1. PowerPoint ® Lecture Slides prepared by Barbara Heard, Atlantic Cape Community College C H A P T E R © 2013 Pearson Education, Inc.© Annie Leibovitz/Contact Press Images The Immune System: Innate and Adaptive Body Defenses: Part A 21

2. © 2013 Pearson Education, Inc. Immunity Resistance to disease Immune system –Two intrinsic systems Innate (nonspecific) defense system Adaptive (specific) defense system

3. © 2013 Pearson Education, Inc. Immune System Functional system rather than organ system Innate and adaptive defenses intertwined Release and recognize many of same defensive molecules Innate defenses do have specific pathways for certain substances Innate responses release proteins that alert cells of adaptive system to foreign molecules

4. © 2013 Pearson Education, Inc. Immunity Innate defense system has two lines of defense –First - external body membranes (skin and mucosae) –Second - antimicrobial proteins, phagocytes, and other cells Inhibit spread of invaders Inflammation most important mechanism

5. © 2013 Pearson Education, Inc. Immunity Adaptive defense system –Third line of defense attacks particular foreign substances Takes longer to react than innate system

6. © 2013 Pearson Education, Inc. Figure 21.1 Overview of innate and adaptive defenses. Innate defenses Surface barriers Skin Mucous membranes Internal defenses Phagocytes Natural killer cells Inflammation Antimicrobial proteins Fever Adaptive defenses Humoral immunity B cells Cellular immunity T cells

7. © 2013 Pearson Education, Inc. Innate Defenses Surface barriers ward off invading pathogens –Skin, mucous membranes, and their secretions Physical barrier to most microorganisms Keratin resistant to weak acids and bases, bacterial enzymes, and toxins Mucosae provide similar mechanical barriers

8. © 2013 Pearson Education, Inc. Surface Barriers Protective chemicals inhibit or destroy microorganisms –Acidity of skin and secretions – acid mantle – inhibits growth –Enzymes - lysozyme of saliva, respiratory mucus, and lacrimal fluid – kill many microorganisms –Defensins – antimicrobial peptides – inhibit growth –Other chemicals - lipids in sebum, dermcidin in sweat – toxic

9. © 2013 Pearson Education, Inc. Surface Barriers Respiratory system modifications –Mucus-coated hairs in nose –Cilia of upper respiratory tract sweep dust- and bacteria-laden mucus toward mouth Surface barriers breached by nicks or cuts - second line of defense must protect deeper tissues

10. © 2013 Pearson Education, Inc. Internal Defenses: Cells and Chemicals Necessary if microorganisms invade deeper tissues –Phagocytes –Natural killer (NK) cells –Antimicrobial proteins (interferons and complement proteins) –Fever –Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals)

11. © 2013 Pearson Education, Inc. Phagocytes Neutrophils most abundant but die fighting –Become phagocytic on exposure to infectious material Macrophages develop from monocytes – chief phagocytic cells – robust cells Free macrophages wander through tissue spaces, e.g., alveolar macrophages Fixed macrophages permanent residents of some organs; e.g., Kupffer cells (liver) and microglia (brain)

12. © 2013 Pearson Education, Inc. Mechanism of Phagocytosis Phagocyte must adhere to particle –Some microorganisms evade adherence with capsule Opsonization marks pathogens—coating by complement proteins or antibodies Cytoplasmic extensions bind to and engulf particle in vesicle called phagosome Phagosome fuses with lysosome  phagolysosome

13. © 2013 Pearson Education, Inc. Figure 21.2a Phagocytosis. Innate defenses Internal defenses A macrophage (purple) uses its cytoplasmic extensions to pull rod-shaped bacteria (green) toward it. Scanning electron micrograph (4800x).

14. © 2013 Pearson Education, Inc. Figure 21.2b Phagocytosis. Phagocyte adheres to pathogens or debris. 1 Phagocyte forms pseudopods that eventually engulf the particles, forming a phagosome. Lysosome fuses with the phagocytic vesicle, forming a phagolysosome. Lysosomal enzymes digest the particles, leaving a residual body. Exocytosis of the vesicle removes indigestible and residual material. 2 3 4 5 Phagosome (phagocytic vesicle) Lysosome Acid hydrolase enzymes Events of phagocytosis. Slide 1

15. © 2013 Pearson Education, Inc. Phagocyte adheres to pathogens or debris. 1 Lysosome Events of phagocytosis. Figure 21.2b Phagocytosis. Slide 2

16. © 2013 Pearson Education, Inc. Phagocyte adheres to pathogens or debris. 1 Phagocyte forms pseudopods that eventually engulf the particles, forming a phagosome. 2 Phagosome (phagocytic vesicle) Lysosome Events of phagocytosis. Figure 21.2b Phagocytosis. Slide 3

17. © 2013 Pearson Education, Inc. Phagocyte adheres to pathogens or debris. 1 Phagocyte forms pseudopods that eventually engulf the particles, forming a phagosome. Lysosome fuses with the phagocytic vesicle, forming a phagolysosome. 2 3 Phagosome (phagocytic vesicle) Lysosome Acid hydrolase enzymes Events of phagocytosis. Figure 21.2b Phagocytosis. Slide 4

18. © 2013 Pearson Education, Inc. Phagocyte adheres to pathogens or debris. 1 Phagocyte forms pseudopods that eventually engulf the particles, forming a phagosome. Lysosome fuses with the phagocytic vesicle, forming a phagolysosome. Lysosomal enzymes digest the particles, leaving a residual body. 2 3 4 Phagosome (phagocytic vesicle) Lysosome Acid hydrolase enzymes Events of phagocytosis. Figure 21.2b Phagocytosis. Slide 5

19. © 2013 Pearson Education, Inc. Phagocyte adheres to pathogens or debris. 1 Phagocyte forms pseudopods that eventually engulf the particles, forming a phagosome. Lysosome fuses with the phagocytic vesicle, forming a phagolysosome. Lysosomal enzymes digest the particles, leaving a residual body. Exocytosis of the vesicle removes indigestible and residual material. 2 3 4 5 Phagosome (phagocytic vesicle) Lysosome Acid hydrolase enzymes Events of phagocytosis. Figure 21.2b Phagocytosis. Slide 6

20. © 2013 Pearson Education, Inc. Mechanism of Phagocytosis Pathogens killed by acidifying and digesting with lysosomal enzymes Helper T cells cause release of enzymes of respiratory burst, which kill pathogens resistant to lysosomal enzymes by –Releasing cell-killing free radicals –Producing oxidizing chemicals (e.g., H2O2) –Increasing pH and osmolarity of phagolysosome Defensins (in neutrophils) pierce membrane

21. © 2013 Pearson Education, Inc. Natural Killer (NK) Cells Nonphagocytic large granular lymphocytes Attack cells that lack "self" cell-surface receptors –Induce apoptosis in cancer cells and virus- infected cells Secrete potent chemicals that enhance inflammatory response

22. © 2013 Pearson Education, Inc. Inflammatory Response Triggered whenever body tissues injured Prevents spread of damaging agents Disposes of cell debris and pathogens Alerts adaptive immune system Sets the stage for repair

23. © 2013 Pearson Education, Inc. Inflammatory Response Cardinal signs of acute inflammation: 1.Redness 2.Heat 3.Swelling 4.Pain (Sometimes 5. Impairment of function)

24. © 2013 Pearson Education, Inc. Inflammatory Response Begins with chemicals released into ECF by injured tissues, immune cells, blood proteins Macrophages and epithelial cells of boundary tissues bear Toll-like receptors (TLRs) 11 types of TLRs recognize specific classes of infecting microbes Activated TLRs trigger release of cytokines that promote inflammation

25. © 2013 Pearson Education, Inc. Inflammatory Response Inflammatory mediators –Kinins, prostaglandins (PGs), and complement Dilate local arterioles (hyperemia) –Causes redness and heat of inflamed region Make capillaries leaky Many attract leukocytes to area Some have inflammatory roles

26. © 2013 Pearson Education, Inc. Inflammatory Response: Edema  Capillary permeability  exudate to tissues –Fluid containing clotting factors and antibodies –Causes local swelling (edema) –Swelling pushes on nerve endings  pain Pain also from bacterial toxins, prostaglandins, and kinins –Moves foreign material into lymphatic vessels –Delivers clotting proteins and complement

27. © 2013 Pearson Education, Inc. Inflammatory Response Clotting factors form fibrin mesh –Scaffold for repair –Isolates injured area so invaders cannot spread

28. © 2013 Pearson Education, Inc. Figure 21.3 Inflammation: flowchart of events. Innate defenses Internal defenses Initial stimulus Physiological response Signs of inflammation Result Arterioles dilate Local hyperemia (increased blood flow to area) HeatRedness Release of inflammatory chemicals (histamine, complement, kinins, prostaglandins, etc.) Increased capillary permeability Capillaries leak fluid (exudate formation) Leaked protein-rich fluid in tissue spaces Pain Swelling Possible temporary impairment of function Locally increased temperature increases metabolic rate of cells Tissue injury Attract neutrophils, monocytes, and lymphocytes to area (chemotaxis) Leaked clotting proteins form interstitial clots that wall off area to prevent injury to surrounding tissue Temporary fibrin patch forms scaffolding for repair Healing Release of leukocytosis- inducing factor Leukocytosis (increased numbers of white blood cells in bloodstream) Leukocytes migrate to injured area Margination (leukocytes cling to capillary walls) Diapedesis (leukocytes pass through capillary walls) Phagocytosis of pathogens and dead tissue cells (by neutrophils, short-term; by macrophages, long-term) Pus may form Area cleared of debris

29. © 2013 Pearson Education, Inc. Phagocyte Mobilization Neutrophils lead; macrophages follow –As attack continues, monocytes arrive 12 hours after leaving bloodstream  macrophages These "late-arrivers" replace dying neutrophils and remain for clean up prior to repair If inflammation due to pathogens, complement activated; adaptive immunity elements arrive

30. © 2013 Pearson Education, Inc. Phagocyte Mobilization Steps for phagocyte mobilization 1.Leukocytosis: release of neutrophils from bone marrow in response to leukocytosis- inducing factors from injured cells 2.Margination: neutrophils cling to walls of capillaries in inflamed area in response to CAMs 3.Diapedesis of neutrophils 4.Chemotaxis: inflammatory chemicals (chemotactic agent) promote positive chemotaxis of neutrophils

31. © 2013 Pearson Education, Inc. Figure 21.4 Phagocyte mobilization. Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. Leukocytosis. Neutrophils enter blood from bone marrow. Margination. Neutrophils cling to capillary wall. Diapedesis. Neutrophils flatten and squeeze out of capillaries. 1 2 3 Chemotaxis. Neutrophils follow chemical trail. Capillary wall Basement membrane Endothelium 4 Slide 1

32. © 2013 Pearson Education, Inc. Figure 21.4 Phagocyte mobilization. Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. 1 Capillary wall Basement membrane Endothelium Slide 2 Leukocytosis. Neutrophils enter blood from bone marrow.

33. © 2013 Pearson Education, Inc. Figure 21.4 Phagocyte mobilization. Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. Leukocytosis. Neutrophils enter blood from bone marrow. Margination. Neutrophils cling to capillary wall. 1 2 Slide 3 Capillary wall Basement membrane Endothelium

34. © 2013 Pearson Education, Inc. Figure 21.4 Phagocyte mobilization. Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. Leukocytosis. Neutrophils enter blood from bone marrow. Margination. Neutrophils cling to capillary wall. Diapedesis. Neutrophils flatten and squeeze out of capillaries. 1 2 3 Slide 4 Capillary wall Basement membrane Endothelium

35. © 2013 Pearson Education, Inc. Figure 21.4 Phagocyte mobilization. Slide 5 Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. Leukocytosis. Neutrophils enter blood from bone marrow. Margination. Neutrophils cling to capillary wall. Diapedesis. Neutrophils flatten and squeeze out of capillaries. 1 2 3 Chemotaxis. Neutrophils follow chemical trail. Capillary wall Basement membrane Endothelium 4

36. © 2013 Pearson Education, Inc. Antimicrobial Proteins Interferons (IFNs) and complement proteins –Attack microorganisms directly –Hinder microorganisms' ability to reproduce

37. © 2013 Pearson Education, Inc. Interferons Family of immune modulating proteins –Have slightly different physiological effects Viral-infected cells secrete IFNs (e.g., IFN alpha and beta) to "warn" neighboring cells –IFNs enter neighboring cells  produce proteins that block viral reproduction and degrade viral RNA –IFN alpha and beta also activate NK cells

38. © 2013 Pearson Education, Inc. Interferons IFN gamma (immune interferon) –Secreted by lymphocytes –Widespread immune mobilizing effects –Activates macrophages Since IFNs activate NK cells and macrophages, indirectly fight cancer Artificial IFNs used to treat hepatitis C, genital warts, multiple sclerosis, hairy cell leukemia

39. © 2013 Pearson Education, Inc. Figure 21.5 The interferon mechanism against viruses. Slide 1 Innate defensesInternal defenses Virus Viral nucleic acid New viruses Antiviral proteins block viral reproduction. Interferon genes switch on. DNA Antiviral mRNA Nucleus mRNA for interferon Cell produces interferon molecules. Interferon receptor Host cell 1 Host cell 2 Infected by virus; makes interferon; is killed by virus Binds interferon from cell 1; interferon induces synthesis of protective proteins Virus enters cell. 5 Interferon binding stimulates cell to turn on genes for antiviral proteins. 4 1 2 3

40. © 2013 Pearson Education, Inc. Figure 21.5 The interferon mechanism against viruses. Slide 2 Innate defensesInternal defenses Virus Viral nucleic acid Virus enters cell. 1 Host cell 1 Host cell 2 Infected by virus; makes interferon; is killed by virus Binds interferon from cell 1; interferon induces synthesis of protective proteins Nucleus

41. © 2013 Pearson Education, Inc. Figure 21.5 The interferon mechanism against viruses. Slide 3 Innate defensesInternal defenses Virus Viral nucleic acid Interferon genes switch on. DNA Nucleus Host cell 1 Host cell 2 Infected by virus; makes interferon; is killed by virus Binds interferon from cell 1; interferon induces synthesis of protective proteins Virus enters cell. 1 2

42. © 2013 Pearson Education, Inc. Figure 21.5 The interferon mechanism against viruses. Slide 4 Innate defensesInternal defenses Virus Viral nucleic acid Interferon genes switch on. DNA Nucleus mRNA for interferon Cell produces interferon molecules. Interferon Host cell 1 Host cell 2 Infected by virus; makes interferon; is killed by virus Binds interferon from cell 1; interferon induces synthesis of protective proteins Virus enters cell. 1 2 3

43. © 2013 Pearson Education, Inc. Figure 21.5 The interferon mechanism against viruses. Slide 5 Innate defensesInternal defenses Virus Viral nucleic acid Interferon genes switch on. DNA Nucleus mRNA for interferon Cell produces interferon molecules. Interferon Host cell 1 Host cell 2 Infected by virus; makes interferon; is killed by virus Binds interferon from cell 1; interferon induces synthesis of protective proteins Virus enters cell. 1 2 3 Interferon binding stimulates cell to turn on genes for antiviral proteins. 4

44. © 2013 Pearson Education, Inc. Figure 21.5 The interferon mechanism against viruses. Slide 6 Innate defensesInternal defenses Virus Viral nucleic acid New viruses Antiviral proteins block viral reproduction. Interferon genes switch on. DNA Antiviral mRNA Nucleus mRNA for interferon Cell produces interferon molecules. Interferon receptor Host cell 1 Host cell 2 Infected by virus; makes interferon; is killed by virus Binds interferon from cell 1; interferon induces synthesis of protective proteins Virus enters cell. 5 Interferon binding stimulates cell to turn on genes for antiviral proteins. 4 1 2 3

45. © 2013 Pearson Education, Inc. Complement System (Complement) ~20 blood proteins that circulate in inactive form Include C1–C9, factors B, D, and P, and regulatory proteins Major mechanism for destroying foreign substances Our cells contain complement activation inhibitors

46. © 2013 Pearson Education, Inc. Complement Unleashes inflammatory chemicals that amplify all aspects of inflammatory response Kills bacteria and certain other cell types by cell lysis Enhances both innate and adaptive defenses

47. © 2013 Pearson Education, Inc. Complement Activation Three pathways to activation –Classical pathway Antibodies bind to invading organisms and to complement components Called complement fixation First step in activation; more details later

48. © 2013 Pearson Education, Inc. Complement Lectin pathway –Lectins - produced by innate system to recognize foreign invaders –When bound to foreign invaders can also bind and activate complement Alternative pathway –Triggered when activated C3, B, D, and P interact on surface of microorganisms

49. © 2013 Pearson Education, Inc. Complement Activation Each pathway involves activation of proteins in an orderly sequence Each step catalyzes the next Each pathway converges on C3, which cleaves into C3a and C3b Common terminal pathway initiated that –Enhances inflammation, promotes phagocytosis, causes cell lysis

50. © 2013 Pearson Education, Inc. Complement Activation Cell lysis begins when –C3b binds to target cell  insertion of complement proteins called membrane attack complex (MAC) into cell's membrane –MAC forms and stabilizes hole in membrane  influx of water  lysis of cell C3b also causes opsonization C3a and other cleavage products amplify inflammation –Stimulate mast cells and basophils to release histamine –Attract neutrophils and other inflammatory cells

51. © 2013 Pearson Education, Inc. Figure 21.6 Complement activation. Classical pathway Activated by antibodies coating target cell Lectin pathway Activated by lectins binding to specific sugars on microorganism’s surface Alternative pathway Activated spontaneously. Lack of inhibitors on microorganism’s surface allows process to proceed Together with other complement proteins and factors Opsonization: Coats pathogen surfaces, which enhances phagocytosis MACs form from activated complement components (C5b and C6–C9) that insert into the target cell membrane, creating pores that can lyse the target cell. Enhances inflammation: Stimulates histamine release, increases blood vessel permeability, attracts phagocytes by chemotaxis, etc. Pore Complement proteins (C5b–C9) Membrane of target cell C3 C3b C5b C6 C7 C8 C9 C3a C5a MAC

52. © 2013 Pearson Education, Inc. Fever Abnormally high body temperature Systemic response to invading microorganisms Leukocytes and macrophages exposed to foreign substances secrete pyrogens Pyrogens act on body's thermostat in hypothalamus, raising body temperature

53. © 2013 Pearson Education, Inc. Fever Benefits of moderate fever –Causes liver and spleen to sequester iron and zinc (needed by microorganisms) –Increases metabolic rate  faster repair

54. © 2013 Pearson Education, Inc. Adaptive Defenses Adaptive immune (specific defense) system –Protects against infectious agents and abnormal body cells –Amplifies inflammatory response –Activates complement –Must be primed by initial exposure to specific foreign substance Priming takes time

55. © 2013 Pearson Education, Inc. Adaptive Defenses Specific – recognizes and targets specific antigens Systemic – not restricted to initial site Have memory – stronger attacks to "known" antigens Two separate, overlapping arms –Humoral (antibody-mediated) immunity –Cellular (cell-mediated) immunity

56. © 2013 Pearson Education, Inc. Humoral Immunity Antibodies, produced by lymphocytes, circulating freely in body fluids Bind temporarily to target cell –Temporarily inactivate –Mark for destruction by phagocytes or complement

57. © 2013 Pearson Education, Inc. Cellular Immunity Lymphocytes act against target cell –Directly – by killing infected cells –Indirectly – by releasing chemicals that enhance inflammatory response; or activating other lymphocytes or macrophages

58. © 2013 Pearson Education, Inc. Antigens Substances that can mobilize adaptive defenses and provoke an immune response Targets of all adaptive immune responses Most are large, complex molecules not normally found in body (nonself)

59. © 2013 Pearson Education, Inc. Complete Antigens Important functional properties –Immunogenicity: ability to stimulate proliferation of specific lymphocytes –Reactivity: ability to react with activated lymphocytes and antibodies released by immunogenic reactions Examples: foreign protein, polysaccharides, lipids, and nucleic acids

60. © 2013 Pearson Education, Inc. Haptens (Incomplete Antigens) Small molecules (haptens) not immunogenic by themselves –E.g., peptides, nucleotides, some hormones May be immunogenic if attached to body proteins and combination is marked foreign Cause immune system to mount harmful attack Examples: poison ivy, animal dander, detergents, and cosmetics

61. © 2013 Pearson Education, Inc. Antigenic Determinants Only certain parts (antigenic determinants) of entire antigen are immunogenic Antibodies and lymphocyte receptors bind to them as enzyme binds substrate

62. © 2013 Pearson Education, Inc. Antigenic Determinants Most naturally occurring antigens have numerous antigenic determinants that –Mobilize several different lymphocyte populations –Form different kinds of antibodies against it Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity

63. © 2013 Pearson Education, Inc. Figure 21.7 Most antigens have several different antigenic determinants. Antibody A Antigen- binding sites Antibody B Antibody C Antigenic determinants Antigen

64. © 2013 Pearson Education, Inc. Self-antigens: MHC Proteins Protein molecules (self-antigens) on surface of cells not antigenic to self but antigenic to others in transfusions or grafts Example: MHC glycoproteins –Coded by genes of major histocompatibility complex (MHC) and unique to individual –Have groove holding self- or foreign antigen Lymphocytes only bind antigens on MHC proteins

65. © 2013 Pearson Education, Inc. Cells of the Adaptive Immune System Three types of cells –Two types of lymphocytes B lymphocytes (B cells)—humoral immunity T lymphocytes (T cells)—cell-mediated immunity –Antigen-presenting cells (APCs) Do not respond to specific antigens Play essential auxiliary roles in immunity

66. © 2013 Pearson Education, Inc. Lymphocyte Development, Maturation, and Activation Five general steps –Origin – all originate in red bone marrow –Maturation –Seeding secondary lymphoid organs and circulation –Antigen encounter and activation –Proliferation and differentiation

67. © 2013 Pearson Education, Inc. Maturation "Educated" as mature; B cells in bone marrow, T cells in thymus –Immunocompetence – lymphocyte can recognize one specific antigen by binding to it B or T cells display unique receptor on surface when achieve maturity – bind only one antigen –Self-tolerance Lymphocytes unresponsive to own antigens

68. © 2013 Pearson Education, Inc. T cells T cells mature in thymus under negative and positive selection pressures ("tests") –Positive selection Selects T cells capable of recognizing self-MHC proteins (MHC restriction); failures destroyed by apoptosis –Negative selection Prompts apoptosis of T cells that bind to self- antigens displayed by self-MHC Ensures self-tolerance

69. © 2013 Pearson Education, Inc. Figure 21.8 Lymphocyte development, maturation, and activation. Adaptive defenses Humoral immunity Cellular immunity Primary lymphoid organs (red bone marrow and thymus) Secondary lymphoid organs (lymph nodes, spleen, etc.) Origin Both B and T lymphocyte precursors originate in red bone marrow. Maturation Lymphocyte precursors destined to become T cells migrate (in blood) to the thymus and mature there. B cells mature in the bone marrow. During maturation lymphocytes develop immunocompetence and self-tolerance. Seeding secondary lymphoid organs and circulation Immunocompetent but still naive lymphocytes leave the thymus and bone marrow. They “seed” the secondary lymphoid organs and circulate through blood and lymph. Antigen encounter and activation When a lymphocyte’s antigen receptors bind its antigen, that lymphocyte can be activated. Proliferation and differentiation Activated lymphocytes proliferate (multiply) and then differentiate into effector cells and memory cells. Memory cells and effector T cells circulate continuously in the blood and lymph and throughout the secondary lymphoid organs. Red bone marrow Lymphocyte precursors Thymus Red bone marrow Lymph node Antigen 1 2 3 4 5 Slide 1

70. © 2013 Pearson Education, Inc. Figure 21.8 Lymphocyte development, maturation, and activation. Adaptive defenses Humoral immunity Cellular immunity Primary lymphoid organs (red bone marrow and thymus) Secondary lymphoid organs (lymph nodes, spleen, etc.) Origin Both B and T lymphocyte precursors originate in red bone marrow. Red bone marrow Lymphocyte precursors Thymus Red bone marrow 1 Slide 2

71. © 2013 Pearson Education, Inc. Figure 21.8 Lymphocyte development, maturation, and activation. Adaptive defenses Humoral immunity Cellular immunity Primary lymphoid organs (red bone marrow and thymus) Secondary lymphoid organs (lymph nodes, spleen, etc.) Origin Both B and T lymphocyte precursors originate in red bone marrow. Red bone marrow Lymphocyte precursors Thymus Red bone marrow 1 Maturation Lymphocyte precursors destined to become T cells migrate (in blood) to the thymus and mature there. B cells mature in the bone marrow. During maturation lymphocytes develop immunocompetence and self-tolerance. 2 Slide 3

72. © 2013 Pearson Education, Inc. Figure 21.8 Lymphocyte development, maturation, and activation. Adaptive defenses Humoral immunity Cellular immunity Primary lymphoid organs (red bone marrow and thymus) Secondary lymphoid organs (lymph nodes, spleen, etc.) Origin Both B and T lymphocyte precursors originate in red bone marrow. Maturation Lymphocyte precursors destined to become T cells migrate (in blood) to the thymus and mature there. B cells mature in the bone marrow. During maturation lymphocytes develop immunocompetence and self-tolerance. Seeding secondary lymphoid organs and circulation Immunocompetent but still naive lymphocytes leave the thymus and bone marrow. They “seed” the secondary lymphoid organs and circulate through blood and lymph. Red bone marrow Lymphocyte precursors Thymus Red bone marrow Lymph node Antigen 1 2 3 Slide 4

73. © 2013 Pearson Education, Inc. Figure 21.8 Lymphocyte development, maturation, and activation. Adaptive defenses Humoral immunity Cellular immunity Primary lymphoid organs (red bone marrow and thymus) Secondary lymphoid organs (lymph nodes, spleen, etc.) Origin Both B and T lymphocyte precursors originate in red bone marrow. Maturation Lymphocyte precursors destined to become T cells migrate (in blood) to the thymus and mature there. B cells mature in the bone marrow. During maturation lymphocytes develop immunocompetence and self-tolerance. Seeding secondary lymphoid organs and circulation Immunocompetent but still naive lymphocytes leave the thymus and bone marrow. They “seed” the secondary lymphoid organs and circulate through blood and lymph. Red bone marrow Lymphocyte precursors Thymus Red bone marrow Lymph node Antigen 1 2 3 Antigen encounter and activation When a lymphocyte’s antigen receptors bind its antigen, that lymphocyte can be activated. 4 Slide 5

74. © 2013 Pearson Education, Inc. Figure 21.8 Lymphocyte development, maturation, and activation. Adaptive defenses Humoral immunity Cellular immunity Primary lymphoid organs (red bone marrow and thymus) Secondary lymphoid organs (lymph nodes, spleen, etc.) Origin Both B and T lymphocyte precursors originate in red bone marrow. Maturation Lymphocyte precursors destined to become T cells migrate (in blood) to the thymus and mature there. B cells mature in the bone marrow. During maturation lymphocytes develop immunocompetence and self-tolerance. Seeding secondary lymphoid organs and circulation Immunocompetent but still naive lymphocytes leave the thymus and bone marrow. They “seed” the secondary lymphoid organs and circulate through blood and lymph. Antigen encounter and activation When a lymphocyte’s antigen receptors bind its antigen, that lymphocyte can be activated. Proliferation and differentiation Activated lymphocytes proliferate (multiply) and then differentiate into effector cells and memory cells. Memory cells and effector T cells circulate continuously in the blood and lymph and throughout the secondary lymphoid organs. Red bone marrow Lymphocyte precursors Thymus Red bone marrow Lymph node Antigen 1 2 3 4 5 Slide 6

75. © 2013 Pearson Education, Inc. Cellular immunityAdaptive defenses 1. Positive Selection T cells must recognize self major histocompatibility proteins (self-MHC) Antigen- presenting thymic cell Developing T cell Failure to recognize self- MHC results in apoptosis (death by cell suicide). T cell receptor Self-MHC Self-antigen Recognizing self-MHC results in survival. Survivors proceed to negative selection. 2. Negative Selection T cells must not recognize self-antigens Recognizing self-antigen results in apoptosis. This eliminates self-reactive T cells that could cause autoimmune diseases. Failure to recognize (bind tightly to) self-antigen results in survival and continued maturation. Figure 21.9 T cell education in the thymus.

76. © 2013 Pearson Education, Inc. B cells B cells mature in red bone marrow Positively selected if successfully make antigen receptors Those that are self-reactive –Eliminated by apoptosis (clonal deletion)

77. © 2013 Pearson Education, Inc. Seeding Secondary Lymphoid Organs and Circulation Immunocompetent B and T cells not yet exposed to antigen called naive Exported from primary lymphoid organs (bone marrow and thymus) to "seed" secondary lymphoid organs (lymph nodes, spleen, etc.) –Increases chance of encounter with antigen

78. © 2013 Pearson Education, Inc. Antigen Encounter and Activation Clonal selection –Naive lymphocyte's first encounter with antigen  selected for further development –If correct signals present, lymphocyte will complete its differentiation

79. © 2013 Pearson Education, Inc. Proliferation and Differentiation Activated lymphocyte proliferates  exact clones Most clones  effector cells that fight infections Few remain as memory cells –Able to respond to same antigen more quickly second time B and T memory cells and effector T cells circulate continuously

80. © 2013 Pearson Education, Inc. Antigen Receptor Diversity Genes, not antigens, determine which foreign substances immune system will recognize –Immune cell receptors result of acquired knowledge of microbes likely in environment Lymphocytes make up to billion different types of antigen receptors –Coded for by ~25,000 genes –Gene segments are shuffled by somatic recombination

81. © 2013 Pearson Education, Inc. Antigen-presenting Cells (APCs) Engulf antigens Present fragments of antigens to T cells for recognition Major types –Dendritic cells in connective tissues and epidermis –Macrophages in connective tissues and lymphoid organs –B cells

82. © 2013 Pearson Education, Inc. Dendritic Cells and Macrophages Dendritic cells phagocytize pathogens, enter lymphatics to present antigens to T cells in lymph node –Most effective antigen presenter known –Key link between innate and adaptive immunity Macrophages widespread in lymphoid organs and connective tissues Can activate naive T cells Present antigens to T cells to activate themselves into voracious phagocytes that secrete bactericidal chemicals

83. © 2013 Pearson Education, Inc. Figure 21.10 Dendritic cell. Scanning electron micrograph (1050x).

84. © 2013 Pearson Education, Inc. B lymphocytes Do not activate naive T cells Present antigens to helper T cell to assist own activation

85. © 2013 Pearson Education, Inc. Adaptive Immunity: Summary Uses lymphocytes, APCs, and specific molecules to identify and destroy nonself substances Depends upon ability of its cells to –Recognize antigens by binding to them –Communicate with one another so that whole system mounts specific response

86. © 2013 Pearson Education, Inc. Activation and Differentiation of B Cells B cell activated when antigens bind to its surface receptors and cross-link them  Receptor-mediated endocytosis of cross- linked antigen-receptor complexes (clonal selection)  Proliferation and differentiation into effector cells

87. © 2013 Pearson Education, Inc. Fate of the Clones Most clone cells become plasma cells –Secrete specific antibodies at rate of 2000 molecules per second for four to five days, then die –Antibodies circulate in blood or lymph Bind to free antigens and mark for destruction by innate or adaptive mechanisms

88. © 2013 Pearson Education, Inc. Fate of the Clones Clone cells that do not become plasma cells become memory cells –Provide immunological memory –Mount an immediate response to future exposures to same antigen

89. © 2013 Pearson Education, Inc. Figure 21.11a Clonal selection of a B cell. Adaptive defenses Humoral immunity Primary response (initial encounter with antigen) Antigen Antigen binding to a receptor on a specific B lymphocyte (B lymphocytes with noncomplementary receptors remain inactive) Proliferation to form a clone Activated B cells Plasma cells (effector B cells) Memory B cell— primed to respond to same antigen Secreted antibody molecules

90. © 2013 Pearson Education, Inc. Immunological Memory Primary immune response –Cell proliferation and differentiation upon first antigen exposure –Lag period: three to six days –Peak levels of plasma antibody are reached in 10 days –Antibody levels then decline

91. © 2013 Pearson Education, Inc. Immunological Memory Secondary immune response –Re-exposure to same antigen gives faster, more prolonged, more effective response Sensitized memory cells respond within hours Antibody levels peak in two to three days at much higher levels Antibodies bind with greater affinity Antibody level can remain high for weeks to months

92. © 2013 Pearson Education, Inc. Adaptive defensesHumoral immunity Primary response (initial encounter with antigen) Antigen Antigen binding to a receptor on a specific B lymphocyte (B lymphocytes with noncomplementary receptors remain inactive) Proliferation to form a clone Activated B cells Plasma cells (effector B cells) Memory B cell— primed to respond to same antigen Secondary response (can be years later) Clone of cells identical to ancestral cells Subsequent challenge by same antigen results in more rapid response Plasma cells Secreted antibody molecules Memory B cells Secreted antibody molecules Figure 21.11 Clonal selection of a B cell.

93. © 2013 Pearson Education, Inc. Figure 21.12 Primary and secondary humoral responses. Antibody titer (antibody concentration) in plasma (arbitrary units) 10 0 10 1 10 2 10 3 10 4 0 71421 2835424956 First exposure to antigen A Second exposure to antigen A; first exposure to antigen B Primary immune response to antigen A occurs after a delay. Secondary immune response to antigen A is faster and larger; primary immune response to antigen B is similar to that for antigen A. Time (days) Anti- Bodies to A Anti- Bodies to B

94. © 2013 Pearson Education, Inc. Active Humoral Immunity When B cells encounter antigens and produce specific antibodies against them Two types of active humoral immunity: –Naturally acquired—response to bacterial or viral infection –Artificially acquired—response to vaccine of dead or attenuated pathogens

95. © 2013 Pearson Education, Inc. Active Humoral Immunity Vaccines –Most of dead or attenuated pathogens –Spare us symptoms of primary response –Provide antigenic determinants that are immunogenic and reactive –Can cause illness trying to vaccinate against; can cause allergic responses "Naked DNA" and oral vaccines help prevent

96. © 2013 Pearson Education, Inc. Passive Humoral Immunity Readymade antibodies introduced into body B cells are not challenged by antigens Immunological memory does not occur Protection ends when antibodies degrade

97. © 2013 Pearson Education, Inc. Passive Humoral Immunity Two types 1.Naturally acquired—antibodies delivered to fetus via placenta or to infant through milk 2.Artificially acquired—injection of serum, such as gamma globulin Protection immediate but ends when antibodies naturally degrade in body

98. © 2013 Pearson Education, Inc. Figure 21.13 Active and passive humoral immunity. Humoral immunity Active Passive Naturally acquired Infection; contact with pathogen Artificially acquired Vaccine; dead or attenuated pathogens Naturally acquired Antibodies passed from mother to fetus via placenta; or to infant in her milk Injection of exogenous antibodies (gamma globulin) Artificially acquired