Chapter 22: The Lymphatic System and Immunity

BIO 211 Lecture Instructor: Dr. Gollwitzer

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• Today in class we will discuss: – Body defenses and the components, mechanisms and functions of: • Nonspecific defenses – Physical Barriers – Phagocytes – Immunological surveillance – Interferons – Complement system – Inflammatory response – Fever • Specific defenses – Immune response » T cells » B cells » Types of immunity » Properties of immunity

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Immune System

• A physiological system that includes several organ systems – Primary = lymphatic system – Plus components of integumentary, cardiovascular, respiratory, digestive, and other anatomic systems – e.g., interactions between lymphocytes and Langerhans cells of skin important in defenses against skin infections

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Immune System

• • • Specialized sensory “megaorgan” Enables us to detect things that are foreign or cannot be seen with the naked eye (microbes, allergens…) Allows us to fight (defend against) pathogenic microbes while normal flora left alone

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Body Defenses

• • Physical and chemical barriers that prevent or slow entry/progress of infectious organisms 2 Types of defenses – Nonspecific defenses – Specific defenses

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Body Defenses

• Nonspecific defenses – NOT unique – Against any invading agent – Many different threats elicit same response – Present from birth (innate) – e.g., physical barriers, phagocytic cells, immunological surveillance, interferons, complement, inflammation, fever

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Body Defenses

• Specific defenses (AKA: Adaptive defenses) – Protect against specific threats (e.g., one type of bacterium or virus) – Develop after birth as a result of exposure – Depend on activities of lymphocytes – Result in specific resistance or immunity = ability to resist infection and disease through activation of specific defenses

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Figure 22-11

Nonspecific Defenses

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Nonspecific Defenses: Physical Barriers

• Keep pathogens from entering body – Epithelial linings • Skin surface layers with keratin and desmosomes  water resistant, impregnable wall – Epithelial accessory structures (e.g., hair, cilia) • • Protect against mechanical abrasion Prevent hazardous contact with skin – Epithelial secretions • • Mechanical barrier, e.g., mucous in respiratory tract, stomach Antibacterial, e.g. sebum (oily secretion from sebaceous gland), lysozyme enzyme in tears • Flushing action (tears, urine, mucus in respiratory tract)

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Nonspecific Defenses: Phagocytes

• • • • Perform “police,” “first-responder,” “janitorial” services in peripheral tissues First line of cellular defense – Roving cells on look-out for foreign invaders – Remove pathogens and cell debris (cell eaters) – Often attack and remove invaders before lymphocytes aware of them Attracted to chemicals (chemotaxis) – Chemicals released: • From damaged body cells • By pathogens into surrounding fluids, e.g., cytokines Move out of bloodstream by squeezing between endothelial cells (diapedesis)

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Nonspecific Defenses: Phagocytes

• • • Must be activated Respond to invasion by foreign compounds or pathogens in several ways – Engulf pathogen or foreign object and destroy with lysozymes – Bind or remove pathogen from interstitial fluid but not able to destroy without assistance from other cells – Destroy pathogen by releasing: • TNF (tumor necrosis factor), NO (nitric oxide), or H 2 O 2 peroxide) (hydrogen Brief lifespan for active phagocytes (30 min – 1 hr)

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Nonspecific Defenses: Phagocytes

• 2 Classes of phagocytes – Microphages (“small eaters”) – Macrophages (“big eaters”)

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• • •

Nonspecific Defenses: Microphages

Circulating neutrophils and eosinophils that leave bloodstream and enter injured or infected tissues Neutrophils – Abundant, quick, mobile – Engulf pathogens or cellular debris Eosinophils – Much rarer cells – Target foreign compounds or pathogens (antigens) coated with antibodies, e.g., allergens

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Nonspecific Defenses: Macrophages

• • • Large, actively phagocytic cells derived from monocytes Spend very little time in blood 2 Types – Fixed/resident macrophages • Permanent cells in certain tissues, e.g., – Microglia in CNS, Kupffer cells in liver, alveolar macrophages in lungs – Free macrophages • Mobile; travel throughout body through tissues or blood

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Nonspecific Defenses: Immunological Surveillance

• • Immune system programmed to ignore cells of own body (e.g., intestinal bacteria) unless they become abnormal Normal tissues constantly monitored by natural killer (NK) cells looking for: – Abnormal cells (cancer cells with tumor-specific antigens) – Cells infected with viruses

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Nonspecific Defenses: Immunological Surveillance

• NK cells – Lymphocyte “spy system” in peripheral tissue – Recognize/respond to wide variety of proteins on cell membranes • vs. T cells or B cells that can be activated only by exposure to a specific antigen at a specific site on a cell membrane – Respond immediately on contact with abnormal cell • Much more rapidly than T or B cells whose activation is complex and time consuming

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Nonspecific Defenses: Immunological Surveillance

• NK cell – Attaches to abnormal cell – Producess protein (perforin) that creates large pores in cell membrane  lyses cell – Especially important opponent for cancer cells

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Fig. 22-12

How NK Cells Kill Cellular Targets

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Nonspecific Defenses: Interferons

• • • Small protein chemical messengers (type of cytokine) produced by: – Macrophages – Cells infected with viruses – Activated lymphocytes Interfere with spread of disease – Coordinate local defenses against viral infection – Stimulate macrophages and NK cells – Signal WBCs and lymphatic system (“tattle tales”) Increase resistance of cells to viral infections – Trigger production of antiviral proteins that inhibit replication within cells

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Nonspecific Defenses: Complement System

• • S ystem of 11 blood proteins that interact in a chain reaction (cascade) Assists (complements, supplements) antibodies in destroying pathogens – Begins when first complement protein (C1) binds to antibody (Ab) attached to its specific antigen – Ends with pore formation and lysis of target cell membrane

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Figure 22–12, 7 th edition

Complement System

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Nonspecific Defenses: Complement System

• • • Attracts phagocytes to injury or infection (via chemotaxis) Enhances phagocytosis of antibody-antigen (pathogen) complex Stimulates inflammation – Enhances histamine release by mast cells (basophils in tissues) • Increases local inflammation and accelerates blood flow

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Nonspecific Defenses: Inflammation

• • Local tissue response to injury or infection Stimulus – Anything that changes cell and alters chemical composition of interstitial fluid – Anything that kills cells, damages CT fibers, or injures tissue – e.g., impact, abrasion, chemical irritation, infection by pathogens, extreme temperatures

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Nonspecific Defenses: Inflammation

• • Stimulus causes mast cells  – Histamine – Heparin  – Local vasodilation  redness and heat increased blood flow  – Increased capillary permeability  into injured tissue  local swelling blood proteins – Stimulation of pain receptors  pain

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Nonspecific Defenses: Inflammation

• Inflammatory response – Walls off region, slows spread of injury/ pathogens from site – Combats infection by activating: • Phagocytes • Complement • Specific defenses – Performs temporary repair and prevents access of other pathogens – Mobilizes regeneration (permanent repair)

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Figure 22-15 26

Nonspecific Defenses: Fever

• • • High body temperature (>99 F) Caused by pyrogens – = Proteins released by macrophages that can raise body temperature – Affect temperature-regulating center in hypothalamus Stimuli for pyrogens – Pathogens – Bacterial toxins – Antigen-antibody complexes • Act directly as pyrogens • Stimulate release of pyrogens by macrophages

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Nonspecific Defenses: Fever

• Beneficial phenomenon – Increases body’s metabolic rate so more enzyme made to fight infection – Inhibits pathogenic enzymes – Stimulates cell repair

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Specific/Adaptive Defenses: The Immune Response

• • • Immunity – Specific resistance to injury and disease caused by foreign compounds, toxins, or pathogens Provided by coordinated effort of 2 types of lymphocytes: T and B cells Lymphocytes – Respond to presence of specific antigens – “Organize” the defense

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Figure 22-17 30

Specific Defenses: The Immune Response

• T cells (thymus-dependent) – Initiate, maintain, control the immune response – Responsible for cell-mediated immunity – Defend against abnormal cells and pathogens inside cells (do not respond to pathogens in body fluids) – 3 Major types of T cells • Cytotoxic • Helper • Suppressor

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Specific Defenses: The Immune Response

• B cells (bone marrow-derived) – Responsible for antibody-mediated (humoral) immunity – Differentiate into plasma cells that produce antibodies – Defend against antigens and pathogens in body fluids (antibodies can’t cross cell membranes)

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Specific Defenses: The Immune Response

• Types of immunity – Innate immunity • Present at birth (genetically determined) • Does not require exposure to antigen or antibody production •  Diseases that are species specific – Acquired/Adaptive immunity • • Not present at birth Produced by prior exposure to specific antigen or antibody production • 4 types

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Figure 22-14, 7 th edition 34

Specific Defenses: Acquired Immunity

• Active immunity – Appears after exposure to an antigen – Requires active response by body, i.e., antibody production (immune response) – Two types • Naturally acquired (active) immunity – Through environmental exposure to pathogens • Induced (active) immunity – – Through vaccines containing dead/inactive pathogens or antigens Antibody production stimulated before possible future exposure

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Specific Defenses: Acquired Immunity

• Passive immunity – Requires no response by body – Produced by transfer of antibodies from one individual to another – Two types • Natural passive immunity – Antibodies acquired from mother during development (across placenta) or in early infancy (through breast milk) • Induced passive immunity – Antibodies (developed in another body) administered via injection – e.g., IG injected into Rh- mother after first Rh+ baby; antirabies virus antibodies injected into person bitten by rabid animal, antivenom…snake bite

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Specific Defenses: The Immune Response

• Properties of immunity that enable body to respond with a specific defense – Specificity – Versatility – Memory – Tolerance

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Specific Defenses: 4 Properties of Immunity

• Specificity – Specific defenses activated by one specific antigen • Immune response targets that antigen ONLY – Each T and B lymphocyte has receptors that bind to only one specific antigen and ignore all others – T or B cells will destroy or inactivate that antigen without affecting other antigens or normal tissues

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Specific Defenses: 4 Properties of Immunity

• Versatility – – Ability of immune system to confront any antigen any time Results from large diversity of lymphocytes in body • During development, cell differentiation in lymphatic system produces millions of different lymphocyte populations (each has several 1000 identical cells) • Each lymphocyte population responds to a different antigen – – Several 1000 lymphocytes not enough to overcome pathogenic invasion, but begin dividing when activated in presence of appropriate antigen Produce more lymphocytes with same specificity  clone

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Specific Defenses: 4 Properties of Immunity

• Memory – Lymphocytes remember antigens they’ve encountered before – During initial response to antigen, lymphocytes undergo repeated cycles of cell division – Produce 2 types of cells • Activated lymphocytes that attack antigen invader • Memory cells that remain inactive until exposed to same antigen again at a later time – After second exposure, response is faster, stronger, and lasts longer than first time

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Specific Defenses: 4 Properties of Immunity

• Tolerance – Immune system • Ignores “normal” (self) antigens • Attacks foreign (nonself) antigens – Can also develop in response to chronic (long-term) exposure to antigen in environment; lasts only as long as exposure continues – Failure  autoimmune diseases

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• Today in class we will discuss: – The immune process • Antigens • T cells • B cells • Types of immune responses – Cell-mediated immunity • Antigen presentation • Antigen recognition • T cell activation • Destruction/elimination of target cell/antigen

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Immune Response Process

• Antigen – = Foreign substance capable of inducing antibody production – Triggers immune response – Activates • • Phagocytes  activation of T cells B cells

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Immune Response Process

• • T cells – Initiate, maintain, control immune response – Carry out direct physical/chemical attack on antigen – Stimulate activation of B cells B cells – Mature into plasma cells that produce antibodies – Antibodies in bloodstream bind to/attack antigen  antigen-antibody complex that is eliminated from system

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Figure 22-17 45

Immune Responses

• 2 types – Cell-mediated immunity – (T cells) Antibody-mediated (humoral) immunity (B cells)

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Immune Responses

• Cell-mediated immunity – Involves T cells – Process • Antigen presentation • Antigen recognition • T cell activation • Destruction/elimination of target cell/antigen (cytotoxic T cells)

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T Cells and Cell-mediated Immunity

• Antigen presentation – = Process whereby foreign antigen is displayed (“presented”) on cell membrane – Requires combining foreign antigen + glycoprotein (e.g., MHC protein) Antigen = foreign peptide that has potential to induce antibody formation

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T Cells and Cell-mediated Immunity

• MHC proteins – Membrane glycoproteins – Synthesis controlled by group of genes called the major histocompatability complex (MHC) – Bind antigens – Differ among individuals – Two classes of MHC proteins • MHC I • MHC II

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T Cells and Cell-mediated Immunity

• • MHC I proteins – Continuously being formed in all normal, healthy cells that have a nucleus MHC II proteins – In: • Antigen-presenting cells (APCs) – Present only when cell actively processing foreign antigen • Lymphocytes (B cells and helper T cells) NOTE: these cells also have MHC I proteins

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T Cells and Cell-mediated Immunity

• Antigen-presenting cells (APCs) – Phagocytic APCs • Free and fixed macrophages in CT – Engulf and break down foreign cells (bacteria or cancer) and viruses – –  Foreign antigens e.g., microglia in CNS, Kuppfer cells in liver – Nonphagocytic APCs • Remove foreign antigens from their surroundings by pinocytosis • e.g., Langerhans cells of skin, dendritic cells of lymph nodes and spleen

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T Cells and Cell-mediated Immunity

• Antigen presentation (continued) – As MHC proteins are formed they pick up small peptides/antigens from cytoplasm – Carry them to cell membrane – Peptide/antigen-MHC protein complex inserted into cell membrane – Peptide/antigen “presented” to circulating T cells

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Figure 22-18a 53

Figure 22-18b 54

T Cells and Cell-mediated Immunity

• Antigen recognition – Circulating T cells (inactive) have receptors for: • A specific antigen-MHC I or MHC II protein complex – If membrane-bound peptide normal, ignored by circulating T cells – If peptide abnormal (from cancer cell) or foreign (from bacteria or virus that infected cell) and circulating T cell contains appropriate antigen-MHC protein complex, membrane-bound complex will be noticed (“recognized”) by T cell

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T Cells and Cell-mediated Immunity

• • Antigen recognition (continued) – MHC I protein with foreign antigen • Recognized by cytotoxic T cells and suppressor T cells • Tells immune system “I’m an abnormal/infected cell – kill me!” (= cytotoxicity) – MHC II protein with foreign antigen • Recognized by helper T cells • Tells immune system “I’m an active APC. This antigen is dangerous – get rid of it.” T cell will bind to antigen-MHC protein receptor on cell membrane

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Antigen Recognition by and Activation of Cytotoxic T Cells Figure 22-19, (Steps 1-3) 57

Antigen Recognition by and Activation of Cytotoxic T Cells Figure 22-19, (Steps 4) 58

T Cells and Cell-mediated Immunity

• T cell activation – Must occur before immune response can begin – When T cell released from antigen-MHC protein receptor on cell membrane it is “activated” – Activated T cell divides to produce: • • Active cells (cytotoxic, helper T cells) Memory cells – – Reserve (“sleeper”) cells Immediately become active T cells when antigen appears a second time

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Antigen Recognition and Activation of Helper T Cells Antigen Recognition by CD4 T Cell Foreign antigen Antigen-presenting cell (APC

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Class II MHC APC Antigen Costimulation CD4 protein T cell receptor T H cell Figure 22-20, (Part 1 of 2) Inactive CD4 (T H ) cell 60

Antigen Recognition and Activation of Helper T Cells CD4 T Cell Activation and Cell Division Memory T H (inactive) cells Active helper T cells secrete cytokines that stimulate both cell-mediated and antibody-mediated immunity.

Active T H cells Cytokines Cytokines Cytokines Figure 22-20, (Part 2 of 2) 61

T Cells and Cell-mediated Immunity

• • End result – Activated cytotoxic T cells (Fig 22-19) • Destroy abnormal or infected cells that “display” its target antigen and MHC I protein (cytotoxicity) – Activated helper T cells (Fig 22-20) • Secrete cytokines when exposed to cells that “display” its target antigen and MHC II protein • Cytokines interact with sensitized B cells (see Fig 22-22) Summary of T cell activation (Fig 22-21)

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Figure 22–21

Pathways of T Cell Activation

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• Today in class we will discuss: – Antibody-mediated immunity • T cells • B cell activation • Antibodies and their classification • Primary response in antibody-mediated immunity • Secondary response in antibody-mediated immunity – Body responses to • Bacterial infection • Viral infection – Immune disorders – Aging and the immune response

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Immune Responses

• Antibody-mediated (humoral) immunity – Involves B cells – Process • B cell sensitivation • B cell activation (by helper T cells) • Antibody production (by plasma cells) • Destruction/elimination of target antigen-antibody complex

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B Cells and Antibody-mediated Immunity

• B cell sensitization – Each B cell carries its own antibody molecules on its cell membrane – As it migrates through tissues, it finds appropriate antigen that binds to its antibodies = “sensitization” (like antigen presentation in T cells) • Usually occurs in lymph node nearest site of infection/injury – Antigens brought into B cell and appear on cell membrane bound to MHC II proteins

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The Sensitization and Activation of B Cells Figure 22-22 67

B Cells and Antibody-mediated Immunity

• B cell activation – Sensitized B cell on “standby” until it meets appropriate, activated helper T cell – T cell • Recognizes antigen-MHC protein complex • Binds to it • Secretes cytokines – Cytokines stimulate B cell activation

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B Cells and Antibody-mediated Immunity

• B cell activation (continued) – B cell divides to form: • Activated B cells – Become plasma cells » Produce antibodies specific for that antigen • Memory B cells – Remain in reserve to deal with subsequent injuries/infections that involve same antigen

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B Cells and Antibody-mediated Immunity

• Antibodies (immunoglobulins, Igs) – Found in body fluids, not cells – Y-shaped, 2 parallel pairs of polypeptide chains – 5 classes determined by structural differences • IgG = largest, most common; only one that crosses the placenta • IgE = important in allergic responses • IgD = helps B cells • IgM = first Ab produced during immune response, then declines when IgG increases • IgA = found in glandular secretions (mucus, tears, saliva)

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Figure 22-23 71

Table 22–1

5 Classes of Antibodies

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B Cells and Antibody-mediated Immunity

• Immune response – Occurs after exposure to an antigen – 2 types of responses • Primary • Secondary

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B Cells and Antibody-mediated Immunity

• Primary response – Initial response – Develops slowly, takes 1-2 weeks to peak after exposure • Antigen must activate appropriate B cells, which then differentiate into plasma cells – IgM is first antibody to appear • Provides immediate, limited defense that fights infection until IgG can be produced – Concentrations of IgM and IgG relatively low and do not remain elevated • Plasma cells have short life spans • Production of new cells inhibited by suppressor T cells – May not prevent an infection

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Figure 22-24, 7 th edition 75

B Cells and Antibody-mediated Immunity

• Secondary response – Response after second exposure – More extensive and prolonged; more effective defense – Due to large numbers of memory B cells primed for arrival of antigen (may last > 20 years!) – When same antigen appears a second time, memory B cells differentiate into plasma cells that secrete huge quantities of IgG antibodies – IgG antibody activity stays elevated for extended period – Response very adequate for preventing infection – Effectiveness of secondary response is basic principle behind use of immunization to prevent disease

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Figure 22-24b, 7 th edition 77

B Cells and Antibody-mediated Immunity

• • Antibody molecule binds to corresponding antigen molecule  antigen-antibody complex Elimination of antigen-antibody complex – Destroyed by phagocytes – Destroyed by complement system – Complexes may be insoluble and precipitate – Form large complexes through agglutination

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Overall Summary of Defense Mechanisms

Figure 22-26 79

Body Responses to Bacterial Infection

Figure 22–24 80

Figure 22-27

Responses to Bacteria & Viruses

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Key Concepts

• • • • • Viruses replicate inside cells Bacteria may live independently Antibodies (and antibiotics) work outside cells, so are primarily effective against bacteria rather than viruses Antibiotics can’t fight common cold or flu (caused by viruses) Primary defense against viral infection – NK cells, interferon, T cells

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Immune Disorders

• • • Allergies – over-reaction of immune system; anaphylaxis = most extreme form Autoimmune diseases – produce (auto)antibodies against own tissues – Rheumatoid arthritis (connective tissue and joints) – Thyroiditis (anti-thyroglobulin) – Insulin-dependent diabetes mellitus (pancreas) Immunodeficiency diseases – problems with: – Development of lymphoid tissues (genetic) – Viral infection (AIDS – interferes with helper T cells) – Treatment with immunosuppressive drugs (steroids, antineoplastics) or radiation

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Aging and the Immune Response

• • • • • Immune system less effective Some effects may be related to involution of thymus and decreased thymic hormones T cells less responsive to antigens so fewer cells respond to infection B cells less responsive so Ab levels don’t increase as quickly  increased susceptibility to viral and bacterial infections (Note: reason vaccinations for flu, pneumonia recommended for elderly persons) Decreased immune surveillance (NK cells)  cells aren’t eliminated as effectively  cancer rate tumor increased

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