are particularly abundant in crevices around hairs and in the ducts of glands; usually they are nonpathogenic. In summary, the skin is a complex barrier that limits access by microbes. providing an effective barrier to most microorganisms. ­ ­ ­ The epidermis also contains defensive cells called dendritic cells.1 The slender, fingerlike processes of dendritic cells extend among the surrounding cells, forming an almost continuous network to intercept invaders. Dendritic cells both devour pathogens nonspecifically and play a role in adaptive immunity (see Chapter 16). The combination of the barrier function of the epidermis, its continual replacement, and the presence of phagocytic dendritic cells provides significant nonspecific defense against colonization and infection by pathogens. The dermis also defends nonspecifically. It contains tough fibers of a protein called collagen, which give the skin strength and pliability to prevent many jabs and scrapes from penetrating the skin and introducing microorganisms. Blood vessels in the dermis deliver defensive cells and chemicals, which will be discussed shortly. In addition to its physical structure, the skin has a number of chemical substances that nonspecifically defend against pathogens. Dermal cells secrete antimicrobial peptides, and sweat glands secrete perspiration, which contains salt, antimicrobial peptides, and an enzyme—lysozyme. Salt draws water osmotically from invading cells, inhibiting their growth and killing them. Antimicrobial peptides are positively charged chains of 20 to 50 amino acids that act against microorganisms. Sweat glands secrete a class of antimicrobial peptides called dermcidins. Dermcidins are broad-spectrum antimicrobials that are active against many Gram-negative and Gram-positive bacteria and fungi. As expected of a peptide active on the surface of the skin, dermcidins are insensitive to low pH and salt. The exact mechanism of dermcidin action is not known. Lysozyme (lī’sō-zīm) is an enzyme that destroys the cell walls of bacteria by cleaving the bonds between the sugar 1From Greek dendron, meaning “tree,” referring to their branched appearance. M15_BAUM7206_05_SE_C15.indd 445 The Role of Mucous Membranes in Innate Immunity LE A R N I N G O UTC O M E S 15.4 Identify the locations of the body’s mucous membranes. 15.5 Explain how mucous membranes protect the body both physically and chemically. Mucus-secreting (mucous) membranes, another major part of the first line of defense, cover all body cavities that are open to the outside environment. Thus, mucous membranes line the lumens2 of the respiratory, urinary, digestive, and reproductive tracts. Like the skin, mucous membranes act nonspecifically to limit infection both physically and chemically. Mucous membranes are moist and have two distinct layers: an epithelium, in which cells form a covering that is superficial (closer to the surface, in this case, the lumen), and a deeper connective tissue layer that provides mechanical and nutritive support for the epithelium. Epithelial cells of mucous membranes are packed closely together, like those of the epidermis, but they form only a thin layer. Indeed, in some mucous membranes, the epithelium is only a single cell thick. Unlike surface epidermal cells, surface cells of mucous membranes are alive and play roles in the diffusion of nutrients and oxygen (in the digestive, respiratory, and female reproductive systems) and in the elimination of wastes (in the urinary, respiratory, and female reproductive systems). The thin epithelium on the surface of a mucous membrane provides a less efficient barrier to the entrance of pathogens than the multiple layers of dead cells found at the skin’s surface. So how are microorganisms kept from invading through thin mucous membranes? In some cases, they are not, which is why mucous membranes, especially those of the respiratory and reproductive systems, are common portals of entry for pathogens. Still, the epithelial cells of mucous membranes are tightly 2A lumen is a cavity or channel within any tubular structure or organ. 11/23/16 3:32 AM t packed to prevent the entry of many pathogens, and the cells are continually shed and then replaced by stem cells, which are generative cells capable of dividing to form daughter cells of various types. One effect of mucosal shedding is that it carries attached microorganisms away. Dendritic cells reside below the mucous epithelium to phagocytize invaders. These cells are also able to extend cytoplasmic extensions (pseudopods) between epithelial cells to “sample” the contents of the lumen, helping to prepare adaptive immune responses against particular pathogens that might breach the mucosal barrier (a subject covered more fully in Chapter 16). In addition, epithelia of some mucous membranes have still other means of removing pathogens. In the mucous membrane of the trachea, for example, stem cells produce both goblet cells, which secrete an extremely sticky mucus that acts as a barrier, trapping bacteria and other pathogens, and ciliated columnar cells, whose cilia propel the mucus and its trapped particles and pathogens up and away from the lungs (FIGURE 15.2). The effect of the action of the cilia is often likened to that of an escalator. Mucus carried into the throat is coughed up and either swallowed or expelled, again illustrating the barrier and clearance characteristics of innate immunity. Because poisons and tars in tobacco smoke damage cilia, the lungs of smokers are not properly cleared of mucus, so smokers may develop severe coughs as their respiratory tracts attempt to expel excess mucus. Smokers may succumb to many respiratory pathogens because they are unable to effectively clear pathogens from their lungs. In addition to these physical actions, mucous membranes produce chemicals that defend against pathogens. For example, mucus contains antimicrobial peptides. Nasal mucus also TABLE 15.1 The First Line of Defense: A Comparison of the Skin and Mucous Membranes ­ a       Ch p er 15   Innate Immunity Skin Mucous Membrane Number of Cell Layers Many One to a few Cells Tightly Packed? Yes Yes Cells Dead or Alive? Outer layers: dead; inner layers: alive Alive Mucus Present? No Yes Relative Water Content Dry Moist Defensins Present? Yes With some Lysozyme Present? Yes With some Sebum Present? Yes No Cilia Present? No Trachea, uterine tubes Constant Shedding and Replacement of Cells? Yes Yes contains lysozyme. TABLE 15.1 compares some physical and chemical actions of the skin and mucous membranes in the body’s first line of defense. The Role of the Lacrimal Apparatus in Innate Immunity LE A R N I N G O UTC O M E 15.6 Describe the lacrimal apparatus and the role of tears in combating infection. Tongue Larynx (voice box) Trachea Bronchus ▲ FIGURE 15.2 The structure of the respiratory system, which is lined with a mucous membrane. The epithelium of the trachea contains mucus-secreting goblet cells and ciliated cells whose cilia propel the mucus (and the microbes trapped within it) up to the larynx for removal. What is the function of stem cells within the respiratory epithelium? Figure 15.2 Stem cells in the respiratory epithelium undergo cytokinesis to form both ciliated cells and goblet cells to replace those lost during normal shedding. M15_BAUM7206_05_SE_C15.indd 446 The lacrimal apparatus is a group of structures that produce and drain away tears (FIGURE 15.3). Lacrimal glands, located above and to the sides of the eyes, secrete tears into lacrimal gland ducts and onto the surface of the eyes. The tears either evaporate or drain into small lacrimal canals, which carry them into nasolacrimal ducts that empty into the nose. There, the tears join the nasal mucus and flow into the pharynx, where they are swallowed. The blinking action of eyelids spreads the tears and washes the surfaces of the eyes. Normally, evaporation and flow into the nose balance the flow of tears onto the eye. However, if the eyes are irritated, increased tear production floods the eyes, carrying the irritant away. In addition to their washing action, tears contain lysozyme, which destroys bacteria. The Role of the Microbiome in Innate Immunity LE A R N I N G O UTC O M E 15.7 Define microbiome, and explain how it helps provide protection against disease. ­ Pharynx 11/23/16 3:32 AM       The Body’s First Line of Defense ◀ FIGURE15.3 The lacrimal apparatus. These structures (in green) function ­ Nasolacrimal duct ­ in the body’s first line of defense by bathing the eye with tears. Arrows indicate the route tears take across the eye and into the throat. Name an antimicrobial protein found in tears. Lacrimal canal Lacrimal gland duct Paranasal sinus Lacrimal glands Figure 15.3 Tears contain lysozyme, an antimicrobial protein which acts against the peptidoglycan of bacterial cell walls. Lacrimal apparatus Pharynx Nasolacrimal duct Trachea Anterior view Lateral view ­ ­ The skin and mucous membranes of the body are home to a variety of protozoa, fungi, bacteria, and viruses. This microbiome (including normal members, the normal microbiota) plays a role in protecting the body by competing with potential pathogens in a variety of ways, a situation called competitive inhibition or microbial antagonism. The microbiome carries out various activities that impede a pathogen’s efforts to invade and produce disease: • Members of the microbiome consume nutrients, making them unavailable to pathogens. • The microbiome can change the pH of regions of the body, creating an environment that is favorable for themselves but unfavorable to other microorganisms, such as acid in the vagina. • The microbiome can attach to all of the sites on human cells, blocking pathogens from attaching. • The microbiome stimulates the body’s second line of defense (discussed shortly), boosting the body’s production of antimicrobial substances. Researchers have observed that animals raised in an axenic3 (ā-zen’ik) environment— that is, one free of all other organisms or viruses—are slower to defend themselves when exposed to a pathogen. • Members of the microbiome can themselves generate antimicrobial compounds to defend their “turf,” the human body. • Nutritionally, the resident microbiota of the intestines improve overall health by providing several vitamins, including biotin (vitamin B7) and pantothenic acid 3From Greek a, meaning “no,” and xenos, meaning “foreigner.” M15_BAUM7206_05_SE_C15.indd 447 Esophagus (vitamin B5), which are important in glucose metabolism; folic acid, which is essential for the production of the purine and pyrimidine bases of nucleic acids; and the precursor of vitamin K, which has an important role in blood clotting. Thus, the human microbiome plays many roles in protecting us from infection, from inhibiting invading pathogens and training the immune system, to strengthening immune responses. Given these facts, you can see that using antimicrobial soaps and shampoos to remove all microbes from your body is neither medically wise nor ecologically sound; in fact, it may make you more sensitive to infection. A significant component of medicine in the future may include the use of probiotics—giving live bacteria to patients to rebalance their microbiome to prevent or treat infection. Other First-Line Defenses LE A R N I N G O UTC O M E 15.8 Describe antimicrobial peptides as part of the body’s defenses. Besides the physical barrier of the skin and mucous membranes, there are other hindrances to microbial invasion. Among these are additional antimicrobial peptides and other processes and chemicals. Antimicrobial Peptides As we saw in our examination of skin and mucous membranes, antimicrobial peptides (sometimes called defensins) act against microorganisms. Scientists have discovered hundreds 11/23/16 3:32 AM t a       Ch p er 15   Innate Immunity TABLE 15.2 Secretions and Activities That Contribute to the First Line of Defense Secretion/Activity Function Digestive System Saliva Washes microbes from teeth, gums, tongue, and palate; contains lysozyme, an antibacterial enzyme Stomach acid Digests and/or inhibits microorganisms Gastroferritin Sequesters iron being absorbed, making it unavailable for microbial use Bile Inhibitory to most microorganisms Intestinal secretions Digests and/or inhibits microorganisms Vomiting Urine The Body’s Second Line of Defense LE A R N I N G O U TC O M E 15.9 Compare and contrast the body’s first and second lines of defense against disease. When pathogens succeed in penetrating the skin or mucous membranes, the body’s second line of innate defense comes into play. Like the first line of defense, the second line operates against a wide variety of pathogens, from parasitic worms to viruses. But unlike the first line of defense, the second line includes no barriers; instead, it is composed of cells (especially phagocytes), antimicrobial chemicals (peptides, complement, interferons), and processes (inflammation, fever). Some cells and chemicals from the first line of defense play additional roles in the second line of defense. We will consider each component of the second line of defense in some detail shortly, but because many of them either are contained in or originate in the blood, we first consider the components of blood. M15_BAUM7206_05_SE_C15.indd 448 E Contains lysozyme; urine’s acidity inhibits microorganisms; may wash microbes from ureters and urethra during urination Vaginal secretions Acidity inhibits microorganisms; contains ironbinding proteins that sequester iron, making it unavailable for microbial use Menstrual flow Cleanses uterus and vagina rostate secretion Contains iron-binding proteins that sequester iron, making it unavailable for microbial use Cardiovascular System Blood flow Coagulation R Some strains of Staphylococcus aureus produce exfoliative toxin, a chemical that causes portions of the entire outer layer of the skin to be sloughed off in a disease called scalded skin syndrome. Given that cells of the outer layer are going to fall off anyway, why is this disease dangerous? liminates microorganisms Reproductive System P TELL ME WHY liminates microorganisms Urinary System ­ Many other body organs contribute to the first line of defense by secreting chemicals with antimicrobial properties that are secondary to their prime function. For example, stomach acid is present primarily to aid digestion of proteins, but it also prevents the growth of many potential pathogens. The contributions of these and other processes and chemicals to the first line of defense are listed in TABLE 15.2. Defecation Moves gastrointestinal (GI) contents through GI tract, constantly eliminating potential pathogens P Other Processes and Chemicals eristalsis E ­ P ­ ­ of types of antimicrobial peptides in organisms as diverse as silkworms, frogs, and humans. Besides being secreted onto the surface of the skin, antimicrobial peptides are found in mucous membranes and in certain white blood cells called neutrophils. These peptides act against a variety of potential pathogens, being triggered by sugar and protein molecules on the external surfaces of microbes. Some antimicrobial peptides act only against Gram-positive bacteria or Gram-negative bacteria, others act against both, and still others act against protozoa, enveloped viruses, or fungi. Researchers have elucidated several ways in which antimicrobial peptides work. Some punch holes in the cytoplasmic membranes of the pathogens, and others interrupt internal signaling or enzymatic action. Some antimicrobial peptides act as chemotactic factors—chemicals that recruit leukocytes to a site—while others assemble to form fibers and microscopic nets that ensnare invading bacteria. emoves microorganisms from wounds revents entrance of many pathogens Defense Components of Blood LE A R N I N G O UTC O M E S 15.10 Discuss the components of blood and their functions in the body’s defense. 15.11 Explain how macrophages are named. Blood is a complex liquid tissue composed of cells and portions of cells within a fluid called plasma. We begin our discussion of the defense functions of blood by briefly considering plasma. Plasma Plasma is mostly water containing electrolytes (ions), dissolved gases, nutrients, and—most relevant to the body’s defenses—a variety of proteins. Some plasma proteins are involved in inflammation (discussed later) and in blood clotting, a defense mechanism that reduces both blood loss and the risk of infection. When clotting factors have been removed from the plasma, as when blood clots, the remaining liquid is called serum. Humans require iron for metabolism: it is a component of cytochromes of electron transport chains, functions as an enzyme cofactor, and is an essential part of hemoglobin—the oxygen-carrying protein of red blood cells. Because iron is 11/23/16 3:32 AM       The Body’s Second Line of Defense ­ ◀ FIGURE 15.4 A schematic representation of hematopoiesis. In this process, the division of stem cells in the bone ­ marrow produces three types of formed (cellular) elements: erythrocytes, platelets, and leukocytes. Blood stem cell in bone marrow Erythroid stem cell Erythrocyte Gas transportation Myeloid stem cell Platelets Basophil Clotting, inflammation Inflammation Neutrophil Lymphoid stem cell Monocyte Eosinophil Lymphocyte Phagocytosis Innate immunity, second line of defense Adaptive immunity Granulocytes Agranulocytes Leukocytes M15_BAUM7206_05_SE_C15.indd 449 Defensive Blood Cells: Leukocytes Cells and cell fragments suspended in the plasma are called formed elements. In a process called hematopoiesis,4 blood stem cells located principally in the bone marrow within the hollow cavities of larger bones produce three types of formed elements: • So-called erythroid stem cells form erythrocytes5 (ě-rith’rō-sītz; red blood cells) • Myeloid stem cells produce platelets6 (plāt’letz) and four kinds of leukocytes7 (loo’kō-sīts; white blood cells) • Lymphoid stem cells produce a fifth kind of leukocyte (FIGURE 15.4). ­ Erythrocytes are the most numerous of the formed elements and carry oxygen and carbon dioxide in the blood. Platelets, which are pieces of large cells called megakaryocytes that have split into small portions of cytoplasm surrounded by cytoplasmic membranes, are involved in blood clotting. Leukocytes, the formed elements that are directly involved in defending the body against invaders, are commonly called white blood cells because Greek haima, meaning “blood,” and poiein, meaning “to make.” Greek erythro, meaning “red,” and cytos, meaning “cell.” 6French for “small plates.” Platelets are also called thrombocytes, from Greek thrombos, meaning “lump,” and cytos, meaning “cell,” though they are technically not cells but instead pieces of cells. 7 From Greek leuko, meaning “white,” and cytos, meaning “cell.” 4From 5From  ­ relatively insoluble, in humans it is transported in plasma to cells by a transport protein called transferrin. When transferrin-iron complexes reach cells with receptors for transferrin, the binding of the protein to the receptor stimulates the cell to take up the iron via endocytosis. Excess iron is stored in the liver bound to another protein called ferritin. Though the main function of iron-binding proteins is transporting and storing iron, they play a secondary, defensive role—sequestering iron so that it is unavailable to microorganisms. Some bacteria, such as Staphylococcus aureus (o’rē-ŭs), respond to a shortage of iron by secreting their own iron-binding compounds called siderophores. Because siderophores have a greater affinity for iron than does transferrin or other proteins, bacteria that produce siderophores can in effect steal iron from the body. Some pathogens bypass this contest altogether. For example, S. aureus and related pathogens can secrete the protein hemolysin, which punches holes in the cytoplasmic membranes of red blood cells, releasing iron-containing hemoglobin. Other bacterial proteins then bind hemoglobin to the bacterial membrane and strip it of its iron. Neisseria meningitidis (nī-se’rē-ă me-nin-ji’ti-dis), a pathogen that causes often fatal meningitis, produces receptors for transferrin and plucks iron from the bloodstream as it flows by. Another group of plasma proteins, called complement proteins, is an important part of the second line of defense and is discussed shortly. Still other plasma proteins, called antibodies or immunoglobulins, are a part of adaptive immunity, the body’s third line of defense. 11/23/16 3:32 AM t a       Ch p er 15   Innate Immunity ­ they form a whitish layer when the components of blood are separated within a test tube. Based on their appearance in stained blood smears when viewed under the microscope, leukocytes are divided into two groups: granulocytes (gran’ū-lō-sītz) and agranulocytes (ā-gran’ū-lō-sītz) (FIGURE 15.5). Granulocytes have large granules in their cytoplasm that stain different colors depending on the type of granulocyte and the dyes used: basophils (bā’sō-fils) stain blue with the basic dye methylene blue, eosinophils (ē-ō-sin’ō-fils) stain red to orange with the acidic dye eosin, and neutrophils (noo’trō-fils), also known as polymorphonuclear leukocytes (PMNs), stain lilac with a mixture of acidic and basic dyes. Both neutrophils and eosinophils phagocytize pathogens, and both can exit the blood to attack invading microbes in the tissues by squeezing between the cells lining capillaries (the smallest blood vessels). This process is called diapedesis8 (dī’a-pě-dē’sis). As we will see later in the chapter, eosinophils are also involved in defending the body against parasitic worms and are present in large number during many allergic reactions, though their exact function in allergies is disputed. Basophils can also leave the blood by diapedesis, though they are not phagocytic; instead, they release inflammatory chemicals, an aspect of the second line of defense that will be discussed shortly. The cytoplasm of agranulocytes appears uniform when viewed via light microscopy, though granules are visible with an electron microscope. Agranulocytes are of two types: monocytes (mon’ō-sītz), which are large agranulocytes with slightly lobed nuclei, and lymphocytes (lim’fō-sītz), which are the smallest leukocytes and have nuclei that nearly fill the cells. Although most lymphocytes are involved in adaptive immunity, natural killer (NK) lymphocytes function in innate defense and thus are discussed later in this chapter. Monocytes also leave the blood by diapedesis and mature into macrophages (mak’rōfāj-ĕz), which are phagocytic cells of the second line of defense. Their initial function is to devour foreign objects, including bacteria, fungi, spores, and dust as well as dead body cells. Macrophages are often named for their location in the body, because they specialize for each body tissue. Wandering macrophages leave the blood via diapedesis and perform their scavenger function while traveling throughout the body in intracellular spaces. Other macrophages are fixed and do not wander. These include alveolar macrophages (al-vē’ō-lăr)9 of the lungs and microglia (mī-kroglē-ă) of the central nervous system. Fixed macrophages generally phagocytize within specific organs, such as the heart chambers, blood vessels, and lymphatic vessels. (The lymphatic system is discussed in Chapter 16.) A special group of phagocytes are not white blood cells. These are the dendritic cells, mentioned previously, which are multibranched cells plentiful throughout the body, particularly in the skin and mucous membranes. Dendritic cells await Basophil 0.5–1% LM 7.5 µm Granulocytes LM Neutrophil 60–70% LM 7.5 µm ­ ­ Eosinophil 2–4% 7.5 µm Lymphocyte 20–25% LM Monocyte 3–8% LM 7.5 µm Agranulocytes ­ ­ (a)  M15_BAUM7206_05_SE_C15.indd 450 ▲ FIGURE 15.5 Leukocytes as seen in stained blood smears. (a) Granulocytes: basophil, eosinophil, and neutrophil. (b) Agranulocytes: lymphocyte and monocyte. The numbers are the normal percentages of each cell type among all leukocytes. ­ Greek dia, meaning “through,” and pedan, meaning “to leap.” 9Alveoli are small pockets at the end of respiratory passages where oxygen and carbon dioxide exchange occurs between the lungs and the blood. 8From 7.5 µm (b) 11/23/16 3:32 AM       The Body’s Second Line of Defense 15.12 Name and describe the six stages of phagocytosis. ­ Phagocytosis, which means “eating by a cell,” is a way that some microbes obtain nutrients (see Chapter 3), but phagocytes (fag’ō-sītz)—phagocytic defense cells of the body—use phagocytosis to rid the body of pathogens that have evaded the body’s first line of defense. ▶ ANIMATION: Phagocytosis: Overview For improved understanding, we will consider the process of phagocytosis in six steps: chemotaxis, adhesion, ingestion, maturation, killing, and elimination (FIGURE 15.6). However, the process is actually continuous and doesn’t proceed in a discrete step-wise manner. Chemotaxis ­ Chemotaxis is movement of a cell either toward a chemical stimulus (positive chemotaxis) or away from a chemical stimulus (negative chemotaxis). In the case of phagocytes, positive chemotaxis involves the use of pseudopods (soo’dō-podz) to crawl toward ­ c Clini al C SE STUDY LE A R N I N G O UTC O M E ­ Lab Analysis of Leukocytes Analysis of blood for diagnostic purposes, including white blood cell counts, is one task of medical lab technologists. The proportions of leukocytes, as determined in a differential white blood cell count, can serve as a sign of disease. For example, an increase in the percentage of eosinophils can indicate allergies or infection with parasitic worms; bacterial diseases typically result in an increase in the number of leukocytes and an increase in the percentage of neutrophils, whereas viral infections are associated with an increase in the relative number of lymphocytes. An increase in the number of a certain leukocyte over normal can indicate cancer, and a decrease in the number can reveal immunodeficiency. The ranges for the normal values for each kind of white blood cell, expressed as a percentage of the total leukocyte population, are shown in Figure 15.5. Now that we have some background concerning the defensive properties of plasma components and leukocytes, we turn our attention to the details of the body’s second line of defense: phagocytosis, nonphagocytic killing by leukocytes, nonspecific chemical defenses, inflammation, and fever. Phagocytosis ­ microbial invaders, phagocytize them, and inform cells of adaptive immunity that there is a microbial invasion. A Evaluating an Abnormal CBC R oger Brown, an African American cancer patient, received a chemotherapeutic agent as a treatment for his disease. The drug used to destroy the cancer also produced an undesirable condition known as bone marrow depression. The complete blood count (CBC) profile shown here indicates that this patient is in trouble. eview the lab values, and answer the following questions. CBC Profile Age/Sex: 61/M Status: ADM IN Attend Dr: Kevin, Larry ­ R Name: Brown, Roger Acct#: 04797747 Reg: 11/27/12 SPEC #: 0303:AS:H00102T COLL: 12 / 03 / 12-0620 RECD: 12 / 03 / 12-0647 OTHER DR: NONE, PER PT CBC WBC (white blood cells) RBC (red blood cells) HGB (hemoglobin) HCT (hematocrit) MCV MCH MCHC RDW PLT (platelets) MPV DIFF CELLS COUNTED SEGS BAND LYMPH (lymphocytes) MONO (monocytes) EOS (eosinophils) NEUT# (# neutrophils) LYMPH# MONO# EOS# PLATELET EST M15_BAUM7206_05_SE_C15.indd 451 1. Note that the platelet count is very low. ow does this affect the patient? Discuss measures to protect him. 2. Note that the white blood cell count is abnormally low. With the second line of defense impaired, how should the first line of defense be protected? H ENTERED: 12 / 03 / 12-0002 ORDERED: CBC W/ MAN DIFF Test STATUS: COMP SUBM DR: Kevin, Larry REQ #: 01797367 Result 0.8 3.09 9.6 28.2 91.3 31.1 34.1 17.1 21 8.7 100 39 4 41 15 1 0.3 0.3 0.1 0.0 DECREASED Normal range 4.8–10.8 K/mm3 4.20–5.40 M/mm3 12.0–16.0 g/dL 37.0–47.0 % 81.0–99.0 fL 27.0–31.0 pg 32.0–36.0 g/dl 11.5–14.5 % 150–450 K/mm3 7.4–10.4 fL #CELLS 1.9–8.0 K/mm3 0.9–5.2 K/mm3 0.1–1.2 K/mm3 0–0.8 K/mm3 11/23/16 3:32 AM t a       Ch p er 15   Innate Immunity 1 Chemotaxis of phagocyte to microbes Microbes 2 Adhesion Pseudopods move (chemotaxis) 3 Ingestion of microbes by phagocytes 4 Fusion of a series of vessicles, including lysosomes Phagosome TEM 1 µm Golgi body 5 Killing of microbes by enzymes and other chemicals Lysosome Nucleus Phagolysosome Residual body Pseudopod Phagocyte 6 Elimination (exocytosis) H ▲ FIGURE 15.6 The events in phagocytosis. ere, a neutrophil phagocytizes Neisseria gonorrhoeae. are called opsonins. Generally, opsonins increase the number and kinds of binding sites on a microbe’s surface. Ingestion Adhesion Phagosome Maturation and Microbial Killing ­ ­ ­ ­ ­ ­ microorganisms at a site of an infection 1 . Chemicals that attract phagocytic leukocytes include microbial secretions, parts of microbial cells, components of damaged tissues and white blood cells, and chemotactic factors (kem-ō-tak’tik). Chemotactic factors include defensins, peptides derived from complement (discussed later in this chapter), and chemicals called chemokines (kē’mō-kīnz), which are released by leukocytes already at the site of infection.  ­ ­ After arriving at the site of an infection, phagocytes attach to microorganisms through the binding of complementary chemicals, such as glycoproteins, found on the membranes of cells 2 . This process is called adhesion or attachment. Some bacteria have virulence factors, such as slippery capsules, which hinder adhesion by phagocytes. All pathogens are more readily phagocytized if they are first covered with antimicrobial proteins, such as complement proteins (discussed later) or specific antimicrobial proteins of adaptive immunity called antibodies (discussed in Chapter 16). This coating process is called opsonization10 (op’sŭ-nī-za’shun), and the proteins Greek opsonein, meaning “to supply food,” and izein, meaning “to cause”; thus, loosely, “to prepare for dinner.”  10From M15_BAUM7206_05_SE_C15.indd 452 After phagocytes adhere to pathogens, they extend pseudopods to surround the microbe 3 . The encompassed microbe is internalized as the pseudopods fuse to form a food vesicle called a phagosome. A membranous organelle called a lysosome adds digestive chemicals to the maturing phagosome, which is now called a phagolysosome (fag-ō-lī’sō-sōm) 4 . Phagolysosomes contain antimicrobial substances, such as highly reactive, toxic forms of oxygen, in an environment with a pH of about 5.5 due to active pumping of H + from the cytosol into the phagolysosome. These substances, along with 30 or so different enzymes, such as lipases, proteases, and nucleases, destroy the engulfed microbes 5 . Most pathogens are dead within 30 minutes of the phagolysosome’s formation, though some bacteria contain virulence factors (such as waxy cell walls) that resist a lysosome’s action. In the end, a phagolysosome is known as a residual body. 11/23/16 3:32 AM       The Body’s Second Line of Defense Elimination express membrane proteins similar to those on the NK cells. The name natural killer comes from the fact that NK cells are programmed to kill other cells unless they receive an inhibitory signal. ­ ­ ­ Digestion is not always complete, and phagocytes eliminate remnants of microorganisms via exocytosis, a process that is essentially the reverse of ingestion 6 . Some microbial components are specially processed and remain attached to the cytoplasmic membrane of some phagocytes, particularly dendritic cells, a phenomenon that plays a role in the adaptive immune response (discussed in Chapter 16). ▶ ANIMATION: Phagocytosis: Mechanism How is it that phagocytes destroy invading pathogens and leave the body’s own healthy cells unharmed? At least two mechanisms are responsible for this: • Some phagocytes have cytoplasmic membrane receptors for various microbial surface components lacking on the body’s cells, such as microbial cell wall components or flagellar proteins. • Opsonins such as certain blood proteins and immune molecules called antibodies provide a signal to the phagocyte. Nonphagocytic Killing LE A R N I N G O U TC O M E 15.13 Describe the role of eosinophils, NK cells, and neutro- phils in nonphagocytic killing of microorganisms and parasitic helminths. Phagocytosis involves killing a pathogen once it has been ingested—that is, once it is inside the phagocyte. In contrast, eosinophils, natural killer cells, and neutrophils can accomplish killing without phagocytosis. Killing by Eosinophils ­ Neutrophils can also destroy nearby microbial cells without phagocytosis, though phagocytosis is more common. They do this in several ways: • Enzymes in a neutrophil’s cytoplasmic membrane add electrons to oxygen, creating highly reactive superoxide radical O2- and hydrogen peroxide (H2O2). Another enzyme converts these into hypochlorite, the active antimicrobial ingredient in household bleach. These chemicals can kill nearby invaders. • Yet another enzyme in the neutrophil’s membrane makes nitric oxide, which is a powerful inducer of inflammation. • Neutrophils also generate webs of extracellular fibers nicknamed NETs, for neutrophil extracellular traps. Neutrophils synthesize NETs via a unique form of cellular suicide involving the disintegration of their nuclei. As the nuclear envelope breaks down, DNA and histones are released into the cytosol, and the mixing of nuclear components with membranes and proteins derived from cytoplasmic granules combine to form NET fibers. The neutrophil then kills itself using superoxide and peroxide. The dying cell releases the NETs as its cytoplasmic membrane ruptures. NETs trap both Gram-positive and Gram-negative bacteria, immobilizing them and sequestering them along with antimicrobial peptides, which kill the bacteria. Thus even in their dying moments, neutrophils fulfill their role as defensive cells. Nonspecific Chemical Defenses Against Pathogens LE A R N I N G O UTC O M E S 15.14 Define Toll­like receptors, and describe their action in relation to pathogen-associated molecular patterns. 15.15 Describe the location and functions of NOD proteins. 15.16 Explain the roles of interferons in innate immunity. 15.17 Describe the complement system, including its three activation pathways. ­ ­ ­ ­ ­ As discussed earlier, eosinophils can phagocytize; however, this is not their usual mode of attack. Instead, eosinophils secrete antimicrobial chemicals against pathogens that are too large to ingest. They attack parasitic helminths (worms) by adhering to the worm’s surface, where they secrete toxins onto the surface of the worms. These toxins weaken the helminth and may even kill it. Eosinophilia (ē-ō-sin’ō-fil-e-ă), an abnormally high number of eosinophils in the blood, is often indicative of helminth infestation, though it is also commonly seen in patients with allergies. Besides their attacks against parasitic helminths, eosinophils have recently been discovered to use a never-before-seen tactic against bacteria: Lipopolysaccharide from Gram-negative bacterial cell walls triggers eosinophils to rapidly eject their mitochondrial DNA, which combines with previously extruded eosinophil proteins to form a physical barrier. This extracellular structure binds to and then kills the bacteria. This is the first evidence that DNA can have antimicrobial activity, and scientists are investigating exactly how mitochondrial DNA might act as an antibacterial agent. Killing by Neutrophils Toll-Like Receptors Killing by Natural Killer Lymphocytes ­ Natural killer lymphocytes (NK cells) are another type of defensive leukocyte of innate immunity that works by secreting toxins onto the surfaces of virally infected cells and neoplasms (tumors). NK cells identify and spare normal body cells because the latter M15_BAUM7206_05_SE_C15.indd 453 Chemical defenses augment phagocytosis in the second line of defense. The chemicals assist phagocytic cells either by enhancing other features of innate immunity or by directly attacking pathogens. Defensive chemicals include lysozyme and defensins (examined previously) as well as Toll-like receptors, NOD proteins, interferons, and complement. A key function of immunity is to distinguish normal chemical shapes, “self,” from foreign chemical shapes, “nonself.” The immune system then degrades and removes objects with nonself features, such as pathogens, while leaving self-tissues and cells alone. How does innate immunity accomplish recognition 11/23/16 3:32 AM t ­ ­ TABLE 15.3 Toll-Like Receptors and Their Natural Microbial Binding Partners PAMP (Microbial Molecule) ­ ­  ­ ­ ­ NOD proteins12 are another set of receptors for microbial molecules, such as PAMPs, but NOD proteins are located in a cell’s cytoplasm rather than as part of a membrane. Scientists have studied NOD proteins that bind to components of Gram-negative bacteria’s cell walls and RNA of viruses, such as those that cause AIDS, hepatitis C, and mononucleosis. NOD proteins trigger inflammation, apoptosis, and other innate immune responses against bacterial pathogens, though researchers are still elucidating their exact method of action. Mutations in NOD genes are associated with several inflammatory bowel diseases, including Crohn’s disease. Interferons So far in this chapter we have focused primarily on how a body defends itself against bacterial and eukaryotic pathogens. Now we consider how chemicals in the second line of defense act against viruses. Viruses use their host’s metabolic machinery to produce new viruses. For this reason, it is often difficult to interfere with virus replication without harming the host. Interferons (in-terfēr’onz) (IFNs) are protein molecules released by host cells to nonspecifically inhibit the spread of viral infections. Their lack of specificity means that interferons produced against one viral invader protect somewhat against infection by other types of viruses as well. However, interferons also cause malaise, muscle aches, chills, headache, and fever, which are typically associated with viral infections. Different cell types produce one of two basic types of interferon when stimulated by viral nucleic acid binding to certain Toll-like receptors (TLR3, TLR7, or TLR8). Interferons within any given type share certain physical and chemical features, though they are specific to the species that produces them. In general, type I interferons—also known as alpha and beta interferons— are present early in viral infections, whereas type II (gamma) interferon appears somewhat later in the course of infection. Type I (Alpha and Beta) Interferons Within hours after infection, virally infected monocytes, macrophages, and some lymphocytes secrete small amounts of alpha interferon (IFN@A); similarly, fibroblasts, which are undifferentiated cells in such connective tissues as cartilage, tendon, and bone, secrete small amounts of beta interferon (IFN@B) when they are infected by viruses. The structures of alpha and beta interferons are similar, and their actions are identical; therefore, they are classed together as type I interferons. Type I interferons can act on the cells that secrete them, cells already infected with viruses, and trigger protective steps in neighboring uninfected cells. Alpha and beta interferons bind to interferon receptors on the cytoplasmic membrane. Such binding triggers the production of antiviral proteins (AVPs), which remain inactive within these cells until AVPs encounter viral nucleic acids, particularly double-stranded RNA, a molecule that is common among viruses but generally absent in eukaryotic cells (FIGURE 15.7). ­ TLR NOD Proteins ­ ­ of nonself chemicals? Certain structures are present on bacteria, fungi, and other microbes that are lacking on human cells. These structures, called pathogen-associated molecular patterns (PAMPs), are critical components to the microbes and thus cannot be easily altered by mutation. Some examples of PAMPs are lipopolysaccharide, peptidoglycan, and flagellin (see Chapter 3). Pattern recognition receptors are proteins on the surface of and inside human cells that can recognize PAMPs. The best-understood receptors, Toll-like receptors (TLRs)11, are integral proteins of the cytoplasmic membranes of phagocytic cells. Ten TLRs are known for humans. TLRs 1, 2, 4, 5, and 6 are found in cytoplasmic membranes, whereas TLRs 3, 7, 8, and 9 are added to phagosome membranes. Some TLRs act alone; others act in pairs to recognize a particular PAMP. For example, TLR3 binds to double-stranded RNA from viruses such as West Nile virus, and TLR2 and TLR6 in conjunction bind to lipoteichoic acid—a component of Gram-positive cell walls. TABLE 15.3 summarizes the membrane locations of the 10 known TLRs of humans and the PAMPs they bind. Binding of a PAMP to a Toll-like receptor initiates a number of possible defensive responses, including secretion of inflammatory mediators or interferons (both discussed shortly), production of chemical stimulants of adaptive immune responses (discussed in Chapter 16), or apoptosis (cell suicide) of an infected cell. If TLRs fail, much of an immune response collapses, leaving the body open to attack by myriad pathogens. Scientists are actively seeking ways to stimulate TLRs so as to enhance a body’s immune response to pathogens and immunizations. In contrast, methods to inhibit TLRs may provide us with ways to counter inflammatory disorders and hyperimmune responses. ­ a       Ch p er 15   Innate Immunity In Cytoplasmic Membrane eptidoglycan, lipoteichoic acid (found in Gram-positive cell wall), and cell wall of yeast TL 4 Lipid A in L S (found in outer membrane of Gram-negative bacteria) TL 5 Flagellin (bacterial flagella) TL 6 Bacterial lipopeptides, lipoteichoic acid, and cell wall of yeast TL 10 Unknown component of influenzaviruses P R R R R R P Bacterial lipopeptides and certain proteins in multicellular parasites TL 2 R TL 1 In Phagosome Membrane TL 7 Single-stranded viral NA TL 8 Single-stranded viral NA TL 9 Unmethylated cytosine-guanine pairs of viral and bacterial DNA R R R R R R Double-stranded NA (found only in viruses) R TL 3 11Toll  is a German word meaning “fantastic,” originally referring to a gene of fruit flies, mutations of which cause the flies to look bizarre. Toll-like proteins are similar to fruit fly Toll proteins in their amino acid sequence, though not in their function. M15_BAUM7206_05_SE_C15.indd 454 oligomerization domains, referring to their ability to bind a region of a finite number (oligomer) of DNA nucleotides.  12Nucleotide-binding 11/23/16 3:32 AM       The Body’s Second Line of Defense Infected cell Uninfected neighboring cell 1 Virus infects cell. Virus Doublestranded RNA Nucleus Interferon receptors IFN mRNA gene IFN mRNA Inactive AVPs AVP gene 2 Viral components trigger activation of type I IFN genes. 3 IFN-c and -d are released and bind to receptors on the same and nearby cells. 4 Binding activates genes for antiviral proteins (AVPs), though AVPs remain inactive at this time. Time passes Time passes Later, the infected cell may die, releasing viruses Same neighboring cell, now protected at the later time Inactive AVPs Active AVPs 5 Meanwhile, the infected cell dies, releasing viruses. 6 If this cell is infected, viral components activate the AVPs. Ribosome mRNA 7 Active AVPs degrade mRNA and bind to ribosomes, which stops protein synthesis, preventing viral replication. ▲ FIGURE 15.7 The actions of alpha and beta interferons. Type II (Gamma) Interferon Gamma interferon (IFN@G) is produced by activated T lymphocytes and by natural killer (NK) lymphocytes. Because T lymphocytes are usually activated as part of an adaptive immune response (see Chapter 16) days Complement M15_BAUM7206_05_SE_C15.indd 455 ­ after an infection has occurred, gamma interferon appears later than either alpha or beta interferon. Its action in stimulating the activity of macrophages gives IFN@g its other name: macrophage activation factor. Gamma interferon plays a small role in protecting the body against viral infections; mostly, IFN@g regulates the immune system, as in its activation of phagocytic activity. Physicians can administer interferons created using recombinant DNA techniques to patients with viral infections or cancers. This treatment can activate immunological responses. TABLE 15.4 on p. 456 summarizes various properties of interferons in humans. ­ At least two types of antiviral proteins are produced: oligo adenylate synthetase, the action of which results in the destruction of RNA, and protein kinase R, which inhibits protein synthesis by ribosomes. Between them, these AVP enzymes essentially destroy the protein production system of the cell, preventing viruses from being replicated. Of course, cellular metabolism is also affected negatively. The antiviral state lasts three to four days, which may be long enough for oligoadenylate synthetase to rid the cell of viral RNA but still a short enough period for the cell to survive without protein production. Type I interferons also activate NK and other lymphocytes, which kill virally infected cells, halting virus reproduction. The complement system—or complement for short—is a set of serum proteins, many of which are designated numerically according to the order of their discovery (C1, C2, C3, etc.). 11/23/16 3:32 AM TABLE 15.4 t a       Ch p er 15   Innate Immunity The Characteristics of Human Interferons Type I Alpha Interferon (IFN@A) rincipal source E P Property Type II pithelium, leukocytes Beta Interferon (IFN@B) Gamma Interferon (IFN@G) Fibroblasts Activated T lymphocytes and NK lymphocytes Inducing agent Viruses Viruses Adaptive immune responses Action Stimulates production of antiviral proteins Stimulates production of antiviral proteins Stimulates phagocytic activity of macrophages and neutrophils Other names Leukocyte-IFN Fibroblast-IFN Immune-IFN, macrophage activation factor cascade. The complement system was so named because its various proteins act to “complement,” or act in conjunction with, antibodies. • In the alternative pathway, activation occurs independently of antibodies with the cleavage of C3 into two fragments, C3a and C3b. This naturally occurs at a slow rate in the plasma, but in the absence of infection proceeds no further because C3b is cleaved into inactive fragments almost immediately. However, when C3b binds to microbial surfaces, it stabilizes long enough to work with three other plasma proteins (called factors B, D, and P) to split more C3 into more C3a and C3b. As C3b accumulates on the surface of the microbe, it acts as an opsonin and also triggers a complement cascade. The alternative pathway is useful in the early stages of an infection, before the adaptive immune response has created the antibodies needed to activate the classical pathway. • In the lectin pathway, mannose sugar, which is found on the surfaces of fungi, bacteria, and viruses, attaches to activating molecules called lectins.13 This begins the series of enzyme activities as in the classical activation pathway, leading to a complement cascade. ▶ ANIMATIONS: These proteins initially act as opsonins and chemotactic factors and indirectly trigger inflammation and fever. The end result of full complement activation can be destruction of foreign cells. Complement needs to act quickly without destroying normal cells surrounding a pathogen or virally infected cell. This is accomplished by utilizing proteins in the blood that are not activated until needed, like horses in a starting cage, poised to run when the gate opens. ▶ ANIMATION: Complement: Overview Complement Activation Complement is activated in three ways (FIGURE 15.8): • In the classical pathway, antibodies, which are part of adaptive immunity (and discussed in detail in Chapter 16), bind to foreign substances (called antigens), and this binding begins a series of enzyme activities called a complement Classical pathway Alternative pathway Lectin pathway Mannose C3b Microbe Foreign substance (antigen) Complement: Activation, Results C3b Antibody Factors B, D, and P Complement proteins 1, 2, 4 Complement system activation (C3 S C3a + C3b) (See next figure) ­ Lectins Complement Cascade Complement proteins react with one another in an amplifying sequence of chemical reactions in which the product of each reaction becomes an enzyme that catalyzes the next reaction many times over. For example, a single molecule of complement protein might activate 50 molecules of a second complement protein, each of which might in turn activate 30 molecules of a third complement protein, ending up with activation of 1500 of the third molecule. Such reactions are called cascades because they progress in a way that can be likened to a rock avalanche in which one rock dislodges several other rocks, each of which dislodges many others until a whole cascade of rocks is tumbling down the mountain. As you study the depiction of the classical complement cascade in FIGURE 15.9, keep the following concepts in mind: • Complement enzymes cleave other, inactive complement proteins, producing fragments that are active and are designated with lowercase letters. For example, inactive complement protein 3 (C3) is cleaved into active fragments C3a and C3b. ▲ FIGURE 15.8 Pathways by which complement is activated. P ­ In the classical pathway, the binding of antibodies to foreign substances (antigens) activates complement. In the alternative pathway, the binding of complement fragment C3b and factors B, D, and to surfaces of microbes activates complement. In the lectin pathway, mannose, a sugar found on many fungi, bacteria, and viruses, binds to lectins, thereby activating complement. How did complement get that name? Latin lēct, meaning “selected”; these carbohydrate-binding proteins are highly specific for certain sugar molecules. Figure 15.8 Complement proteins add to—or complement—the action of antibodies. M15_BAUM7206_05_SE_C15.indd 456 ­  13From 11/23/16 3:32 AM       The Body’s Second Line of Defense H2O H2O H2O C9 C7 C6 C5b C8 Membrane attack complex (MAC) C1 Antigen Antibody 1 C1 becomes an active enzyme when it binds to antibody-antigen complexes. Enzymatic C1 6 C5b combines with C6, C7, C8, and several molecules of C9 to form a membrane attack complex (MAC). A MAC drills a circular hole in the pathogen’s cytoplasmic membrane, leading to lysis of the cell. C2 C4 C2a 2 Enzyme C1 splits molecules of C2 and of C4. C5a C2b Triggers inflammation C4b C4a C5b 5 Third enzyme cleaves C5 into C5a and C5b. C5 Triggers inflammation Second enzyme C3b C4b C2a C2a 3 Fragments of C2 and C4 combine to form a second enzyme that splits C3 into C3a and C3b. Enzyme C4b 4 C3b combines with the second enzyme to form a third enzyme. C3 C3a C3b Acts as opsonin Triggers inflammation ­ ▲ FIGURE 15.9 The classical pathway and the complement cascade. Steps 2 to 6 are illustrated apart from the pathogen’s membrane for clarity; in reality, a complement cascade occurs at the site where antibodies on the membrane activate C1. The major functions of complement are opsonization and mediation of chemotaxis and inflammation. A membrane attack complex can form in a pathogen’s membrane, resulting in lysis of the pathogen. What proteins would be involved in activating a complement cascade if this were the alternative pathway? ­ Figure 15.9 Whereas the classical pathway of complement activation involves proteins C1, C2, and C4, the alternative pathway involves factors B, D, and P. M15_BAUM7206_05_SE_C15.indd 457 11/23/16 3:32 AM t a       Ch p er 15   Innate Immunity • Most fragments have specific and important roles in achieving the functions of the complement system. Some combine to form new enzymes; some act to increase vascular permeability, which increases diapedesis; others enhance inflammation; some act as opsonins; and still others are involved as positive chemotactic factors, attracting phagocytes. • One end product of a full cascade is a membrane attack complex (MAC), which forms a circular hole in a pathogen’s membrane. The production of numerous MACs (FIGURE 15.10) leads to lysis of the pathogen. The bacterium causing gonorrhea is particularly sensitive to MACs. ­ Membrane attack complex ­ In addition to its enzymatic role, fragment C3b acts as an opsonin. Fragment C5a is chemotactic, attracting phagocytes to the site of infection. C3a, C4a, and C5a are each inflammatory agents that cause localized vascular dilation, leading to inflammation. C3a and C5a also trigger the release of other inflammatory chemicals; their role is discussed in more detail shortly. electron micrograph of a cell damaged by hundreds of punctures produced by membrane attack complexes. LE A R N I N G O U TC O M E 15.18 Discuss the process and benefits of inflammation. ­ Inflammation is a general, nonspecific response to tissue damage resulting from a variety of causes, including heat, AL chemicals, ultraviolet light (sunburn), abrasions, cuts, and pathogens. Acute inflammation develops quickly, is short lived, is typically beneficial, and results in the elimination or resolution of whatever condition precipitated it. Long-lasting The Stealth Invader A LINI C C SE STUDY 1 µm ▲ FIGURE 15.10 Membrane attack complexes. Transmission Inflammation C TEM ­ P ­ R R P up from Tim’s lungs), which comes back negative. Tim is sent home with the advice to quit smoking. A week later, he’s back, coughing nonstop, short of breath, sweaty, and aching. A different doctor orders a chest X-ray exam and several blood tests. The X-ray film reveals fluid in Tim’s lungs, and real-time C confirms an infection with Mycoplasma pneumoniae, which is an atypical Gram-positive bacterium. egular sputum microscopy doesn’t detect this pathogen, which lacks cell walls and doesn’t stain well. Mycoplasma pneumoniae infects and disrupts the mucous membranes of the lungs, invading and disrupting the epithelium. neumonia caused by M. pneumoniae is called “walking pneumonia” because the symptoms are often milder and come and go, making this disease different from streptococcal pneumonia. Most patients get better on their own, but not Tim. Smoke has compromised the lungs’ innate immunity. A course of an antimicrobial drug—azithromycin—clears Tim’s lungs of the bacterium within a week. Tim decides to quit smoking. H R H Tim is often seen walking around campus, hanging out at the coffee shop, laughing with his friends, and, as he puts it, “investing time with the ladies.” Tim started smoking in high school and has never tried to kick the habit. e jokes about the “smoker’s cough” that has punctuated his conversations over the summer and start of the fall semester. ecently, the cough has been getting worse, his throat is scratchy, his head hurts, and he is tired all the time. Tim wonders if he has some long-lasting flu, though he hasn’t had a fever. e decides not to waste time with a doctor’s visit, but the cough starts keeping him up at night. In October, after a month of progressively worse coughing, he’s had enough; he heads to the campus clinic right after his morning classes. The clinic physician notes the persistence and worsening of Tim’s cough and confirms that Tim has no fever. To rule out a bacterial infection, she orders a routine sputum culture (a test of the material coughed M15_BAUM7206_05_SE_C15.indd 458 R 1. Which Toll-like receptors (TL s) might have been involved in Tim’s innate immune response to Mycoplasma? 2. Why didn’t Tim’s naturally occurring interferons help clear the infection? 3. What structures and chemicals normally fend off lung infections? 4. Why didn’t Tim’s innate lung defenses operate properly? 11/23/16 3:32 AM       The Body’s Second Line of Defense Arteriole ­ ­ Venule of mediators from damaged tissue causes nearby arterioles to dilate. Vasodilation causes capillaries to expand and enables more blood to be delivered to the affected site. Increased blood flow causes the reddening and heat associated with inflammation. Blood flow Before After chronic inflammation causes damage (even death) to tissues, resulting in disease. Both acute and chronic inflammation exhibit similar signs and symptoms, including redness in light-colored skin (rubor), localized heat (calor), edema (swelling), and pain (dolor). ▶ ANIMATION: Inflammation: Overview It may not be obvious from this list of signs and symptoms that acute inflammation is beneficial; however, acute inflammation is an important part of the second line of defense because it results in (1) dilation and increased permeability of blood vessels, (2) migration of phagocytes, and (3) tissue repair. Although the chemical details of inflammation are beyond the scope of our study, we now consider these three aspects of acute inflammation. Dilation and Increased Permeability of Blood Vessels Part of the body’s initial response to an injury or invasion of pathogens is localized vasodilation—an increase in diameter of blood vessels in the affected region (FIGURE 15.11). Dilation of blood vessels results in the redness and localized heat associated with inflammation. Many chemicals can trigger and promote dilation. These include: • Bradykinin (brad-e-kī’nin), which forms when the processes of blood clotting following damage to a blood vessel trigger conversion of a plasma protein into a peptide that is a powerful vasodilator. • Prostaglandins (pros-tă-glan’dinz) released by patrolling macrophages, using Toll-like receptors and NOD proteins to identify invaders. • Leukotrienes (loo-kō-trī’ēnz), which are released by the same cells that release prostaglandins. • Histamine (his’tă-mēn) released by basophils, platelets, and mast cells—specialized cells located in connective tissue—when they are exposed to either complement fragment C3a or C5a (FIGURE 15.12). Recall that these complement fragments were cleaved from larger complement proteins during a complement cascade. Bradykinin and histamine cause vasodilation of the body’s smallest arteries (arterioles), resulting in the delivery of more blood and thus more phagocytes, oxygen, and nutrients to ◀ FIGURE 15.12 The stimulation of inflammation by complement. Complement fragments C3a and C3a C5a C3a C5a C5a can each bind to platelets (not shown), basophils, or mast cells, causing them to release inflammatory mediators such as histamine, which in turn stimulates the dilation of arterioles. What kind of white blood cell does the drawing on the left represent? Figure 15.12 Basophil. Blood flow ­ Mediator ◀ FIGURE 15.11 The dilating effect of inflammatory mediators on small blood vessels. The release ­ Dilated capillaries Capillaries Granule containing chemicals Inflammatory mediators M15_BAUM7206_05_SE_C15.indd 459 Inflammatory mediators 11/23/16 3:32 AM t ­ lining the vessels in a process called margination. They then squeeze between the cells of the vessel’s wall (diapedesis) and enter the site of infection, usually within an hour of tissue damage. The phagocytes can then destroy pathogens via phagocytosis. As mentioned previously, phagocytes are attracted to the site of infection by chemotactic factors, including C5a, leukotrienes, and microbial components and toxins. The first phagocytes to arrive are often neutrophils, which are then followed by monocytes. Once monocytes leave the blood, they are called wandering macrophages, which are especially active phagocytic cells that devour pathogens, damaged tissue cells, and dead neutrophils. Wandering macrophages are a major component of pus. Increased blood flow due to vasodilation delivers more neutrophils and monocytes to the site of infection. These leukocytes arrive at the site of dilation where they adhere to receptors Normal permeability of venule Venule wall Monocyte Small amount of fluid Small amount of fluid The final stage of inflammation is tissue repair, which in part involves the delivery of extra nutrients and oxygen to the site via dilated blood vessels. Areas of the body where cells regularly divide, such as the skin and mucous membranes, are usually repaired rapidly. Some sites are not fully reparable and instead form scar tissue. If a damaged tissue contains undifferentiated stem cells, tissues can be fully restored. For example, a minor skin cut is repaired to such an extent it is no longer visible. However, if undifferentiated connective tissue cells called fibroblasts are involved to a significant extent, scar tissue forms, inhibiting normal function. Some tissues, such as cardiac muscle and parts of the brain, do not replicate, and thus tissue damage cannot be repaired. As a result, these tissues remain damaged following heart attacks and strokes. FIGURE 15.14 gives an overview of the entire inflammatory process. TABLE 15.5 summarizes the chemicals involved in inflammation. ▶ ANIMATION: Inflammation: Steps ­ Migration of Phagocytes Tissue Repair ­ ­ ­ the site of infection. These two vasodilators, prostaglandins, and leukotrienes also make small veins (venules) more permeable—that is, they cause cells lining the vessels to contract and pull apart, leaving gaps in the walls through which phagocytes can move into the damaged tissue and fight invaders (FIGURE 15.13). Increased permeability also allows delivery of more bloodborne antimicrobial chemicals to the site. Fluid leaking from the more permeable blood vessels accumulates in the surrounding tissue, resulting in edema (swelling), which puts pressure on nerve endings, producing much of the pain of inflammation. Vasodilation and increased permeability also deliver fibrinogen, the blood’s clotting protein. Clots forming at the site of injury or infection wall off the area and help prevent pathogens and their toxins from spreading. One result is the formation of pus, a fluid containing dead tissue cells, leukocytes, and pathogens in the walled-off area. Pus may push up toward the surface and erupt, or it may remain isolated in the body, where it is slowly absorbed over a period of days. Such an isolated site of infection is called an abscess. Pimples, boils, and pustules are examples of abscesses. The signs and symptoms of inflammation can be treated with antihistamines, which block histamine receptors on blood vessel walls, or with antiprostaglandins. One of the ways aspirin and ibuprofen reduce pain is by preventing synthesis of prostaglandins, which drive fever and pain. Physicians are divided on whether relief from the symptoms outweighs the loss of the positive effects of histamine and prostaglandins. ­ a       Ch p er 15   Innate Immunity Increased permeability of venule during inflammation Interstitial space Monocyte squeezing through interstitial space (diapedesis) More fluid and antimicrobial chemicals More fluid ▲ FIGURE 15.13 Increased vascular permeability during inflammation. The presence of uto M15_BAUM7206_05_SE_C15.indd 460 e o V T id bradykinin, prostaglandins, leukotrienes, or histamine causes cells lining venules to pull apart, allowing phagocytes to leave the bloodstream and more easily reach a site of infection. The leakage of fluid and cells causes the edema and pain associated with inflammation. r 11/23/16 3:32 AM       The Body’s Second Line of Defense ◀ FIGURE 15.14 An overview of the events in inflammation following a cut and infection. The process, which is characterized by redness, swelling, heat, and pain, ends with tissue repair. In general, what types of cells are involved in tissue repair? Figure 15.14 Tissue repair is effected by cells that are capable of cytokinesis and differentiation. If fibroblasts are among them, scar tissue is laid down. 1 A cut penetrates the epidermis barrier, and bacteria invade. 2 Damaged cells release prostaglandins, leukotrienes, and histamine (shown in green here). 3 Prostaglandins and leukotrienes make vessels more permeable. Histamine causes vasodilation, increasing blood flow to the site. Vasodilating Chemicals istamine, serotonin, bradykinin, prostaglandins Chemotactic Factors Fibrin, collagen, mast cell chemotactic factors, bacterial peptides Substances with Both Vasodilating and Chemotactic Effects Complement fragment C5a, interferons, interleukins, leukotrienes, platelet secretions Fever LE A R N I N G O UTC O M E 15.19 Explain the benefits of fever in fighting infection. Fever is a body temperature above normal, which averages 37°C. Fever augments the beneficial effects of inflammation, but like inflammation it also has unpleasant side effects, including malaise, body aches, and tiredness. The hypothalamus, a portion of the brain just above the brain stem, controls the body’s internal (core) temperature. Fever results when the presence of chemicals called pyrogens14 (pī’rō-jenz) trigger the hypothalamic “thermostat” to reset at a higher temperature. Pyrogens include bacterial toxins, cytoplasmic contents of bacteria that are released upon lysis, antibody-antigen complexes formed in adaptive immune responses, and pyrogens released by phagocytes that have phagocytized bacteria. Although the exact mechanism of fever production is not known, the following discussion and FIGURE 15.15 present one possible explanation. Chemicals produced by phagocytes 1 cause the hypothalamus to secrete prostaglandin, which resets the hypothalamic thermostat by an unknown mechanism 2 . The hypothalamus then communicates the new temperature setting to other parts of the brain, initiating nerve impulses that produce rapid and repetitive muscle contractions (shivering), an increase in metabolic rate, inhibition of sweating, and constriction of blood vessels of the skin 3 . These processes combine to raise the body’s core temperature until it equals the prescribed temperature setting 4 . Because blood vessels in the skin constrict as fever progresses, one effect of inflammation (vasodilation) is undone. The constricted vessels carry less blood to the skin 5 Increased permeability allows antimicrobial chemicals and clotting proteins to seep into damaged tissue but also results in swelling, pressure on nerve endings, and pain. ­ Heat ­ ­ Swelling ­ ­ ­ ­ 4 Macrophages and neutrophils squeeze through walls of blood vessels (diapedesis). TABLE 15.5 Chemical Mediators of Inflammation H Bacteria ­ Nerve ending 6 Blood clot forms. 7 More phagocytes migrate to the site and devour bacteria. 8 Accumulation of damaged tissue and leukocytes forms pus. 9 Undifferentiated stem cells repair the damaged tissue. Blood clot is absorbed or falls off as a scab. 14From M15_BAUM7206_05_SE_C15.indd 461 Greek pyr, meaning “fire,” and genein, meaning “to produce.” 11/23/16 3:32 AM t a       Ch p er 15   Innate Immunity Hypothalamus 2 Hypothalamus secretes prostaglandin, which resets hypothalamic thermostat. 1 Chemicals secreted by phagocytes travel in blood to hypothalamus. 3 Nerve impulses cause shivering, higher metabolic rate, inhibition of sweating, and vasoconstriction. Wound 4 These processes increase body temperature to the point set by the hypothalamic thermostat. ▲ FIGURE 15.15 One theoretical explanation for the TELL ME WHY Why are pathogen-associated molecular patterns (PAMPs) necessary for Toll-like receptors (TLRs) to fully function? ­ ­ production of fever in response to infection. Fever continues as long as pyrogens are present. As an infection comes under control and fewer active phagocytes are involved, the level of pyrogens decreases, the thermostat is reset to 37°C, and the body begins to cool by perspiring, lowering the metabolic rate, and dilating blood vessels in the skin. These processes, collectively called the crisis of a fever, are a sign that the infection has been overcome and that body temperature is returning to normal. The increased temperature of fever enhances the effects of interferons, inhibits the growth of some microorganisms, and is thought to enhance the performance of phagocytes, the activity of lymphocytes involved in adaptive immunity, and the process of tissue repair. However, if fever is too high, critical proteins are denatured; additionally, nerve impulses are inhibited, resulting in hallucinations, coma, and even death. Because of the potential benefits of fever, many doctors recommend that patients refrain from taking fever-reducing drugs unless the fever is prolonged or extremely high. Other physicians believe that the benefits of fever are too slight to justify enduring the adverse symptoms. TABLE 15.6 summarizes the barriers, cells, chemicals, and processes involved in the body’s first two, nonspecific lines of defense. of the trunk, arms, and legs, causing them to appear less red and feel cold to the touch, even though the body’s core temperature is higher. This symptom is the chill associated with fever. TABLE 15.6 A Summary of Some Nonspecific Components of the First and Second Lines of Defense (Innate Immunity) First Line Second Line Phagocytes Extracellular Killing Complement Interferons Antimicrobial Peptides Inflammation Fever Skin and mucous membranes prevent entry of pathogens; chemicals (e.g., sweat, acid, lysozyme, mucus) enhance the protection Macrophages, neutrophils, and eosinophils ingest and destroy pathogens osinophils and NK lymphocytes kill pathogens without phagocytizing them; neutrophils can also kill without phagocytosis Components attract phagocytes, stimulate inflammation, and attack a pathogen’s cytoplasmic membrane Increase resistance of cells to viral infection, slow the spread of disease Interfere with membranes, internal signaling, and metabolism; act against pathogens Increases blood flow, capillary permeability, and migration of leukocytes into infected area; walls off infected region; increases local temperature Mobilizes defenses, accelerates repairs, inhibits pathogens M15_BAUM7206_05_SE_C15.indd 462 E Barriers and Associated Chemicals 11/23/16 3:32 AM       Chapter Summary Allergies in Bloom? 1. Alice’s symptoms are a result of an infection of the conjunctiva, the lining that covers the white part of the eye and eyelid. What innate mechanisms protect the eye from infection? P ­ ­ H When Alice wakes up the next morning, she can barely open her eyes. er eyelids are swollen, and there is a crust on her eyes. She puts a warm washcloth on her eyes to help get rid of the crust, but the swelling is significant enough that she asks her roommate to give her a ride to the doctor’s office. Dr. Danby examines Alice’s eyes and tells her that it’s not allergies—Alice has conjunctivitis, or pinkeye. It’s likely that one of the children in Alice’s preschool had pinkeye and transmitted it to Alice. inkeye is highly contagious; to minimize the chance of transmission, Alice needs to wash her hands frequently with soap and water, avoid touching her eyes, wash all of her bedding and towels, and get rid of her makeup and brushes. Dr. Danby prescribes antibiotic eye drops and instructs Alice to thoroughly wash her hands before and after using the drops. Dr. Danby also tells Alice to have her roommate follow all of the precautions he outlined to avoid infection. Alice alerts the preschool to her infection so other teachers and parents can watch for signs of infection in the children. Within a couple of days of using the antibiotic eye drops, Alice’s symptoms begin to disappear; and within a week, her eyes are completely back to normal. 2. Conjunctivitis is inflammation of the conjunctiva. What are the steps in an inflammatory response? How do these steps correspond to Alice’s symptoms? CHAPTER SUMMARY 1. The first line of defense includes the skin, composed of an outer epidermis and a deeper dermis. Dendritic cells of the epidermis devour pathogens. Sweat glands of the skin produce salty sweat containing the enzyme called lysozyme and antimicrobial peptides (defensins), which are small peptide chains that act against a broad range of pathogens. Sebum is an oily substance of the skin that lowers pH, deterring the growth of many pathogens. 2. The mucous membranes, another part of the body’s first line of defense, are composed of tightly packed cells that are replaced frequently by stem cell division and often coated with sticky mucus secreted by goblet cells. 3. Tears contain antibacterial lysozyme and also flush invaders from the eyes. Saliva similarly protects the teeth. The low pH of the stomach inhibits most microbes that are swallowed. 4. Competitive inhibition, the competition between the microbiome and potential pathogens, also contributes to the body’s first line of defense. A probiotic is a beneficial microbe administered to improve health or prevent disease. M15_BAUM7206_05_SE_C15.indd 463 1. The second line of defense includes cells (especially phagocytes), antimicrobial chemicals (Toll-like receptors, NOD proteins, interferons, complement, lysozyme, and antimicrobial peptides), and processes (phagocytosis, inflammation, and fever). 2. Blood is composed of formed elements (cells and parts of cells) within a fluid called plasma. Serum is that portion of plasma without clotting factors. The formed elements are erythrocytes (red blood cells), leukocytes (white blood cells), and platelets. 3. Based on their appearance in stained blood smears, leukocytes are grouped as either granulocytes (basophils, eosinophils, and neutrophils) or agranulocytes (lymphocytes, monocytes). When monocytes leave the blood, they become macrophages. ­ The Body’s First Line of Defense (pp. 444–448) The Body’s Second Line of Defense (pp. 448–462) ­ 1. Humans have species resistance to certain pathogens as well as three overlapping lines of defense. The first two lines of defense comprise innate immunity, which is generally nonspecific and protects the body against a wide variety of potential pathogens. A third line of defense is adaptive immunity, in which each response is specifically generated against each particular antigen. ▶ ANIMATION: Host Defenses: Overview 5. Antimicrobial peptides (defensins) act against pathogens on the skin and mucous membranes and in neutrophils. ­ (p. 444) ­ An Overview of the Body’s Defenses 4. Basophils function to release histamine during inflammation, whereas eosinophils and neutrophils phagocytize pathogens. All three exit capillaries via diapedesis. 5. Macrophages, neutrophils, and dendritic cells are phagocytic cells of the second line of defense. Many macrophages are named for their location in the body, for example, alveolar macrophages (the lungs) and microglia (the nervous system). 6. A differential white blood cell count is a lab technique that indicates the relative numbers of leukocyte types; it can be helpful in diagnosing disease. 11/23/16 3:32 AM t ­ o e r 15. The process of blood clotting triggers formation of bradykinin—a potent mediator of inflammation. 16. Macrophages with Toll-like receptors or NOD proteins release prostaglandins and leukotrienes, which increase permeability of blood vessels. Mast cells, basophils, and platelets release histamine when exposed to peptides from the complement system. Blood clots may isolate an infected area to form an abscess, such as a pimple or boil. ­ 10. Eosinophils and natural killer lymphocytes (NK cells) attack nonphagocytically, especially in the case of helminth infections and cancerous cells. Eosinophilia—an abnormally high number of eosinophils in the blood—typically indicates such a helminth infection. Neutrophils can also kill nonphagocytically by making toxic forms of oxygen and NETs—neutrophil extracellular traps. id 9. Leukocytes can distinguish the body’s normal cells from foreign cells because leukocytes have receptor molecules for foreign cells’ components or because the foreign cells are opsonized by complement or antibodies. 14. Acute inflammation develops quickly and damages pathogens, whereas chronic inflammation develops slowly and can cause tissue damage that can lead to disease. Signs and symptoms of inflammation include redness, heat, swelling, and pain. ▶ ­ANIMATIONS: V T Inflammation: Overview, Steps uto ­ 8. Opsonization, the coating of pathogens by proteins called opsonins, makes those pathogens more vulnerable to phagocytes. A phagocyte’s pseudopods then surround the microbe to form a sac called a phagosome, which fuses with a lysosome to form a phagolysosome, in which the pathogen is killed. ▶ ANIMATION: Phagocytosis: Mechanism fever, and can effect the destruction of foreign cells via the formation of membrane attack complexes (MACs), which result in multiple, fatal holes in pathogens’ membranes. A complement cascade is activated by a classical pathway involving antibodies, by an alternative pathway triggered by bacterial chemicals, or by a lectin pathway triggered by mannose found on microbial surfaces. ▶ ANIMATIONS: Complement: Overview, Activation, Results ­ 7. Chemotactic factors, such as chemicals called chemokines, attract phagocytic leukocytes to the site of damage or invasion. Phagocytes attach to pathogens via a process called adhesion. ▶ ­ANIMATION: Phagocytosis: Overview ­ a       Ch p er 15   Innate Immunity 17. When leukocytes rolling along blood vessel walls reach a site of infection, they stick to the wall in a process called margination and then undergo diapedesis to arrive at the site of tissue damage. The increased blood flow of inflammation also brings extra nutrients and oxygen to the infection site to aid in repair. VI W E RE E QU STIONS FO R 13. The complement system, or complement, is a set of proteins that act as chemotactic attractants, trigger inflammation and 18. Fever results when chemicals called pyrogens, including substances released by bacteria and phagocytes, affect the hypothalamus in a way that causes it to reset body temperature to a higher level. The exact process of fever and its control are not fully understood. ­ ­ ­ 12. Interferons (IFNs) are protein molecules that inhibit the spread of viral infections. Alpha interferons (IFN@A) and beta interferons (IFN@B), which are released within hours of infection, trigger antiviral proteins (AVPs) to prevent viral reproduction in neighboring cells. Gamma interferons (IFN@G), produced days after initial infection, activate macrophages and neutrophils. ­ ­ 11. Microbial molecules called pathogen-associated molecular patterns (PAMPs) bind to Toll-like receptors (TLRs) on host cells’ membranes or to NOD proteins inside cells, triggering innate immune responses. Answers to the Questions for Review (except Short Answer questions) begin on p. A-1. Multiple Choice 1. Phagocytes of the epidermis are called __________________. a. microglia c. alveolar macrophages b. goblet cells d. dendritic cells 2. Mucus-secreting membranes are found in ________________. a. the urinary system c. the respiratory passages b. the digestive cavity d. all of the above 3. The complement system involves _____________. a. the production of antigens and antibodies b. serum proteins involved in nonspecific defense c. a set of genes that distinguish foreign cells from body cells d. the elimination of undigested remnants of microorganisms M15_BAUM7206_05_SE_C15.indd 464 4. The alternative complement activation pathway involves ________________. a. factors B, D, and P b. the cleavage of C5 to form C9 c. binding to mannose sugar d. recognition of antigens bound to specific antibodies 5. Which of the complement fragments is inflammatory? a. C3a c. C5a b. C4a d. all of the above 6. The type of interferon present late in an infection is ___________________. a. alpha interferon c. gamma interferon b. beta interferon d. delta interferon 11/23/16 3:32 AM 8. Which of the following is not targeted by a Toll-like receptor? a. lipid A c. single-stranded RNA b. eukaryotic flagellar protein d. lipoteichoic acid 9. Toll-like receptors (TLRs) act to _____________. a. bind microbial proteins c. cause phagocytic and polysaccharides chemotaxis b. induce phagocytosis d. destroy microbial cells 10. Which of the following binds iron? a. lactoferrin c. transferrin b. siderophores d. all of the above Modified True/False Indicate which statements are true. Correct all false statements by changing the underlined words. Matching In the blank beside each cell, chemical, or process in the left column, write the letter of the line of defense that first applies. Each letter may be used several times. 1. ______ Inflammation A. First line of defense 2. ______ Monocytes B. Second line of defense 3. ______ Lactoferrin C. Third line of defense 4. ______ Fever 5. ______ Dendritic cells 6. ______ Alpha interferon 7. ______ Mucous membrane of the digestive tract  7. Interferons ____________. a. do not protect the cell that secretes them b. stimulate the activity of macrophages c. cause muscle aches, chills, and fever d. all of the above       R Questions for eview 8. ______ Neutrophils 9. ______ Epidermis 10. ______ Lysozyme 11. ______ Goblet cells 2. ___________________ The surface cells of mucous membranes are alive. 13. ______ Sebum  3. ___________________ Wandering macrophages experience diapedesis. 4. ___________________ Monocytes are immature macrophages. 5. ___________________ Lymphocytes are large agranulocytes.  6. ___________________ Phagocytes exhibit chemotaxis toward a pathogen. 14. ______ T lymphocytes 15. ______ Antimicrobial peptides Write the letter of the description that applies to each of the following terms. 1. ______ Goblet cell 2. ______ Lysozyme  7. ___________________ In phagocytosis, adhesion involves the binding between complementary chemicals on a phagocyte and on the membrane of a body cell. 12. ______ Phagocytes    1. ___________________ The surface cells of the epidermis of the skin are alive. 4. ______ Dendritic cell  5. ______ Cell from sebaceous gland 6. ______ Bone marrow stem cell   8. ___________________ Opsonization occurs when a phagocyte’s pseudopods surround a microbe and fuse to form a sac. 3. ______ Stem cell  11. ___________________ Rubor, calor, swelling, and dolor are associated with fever.  12. ___________________ Acute and chronic inflammation exhibit similar signs and symptoms.  13. ___________________ The hypothalamus of the brain controls body temperature. C. Secretes sebum D. Devours pathogens in epidermis E. Breaks bonds in bacterial cell wall 7. ______ Eosinophil F. Phagocytic cell in central nervous system 8. ______ Alveolar macrophage G. Generative cell with many types of offspring 9. ______ Microglia H. Develops into formed elements of blood   10. ___________________ A membrane attack complex drills circular holes in a macrophage. B. Phagocytic cell in lungs 10. ______ Wandering macrophage   9. ___________________ Lysosomes fuse with phagosomes to form peroxisomes. A. Leukocyte that primarily attacks parasitic worms I. Intercellular scavenger J. Secretes mucus  14. ___________________ Defensins are phagocytic parts of the first line of defense.  15. ___________________ NETs are webs produced by neutrophils to trap microbes. M15_BAUM7206_05_SE_C15.indd 465 11/23/16 3:32 AM t a       Ch p er 15   Innate Immunity 2. Name the cells. VISUALIZE IT! 1. Label the steps of phagocytosis. a. _______________ b. _______________ c. _______________ a. ____________ d. _______________ b. ____________ c. _____________ e. ______________ d. ____________ e. ____________ f. ______________ Short Answer 1. In order for a pathogen to cause disease, what three things must happen? 4. What is the role of Toll-like receptors in innate immune responses? 2. How does a phagocyte “know” it is in contact with a pathogen instead of another body cell? 5. Describe the classical complement cascade pathway from C1 to the MAC. 3. Give three characteristics of the epidermis that make it an intolerable environment for most microorganisms. 6. How do NOD proteins differ from Toll-like receptors? H 1. John received a chemical burn on his arm and was instructed by his physician to take an over-the-counter anti-inflammatory medication for the painful, red, swollen lesions. When Charles suffered pain, redness, and swelling from an infected cut on his foot, he decided to take the same anti-inflammatory drug because his symptoms matched John’s symptoms. How is Charles’s inflammation like that of John? How is it different? Is it appropriate for Charles to medicate his cut with the same medicine John used? 2. What might happen to someone whose body did not produce C3? C5? 3. Mary, age 65, has had diabetes for 40 years, with resulting damage to the small blood vessels in her feet and toes. Her circulation is impaired. How might this condition affect her vulnerability to infection? ­ 4. A patient’s chart shows that eosinophils make up 8% of his white blood cells. What does this lead you to suspect? Would your suspicions change if you learned that the patient had spent the previous three years as an anthropologist living in an African jungle village? What is the normal percentage of eosinophils? 5. There are two kinds of agranulocytes in the blood—monocytes and lymphocytes. Janice noted that monocytes are phagocytic and that lymphocytes are not. She wondered why two agranulocytes would be so different. What facts of hematopoiesis can help her answer her question? M15_BAUM7206_05_SE_C15.indd 466 6. A patient has a genetic disorder that prevents him from synthesizing C8 and C9. What effect does this have on his ability to resist bloodborne Gram-negative and Gram-positive bacteria? What would happen if C3 and C5 fragments were also inactivated? ­ R C ITICAL T INKING 7. Sweat glands in the armpits secrete perspiration with a pH close to neutral (7.0). How does this fact help explain body odor in this area as compared to other parts of the skin? 8. Scientists can raise “germ-free” animals in axenic environments. Would such animals be as healthy as their worldly counterparts? 9. Compare and contrast the protective structures and chemicals of the skin and mucous membranes. 10. Scientists are interested in developing antimicrobial drugs that act like the body’s normal antimicrobial peptides. What advantage might such a drug have over antibiotics? 11. A medical laboratory scientist argues that granulocytes are a natural group, whereas agranulocytes are an artificial grouping. Based on Figure 15.4, do you agree or disagree with the lab scientist? What evidence can you cite to justify your conclusion? 12. A patient has a genetic disorder that makes it impossible for her to synthesize complement protein 8 (C8). Is her complement system nonfunctional? What major effects of complement could still be produced? 11/23/16 3:32 AM       Questions for Review 13. While using a microscope to examine a sample of pus from a pimple, Maria observed a large number of macrophages. Is the pus from an early or a late stage of infection? How do you know? 14. How do drugs such as aspirin and ibuprofen act to reduce fever? Should you take fever-reducing drugs or let a fever run its course? CONCEPT MAPPING Using the following terms, fill in the following concept map that describes phagocytosis. Macrophages Neutrophils Opsonins Phagolysosome Phagosome Eosinophils Exocytosis Ingestion Killing Lysosome Adhesion Chemotactic factors Chemotaxis Dendritic cells Elimination Phagocytosis 1 2 participating cells include 3 involves the following 5 steps 4 5 6 7 8 9 enhanced by enhanced by forming a involves fusion of a through 10 11 12 13 15 forming 14 M15_BAUM7206_05_SE_C15.indd 467 3/6/18 4:58 PM