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Defense against the dark arts Section 1: Lymphatic System Anatomy • Lymphatic system includes cells, tissues, and organs responsible for defending the body against: – Environmental hazards (such as various pathogens) – Internal threats (such as cancer cells) • Lymphatics – Network of lymphatic vessels • Contains lymphocytes surrounded by lymph similar to interstitial fluid) (fluid – Also includes array of lymphoid organs and tissues Section 1: Lymphatic System Anatomy • Lymphocytes (primary cells of lymphatic system) – Respond to: • Invading pathogens (such as bacteria and viruses) • Abnormal body cells (such as virus-infected or cancer cells) • Foreign proteins (such as bacterial toxins) – Mostly produced in lymphoid organs and tissues but also in red bone marrow Lymph Lymphocyte The components of the lymphatic system Lymphatic Vessels and Lymph Nodes Cervical lymph nodes Thoracic duct Right lymphatic duct Axillary lymph nodes Lymphatics of mammary gland Lymphoid Tissues and Organs Tonsil Thymus Cisterna chyli Lymphatics of upper limb Lumbar lymph nodes Pelvic lymph nodes Spleen Mucosa-associated lymphoid tissue (MALT) in digestive, respiratory, urinary, and reproductive tracts Appendix Inguinal lymph nodes Lymphatics of lower limb Figure 19 Section 1 Module 19.1: Lymphatic capillaries • Lymphatic vessels – Carry lymph from peripheral tissues to venous system – Network begins with lymphatic capillaries (smallest vessels) • Collect interstitial fluid (then called lymph) and transport it to larger lymphatic vessels – Larger vessels are similar in structure to veins • Have valves The flow of interstitial fluid into lymphatic capillaries, where it is called lymph Arteriole Smooth muscle Endothelial cells Lymphatic capillary Blood capillaries Loose connective tissue Venule Interstitial fluid Lymph flow Figure 19.1 1 Artery Vein Lymphatic vessel The flow of lymph from lymphatic capillaries to larger lymphatic vessels on the way to the venous system Vein Artery Lymphatic vessel To larger lymphatic vessels that deliver lymph to the venous system Lymphatic valve From lymphatic capillaries Lymphatic valve Lymphatic vessel Valve in lymphatic vessel LM x 65 Figure 19.1 3 – 4 Module 19.1: Lymphatic capillaries • Lymphatic capillaries – Present in almost every tissue, alongside cardiovascular capillaries • Differ from blood capillaries 1. 2. 3. 4. 5. Originate as pockets rather than continuous tubes Have larger diameters Have thinner walls » Basal lamina is incomplete or absent Typically have a flattened or irregular outline in sectional view Endothelial cells overlap to form one-way valves » Collect fluids as well as larger solutes The structure of lymphatic capillaries Lymphocyte Loose connective tissue Incomplete or absent basal lamina Lymph flow To larger lymphatics Overlapping endothelial cells Interstitial fluid Interstitial fluid Loose connective tissue Lymphatic capillary Blood capillary Sectional view Figure 19.1 2 Module 19.1 Review a. What is the function of lymphatic vessels? b. What structure prevents the backflow of lymph in some lymphatic vessels? c. What is the function of overlapping endothelial cells in lymphatic capillaries? Module 19.2: Lymphatic vessels • Lymphatic vessel location – Superficial lymphatics • • • Subcutaneous layer deep to skin Areolar tissues of mucous membranes (digestive, respiratory, urinary, and reproductive tracts) Areolar tissues of serous membranes (pleural, pericardial, and peritoneal cavities) – Deep lymphatics • Accommodate deep arteries and veins supplying skeletal muscles and other torso organs Some characteristics of superficial and deep lymphatics Lymphatic Vessels Superficial Lymphatics Deep Lymphatics Are located in the subcutaneous layer deep to the skin; in the areolar tissues of the mucous membranes lining the digestive, respiratory, urinary, and reproductive tracts; and in the areolar tissues of the serous membranes lining the pleural, pericardial, and peritoneal cavities Accompany deep arteries and veins supplying skeletal muscles and other organs of the neck, limbs, and trunk, and the walls of visceral organs Superficial inguinal lymph nodes and lymphatic vessels Deep inguinal lymph nodes and lymphatic vessels Figure 19.2 1 Module 19.2: Lymphatic vessels • Large lymphatic vessels – Lymphatic trunks (drain lymph from large body regions) • • • • • Jugular trunks Subclavian trunks Bronchomediastinal trunks Lumbar trunks Intestinal trunk – Cisterna chyli • Expanded chamber receiving lymph from lumbar trunks and intestinal trunk Module 19.2: Lymphatic vessels • Large lymphatic vessels (continued) – Lymphatic ducts (empty into subclavian veins) • Right lymphatic duct – • Drains lymph from right arm, right upper torso, right head and neck Thoracic duct – Drains lymph from rest of body » Left arm, lower limbs, lower torso, upper left torso, left head and neck Areas of the body drained by the right lymphatic and thoracic ducts Drainage of right lymphatic duct Drainage of thoracic duct Figure 19.2 2 The relationship between the right lymphatic and thoracic ducts and the venous system Right internal jugular vein Right Lymphatic Duct Is formed by the merging of the trunks labeled below Brachiocephalic veins Left internal jugular vein Thoracic Duct Collects lymph from the trunks labeled below Right jugular trunk Left jugular trunk Right subclavian trunk Left subclavian trunk Right lymphatic duct entering right subclavian vein Thoracic duct entering left subclavian vein Left bronchomediastinal trunk Right bronchomediastinal trunk Superior vena cava (cut) Rib (cut) Thoracic duct Azygos vein Thoracic lymph nodes Parietal pleura (cut) Diaphragm Intestinal trunk Interior vena cava (cut) Cisterna chyli Right lumbar trunk Left lumbar trunk Figure 19.2 3 Module 19.2: Lymphatic vessels • Lymphedema – Blockage of lymphatic drainage Interstitial fluids accumulate and affected area swells Most often seen in limbs Can become permanent and lead to infection – – – • Interstitial fluid is stagnant and pathogens accumulate Module 19.2 Review a. Name the two large lymphatic vessels into which the lymphatic trunks empty. b. Explain lymphedema. Module 19.3: Lymphocytes • Lymphocytes – Account for 20%–30% of circulating leukocytes • • Most lymphocytes are out in lymphatic tissues Three classes circulate in blood 1. 2. 3. T cells (80% of circulating lymphocytes) » Cell-mediated immunity B cells (10%–15% of circulating lymphocytes) » Antibody-mediated immunity NK cells (5%–10% of circulating lymphocytes) » Immunological surveillance Module 19.3: Lymphocytes • All lymphocytes are sensitive to specific chemicals (antigens) – Antigens can be: • • • Pathogens Parts or products of pathogens Other foreign compounds – Are usually proteins but can be other common organic molecules as well – Stimulate an immune response that leads to destruction of target compound or organism Module 19.3: Lymphocytes • Lymphocyte classes – T cells (three major categories) 1. Cytotoxic T cells – 2. Helper T cells – 3. Attack foreign cells or virus-infected body cells » Commonly use direct contact Stimulate T cell and B cell activation and function Suppressor T cells – – Inhibit T cell and B cell activation and function Work with helper T cells to control immune response sensitivity Module 19.3: Lymphocytes • Lymphocyte classes (continued) – B cells • When stimulated, become plasma cells that produce and secrete antibodies – Antibodies then circulate in body fluids to attack targets throughout the body – NK (natural killer) cells • • Attack foreign cells, virus-infected body cells, and cancer cells Provide continuous monitoring of peripheral tissues The three classes of lymphocytes circulating in the bloodstream Classes of Lymphocytes T Cells B Cells NK Cells Account for approximately 80 percent of circulating lymphcytes; are of three major types Account for 10–15 percent of circulating lymphocytes Account for 5–10 percent of circulating lymphocytes; perform immune surveillance, attacking foreign cells, body cells infected with viruses, and cancer cells that appear in normal tissues Cytotoxic T Cells Helper T Cells Suppressor T Cells Plasma Cells Attack foreign cells or body cells infected by viruses, commonly by direct contact; are the primary cells involved in the production of cell-mediated immunity (cellular immunity) Stimulate the activation and function of both T cells and B cells Inhibit the activation and function of both T cells and B cells; the interplay between suppressor T cells and helper T cells helps establish and control the sensitivity of the immune response When stimulated can differentiate into plasma cells, which produce and secrete antibodies; are said to be responsible for antibody-mediated immunity (humoral immunity) because antibodies circulate widely in body fluids Figure 19.3 1 Module 19.3: Lymphocytes • Lymphopoiesis (lymphocyte production) – Occurs mainly in red bone marrow • Lymphocyte stem cells – – Develop from hemocytoblasts Produce all lymphocyte types from two groups 1. Group migrates to thymus » Isolated by blood–thymus barrier » Become T cells and reenter bloodstream 2. Group remains in bone to finish development » Become B cells and NK cells – Mature T cells and B cells can reproduce Module 19.3 Review a. Identify the three main classes of lymphocytes. b. Which cells are responsible for antibodymediated immunity? c . What tissues are involved in lymphopoiesis? Module 19.4: Lymphatic tissues and organs • Lymphatic tissues – Connective tissues dominated by lymphocytes • May form aggregations of lymphocytes (lymphoid nodules) – Examples: • Aggregated lymphoid nodules (Peyer patches) – • Deep to epithelium in small intestine Mucosa-associated lymphoid tissue (MALT) – Protect epithelia of digestive, respiratory, urinary, and reproductive tracts A photomicrograph and a drawing of aggregated lymphoid nodules in the intestinal mucosa An aggregated lymphoid nodule in the intestinal mucosa Intestinal lumen Mucous membrane of intestinal wall Germinal center Aggregated lymphoid nodule in intestinal mucosa Underlying connective tissue Aggregated lymphoid nodules LM x 20 Figure 19.4 1 Module 19.4: Lymphatic tissues and organs • Tonsils – Lymphoid nodules in pharynx wall • Inflammation of tonsils = tonsillitis – Palatine (posterior, inferior margin of oral cavity) • Paired – Pharyngeal (posterior, superior wall of pharynx) • • Often called adenoid Single – Lingual (deep to epithelium at base of tongue) • Paired The location and histology of tonsils Germinal centers within nodules Pharyngeal epithelium The location of the tonsils Pharyngeal tonsil LM x 40 Pharyngeal tonsil Hard palate Palatine tonsil Lingual tonsil Figure 19.4 2 Module 19.4: Lymphatic tissues and organs • Lymph nodes – Small lymphoid organs surrounded by fibrous connective tissue capsule – Diameter range 1–25 mm (about 1 in.) – Large lymph nodes (lymph glands) located in neck, groin, axillae – Function as filters, removing 99% of pathogens from lymph before fluid returns to bloodstream Module 19.4: Lymphatic tissues and organs • Pathway through lymph node – Afferent lymphatics (afferens, to bring to) bring lymph to node on opposite side from hilum (indentation) Subcapsular space – • – Outer cortex • – B cells in germinal centers Deep cortex • – T cells Medullary sinus • – Macrophages and dendritic cells (immune response) B cells and plasma cells Exit node through efferent (efferens, to bring out) lymphatics Lymph node Lymph vessel Lymph nodes The functional anatomy of lymph nodes Path of Lymph Flow through a Lymph Node Efferent lymphatics (efferens, to bring out) leave the lymph node at the hilum. These vessels collect lymph from the medullary sinus and carry it toward the venous circulation. Lymph node artery and vein Hilum Lymph continues into the medullary sinus at the core of the lymph node. This region contains B cells and plasma cells. Lymph then flows through lymph sinuses in the deep cortex, which is dominated by T cells. Lymph next flows into the outer cortex, which contains B cells within germinal centers that resemble those of lymphoid nodules. The afferent vessels deliver lymph to the subcapsular space, a meshwork of reticular fibers, macrophages, and dendritic cells. Dendritic cells are involved in the initiation of the immune response. Start Afferent lymphatics (afferens, to bring to) carry lymph to the lymph node from peripheral tissues. The afferent lymphatics penetrate the capsule of the lymph node on the side opposite the hilum. Germinal center Trabeculae Figure 19.4 3 Module 19.4 Review a. Define tonsil. b. Name the lymphoid tissue that protects epithelia lining the digestive, respiratory, urinary, and reproductive tracts. Module 19.5: Thymus • Function of the thymus and age-related effects – Produces several hormones (thymosins) important in functional T cell development • More important in children – Size is largest (40 g) before puberty – Diminishes in size and becomes fibrous (involution) • After age 50, size can be <12 g and secretions decline – May lead to increased susceptibility to disease Module 19.5: Thymus • Structure of the thymus – Bilobed gland in mediastinum, posterior to sternum • Left and right lobes with smaller partitions (septa) dividing it into lobules • Each lobule contains: – Cortex (reticular epithelial cells and lymphocytes) » Has blood–thymus barrier to isolate developing T cells – Medulla (reticular epithelial cells and lymphocytes organized into thymic corpuscles) » Developed T cells enter bloodstream (no barrier) The surface anatomy of the thymus Septa Lobule Left lobe Right lobe Figure 19.5 2 The histology of the thymus Medulla Septa Cortex Lobule Lobule LM x 50 Thymus gland Lymphocytes Thymic corpuscle Reticular epithelial cells Thymic corpuscle LM x 532 Figure 19.5 3 – 4 Module 19.5 Review a. Where is the thymus located? b. Which cells constitute and maintain the blood–thymus barrier? c. Describe the gross anatomy of the thymus. Module 19.6: Spleen • Similar to a lymph node: filters blood for the body to prevent pathogens from reaching vital organs • Extremely delicate tissue – If damaged or ruptured it is to difficult to fix surgically and a slenectomy is usually done Spleen A transverse section of the trunk showing the location of the spleen within the abdominopelvic cavity Diaphragm Stomach Rib Gastrosplenic ligament Liver Gastric area Pancreas Aorta Spleen Kidneys Diaphragmatic surface of the spleen Hilum Renal area Figure 19.6 1 Module 19.6: Spleen • Internal functional anatomy – Outer capsule of collagen and elastic fibers • Protects but overall spleen structure is delicate – – Damage can necessitate removal (splenectomy) Trabeculae • – Fibrous partitions that allow room for blood vessels Pulp (cellular components allowing identification and removal of damaged or infected cells in bloodstream) • • Red pulp (large quantities of RBCs) White pulp (resemble lymphoid nodules with lymphocytes, macrophages, and dendritic cells) Trabeculae Fibrous partitions within which blood vessels travel Capsule Trabecula Red pulp Trabecular artery White pulp of splenic nodule Central artery in splenic nodule The histological appearance of the spleen LM x 50 Figure 19.6 4 Figure 19.6 5 Module 19.6 Review a. What is the function of the spleen? b. Describe red pulp and white pulp found in the spleen. . Section 2: Nonspecific Defenses • Two complementary mechanisms work to fight infection, illness, and disease 1. Specific defenses (protect against particular threats) • • Depend on specific lymphocyte activities Produce state of protection (immunity or specific resistance) Section 2: Nonspecific Defenses • Two complementary mechanisms work to fight infection, illness, and disease (continued) 2. Nonspecific defenses (present from birth and do not distinguish one type of threat from another) • • • • • • • Physical barriers Phagocytes Immunological surveillance Interferons Complement Inflammatory response Fever Animation: Immunity: Nonspecific Defenses Module 19.7: Physical barriers and phagocytes • Physical barriers – Integumentary system • Secretions from sebaceous and sweat glands wash away microorganisms and chemical agents – May also contain bactericidal chemicals, destructive enzymes (lysozymes), and antibodies • Hair provides protection from mechanical abrasion and prevents hazardous materials or insects from contacting skin • Multiple layers of epithelial cells with keratin that are connected with desmosomes Duct of eccrine sweat gland Hair Secretion Epithelium Structures in the skin that constitute a physical barrier Keratinized cells Sebaceous gland Most epithelia are protected by specialized accessory structures and secretions. The epidermal surface also receives the secretions of sebaceous and sweat glands. These secretions, which flush the surface to wash away microorganisms and chemical agents, may also contain bactericidal chemicals, destructive enzymes (lysozymes), and antibodies. Desmosomes The hairs on most areas of your body’s surface provide some protection against mechanical abrasion (especially on the scalp), and they often prevent hazardous materials or insects from contacting your skin. The epithelial covering of the skin has multiple layers, a coating of keratinized cells, and a network of desmosomes that lock adjacent cells together. Figure 19.7 1 Module 19.7: Physical barriers and phagocytes • Physical barriers (continued) – Other epithelial linings • Found along digestive, respiratory, urinary, and reproductive tracts • Cells provide physical barrier • Secretions (mucus, enzymes, stomach acid) often ensnare, destroy, or wash away pathogenic material The barrier provided by the epithelia lining the digestive, respiratory, urinary, and reproductive tracts Mucus coating Secretory cell Mucus bathes most surfaces of your digestive tract, and your stomach contains a powerful acid that can destroy many pathogens. Mucus moves across the lining of the respiratory tract, urine flushes the urinary passageways, and glandular secretions do the same for the reproductive tract. Special enzymes, antibodies, and an acidic pH add to the effectiveness of these secretions. Tight junctions Basal lamina Epithelial cells tied together by tight junctions and supported by a fibrous basal lamina Figure 19.7 2 Module 19.7: Physical barriers and phagocytes • Phagocytes – Engulf and destroy foreign compounds and pathogens – “First line of cellular defense” against pathogenic invasion – Types 1. Neutrophils (in bloodstream and tissues) – 2. Eosinophils (less abundant) – 3. Phagocytize cellular debris or bacteria Phagocytize foreign compounds and antibody-coated pathogens Macrophages (derived from monocytes) – – Fixed (permanent residents of certain organs) Free (travel throughout body) Types of Phagocytes There are two major classes of macrophages derived from the monocytes of the circulating blood. This collection of phagocytic cells is called the monocyte–macrophage system, or the reticuloendothelial system. 12 μm 8–10 μm Neutrophils are abundant, mobile, and quick to phagocytize cellular debris or invading bacteria. They circulate in the bloodstream and roam through peripheral tissues, especially at sites of injury or infection. Eosinophils, which are less abundant than neutrophils, phagocytize foreign componds or pathogens that have been coated with antibodies. Fixed macrophages are permanent residents of specific tissues and organs and are scattered among connective tissues. They normally do not move within these tissues. Free macrophages travel throughout the body, arriving at the site of an injury by migrating through adjacent tissues or by recruitment from the circulating blood. Figure 19.7 3 Figure 19.7 4 Module 19.7 Review a. Define chemotaxis. b. How does the integumentary system protect the body? c. Identify the types of phagocytes in the body, and differentiate between fixed macrophages and free macrophages. Module 19.8: Immunological surveillance • Immunological surveillance – Constant monitoring of normal tissues by NK cells • • Normal cells are generally ignored by immune system Cancer cells often contain tumor-specific antigens – • NK cells recognize as abnormal and destroy NK cells recognize bacteria, foreign cells, virus-infected cells, and cancer cells Module 19.8: Immunological surveillance • Steps of NK recognition and destruction 1. Presence of unusual plasma membrane activates NK cell • 2. NK cell adheres to target cell Golgi apparatus moves within NK cell near target cell • 3. 4. Produces many secretory vesicles containing perforins Perforins release from NK cell and arrive at target cell Perforins create pores in target cell membrane • Target cell can no longer maintain its internal environment and disintegrates The steps by which NK cells recognize and kill target cells Step 1: If a cell has unusual components in its plasma membrane, an NK cell recognizes that other cell as abnormal. Such recognition activates the NK cell, which then adheres to its target cell. Step 2: The Golgi apparatus moves around the nucleus until the maturing face points directly toward the abnormal cell. A flood of secretory vesicles is then produced at the Golgi apparatus. These vesicles, which contain proteins called perforins, travel through the cytoplasm toward the cell surface. Step 3: The perforins are released at the cell surface by exocytosis and diffuse across the narrow gap separating the NK cell from its target. Step 4: As a result of the pores made of perforin molecules, the target cell can no longer maintain its internal environment, and it quickly disintegrates. Golgi apparatus NK cell Abnormal cell Perforin molecules NK cell Pores produced by the interaction of perforin molecules Abnormal cell Figure 19.8 1 Module 19.8: Immunological surveillance • NK cells also destroy abnormal cells – – Abnormal daughter cells occur during cell division Some abnormal cells become cancer cells The process whereby NK cells detect and destroy abnormal cells resulting from faulty cell division Abnormal cell NK cell identifies and destroys abnormal cell Stem cell Daughter cells Daughter cells Figure 19.8 2 Module 19.8: Immunological surveillance • Immunological escape – Immunological surveillance by NK cells is not perfect • Primary tumors may be surrounded by a capsule and escape detection – • Released malignant cells may be detected and destroyed Daughter tumor cells sometimes do not display tumorspecific antigens or secrete chemicals that kill NK cells – Cancer cells can spread and create secondary tumors The process of immunological escape NK cell The cells within a primary tumor may grow rapidly, and if the tumor has a surrounding capsule, the cells within may not provoke a massive response by NK cells. As malignant tumor cells begin migrating into surrounding tissues, they can be detected and destroyed by NK cells. Sometimes a daughter cell will be produced that either does not display tumor-specific antigens, or that secretes chemicals that destroy NK cells. Such a cell will survive and be free to grow and divide. Once immunological escape has occurred, cancer cells can multiply and spread without interference by NK cells. They can then move throughout the body, establishing potentially lethal secondary tumors. Figure 19.8 3 Module 19.8 Review a. Define immunological surveillance. b. How do NK cells detect cancer cells? c. If NK cells are engaged in immunological surveillance, how do cancer cells spread? Module 19.9: Interferons and the complement system • Interferons – Small proteins released by activated lymphocytes, macrophages, and virus-infected tissues – Trigger antiviral proteins in cytoplasm of nearby cells • Do not prevent entry of viruses but interfere with viral replication – Also stimulate activities of macrophages and NK cells Module 19.9: Interferons and the complement system • Interferons (continued) – Three types 1. Alpha (α) interferons (produced by virus-infected cells) – Attract and stimulate NK cells and give viral resistance 2. Beta (β) interferons (secreted by fibroblasts) – Slow inflammation in damaged area 3. Gamma (γ) interferons (secreted by T cells and NK cells) – Stimulate macrophage activity Three of the types of interferons Alpha (α)-interferons are produced by cells infected with viruses. They attract and stimulate NK cells and enhance resistance to viral infection. Beta (β)-interferons, secreted by fibroblasts, slow inflammation in a damaged area. Gamma ()-interferons, secreted by T cells and NK cells, stimulate macrophage activity. Figure 19.9 1 Module 19.9: Interferons and the complement system • Complement system (complements antibody action) – – 11 plasma proteins that interact to attach to foreign cells Two pathways of activation 1. Classical pathway (most rapid and effective) – – 2. Complement proteins attach to antibody already bound to pathogen Attached protein activates and initiates cascade to activate and attach other complement proteins Alternative pathway – Several complement proteins (notably properdin) activate in plasma after contacting foreign materials Module 19.9: Interferons and the complement system • Complement system effects – Pore formation (formed by many complement proteins) • – Destroys integrity of target cell Enhanced phagocytosis • Attracts phagocytes and makes target cells easier to engulf – – = Opsonization Histamine release • • By mast cells and basophils Increases inflammation and blood flow to region Animation: Immunity: Complement Module 19.9 Review a. Define interferons. b. Briefly explain the role of complement proteins. c. What is the effect of histamine released by complement system activation? Module 19.10: Inflammation and fever • Inflammatory response – Localized tissue response that produces: • • • • Local swelling Redness Heat Pain – Complex process of inflammation can be triggered by: • • Cells that are damaged from any source release prostaglandins, proteins, and potassium ions Foreign proteins or pathogens Module 19.10: Inflammation and fever • The events in inflammation – – Tissue damage causes chemical change in interstitial fluid Mast cell activation • Release of histamine and heparin – – Causes: » Increased blood flow to area » Clot formation » Phagocyte attraction (removes debris and activates specific defenses) Tissue repair • Pathogen removal, clot erosion, scar tissue formation Module 19.10: Inflammation and fever • Fever – Maintenance of body temperature >37.2°C (99°F) – Pyrogens (pyro-, fever or heat, + -gen, substance) • Reset temperature thermostat in hypothalamus – • Raises body temperature Functions – – May inhibit some viruses and bacteria Increases metabolic rate which may accelerate tissue defenses and repair process A summary of the body’s nonspecific defenses Physical Barriers Prevent approach of and deny access to pathogens Secretions Epithelium Duct of eccrine sweat gland Hair Phagocytes Remove debris and pathogens Neutrophil Eosinophil Monocyte Free macrophage Fixed macrophage Immunological Surveillance Destroys abnormal cells Lysed abnormal cell Natural killer cell Interferons Increase resistance of cells to viral infection; slow the spread of disease Interferons released by activated lymphocytes, macrophages, or virus-infected cells Figure 19.10 3 A summary of the body’s nonspecific defenses Complement System Attacks and breaks down the surfaces of cells, bacteria, and viruses; attracts phagocytes; stimulates inflammation Lysed pathogen Complement Inflammatory Response Multiple effects Mast cell • Blood flow increased • Phagocytes activated • Damaged area isolated by clotting reaction • Capillary permeability increased • Complement activated • Regional temperature increased • Specific defenses activated Fever Mobilizes defenses; accelerates repairs; inhibits pathogens Body temperature rises above 37.2°C in response to pyrogens Figure 19.10 3 Module 19.10 Review a. List the body’s nonspecific defenses. b. A rise in the level of interferons in the body suggests what kind of infection? c. What effects do pyrogens have in the body? Section 3: Specific Defenses • Specific defenses – Coordinated activities of T cells and B cells • Produce immunity – • T cells (cell-mediated immunity) – • Specific resistance against potentially dangerous antigens Defend against abnormal cells and pathogens inside cells B cells (antibody-mediated immunity) – Defend against antigens and pathogens in body fluids The various forms of immunity Specific Defenses (Immunity) Respond to threats on an individualized basis Aquired Immunity Innate Immunity Is not present at birth; is acquired against a specific antigen only upon exposure to that antigen or receipt of antibodies from some other source Genetically determined—no prior exposure or antibody production involved Passive Immunity Active Immunity (Immune Response) Produced by transfer of antibodies from another source Develops in response to antigen exposure Naturally acquired passive immunity Artificially acquired passive immunity Naturally acquired active immunity Conferred by transfer of maternal antibodies across placenta or in breast milk Conferred by administration of antibodies to combat infection Develops after exposure to antigens in environment Artificially acquired active immunity Develops after administration of an antigen (usually through vaccination). These activities stimulate an immune response and promote immunity to that particular antigen. Figure 19 Section 3 1 Section 3: Specific Defenses • Properties of immunity 1. Specificity • T cells and B cells bind only one antigen 2. Versatility • Millions of lymphocytes, each sensitive to a different antigen 3. Immunologic memory • Memory cells “remember” antigens for future attacks 4. Tolerance • Ignoring normal “self” tissues Module 19.11: Triggering an immune response • Phagocytes activated by antigen exposure stimulate specific immune responses • To trigger a response, antigens or antigenic fragments must appear in plasma membranes from: – Infecting cells or being “processed” by phagocytes • = Antigen presentation An overview of the immune response Antigens or Antigenic Fragments in Body Fluids Most antigens must either infect cells or be “processed” by phagocytes before specific defenses are activated. The trigger is the appearance of antigens of antigenic fragments in plasma membranes; this is called antigen presentation. Cell-Mediated Immunity Direct Physical and Chemical Attack Phagocytes activated Activated T cells find the pathogens and attack them through phagocytosis or the release of chemical toxins. Specific Defenses Antigen presentation triggers specific defenses, or an immune response. T cells activated Destruction of antigens Communication and feedback Antibody-Mediated Immunity Attack by Circulating Antibodies Activated B cells give rise to cells that produce antibodies. Figure 19.11 1 Module 19.11: Triggering an immune response • Major histocompatibility complex (MHC) proteins – Genetically determined membrane glycoproteins present on all cells • Synthesis controlled by portion of chromosome 6 – = Major histocompatibility complex – Foreign antigens are attached to newly synthesized MHC proteins and appear on cell surface – T cells bind antigen-MHC complex and become activated Module 19.11: Triggering an immune response • MHC proteins – Two classes 1. Class I MHC proteins – – Present on all cells Create complex when cell is infected with bacteria or viruses 2. Class II MHC proteins – – Only in membranes of antigen-presenting cells (APC) » Examples: monocyte–macrophages, dendritic cells Create complex with phagocytized pathogens The events of antigen presentation in an infected body cell Plasma membrane Antigen presentation by Class I MHC proteins is triggered by viral or bacterial infection of a body cell. Viral or bacterial pathogen Transport vesicle The infection results in the appearance of abnormal peptides in the cytoplasm. The abnormal peptides are incorporated into Class I MHC proteins as they are synthesized at the endoplasmic reticulum. The abnormal peptides are displayed by Class I MHC proteins on the plasma membrane. Endoplasmic reticulum After export to the Golgi apparatus, the MHC proteins reach the plasma membrane within transport vesicles. Figure 19.11 2 The events of antigen presentation in a phagocytic cell Plasma membrane Phagocytic APCs engulf the extracellular pathogens. Antigenic fragments are displayed by Class II MHC proteins on the plasma membrane. Antigenic fragments are bound to Class II MHC proteins. Lysosomal action produces antigenic fragments. The endoplasmic reticulum produces Class II MHC proteins. Lysosome Nucleus Endoplasmic reticulum Phagocytic cell Figure 19.11 3 Module 19.11 Review a. Describe antigen presentation. b. What is the major histocompatibility complex (MHC)? c. Where are Class I MHC proteins and Class II MHC proteins found? Module 19.12: T cell activation by infected cells • Inactive T cells must bind the specific MHCantigen complex that the T cell is programmed to detect – = Antigen recognition – Two classes of T cell CD (cluster of differentiation) markers can recognize antigens 1. CD8 markers (on CD8 T cells) – Respond to Class I MHC proteins 2. CD4 markers (on CD4 T cells) – Respond to Class II MHC proteins The structures involved in the process of antigen recognition Inactive T cell Receptor Antigen recognition protein Antigen MHC protein Infected body cell (including APCs) Figure 19.12 1 CD (cluster of differentiation) markers, the membrane proteins involved in antigen recognition CD Markers There are at least 70 different CD markers, but only two associated with T cells are important to our discussion. CD8 Markers CD4 Markers CD8 markers are found on CD8 T cells. CD8 T cells respond to antigens presented by Class I MHC proteins. CD4 markers are found on CD4 T cells. CD4 T cells, discussed further in the next module, respond to antigens presented by Class II MHC proteins. Figure 19.12 2 Module 19.12: T cell activation by infected cells • Steps of CD8 T cell activation 1. Antigen recognition 2. Costimulation • Physical or chemical stimulation of T cell in addition to the Class I MHC molecule 3. T cell activation and cell division • Three CD8 T cells produced 1. 2. 3. Cytotoxic T cells (TC cells) Memory TC cells Suppressor T cells (TS cells) Events in the stimulation and formation of cytotoxic, memory TC, and suppressor T cells Cytotoxic T Cells Seek Out Antigen-Bearing Cells Activation and Cell Division Antigen Recognition Antigen recognition occurs when a CD8 T cell encounters an appropriate antigen on the surface of another cell, bound to a Class I MHC protein. Infected cell Viral or bacterial antigen Antigen recognition results in T cell activation and cell division, producing three different types of CD8 T cells. Inactive CD8 T cell Cytotoxic T cells, also called TC cells, seek out and destroy abnormal and infected cells. Cytotoxic T cells are highly mobile cells that roam throughout injured tissues. When a T C cell encounters its target antigens bound to Class I MHC proteins, it attacks the target cell. Destruction of Target Cells The TC cell destroys the antigenbearing cell. It may use several different mechanisms to kill the target cell. Memory TC Cells Are Produced Memory TC cells are produced by the same cell divisions that produce cytotoxic T cells. Thousands of these cells are produced, but they do not differentiate further the first time the antigen triggers an immune response. Costimulation Suppressor T Cells Provide a Delayed Suppression Costimulation activates CD8 T cell CD8 Class I MHC T cell receptor Antigen Infected cell Memory TC cells (inactive) Suppressor T cells (TS cells) suppress the responses of other T cells and B cells by secreting suppression factors that limit the degree of immune system activation. Suppression does not occur immediately, because suppressor T cell activation takes much longer than the activation of other types of T cells, and so suppressor T cells act only after the initial immune response. Destruction of target cell membrane through the release of perforins Activation of genes within the target cell nucleus that results in the self-destruction of the cell through a process called apoptosis (ap-op-TŌ-sis) Disruption of cell metabolism through the release of lymphotoxin (lim-fō-TOK-sin) Suppressor T cells CD8 T cell Before activation can occur, a T cell must be chemically or physically stimulated by the abnormal target cell. This vital secondary binding process, called costimulation, confirms the activation signal. Costimulation is like the safety on a gun: It helps prevent T cells from mistakenly attacking normal (self) tissues. Figure 19.12 3 – 4 Module 19.12: T cell activation by infected cells • CD8 T cell types 1. Cytotoxic TC cells • Seek out and destroy abnormal and infected cells in injured tissues – – Target cells must have specific Class I MHC proteins Destructive mechanisms » Release of perforins » Activate target cell self-destruction genes for cell death (apoptosis) » Disruption of cell metabolism with lymphotoxin Module 19.12: T cell activation by infected cells • CD8 T cell types (continued) 2. Memory TC cells • • 3. Produced but do not differentiate further during first antigen exposure Upon 2nd exposure to same antigen, memory TC cells become cytotoxic T cells Suppressor T cells • • Secrete suppression factors to limit responses of other T cells and B cells Also act only after first antigen exposure (initial immune response) Module 19.12 Review a. Identify the three major types of T cells activated by Class I MHC proteins. b. Describe CD markers. c. How can the presence of an abnormal antigen in the cytoplasm of a cell initiate an immune response? Module 19.13: CD4 T cell and B cell activation • B cell activation – – Must bind specific antigen Antigens are brought into cell through endocytosis and then placed on surface of cell bound to Class II MHC proteins • – = Sensitization Full activation occurs when activated helper T cell binds to sensitized B cell antigen-Class II MHC complex Activated B cells produce: – • • Memory B cells (inactive until 2nd exposure to antigen) Plasma cells (activated B cells that produce antibodies) Module 19.13: CD4 T cell and B cell activation Animation: B Cell Sensitization The process whereby stimulation of CD4 T cells results in the production of antibodies Antigen Recognition by CD4 T Cell Foreign antigen Antigen Class II MHC Antigens Antigen-presenting cell (APC) Class II MHC B Cell Activation B Cell Sensitization Class II MHC APC Antigen Inactive B cell Inactive CD4 (TH) cell Sensitized B cell Costimulation by cytokines T cell receptor Antibodies Costimulation CD4 protein Division, Differentiation, and Antibody Production Antigens bound to antibody molecules Sensitized B cell Memory B cells (inactive) Memory B cells remain in reserve to deal with subsequent injuries of infections that involve the same antigens. On subsequent exposure, the memory B cells respond by differentiating into plasma cells that secrete antibodies in massive quantities. Helper T cell Sensitized B cell Activated B cell T cell receptor Cell division TH cell The Golgi apparatus is packaging membrane receptors (red) that will be incorporated into the surface of the cell. These receptors are essential to the costimulation of B cells. CD4 T Cell Activation and Cell Division Cytokines Active B cells Active helper T cell Stimulation by cytokines Active helper T cell Memory TH cells (inactive) Plasma cells Cytokines Active helper T cells Active helper T cells secrete cytokines that stimulate both cell-mediated and antibody-mediated immunity. Under stimulation by cytokines from helper T cells, clones of active B cells differentiate into plasma cells, each capable of secreting up to 100 million antibody molecules each hour. Antibody molecules An activated helper T cell Fluorescent LM x 400 Figure 19.13 Module 19.13 Review a. Define sensitization. b. Explain the function of cytokines secreted by helper T cells. c. If you observed a higherthan-normal number of plasma cells in a sample of lymph, would you expect antibody levels in the blood to be higher or lower than normal? Module 19.14: Antibodies • Antibody molecules – Consist of two parallel polypeptide chains • • One pair of heavy chains One pair of light chains – Each pair contains: • Constant segments – • On heavy chains, form the base of antibody molecule Variable segments – – Free tips are antigen binding sites Differences in amino acid sequences produce variability needed for different antibodies The structure of an antibody molecule Antigen binding site Variable segment Antigen binding sites Heavy chain Disulfide bond Light chain Constant segments of light and heavy chains Binding sites that can activate the complement system are covered when the antibody is secreted but become exposed when the antibody binds to an antigen. Binding sites may also be present that attach the secreted antibody to the surfaces of macrophages, basophils, or mast cells. Figure 19.14 1 Module 19.14: Antibodies • Antigen-antibody complex – When a specific antibody binds to corresponding antigenic determinant sites (binding sites) on antigen • Complete antigens – – • Have at least two antigenic determinant sites, one for each binding site on antibody Large antigens (like bacteria) may have millions of antigenic determinant sites Partial antigens (haptens) – – Do not have enough binding sites to bind antibody Antibody may bind to hapten and carrier molecule » Response will then be against body cell carrier molecule as well The formation of an antigen-antibody complex Carrier molecule Antibodies bind not to the entire antigen, but to specific portions of its exposed surface—regions called antigenic determinant sites. Antibody Antigen-antibody complex A complete antigen is an antigen with at least two antigenic determinant sites, one for each of the antigen binding sites on an antibody molecule. Partial antigen (hapten) Antibody Partial antigens, or haptens, do not ordinarily cause B cell activation. However, they may become attached to carrier molecules, forming combinations that can function as complete antigens. The antibodies produced will attack both the hapten and the carrier molecule. If the carrier molecule is normally present in the tissues, the antibodies may begin attacking and destroying normal cells. This is the basis for several drug reactions, including allergies to penicillin. Figure 19.14 2 A bacterium with numerous antigenic determinant sites, to which antibodies bind Antigen Antigenic determinant sites Antibodies Figure 19.14 3 Module 19.14: Antibodies • Five different classes of antibodies (immunoglobulins or Igs) – 1. Differences in heavy-chain constant segments IgG (80% of all antibodies) • 2. Against many viruses, bacteria, and bacterial toxins IgE • 3. Attaches to basophil and mast cell surfaces IgD • • On B cell surface where it binds antigens in extracellular fluid Plays role in B cell sensitization Module 19.14: Antibodies • Five different classes of antibodies (continued) 4. IgM • First class of antibody secreted after antigen encountered – • Production declines as IgG production increases Anti-A and anti-B antibodies are examples 5. IgA • • Found primarily in glandular secretions such as mucus, tears, saliva, and semen Attack before pathogens gain internal access The five classes of antibodies, or immunoglobulins (Igs) Classes of Antibodies IgG antibodies account for 80 percent of all antibodies. IgG antibodies are responsible for resistance against many viruses, bacteria, and baterial toxins. IgE attaches as an individual molecule to the exposed surfaces of basophils and mast cells. IgD is an individual molecule on the surfaces of B cells, where it can bind antigens in the extracellular fluid. This binding can play a role in the sensitization of the B cell involved. IgM is the first class of antibody secreted after an antigen is encountered. IgM concentration declines as IgG production accelerates. The anti-A and anti-B antibodies responsible for the agglutination of incompatible blood types are IgM antibodies. IgA is found primarily in glandular secretions such as mucus, tears, saliva, and semen. These antibodies attack pathogens before they gain access to internal tissues. Figure 19.14 4 Module 19.14: Antibodies • Primary response – Antibody-mediated response to initial antigen exposure – Is delayed due to time to activate specific B cells • Antibody titer (level of antibody activity) peaks 1–2 weeks after initial exposure • Secondary response – From memory B cells for specific antigen – Antibody titers increase more rapidly and reach higher concentrations The time course and amount of antibody production for an initial exposure to an antigen and for a subsequent exposure to the same antigen Antibody concentration in plasma Primary response Secondary response IgG IgG IgM Time (weeks) A primary antibody response, which occurs after an initial exposure to an antigen IgM Time (weeks) A secondary antibody response, which occurs after the eliciting antigen has been encountered before Figure 19.14 5 – 6 Module 19.14 Review b. Describe the structure of an antibody. c. Which would be more affected by a lack of memory B cells and memory T cells: the primary response or the secondary response? Module 19.15: Antibody defenses • Antibody defenses – Neutralization • Antibodies occupy binding sites on viruses and bacterial toxins preventing them from affecting body cells – Prevention of pathogen adhesion • IgA antibodies in glandular secretions cover bacteria or viruses preventing adhesion and infection of body cells – Activation of complement • After antigen binding, complement also can bind to the antibody, accelerating the complement cascade Module 19.15: Antibody defenses • Antibody defenses (continued) – Stimulation of inflammation • Basophil and mast cell stimulation to release chemicals – Opsonization • Coating of pathogen with antibodies allows phagocytes to bind easier – Attraction of phagocytes • Attached antibodies attract eosinophils, neutrophils, and macrophages Module 19.15: Antibody defenses • Antibody defenses (continued) – Precipitation and agglutination • The linking of multiple pathogens by antibodies creating an immune complex – When target antigen is on cell surface (like RBC) or virus » = Agglutination Module 19.15 Review a. Define opsonization. b. List the ways that antigen-antibody complexes can destroy target antigens. c. Which cells are involved in the inflammatory response? CLINICAL MODULE 19.16: Allergies • Allergies – Inappropriate or excessive immune responses to antigens (allergens) Sensitization and activation of B cells to allergens leads to production of large quantities of IgE Reactions may be: – – • Localized (inflammation, pain, itching at contact area) – • Example: hypersensitivity reaction of allergic rhinitis (hay fever and other environmental allergies) Systemic (allergen in bloodstream, symptoms widespread) – Example: anaphylaxis (circulating allergen causing widespread vasodilation through mast cell activation) The events that result in an allergy First Exposure Allergen fragment Allergens TH cell activation Macrophage B cell sensitization and activation Plasma cell IgE antibodies Subsequent Exposure IgE Allergen Massive stimulation of mast cells and basophils Granules Sensitization of mast cells and basophils Release of histamines, leukotrienes, and other chemicals that cause pain and inflammation Localized Allergic Reactions Systemic Allergic Reactions If the allergen is at the body surface: localized inflammation, pain, and itching Example: allergic rhinitis If the allergen is in the bloodstream: itching, swelling, and difficulty breathing (due to airway constriction) Example: anaphylaxis Figure 19.16 CLINICAL MODULE 19.16 Review a. Define allergy and allergen. b. What is anaphylaxis? c. Which chemicals do mast cells and basophils release when stimulated in an allergic reaction? Module 19.17: Integrated defense responses • Exposure to antigens triggers both specific and nonspecific defenses – Neither branch works alone – Many times, activities from each branch will enhance the other • Responses will vary based on antigen type The relationships among the elements of the nonspecific defenses and the specific defenses (immune response) Antigens Trigger Nonspecific Defenses Complement system NK cells Macrophages Specific Defenses (Immune Response) Antigen presentation by APCs Activation by Class I MHC Proteins Activation by Class II MHC Proteins Antigen and Class I MHC Protein Antigen and Class II MHC Protein Indicates that the cell is infected or otherwise abnormal CD8 T cells Cytotoxic T Cells Memory Tc Cells Suppressor T Cells Attack and destroy infected and abnormal cells displaying antigen Await reappearance of the antigen Control of moderate immune response by T cells and B cells Helper T Cells Memory TH Cells Stimulate immune response by T cells and B cells Await reappearance of the antigen Production of memory B cells Production of plasma cells Direct physical and chemical attack Attack by circulating proteins CD4 T cells Activation of B cells Direct physical and chemical attack Indicates the presence of pathogens, toxins, or foreign proteins Destruction of Antigens Secretion of antibodies Figure 19.17 1 An overview of the course of events involved in overcoming a bacterial infection BACTERIA Phagocytosis by macrophages and APCs Antigen presentation Activation of cytotoxic T cells Activation of helper T cells Activation of B cells Destruction of bacteria by cell lysis Antibody production by plasma cells Opsonization and phagocyte attraction Formation of antigen-antibody complexes Figure 19.17 2 An overview of the course of events involved in overcoming a viral infection VIRUSES Release of interferons Increased resistance to viral infection and spread Infection of tissue cells Infection of or uptake by APCs Appearance of antigen in plasma membrane Antigen presentation Stimulation of NK cells Activation of cytotoxic T cells Destruction of virus-infected cells Destruction of viruses or prevention of virus entry into cells Activation of helper T cells Activation of B cells Antibody production by plasma cells Figure 19.17 3 Module 19.17 Review a. Identify the type of T cell whose plasma membrane contains CD8 markers and the type with CD4 markers. b. Which cells can be activated by direct contact with virus-infected cells? c. Which cells produce antibodies? CLINICAL MODULE 19.18: Immune disorders • Excessive or misdirected immune responses – Autoimmune disorders • Activated B cells make antibodies against “self” antigens or body cells and tissues – • = Autoantibodies Likely arise from body cell antigens being too similar to specific foreign antigen CLINICAL MODULE 19.18: Immune disorders • Excessive or misdirected immune responses (continued) – Autoimmune disorders (continued) • Examples: – – – – Thyroiditis (inflammation resulting from autoantibodies attacking thyroglobin) Rheumatoid arthritis (autoantibodies attack connective tissues around joints) Insulin-dependent diabetes mellitus (autoantibodies attack pancreatic islet cells) Multiple sclerosis (autoantibodies attack myelin) CLINICAL MODULE 19.18: Immune disorders • Excessive or misdirected immune responses (continued) – Graft rejection • • Recipient cytotoxic T cells become activated and attack MHC proteins of donated material Reduction in immune response sensitivity (immunosuppression) by drugs can increase transplant success – Example: cyclosporin A (CsA) inhibits helper T cells – Allergies CLINICAL MODULE 19.18: Immune disorders • Inadequate immune responses – Immunodeficiency diseases • Result from: 1. 2. 3. Problems with lymphoid organ and tissue development An infection with a virus that depresses immune function » Example: Acquired immune deficiency syndrome caused by human immunodeficiency virus (HIV) that infects CD4 T cells Treatment with, or exposure to, immunosuppressive agents like radiation or drugs CLINICAL MODULE 19.18: Immune disorders • Inadequate immune responses (continued) – Age-related reductions in immune activity • T cells become less responsive – • B cell response also less due to number of helper T cells reduced – • Fewer cytotoxic T cells respond » Possibly related to thymus involution Vaccinations highly recommended NK cells reduced and immune surveillance compromised – Increased incidence of cancer CLINICAL MODULE 19.18 Review a. Define autoimmune disorders. b. Describe immunosuppression. c. Provide a plausible explanation for the increased incidence of cancer in the elderly.