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Biology Sylvia S. Mader Michael Windelspecht Chapter 33 The Lymphatic and Immune Systems Lecture Outline See separate FlexArt PowerPoint slides for all figures and tables pre-inserted into PowerPoint without notes. Copyright © McGraw-Hill Education. Permission required for reproduction or display. 1 Outline • • • • • 33.1 Evolution of Immune Systems 33.2 The Lymphatic System 33.3 Innate Immune Defenses 33.4 Adaptive Immune Defenses 33.5 Immune System Disorders and Adverse Reactions 2 Foods and Anaphylactic Shock • Seemingly harmless items or foods may pose a threat to some people. – Upon contact with these items, individuals may develop a life-threatening condition known as anaphylactic shock, which if not treated, can result in loss of consciousness and even death. – These strong allergic reactions illustrate the power of the immune system, harmful in some, but not most cases. • Our immune system protects us against viruses, bacteria, fungi, parasites, and environmental toxins. 33.1 Evolution of Immune Systems • Immune System – Protects from bacterial and viral pathogens, toxins, even cancerous cells • Immunity in Cellular Slime Molds – Composed of many individual amoeboid cells living in unison as a “slug” – Sentinel cells – circulate throughout the slug and engulf bacteria and toxins • Eventually remove themselves from the body of the slug • Immunity in Drosophila – Contain cellular receptors capable of recognizing common components of pathogenic microbes • • • • Pathogen-associated molecular patterns (PAMPs) Trigger an immune reaction Receptors for PAMPs found in diverse organisms. May have been one of earliest cellular receptors that evolved for pathogen recognition • Both immunities illustrate a type of defense known as innate immunity. 4 Evolution of Immune Systems • The Rise of Adaptive Immunity – Innate immunity • Recognizes microbial invaders quickly, but shows no signs of an increased response upon repeated exposure – Adaptive immunity • Results in the production of receptors on surface of white blood cells that bind to a foreign antigen – Stimulates lymphocytes to increase in number, resulting in an increased response to specific antigens and immunological memory – Originally developed in an ancestor that gave rise to the jawed vertebrates » Precise mechanism causing adaptive immunity in ancestor not known » Likely involved insertion of transposon or “jumping gene” into a gene coding for an antigen receptor similar to receptor for PAMPs » Gene rearrangement is involved 5 33.2 The Lymphatic System • Lymphatic System – Consists of lymphatic vessels and the lymphatic organs – Three main homeostatic functions: • Lymphatic capillaries take up and return excess fluid to the bloodstream. • Lacteals absorb fats in the form of lipoproteins and transport them to the bloodstream. • Lymphatic system produces, maintains, and distributes lymphocytes. – Lymphocytes resist infection and disease by responding to » Invading pathogens such as bacteria or viruses » Abnormal body cells such as cancer cells » Foreign proteins such as toxins 6 The Lymphatic System • Lymphatic Vessels – One-way system that begins with lymphatic capillaries • Tiny, closed-ended vessels found throughout the body • Take up excess tissue fluid (interstitial) • Lymph – fluid located within lymphatic capillaries – Lymph flows one way » From a capillary to ever-larger lymphatic vessels » Finally to a lymphatic duct, which returns lymph to a subclavian vein » Backflow is prevented by one-way valves 7 Lymphatic System Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Tonsils: aggregates of lymphoid tissue that respond to pathogens in the pharynx Right lymphatic duct: empties lymph into the right subclavian vein Left subclavian vein: transports blood away from the left arm and the left ventral chest wall toward the heart Red bone marrow: site for the origin of all types of blood cells Right subclavian vein: transports blood away from the right arm and the right ventral chest wall toward the h eart Thymus: lymphoid organ where T cells mature Axillary lymph nodes: located in the underarm region Thoracic duct: empties lymph into the left subclavian vein Spleen: resident T cells and B cells respond to the presence of antigen in blood tissue fluid lymphatic capillary Inguinal lymph nodes: located in the groin region tissue cell blood capillary valve 8 The Lymphatic System • Lymphoid (Lymphatic) Organs – Red Bone Marrow • Site of origin for all types of blood cells • Site of maturation for B cells – Thymus Gland • Located between the trachea and the sternum in the upper thoracic cavity • Site of maturation for T cells – T cells migrate to thymus from red bone marrow. • T cells learn to recognize combinations of self and foreign molecules. – Mature T cells in bloodstream encounter foreign molecules or 9 cells and proliferate and become activated. The Lymphatic System • Lymphoid Organs (cont’d) – Lymph Nodes • The capsule surrounds two distinct regions, cortex and medulla. • Macrophages concentrated in medulla cleanse lymph. • Macrophages “present” debris or pathogens to T cells in lymph node. • B and T cells in lymph nodes help destroy pathogens. • Lymph nodes are named for their location. 10 The Lymphatic System • Lymphoid Organs (cont’d): – Spleen • It is located in upper left side of the abdominal cavity just posterior to the stomach. • Macrophages remove old and defective blood cells. • Red pulp filters and cleanses blood. – Tonsils • Patches of lymphatic tissue are located in the pharynx. • They prevent entry of pathogens through the nose and mouth. – Peyer patches • Located in intestinal wall —Vermiform appendix • Attached to cecum 11 The Lymphatic Organs 12 33.3 Innate Immune Defenses • Immunity – The capability of removing or killing foreign substances, pathogens, and cancer cells from the body. • Innate Defenses – – – – Do not distinguish one type of threat from another Are fully functional without previous exposure to invaders Occur immediately or shortly after infection occurs Types of innate immune defenses: • • • • Physical and chemical barriers to entry Inflammatory response Phagocytes and natural killer cells Protective proteins such as complement and interferons 13 Overview of Innate Immune Defenses Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Innate defenses Barriers to entry skin and mucous membranes Protective proteins Phagocytes and natural killer cells Inflammatory response dendritic cell pathogens antimicrobial molecules macrophage cytokines neutrophil monocyte complement proteins and interferons in plasma natural killer cells 14 Innate Immune Defenses • Physical and Chemical Barriers – Skin and mucous membranes lining the respiratory, digestive, and urinary tracts – Cilia lining the respiratory tract sweep mucus and particles into the throat – Antimicrobial molecules in secretions of oil glands, mucous membranes, and the stomach • Lysozyme, in mucus, an enzyme that lyses bacteria • Acidic pH of stomach kills microbes 15 Innate Immune Defenses • Inflammatory Response – Localized tissue response to injury – Damaged cells and mast cells release histamine which causes capillaries to dilate and become more permeable. – Enlarged capillaries cause skin to redden. – Swelling stimulates free nerve endings, causing pain. – Neutrophils and monocytes migrate to the site of injury. • Monocytes differentiate into macrophages. • Macrophages release colony-stimulating factors, stimulating production and release of white blood cells. • Neutrophils, dendritic cells, and macrophages phagocytose pathogens. – Acute-phase proteins, released by the liver in response to inflammatory mediators, make it easier for phagocytes to 16 engulf invaders. Inflammatory Response Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Skin 2. Resident macrophages and dendritic cells phagocytize pathogens and release cytokines, which stimulate the inflammatory response. Tissue mast cell macrophage neutrophil cytokines monocyte histamine 1. Injured tissue cells and mast cells release histamine and other chemical mediators, which cause capillaries to dilate and increase blood flow. injured tissue pathogen dendritic cell blood clot Capillary 4. Blood clotting walls off capillary and prevents blood loss. 3. Neutrophils and monocytes (become macrophages) squeeze through the capillary wall and phagocytize pathogens. 17 Macrophage Engulfing Bacteria Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. cytoplasmic extension from macrophage bacteria SEM 1,075× © Dennis Kunkel/Phototake 18 Innate Immune Defenses • Fever – Maintenance of an elevated body temperature – In some instances, a fever may be beneficial. • It’s the body’s way of informing us that something is wrong. • Certain bacteria or viruses may not survive as well at higher temperatures. • Some immune mechanisms work better at higher body temperatures. 19 Innate Immune Defenses • Phagocytes and Natural Killer (NK) Cells – Neutrophils • Leave the bloodstream and phagocytize bacteria • Release antimicrobial peptides and bacteria-digesting enzymes • Generate free radicals which kill engulfed bacteria – Eosinophils • Phagocytic cells • Also mount an attack against parasites that are too large to be consumed via phagocytosis – Macrophages and dendritic cells • Engulf and destroy pathogens • Stimulate T cells in lymph nodes, which initiate adaptive immune responses – Natural killer (NK) cells • Large, granular lymphocytes • Kill virus-infected cells and cancer cells by cell-to-cell contact • Virus-infected cells, lacking a self molecule (MHC-1) may be recognized and killed. • Numbers don’t increase after stimulation, like lymphocytes. 20 Innate Immune Defenses • Protective Proteins – Complement • A collection of plasma proteins that “complement” certain immune responses • Must be activated by pathogens • Helps to destroy pathogens in three ways – Enhanced inflammation – Bind to pathogens coated with antibodies to ensure phagocytosis – Form a membrane attack complex that produces holes in the surface of some bacteria and viruses – Fluids entering bacterial cell or virus cause bursting. 21 Innate Immune Defenses • Protective Proteins – Interferons • Cytokines that affect the behavior of other cells • Produced by virus-infected cells • Bind to receptors of non-infected cells – Causes them to produce substances that interfere with viral replication • Used to treat certain cancers and viral infections, such as hepatitis C 22 Action of the Complement System Against a Bacterium Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. complement proteins membrane attack complex Complement proteins form a donutlike ring, called a membrane attack complex, in the plasma membrane. Fluid and salts enter susceptible cells through the membrane attack complex. fluids and salts Lysis of the cell results in its destruction. 23 33.4 Adaptive Immune Defenses • Also known as acquired immunity – Because adaptive defenses are not inborn • Take 5–7 days to become activated but last for years • Involve three steps – Recognition of an antigen – Response to the antigen – Memory of the antigen • An antigen is any substance that stimulates the immune system to react. 24 Adaptive Immune Defenses • Lymphocytes – Are capable of “recognizing” and binding to specific antigens – Have antigen receptors on their plasma membrane – The receptor protein’s shape allows it to combine with a specific antigen. – Pathogens, cancer cells, and transplanted tissues and organs bear antigens the immune system recognizes as nonself. 25 Adaptive Immune Defenses • Adaptive immunity is primarily the result of – B cells • B-cell receptors bind directly to antigens. • B cells give rise to plasma cells. • Plasma cells produce and secrete antibodies. – T cells • T-cell receptors bind to antigens presented by antigen-presenting cells. • Helper T cells regulate specific immunity. • Cytotoxic T cells kill virus-infected cells and cancer cells. 26 Overview of Adaptive Immune Defenses Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. memory B cell B cell antibody Antibodymediated immunity plasma cell BCR APC antigen TCR memory TH cell Adaptive defenses activated TH cell TH cell activated TC cell Cellmediated immunity antigen memory TC cell virus-infected cell TC cell TCR 27 Adaptive Immune Defenses • Antibody-Mediated Immunity • Clonal selection theory: – The antigen selects which lymphocyte will • Undergo clonal expansion • Produce more lymphocytes – Most of the cloned lymphocytes become plasma cells that produce specific antibodies. – Some of the cloned lymphocytes become memory B cells. • If the same antigen enters the system again, memory B cells quickly divide and give rise to more lymphocytes capable of quickly producing antibodies. 28 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Clonal Selection Theory as It Applies to B Cells B-cell receptor (BCR) B cell antigens cytokines from T cells Activation 1 Clonal expansion 3 2 antibody Memory B cells Plasma cells Apoptosis Apoptosis 29 Structure of Antibodies • Antibodies (immunoglobulins) • Consist of two heavy and two light polypeptide chains in a Y shape • Both types of chains have variable and constant regions. • Neutralize pathogens by coating their antigens, preventing them from binding to receptors on cells • Attract white blood cells that move in for the kill • Immune complexes may be engulfed by neutrophils or macrophages or may activate the complement system. • Class is determined by the structure of the antibody’s constant region. • • • • IgG – Main type of antibody in circulation IgA – Main type secreted in milk, tears, and saliva IgM – The first antibodies produced; also indicate infection IgE – Bound to receptors on eosinophils and mast cells in tissues 30 Structure of Antibodies Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. antigen antigen-binding sites antigen binds to binding site light chain C C heavy chain C = constant V = variable 31 Adaptive Immune Defenses • Monoclonal Antibodies • Antibodies against a specific antigen • All of the same type • In vitro (outside the body in the laboratory) production of monoclonal antibodies – B cells are removed from an animal and exposed to a particular antigen. – The resulting plasma cells are fused with myeloma cells (malignant plasma cells that live and divide indefinitely). – The fused cells (hybridomas) secrete the monoclonal antibody. 32 Adaptive Immune Defenses • Medical Uses for Monoclonal Antibodies – To make quick and certain diagnoses of various conditions – Used to signify pregnancy by detecting a particular hormone (hCG) in the urine of a pregnant woman – Promise as potential drugs to help fight disease • RSV, a common virus that causes serious respiratory tract infections in very young children, is being treated with a monoclonal antibody drug. • Since the first therapeutic monoclonal antibody was approved by the FDA in 1986, over 20 are now available and hundreds more are being tested. – Adalimumab (Humira) binds to and inhibits tumor necrosis factor and is used to treat several autoimmune diseases. 33 Adaptive Immune Defenses • T-Cells and Cell-Mediated Immunity – T-cells receptor (TCR) recognizes antigens displayed by antigen-presenting cells (APCs). • Antigen is first linked to a major histocompatibility complex (MHC) protein in the plasma membrane of the APC. – After the TCR binds to the antigen, the T cell undergoes clonal expansion. – After the immune response has been successful, most of the T cells undergo apoptosis. – Some T cells remain as memory T cells. 34 Adaptive Immune Defenses • Types of T Cells • Cytotoxic T Cells – Destroy antigen-bearing cells – Contain storage vacuoles containing perforins and granzymes • Helper T Cells – Activate other T cells and B cells – Regulate immunity by secreting cytokines (signaling molecules) • Memory T cells – Persist after a successful immune response – Provide protection if the same antigen is encountered again 35 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Clonal Selection Theory as It Applies to T Cells T-cell receptor (TCR) TC cell Binding to MHC-I + antigen Dendritic cell 1 cytokines MHC-I viral antigen Cytotoxic T cell virus-infected cell Activation and clonal expansion 2 Death by apoptosis 3 Apoptosis 4 Memory T cell 36 Cell-Mediated Immunity Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. cytotoxic T cell antigen fragment MHC-I target cell (virus-infected or cancer cell) cytotoxic T cell Cytotoxic T cell vesicle granzyme perforin Perforin forms hole in target cell. Target cell a. target cell Granzymes enter through the hole and cause target cell to undergo apoptosis. b. SEM 1,250X (b): © Steve Gschmeissner/Photo Researchers, Inc. 37 Adaptive Immune Defenses • HIV Infections – The primary host for HIV is a helper T cell. • The host (helper T cell) produces viruses that go on to destroy more helper T cells. • At first an individual is able to stay ahead of the virus by producing enough helper T cells. • Gradually, the HIV count rises and the helper Tcell count drops. • Affected patients become susceptible to opportunistic infections. – Characteristic of an AIDS diagnosis 38 AIDS and Opportunistic Infections 39 Progression of HIV Infection During Its Three Stages Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 107 Category A: Acute Phase Category B: Chronic Phase Category C: AIDS HIV count in blood peaks. 1000 106 900 Helper T-cell count crashes and then gradually declines. 800 700 105 Person now has AIDS. 600 500 104 HIV count in blood rises dramatically. 400 HIV per ml Plasma Helper T-cell Count in Blood (cells/mm3) 1100 300 103 HIV count crashes due to immune system activity. 200 100 helper T cell HIV 102 0 1 1 – 2 months 2 3 4 5 6 7 8 9 10 11 Years Since Infection 40 Adaptive Immune Defenses • Cytokines as Therapeutic Agents – Cytokine • Soluble protein that acts as a signaling molecule • Cytokines called interleukins are produced by white blood cells. – Stimulate other white blood cells – Interleukins might awaken the immune system and lead to the destruction of the cancer. » IL-2 is being used to treat some forms of melanoma and kidney cancer. • Tumor necrosis factor (TNF) is a cytokine produced by macrophages. – Promotes the inflammatory response – Causes the death of cancer cells • Anti-TNF monoclonal antibodies are being developed as 41 potential treatments for inflammatory diseases. Adaptive Immune Defenses • Active Immunity – It occurs when an individual produces his/her own immune response against an antigen. – Immunization • It involves use of vaccines, substances that contain an antigen to which the immune system responds. • Pathogens or pathogen products treated to remove virulence are introduced to the patient via a vaccine. • It is dependent upon memory B cells and memory T cells capable of responding to lower doses of 42 antigen. Antibody Titers 43 Adaptive Immune Defenses • Passive Immunity – Occurs when an individual receives another person’s antibodies (immunoglobulins) or immune cells to combat a disease • Short-lived • Newborns are often passively immune since antibodies have crossed the placenta from the mother’s blood. – Breast-feeding prolongs natural, passive immunity. – May be used to prevent illness in a patient who has been exposed to certain infectious agents or toxins. ―Examples: Rabies, tetanus, botulism, snake bites – Cells of the immune system may be transferred to a patient in the case of a bone marrow transplant. 44 Passive Immunity Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © Digital Vision/Getty Images 45 33.5 Immune System Disorders and Adverse Reactions • Immunodeficiencies – They result in some degree of increased susceptibility to infection. – Primary immunodeficiencies are genetic, passed from parents to offspring. – Severe Combined Immune Deficiency (SCID) • Neither T nor B cells function • By about 3 months of age, when most of the antibodies an infant has obtained from the mother have been degraded, untreated SCID infants die. – Possible treatments include a bone marrow transplant. – X-Linked Agammaglobulinemia (XLA) • Caused by mutation in a gene on the X chromosome necessary for proper development of B cells 46 Immune System Disorders and Adverse Reactions • Allergies – Hypersensitivities to substances that ordinarily would not harm the body • Immediate allergic response – IgE antibodies – Causes release of histamine, which brings about the symptoms of the allergy – Individuals with asthma have difficulty breathing and wheezing. – Anaphylactic shock – occurs after the allergen has entered the bloodstream. » Life-threatening • Delayed allergic response – Memory T cells regulated by influence of cytokines 47 An Allergic Reaction Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. allergen histamine and other chemicals B cell IgE antibodies plasma cell IgE receptor mast cell © Damien Lovegrove/SPL/Photo Researchers, Inc. 48 Immune System Disorders and Adverse Reactions • Autoimmune Disease – Cytotoxic T cells or antibodies mistakenly attack the body’s own cells or molecules. – There appears to be a genetic tendency to develop autoimmune diseases. – Immune system fails to distinguish between self and nonself antigens. – Certain antigens of microbial pathogens can resemble host antigens (molecular mimicry). – Examples of autoimmune diseases: • Rheumatoid arthritis (inflammation in synovial joints) • Myasthenia gravis • Systemic lupus erythematosus (lupus) 50 Rheumatoid Arthritis 51 Systemic Lupus 52 Immune System Disorders and Adverse Reactions • Transplant Rejection – Antibodies and cytotoxic T cells cause destruction of transplanted foreign tissues in the body. • Immune system is correctly distinguishing between self and nonself antigens. • Xenotransplantation – It is the transplantation of animal tissues and organs into humans. • Potential way to solve human donor organ shortage • Genetic engineering makes animal organs less antigenic by removing MHC antigens. • Tissue Engineering – Production of human organs from stem cells may 53 eliminate rejection problem.