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Immune System http://www.electroresponse.com Lymphatic System, Innate Immunity Much of the text material is from, “Principles of Anatomy and Physiology, 14th edition” by Gerald J. Tortora and Bryan Derrickson (2014). I don’t claim authorship. Other sources are noted when they are used. Mappings of the lecture slides to the 12th and 13th editions are provided in the supplements. 2 Due to the complexity of the conceptual material and how it is presented, most visual references are to the detailed illustrations in the textbook. Very few visuals are included in these lecture notes. 3 Outline • • • • • Introduction Lymphatic system Innate immunity—external defenses Innate immunity—internal defenses Inflammation and fever 4 Introduction 5 Immunity • Most people remain healthy despite constant exposure to pathogens; that is, disease-producing bacteria and viruses. • The body is also susceptible to abrasions and cuts, exposure to ultraviolet (UV) radiation from sunlight, exposure to chemical toxins, and burns. • Immunity—also known as resistance—involves the body’s defenses that respond to diseases and other damage. • The two general types of immunity are known as innate immunity and adaptive immunity. Chapter 22, page 831 6 http://www.rikenresearch.riken.jp Immunity (continued) 7 Innate Immunity • Innate (or nonspecific) immunity involves defenses that are active as early as birth. • The defenses respond rapidly to provide protection against many diseases. • Innate immunity does not recognize specific microbes—its mechanisms respond to all microbes in the same manner and with similar actions. Microbe = a very tiny form of life. Microbes include bacteria, fungi, and protozoan parasites, They are best visualized under a light microscope. (www.emedicinehealth.com) Chapter 22, page 831 8 Innate Immunity (continued) • The first line of defense includes physical and chemical barriers of the skin and mucous membranes. • The second line includes anti-microbial substances, natural killer (NK) cells, phagocytes, inflammation, and fever. • Both lines of defense help prevent microbes from entering the body and eliminate those that do gain access. • Second-line responses also serve as an “early-warning system” for the body. Natural killer cell = a type of lymphocyte (white blood cell) that can kill microbial or tumor cells. Phagocyte = macrophages and neutrophils (white blood cells) that engulf and digest debris and invading microbes. Chapter 22, page 831 9 Adaptive Immunity • Adaptive or specific immunity are defenses involving the recognition of specific microbes when they breach the nonspecific defenses. • Adaptive immunity is slower to respond than innate immunity, but it has “memory” to facilitate the immune response if the microbe is ever encountered again. • The responses involve B lymphocytes (B cells) and T lymphocytes (T cells). B and T lymphocytes = types of white blood cells. Chapter 22, page 831 10 Lymphatic System 11 Lymphatic System • The lymphatic system mediates adaptive immunity and aspects of innate immunity. • It also works with the cardiovascular system, and with the digestive system in the absorption of lipids. Chapter 22, page 831 12 Lymphatic System (continued) • The lymphatic system consists of: Fluid known as lymph - Lymphatic vessels that transport the lymph - Structures and organs containing lymphatic tissue - Red bone marrow where stem cells develop into blood cells - • The lymphatic system, like the cardiovascular system, circulates body fluids. Chapter 22, page 832 Figure 22.1 13 Lymphatic System (continued) http://www.clinic-clinic.com 14 Lymph • Some components of blood plasma filter through capillary walls to form interstitial fluid. • When interstitial fluid passes into lymphatic vessels, it is known as lymph. • The key difference between interstitial fluid and lymph is their locations. • Interstitial fluid is found in the space surrounding cells, and lymph in lymphatic vessels and lymphatic tissue. Chapter 22, page 832 15 Lymphatic Tissue and Lymphocytes • Lymphatic tissue consists of reticular connective tissue containing large numbers of B and T lymphocytes. • Lymphocytes are agranular white blood cells, as discussed in the lecture on blood. Reticular connective tissue = a network of reticular fibers, composed of type III collagen. Agranular = lacking granules when properly stained and viewed under a light microscope. Chapter 22, page 832 16 Lymphatic Functions • The primary functions of the lymphatic system are to: Drain excess fluid from the interstitial spaces and return it to the blood. - Transport lipid-soluble food molecules and lipid-soluble vitamins (A, D, E, and K) absorbed by the gastrointestinal tract. - Initiate immune responses against microbes and abnormal cells. - • These lymphatic functions are covered in subsequent slides and the textbook. Chapter 22, page 832 17 Lymphatic Vessels • Lymphatic vessels begin as lymphatic capillaries in the interstitial space. • Lymphatic capillaries are closed at the end terminating in the interstitial space. • They converge to form larger lymphatic vessels, just as blood capillaries converge to form venules and then veins. • Although lymphatic vessels resemble veins, they have thinner walls and a greater number of valves to assure one-way flow of lymphatic fluid. Chapter 22, page 832 Figure 22.2 18 Lymphatic Vessels (continued) • Once absorbed from the interstitial fluid, lymph passes through the lymph nodes found at intervals along the lymphatic vessels. • Lymph nodes are encapsulated, bean-shaped organs that contain masses of B cells and T cells. Chapter 22, page 832 Figure 22.2 19 Lymphatic Vessels (continued) • Lymphatic vessels in the subcutaneous tissue often follow the same routes as veins. • Lymphatic vessels in the viscera typically follow arteries and form plexuses (networks). Viscera = the internal organs in the main cavities of the body. Chapter 22, page 832 Figure 22.2 20 Lymphatic Vessels (continued) • Some tissues do not have lymphatic capillaries—they include: Avascular tissues including cartilage, epidermis, and cornea of the eye - Central nervous system (brain and spinal cord) - Portions of the spleen - Red bone marrow - Avascular = without blood vessels. Chapter 22, page 832 Figure 22.2 21 Lymphatic Capillaries • Lymphatic capillaries are of slightly larger diameter than blood capillaries. • Their walls have a one-way structure to enable interstitial fluid to flow into, but not out of, the lumen. • The endothelial cells of the lymphatic capillary wall overlap to enable this one-way flow. Chapter 22, page 832 Figure 22.2 22 Lymphatic Capillaries (continued) http://www.web-books.com/elibrary/medicine/hysiology 23 Lymphatic Capillaries (continued) • When the hydrostatic pressure is higher in the interstitial fluid than in the lymphatic capillary, the endothelial cells open slightly, as in a one-way swinging door. • Interstitial fluid enters the lymphatic capillary through the openings. • When the hydrostatic pressure is higher in the lymphatic capillary than in the interstitial fluid, the endothelial cells adhere more closely to close the openings. • Lymph cannot re-enter the interstitial fluid since the openings are now closed. Chapter 22, page 832 Figure 22.2 24 Lymphatic Capillaries (continued) • Further inflow of interstitial fluid occurs when the pressure in the lumen is reduced as lymph flows down the lymphatic capillary. • Lymphatic capillaries are attached to elastic anchoring filaments that connect the lymphatic endothelial cells to surrounding tissues. • The filaments are pulled when excess interstitial fluid accumulates, which causes tissue swelling. • The openings widen between endothelial cells to permit more interstitial fluid to flow into the lymphatic capillary. Chapter 22, page 832 Figure 22.2 25 Lacteals • Lacteals—specialized lymphatic capillaries in the small intestine— transport dietary lipids into lymphatic vessels and into the blood. • The lipids make the lymphatic fluid, known as chyle juice, appear creamy-white. • Lymph is a clear, pale-yellow fluid in the other tissues of the body. Chapter 22, page 832 26 Digestive Tract Note the centrally-located lacteal in the enlarged villus to the right. 27 Lymph Production • Many components of the blood plasma can filter through the walls of blood capillaries to produce interstitial fluid. • The formed elements (RBCs, WBCs, and platelets) usually cannot pass. • More fluid filters out of blood capillaries than is reabsorbed into the capillaries. • The excess fluid—about 3 liters per day—drains into the lymphatic vessels to produce lymph. Chapter 22, page 834 Figure 21.7 28 Lymph Production (continued) • Interstitial fluid contains only a small amount of proteins since most protein molecules are too large to pass through blood capillary walls. • The small amount of proteins in interstitial fluid is not reabsorbed through the blood capillary walls because of the opposing concentration gradient. • These proteins pass into the more readily-permeable lymphatic capillaries. • The proteins are returned to the blood through the lymphatic system. Chapter 22, page 834 Figure 22.4 29 Lymphatic Flow • Lymph flows from lymphatic capillaries, into afferent lymphatic vessels, and then into the lymph nodes. • Efferent lymphatic vessels exit the lymph nodes and converge to form lymph trunks. • Lymph then drains into the thoracic and right lymphatic ducts, and then into venous blood. • The anatomical relationships between the lymphatic system and cardiovascular system are shown in Figure 22.4 in the textbook. Chapter 22, page 834 Figure 22.4 30 Skeletal Muscle Pump • Lymphatic vessels, like veins in the cardiovascular system, have valves that permit one-way flow. • Skeletal muscle and respiratory pumps assist in the flow of lymph, just as they aid in the return of venous blood to the right atrium of the heart. • Skeletal muscle contractions compress the lymphatic vessel walls. • The compressions force lymph toward the junction of the internal jugular and subclavian veins where it empties into venous blood. Chapter 22, page 834 Figure 21.9 31 Respiratory Pump • During inhalation, lymph flows from the abdominal region where the pressure is higher to the thoracic region where the pressure is lower. • When a lymphatic vessel is distended by lymph, the smooth muscle in its wall contracts in response, propelling the lymph from one segment of the vessel to the next. • Valves prevent the backflow of lymph when the pressure differential is reversed during exhalation. Chapter 22, page 834 32 Primary Lymphatic Organs and Tissues • Lymphatic organs and tissues are called primary or secondary based on their functions. • Primary lymphatic organs are sites where stem cells can divide and become immunocompetent—that is, capable of an immune response. • The primary lymphatic organs are the red bone marrow and thymus. Chapter 22, page 834 33 Red Bone Marrow • Pluripotent stem cells in red bone marrow form mature, immunocompetent B cells and pre-T cells. • Pre-T cells migrate to the thymus where they mature into immunocompetent T cells. Chapter 22, page 834 34 Red Bone Marrow (continued) http://gardenrain.files.wordpress.com 35 Secondary Lymphatic Organs and Tissues • Most immune responses occur in the secondary lymphatic organs and tissues. • They include the spleen, lymph nodes, and lymphatic nodules (or follicles). • They also include the thymus, spleen, and lymph nodes which are organs since each one is surrounded by a capsule of connective tissue. • Lymphatic nodules lack this capsule, and are not considered to be organs. Chapter 22, page 836 36 Thymus • The thymus is a bilobed organ located in the mediastinum between the sternum and aorta. • A layer of connective tissue holds the two lobes closely together. • Each lobe is further divided by extensions of the connective tissue capsule to form smaller lobules. • A lobule has a darker-staining outer cortex and lighter-staining central medulla. Bilobed = divided into two lobes. Chapter 22, page 836 Figure 22.5 37 Thymus (continued) http://www.acm.uiuc.edu 38 Thymus—Cortex • The cortex is composed of large numbers of T cells, and dendritic cells, epithelial cells, and macrophages. • Immature pre-T cells migrate from red bone marrow to the cortex where they proliferate and begin to mature. • Dendritic cells, derived from monocytes, assist in the maturation process. Proliferate = to increase in number or spread rapidly. Monocyte = a large phagocytic white blood cell which, when it enters tissue, develops into a macrophage. (http://thyroid.about.com) Chapter 22, page 836 Figure 22.5 39 Thymus—Cortex (continued) • Each epithelial cell has long processes that surround and form a framework for as many as 50 T cells. • They also produce thymic hormones for the maturation of T cells. • About 2 percent of the T cells survive in the cortex—the others die by apoptosis. • Surviving T cells enter the medulla of the thymus—macrophages dispose of the dead and dying T cells in the thymic cortex. Process = a natural prolongation or projection from a part of an organism. (http://wordnetweb.princeton.edu) Apoptosis = normal cellular process involving a genetically programmed series of events leading to the death of a cell. (http://science.education.nih.gov) Chapter 22, page 836 Figure 22.5 40 Thymus—Medulla • The medulla contains mature T cells, epithelial cells, dendritic cells, and macrophages. • Epithelial cells form concentric layers of flat cells that serve as sites for T cell death. • The surviving T cells eventually exit the medulla via the blood, and migrate to the lymph nodes, spleen, and other lymphatic tissues to colonize them. Concentric = circles sharing the same center. Chapter 22, page 837 Figure 22.5 41 Thymus—Age Progression • The thymus is large in infants and young children, weighing about 70 grams. • Adipose and areolar connective tissues begin replacing the thymic tissue at puberty. • The thymus atrophies substantially by adulthood. • It may weigh as little as 3 grams later in life—a 96 percent decrease from infancy. Atrophy = wasting away of tissue or an organ due to the degeneration of cells. (http://medclinic.bli.uci.edu) Chapter 22, page 837 42 Thymus—Age Progression (continued) • The thymus populates the secondary lymphatic organs and tissues with T cells before it atrophies. • Small numbers of T cells continue to proliferate in the thymus during an individual’s lifetime. Chapter 22, page 837 43 Lymph Nodes • About 600 lymph nodes are located among the lymphatic vessels. • Lymph nodes are found in superficial and deep tissues of the body. • The nodes are often grouped, including near the mammary glands and in the groin and axillae. Axillae = plural for axilla; the armpits. Chapter 22, page 837 Figure 22.1 44 Lymph Nodes (continued) http://www.acm.uiuc.edu 45 Lymph Nodes—Structure • Lymph nodes are 1 to 25 mm in length and are enclosed in capsules of dense connective tissue that extends into the nodes. • These trabeculae divide each node into compartments to provide structural support and a path for blood vessels into the node. • The capsule, trabeculae, reticular fibers, and fibroblasts form the supporting connective tissue, known as stroma, of a lymph node. Chapter 22, page 837 Figure 22.6 46 Lymph Nodes—Structure (continued) http://www.acm.uiuc.edu 47 Lymph Nodes—Outer Cortex • The functioning part of a lymph node is known as the parenchyma. • The parenchyma consist of an outer and inner cortex and a deeper medulla. • The outer cortex contains aggregates of B cells known as lymphatic nodules or follicles. Chapter 22, page 839 Figure 22.6 48 Nodules • A nodule consisting mostly of B cells is called a primary lymphatic nodule. • Secondary lymphatic nodules—the more common type—form in response to antigens. • These nodules are sites of plasma cell and memory B cell formation. Antigen = any substance such as a toxin or enzyme that stimulates an immune response in the body, especially the production of antibodies. (http://wordnetweb.princeton.edu) Chapter 22, page 839 Figure 22.6 49 Medulla and Germinal Center • The central, medullary region of a secondary lymphatic nodule has cells that form the germinal center. • The germinal center contains B cells, follicular dendritic cells, and macrophages. Chapter 22, page 839 50 B Cell Responses • B cells proliferate into antibody-producing plasma cells or memory B cells when follicular dendritic cells present an antigen. • Memory B cells persist after the immune response ends to serve as memory of a specific antigen if it is ever encountered again by the body. • B cells that fail to develop properly undergo apoptosis and destruction by macrophages. • The region surrounding the germinal center has dense accumulations of B cells that migrated from their site of origin within the nodules. Antibody = any of a large variety of proteins normally present in the body or produced in response to an antigen which it neutralizes, thus producing an immune response. (http://wordnetweb.princeton.edu) Chapter 22, page 839 51 Inner Cortex • The inner cortex of a lymph node does not contain lymphatic nodules, but it does have T cells and dendritic cells that migrated from other tissues. • Dendritic cells present antigens to T cells, triggering a proliferation of T cells. • Newly-formed T cells migrate from the lymph node to sites of antigen activity in the body. Chapter 22, page 839 52 Medulla • The medulla of a lymph node contains B cells—antibody-producing plasma cells that migrated from the cortex—and macrophages. • The cells are embedded in a network of reticular fibers and reticular cells. Chapter 22, page 839 53 Lymph Nodes and Lymph • Lymph enters the lymph nodes though afferent lymphatic vessels. • The vessels have valves that direct lymphatic flow into the nodes. • The textbook describes the flow of lymph through the sinuses within a lymph node. Chapter 22, page 839 Figure 22.6 54 Filtration • The lymph nodes filter lymph—foreign substances entering a node are trapped by the reticular fibers within the sinuses. • Macrophages destroy some of the foreign substances through phagocytosis, while lymphocytes destroy others through immune responses. • The filtered lymph exits the lymph node into efferent lymphatic vessels. Lymphocyte = a type of white blood cell or leukocyte that occurs in two forms; B-lymphocytes, which produce antibodies in the humoral immune response, and T-lymphocytes, which participates in the cell-mediated immune response. (http://en.wiktionary.org) Chapter 22, page 839 55 Efferent Lymphatic Vessels • The sinuses in the medulla of a lymph node drain into 1 or 2 efferent lymphatic vessels. • The efferent vessels have one-way valves to convey lymph away from the lymph node. • The lymph exiting a lymph node contains activated T cells and antibodies from plasma cells. Chapter 22, page 839 Figure 22.6 56 Spleen http://www.acm.uiuc.edu 57 Spleen • The spleen is the largest single mass of lymphatic tissue—it is oval in shape and measures about 12 cm in length. • The organ is located in the left hypochondriac region (hypochondrium) between the stomach and diaphragm. • The stomach, left kidney, and large intestine make impressions on the surface of the spleen due to their close proximity. • Anatomical details of the spleen are described in Chapter 22 of the textbook. Chapter 22, page 840 Figure 22.7 58 Spleen—White Pulp • The functioning part of the spleen—its parenchyma—has two types of tissue known as white pulp and red pulp. • White pulp is lymphatic tissue arranged around the central arteries of the spleen. • Blood flowing into the spleen through the central arteries enters the white pulp. Chapter 22, page 841 Figure 22.7 59 Functions • White pulp is composed mostly of lymphocytes and macrophages.•• • The B cells and T cells perform immune functions similar to those in lymph nodes. • Macrophages in the white pulp destroy pathogens by phagocytosis. Chapter 22, page 841 60 Spleen—Red Pulp • Red pulp consists of blood-filled venous sinuses and cords of splenic (spleen) tissue known as splenic cords. • The cords contain red blood cells, macrophages, lymphocytes, plasma cells, and granulocytes. • Veins are found in the red pulp. Chapter 22, page 841 Figure 22.7 61 Functions • Red pulp has three functions: Removal of ruptured, worn-out, and defective blood cells and platelets by macrophages. - Storage of up to one-third of the body’s supply of platelets. - Production of blood cells through hemopoiesis during the fetal period. - Chapter 22, page 841 62 Lymphatic Nodules • Lymphatic nodules are small, egg-shaped masses of lymphatic tis-sue, but without a surrounding capsule. • They are also called mucosa-associated lymphatic tissue, or MALT. • The nodules are located in connective tissue of mucous membranes lining the respiratory airways, and in the digestive, urinary, and reproductive tracts. Chapter 22, page 841 63 Lymphatic Nodules (continued) • While some lymphatic nodules are single, many form large aggregations. • Aggregations are found in the tonsils located in the throat’s pharyngeal region, the ileum of the small intestine, and the appendix. • The five tonsils—two adenoid, two lingual, and one palatine—are involved in immune responses to inhaled and ingested foreign substances. Chapter 22, page 841 Figure 23.2 64 Innate Immunity, External Defenses 65 External Defenses • Innate immunity involves external barriers to provide a first line of defense against pathogens. • The barriers include the skin, mucous membranes, body fluids, and chemicals. Chapter 22, page 842 66 Skin • The epidermis—the outer, epithelial layer of the skin—has layers of closely-packed, keratinized cells. • The epidermis is a barrier to microbes and other pathogens for example, bacteria rarely penetrate an intact skin surface. • Pathogens, however, can enter to invade tissues and circulate in the blood when the skin is cut, punctured, or burned. • The periodic shedding of epidermal cells helps remove microbes at the skin surface. Chapter 22, page 842 Figure 5.1 67 Mucous Membranes • The epithelial layer of the mucous membranes secretes mucus, a fluid that lubricates and moistens the surface of the cavity. • Mucous also traps microbes and other foreign substances since it is slightly viscous. • The mucous membrane of the nose has mucous-coated hairs to trap and filter microbes, dust, and pollutants in inhaled air. Viscous = having a high resistance to flow. Chapter 22, page 842 68 Mucous Membranes (continued) • The mucous membranes of the upper respiratory tract contain many cilia. • Cilia are microscopic, hair-like projections composed of protein molecules on the surface of epithelial cells. • The coordinated waving motion helps move microbes and dust trapped in mucus toward the throat. Chapter 22, page 842 69 Coughing, Sneezing, and Swallowing • Coughing and sneezing accelerate the movement of mucus with entrapped microbes and dust out of the body. • Swallowing mucus transports microbes to the stomach where many are destroyed by gastric acid. Chapter 22, page 842 70 Tears and Lysozyme • The lacrimal glands of the eyes produce tears in response to environmental irritants and some emotional states. • Blinking spreads the tears over the surface of the eye to help dilute microbes and keep them from settling on the cornea. • Tears contain lysozyme, an enzyme that breaks-down the cell walls of some bacteria. • Lysozyme is also found in saliva, perspiration, nasal secretions, and tissue fluids. Chapter 22, page 842 Figure 17.6 71 Saliva • Saliva, secreted by the salivary glands, washes microbes from the teeth and mucous membrane of the oral cavity (mouth). • Saliva helps reduce the over-colonization of microbes in the mouth. Colonization = proliferation of microorganisms on or within body sites without detectable host immune response, cellular damage, or clinical expression. (http://www.cdc.gov) Chapter 22, page 842 72 Other Mechanisms • Cleansing of the urethra by urine inhibits microbial colonization of the urinary system. • Vaginal secretions sweep microbes out of the female reproductive tract. • Defecation and vomiting can expel many microbes from the body. • The smooth muscle of the lower gastrointestinal tract contracts vigorously in response to some microbes—diarrhea expels many of them through defecation. Chapter 22, page 842 73 Chemicals • Sebaceous glands secrete sebum, an oily substance, to form a protective film on the surface of the skin. • Unsaturated fatty acids in sebum inhibit the growth of some pathogenic types of bacteria and fungi. • The high acidity of the skin (pH 3 - 5)—which is inhospitable to some pathogens—results from fatty acids and lactic acid secretions. • Perspiration can help flush microbes from the surface of the skin. Pathogenic = a disease-producing agent. Chapter 22, page 842 74 Chemicals (continued) • Gastric juice—secreted by exocrine glands in the stomach wall— contains hydrochloric acid, enzymes, and mucus. • The high acidity (pH 1.2 - 3.5) destroys many bacteria and the toxins they release. • Vaginal secretions are slightly acidic, and hinder bacterial growth. Chapter 22, page 842 75 Innate Immunity, Internal Defenses 76 Internal Defenses • Innate immunity includes internal defenses that respond when the external defenses are breached. • The defenses include antimicrobial substances, natural killer cells, phagocytes, inflammation, and fever. Chapter 22, page 843 77 Antimicrobial Substances • Antimicrobial substances that hinder microbial growth include: - Interferons Complement system Iron-binding proteins Antimicrobial proteins Chapter 22, page 843 78 Interferons • Lymphocytes, macrophages, and fibroblasts infected with viruses produce proteins known as interferons. • When released, interferons diffuse to uninfected cells where they induce the synthesis of antiviral proteins to inhibit virus replication. • Interferons are a important defense mechanism because viruses are only effective when they can replicate and spread to other cells. Chapter 22, page 843 79 Complement System • The complement system consists of a group of normally-inactive proteins found in blood plasma and on the plasma membranes of cells. • The proteins complement, or enhance, some types of immune reactions. • The complement system initiates cytolysis, promotes phagocytosis, and contributes to inflammation. Cytolysis = breakdown of a cell by the destruction of its plasma membrane. Chapter 22, page 843 80 Iron-Binding Proteins • Iron-binding proteins inhibit the growth of some types of bacteria by reducing the amount of available iron. • The proteins include: Hemoglobin in red blood cells - Transferrin in blood and tissue fluids - Ferritin in the liver, spleen, and red bone marrow - Lactoferrin in saliva, mucus, and a nursing mother’s milk - Chapter 22, page 843 81 Antimicrobial Proteins • Antimicrobial proteins (AMPs) are short peptide chains that exert a broad spectrum, or range, of antimicrobial activity. • AMPs destroy many microbes, and attract dendritic cells and mast cells for participation in immune responses. • Antimicrobial proteins include: Dermicidin secreted by sweat glands - Thrombocidin from platelets - Defensins and cathelicidins from neutrophils, macrophages, and epithelium - Chapter 22, page 843 82 Natural Killer Cells • Natural killer (NK) cells and phagocytes can destroy microbes that penetrate the skin or mucous membrane and by-pass antimicrobial substances in the blood. • About 5 - 10 percent of the lymphocytes in blood circulation are NK cells. • NK cells are also found in the spleen, lymph nodes, and red bone marrow. • NK cells lack the membrane molecules that identify other lymphocytes (B and T cells). Chapter 22, page 843 83 Natural Killer Cells (continued) • NK cells can destroy a wide variety of infected body cells and some tumor cells. • They can also attack cells that display abnormal or unusual proteins on their plasma membranes. Chapter 22, page 843 84 http://www.biotechnologie.de Natural Killer Cells (continued) NK cell, in yellow, attacking a cancer cell. Both cells are shown in false color. 85 Perforin • The binding of NK cells to an infected cell triggers the release of granules of toxic substances, including perforin and granzymes. • Perforin is a protein that inserts itself into the plasma membrane of infected cells to create channels or perforations. • Extracellular fluid flows into the cells, causing them to burst (known as cytolysis). Chapter 22, page 843 86 Granzymes • Granzymes released by NK cells are protein-digesting enzymes that induce the infected cell to undergo self-destruction known as apoptosis. • Apoptosis kills infected cells, but not the microbes contained within them. • The microbes released upon the death of the cell are destroyed by phagocytes. Chapter 22, page 843 87 Phagocytes • Phagocytes ingest microbes and cellular debris. • While phagocytes are an innate defense mechanism, they also have roles in active immunity, as will be discussed in part 2 of this material. • The two main types of phagocytes are neutrophils and macrophages. Chapter 22, page 843 Figure 3.13 88 http://www.itb.cnr.it Macrophage False color, electron micrograph. 89 Wandering and Fixed Macrophages • During their migration, monocytes enlarge and develop into active phagocytes called wandering macrophages.• • Wandering macrophages• • Fixed macrophages “stand guard” in tissues—examples include: - Histiocytes in connective tissues Stellate reticuloendothelial cells (also called Kuppfer cells) in the liver Alveolar macrophages in the lungs Microglia in the nervous system Tissue macrophages in the spleen, lymph nodes, and red bone marrow Chapter 22, page 843 90 Phases of Phagocytosis • Chemotaxis • Adherence • Ingestion • Digestion • Destruction Chapter 22, page 844 Figure 22.9 91 Phagocytosis 92 Chemotaxis • Chemotaxis is the chemically-stimulated movement of phagocytes to the site of infection or other tissue damage. • Chemicals that attract phagocytes are released from microbes, white blood cells, activated complement proteins, and damaged tissue cells. Chapter 22, page 844 Figure 22.9 93 Adherence • Adherence is the physical attachment of the phagocyte to a microbe or other foreign substance. • The binding of complement proteins to the microbe enhances adherence. Chapter 22, page 844 Figure 22.9 94 Ingestion • The plasma membrane of a phagocyte extends projections known as pseudopods to engulf the microbe in a process known as ingestion. • The pseudopod fuses to surround the microbe to form a phagosome. Chapter 22, page 844 Figure 22.9 95 Digestion • The phagosomes enter the cytoplasm of the phagocyte and merge with lysosomes to form a large, single phagolysome. • Lysozyme destroys the cell walls of the engulfed microbe, and digestive enzymes breakdown the microbe’s carbohydrates, proteins, lipids, and nucleic acids. • The phagocyte also forms lethal oxidants—including superoxide anion (O2-), hypochlorite anion (OCl-), and hydrogen peroxide (H2O2)—in an oxidative burst. Oxidative or respiratory burst = the rapid release of reactive oxygen (superoxide radical and hydrogen peroxide) from different types of cells. (http://en.wikipedia.org) Chapter 22, page 844 Figure 22.9 96 Destruction • Lysozyme, digestive enzymes, and oxidants destroy many types of microbes. • Remaining materials that cannot be completely digested stay in the phagocyte to form residual bodies. Chapter 22, page 844 Figure 22.9 97 Microbial Evasion • Some microbes, such as bacteria that cause pneumonia, have extracellular structures known as capsules. • The capsules make if difficult for phagocytes to engulf the microbes. • Some toxin-producing microbes, such as those that cause some types of food poisoning, produce leukocidins. • Leukocidins destroy phagocytes by causing the release of the phagocyte’s own destructive enzymes into its cytoplasm. Evasion = elude or escape. Chapter 22, page 843 98 Microbial Evasion (continued) • Other microbes, such as the bacteria that cause tuberculosis, inhibit the fusion of phagosomes and lysosomes, and prevent the exposure of microbes to lysosomal enzymes. • The bacteria within the phagosomes multiplies, which can destroy the phagocyte. • Some bacteria contain chemicals in their cell walls that can counteract the effects of lethal oxidants produced by phagocytes. Phagosome = membrane-bound vacuole within a cell containing foreign material captured by phagocytosis. (http://en.wiktionary.org) Oxidant = compound that donate electrons to other compounds. (http://www.hepatitis-central.com) Chapter 22, page 843 99 Inflammation and Fever 100 Inflammation • Inflammation is a non-specific, defensive response to tissue damage and infection. • Inflammation can result from microbes, abrasions, chemical irritation, various disturbances of cells, and extreme temperatures. • Inflammation is an attempt by the body to dispose of microbes, toxins, or foreign materials at an injury site. • It also helps prevent spread to other tissues, and prepares the site for tissue repair. • The four signs of inflammation are: redness, pain, heat, and swelling. Chapter 22, page 844 101 Inflammation (continued) • Inflammation can cause loss of function in the injured area depending on the location and extent of the injury. • The response is similar to burns, radiation, and bacterial or viral infection. • The inflammatory response has three stages: Vasodilation and increased permeability of blood capillaries - Emigration of phagocytes from the blood into the interstitial fluid - Tissue repair - Chapter 22, page 844 102 Vascular Responses • Increased diameter of the arterioles (vasodilation) and increased permeability of blood capillaries occur in the vicinity of the tissue injury. • Blood flow increases through the damaged area. • The increase in blood flow also helps remove microbes, their toxins, and dead tissue cells. • Increased permeability enables substances, including antibodies and clotting factors, to pass from the blood into the interstitial fluid. • A number of chemicals contribute to vasodilation and permeability. Chapter 22, page 844 Figure 22.10 103 Chemical Contributors • Histamine is released by mast cells in connective tissue and basophils and platelets in the blood. • This chemical promotes vasodilation and increased permeability of blood capillaries. • Kinins, including bradykinin, are polypeptides formed in blood from inactive precursors known as kininogens. • These chemicals promote vasodilation, increase capillary membrane permeability, and serve as chemotaxic agents for migration of phagocytes to the site of infection or injury. Chapter 22, page 845 104 Chemical and Other Contributors • Prostaglandins are lipid molecules released by damaged cells. • They intensify the effects of histamine and kinins, and stimulate the emigration of phagocytes through the membranes of blood capillaries. • Leukotrienes are produced by basophils and mast cells to increase membrane permeability, promote adherence of phagocytes to pathogens, and serve as chemotaxic agents for phagocytes. • The complement system stimulates histamine release, attracts neutrophils via chemotaxis, promotes phagocytosis, and destroys bacteria. Chapter 22, page 845 105 Symptoms of Inflammation • Arteriole dilation and increased permeability of capillaries produce some of the symptoms of inflammation—heat, redness (erythema), and swelling (edema). • Heat and redness result from blood accumulating in the damaged area. • As the local temperature rises, metabolic reactions are more rapid and release even more heat. • Edema results from the increased permeability of blood capillaries, enabling more fluid to move from blood circulation into the interstitial space. Chapter 22, page 845 106 Inflammation and Pain • Pain is a prime symptom of inflammation—it results from injury to nerve fibers and release of microbial toxins. • Kinins can affect nerve endings, and can intensify the pain associated with inflammation. • Prostaglandins intensify and prolong the pain associated with an inflammation. • Pain can also result from the increased mechanical pressure on tissues due to edema. Chapter 22, page 845 107 Clotting Factors • An increase in capillary permeability enables blood-clotting factors, including fibrinogen, to emigrate into tissues. • Fibrinogen is converted to an insoluble, thick mesh of fibrin threads that localizes and trap microbes and hinders their spread to other tissues. • The clotting sequence is described in Chapter 19 of the textbook. Emigrate = to leave and usually not return. Chapter 22, page 845 108 Emigration of Phagocytes • Phagocytes, including neutrophils, emigrate to the site of a tissue injury within about an hour of the start of the inflammation process. • Emigration depends on chemotaxis. • Neutrophils stick to the endothelium or lining of blood vessels as blood accumulates in the injured area. • They squeeze through the blood vessel wall to reach the damaged area. Chapter 22, page 845 Figure 22.10 109 Emigration of Phagocytes (continued) • Neutrophils destroy microbes in the damaged tissue by phagocytosis. • A steady stream of neutrophils is assured through the production and release of additional neutrophils from the red bone marrow. • The increase in the production of neutrophils is known as leukocytosis. Chapter 22, page 845 Figure 22.10 110 Monocytes and Macrophages • Neutrophils rapidly die-off after predominating in the early stages of an infection. • Monocytes move into damaged tissue to prolong the inflammatory response. • Upon entering the tissue, monocytes are transformed into wandering macrophages to supplement the activity of fixed macrophages. • Macrophages are much more potent phagocytes than neutrophils— they are large enough to engulf damaged tissue, dead neutrophils, and microbes. Chapter 22, page 845 111 Pus • Macrophages eventually die-off as the inflammatory response progresses. • A pocket of dead macrophages and damaged tissue forms within a few days—the collection of dead cells and fluids is known as pus. • Pus forms in many inflammatory responses, and usually continues until the infection subsides. Chapter 22, page 845 112 Abcesses and Ulcers • Pus may reach the surface of the body, drain into an internal cavity, or remain in the tissue to be gradually absorbed. • An abscess can form if pus cannot drain out of the inflamed region. • Pimples and boils are examples of abcesses. • An open sore, called an ulcer, results when inflamed tissue sloughs off the surface of the tissue. Chapter 22, page 846 113 Ulcerations in Diabetic Individuals • Individuals with poor blood circulation, such as diabetics who have advanced atherosclerosis, are susceptible to ulcers in the tissues of their legs. • These are known as statis ulcers, which are due to diminished oxygen and nutrient supply to tissues. • The tissues become even more susceptible to mild injury or infection. Atherosclerosis = a type of arteriosclerosis in which the vessels that supply oxygen-rich blood to the heart become clogged with plaque (a fatty substance) and calcium, depriving the heart muscle of the oxygen it needs for normal functioning. (http://www.cardiogenesis.com) Chapter 22, page 846 114 Fever • Fever is an abnormally-high body temperature that occurs due to changes in the thermoregulatory mechanism in the hypothalamus. • Fever can occur during infection and inflammation. • Many bacterial toxins can elevate body temperature by triggering the release of fever-causing cytokines, such as interleukin-1, from macrophages. • An elevated body temperature accelerates the effects of interferons, inhibits the growth of some microbes, and speeds-up cellular actions for tissue repair. Chapter 22, page 846 115