2. Mechanism of Phagocytosis Figure 21.1a, b

3. Natural Killer (NK) Cells Cells that can lyse and kill cancer cells and virus- infected cells Cells that can lyse and kill cancer cells and virus- infected cells Natural killer cells: Natural killer cells: Are a small, distinct group of large granular lymphocytes Are a small, distinct group of large granular lymphocytes React nonspecifically and eliminate cancerous and virus-infected cells React nonspecifically and eliminate cancerous and virus-infected cells Kill their target cells by releasing perforins and other cytolytic chemicals Kill their target cells by releasing perforins and other cytolytic chemicals Secrete potent chemicals that enhance the inflammatory response Secrete potent chemicals that enhance the inflammatory response

4. Immunity: Two Intrinsic Defense Systems Innate (nonspecific) system responds quickly and consists of: Innate (nonspecific) system responds quickly and consists of: First line of defense – intact skin and mucosae prevent entry of microorganisms First line of defense – intact skin and mucosae prevent entry of microorganisms Second line of defense – antimicrobial proteins, phagocytes, and other cells Second line of defense – antimicrobial proteins, phagocytes, and other cells Inhibit spread of invaders throughout the body Inhibit spread of invaders throughout the body Inflammation is its hallmark and most important mechanism Inflammation is its hallmark and most important mechanism

5. Immunity: Two Intrinsic Defense Systems Adaptive (specific) defense system Adaptive (specific) defense system Third line of defense – mounts attack against particular foreign substances Third line of defense – mounts attack against particular foreign substances Takes longer to react than the innate system Takes longer to react than the innate system Works in conjunction with the innate system Works in conjunction with the innate system

6. Types of Immunity Active- uses the immune system Active- uses the immune system Passive - gives the system immunity from another source Passive - gives the system immunity from another source Anti-serum = antibody Blood protein that reacts with specific substances Antigen- substance that induces an immune response to be initiated

7. UN 16.1 - Overview

8. Blood Proteins Serum Electrophoresis Albumin - most abundant, carries hormones, metals etc. Albumin - most abundant, carries hormones, metals etc. Globulins -  Globulins -  Gamma globulins - immunity- antibodies. Gamma globulins - immunity- antibodies. Antibody - Ab half life about 3 weeks. Antibody - Ab half life about 3 weeks.

9. Antigens and Antibodies Antigens usually proteins or carbohydrates (lipids and nucleic acids poor unless coupled with proteins or carbohydtrates). Antigens usually proteins or carbohydrates (lipids and nucleic acids poor unless coupled with proteins or carbohydtrates). Anitgenic determinants - region of antigen molecule that the antibody binds to. Anitgenic determinants - region of antigen molecule that the antibody binds to.

10. Antigens and Antibodies   Haptens- small molecules that bind to large molecules and serve as antigenic determinants. Penicillin binding to serum albumen and be coming antigenic

11. Flowchart of Events in Inflammation

12. The adaptive immune system is a functional system that: The adaptive immune system is a functional system that: Recognizes specific foreign substances Recognizes specific foreign substances Acts to immobilize, neutralize, or destroy foreign substances Acts to immobilize, neutralize, or destroy foreign substances Amplifies inflammatory response and activates complement Amplifies inflammatory response and activates complement Adaptive (Specific) Defenses

13. The adaptive immune system is antigen- specific, systemic, and has memory The adaptive immune system is antigen- specific, systemic, and has memory It has two separate but overlapping arms It has two separate but overlapping arms Humoral, or antibody-mediated immunity Humoral, or antibody-mediated immunity Cellular, or cell-mediated immunity Cellular, or cell-mediated immunity Adaptive Immune Defenses

14. Substances that can mobilize the immune system and provoke an immune response Substances that can mobilize the immune system and provoke an immune response The ultimate targets of all immune responses are mostly large, complex molecules not normally found in the body (nonself) The ultimate targets of all immune responses are mostly large, complex molecules not normally found in the body (nonself) Antigens

15. Important functional properties: Important functional properties: Immunogenicity – the ability to stimulate proliferation of specific lymphocytes and antibody production Immunogenicity – the ability to stimulate proliferation of specific lymphocytes and antibody production Reactivity – the ability to react with the products of the activated lymphocytes and the antibodies released in response to them Reactivity – the ability to react with the products of the activated lymphocytes and the antibodies released in response to them Complete antigens include foreign protein, nucleic acid, some lipids, and large polysaccharides Complete antigens include foreign protein, nucleic acid, some lipids, and large polysaccharides Complete Antigens

16. Small molecules, such as peptides, nucleotides, and many hormones, that are not immunogenic but are reactive when attached to protein carriers Small molecules, such as peptides, nucleotides, and many hormones, that are not immunogenic but are reactive when attached to protein carriers If they link up with the body’s proteins, the adaptive immune system may recognize them as foreign and mount a harmful attack (allergy) If they link up with the body’s proteins, the adaptive immune system may recognize them as foreign and mount a harmful attack (allergy) Haptens are found in poison ivy, dander, some detergents, and cosmetics Haptens are found in poison ivy, dander, some detergents, and cosmetics Haptens (Incomplete Antigens)

17. Only certain parts of an entire antigen are immunogenic Only certain parts of an entire antigen are immunogenic Antibodies and activated lymphocytes bind to these antigenic determinants Antibodies and activated lymphocytes bind to these antigenic determinants Most naturally occurring antigens have numerous antigenic determinants that: Most naturally occurring antigens have numerous antigenic determinants that: Mobilize several different lymphocyte populations Mobilize several different lymphocyte populations Form different kinds of antibodies against it Form different kinds of antibodies against it Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity Antigenic Determinants

18. Figure 21.6

19. Antigens and Antibodies   Monomer - simplest Antibody with 4 protein chains and 2 binding sites.   2 Heavy and 2 light chains coupled by disulfide (-S-S-) bridges.   Variable and Constant regions.

20. Classes of Antibodies or Immunoglobulins

28. Humoral Immunity B - cell Stem cells ---> B - cell ---> (stimulation) --> Plasma cells ----> Abs (Immunity) T-cells T-cells ---> cell mediated immunity

29. Humoral Immunity When presented with a previous antigen, that subset (clone) of memory B-cells is stimulated to convert to plasma cells and make Abs.

30. Humoral Immunity Mecanisms of Ab Protection 1. 1.Agglutination 2. 2.Opsonization 3. 3.Neutralization 4. 4.Activate Complement 5. 5.Inflammation 6. 6.Ab Dependent Cell- Mediated cytotoxicity

31. Humoral Immunity The Anamnestic Response Primary exposure- short duration, moderate response. Secondary exposure- long duration, larger response.

32. Humoral Immunity Monoclonal Antibodies 1. 1.Inject mouse with antigen. 2. 2.Sacrifice mouse remove spleen and mix with myeloma cells.

33. Humoral Immunity Monoclonal Antibodies 3. Some cells fuse to form hybridoma cells. 4. Hybridomas produce MAbs. Each clone’s Ab targets same antigenic determinant.

34. Cellular Immunity Types of T-Cells 1. 1.T H Helper - CD 4 -antigen presenting cells. Stimulated by IL-1, it produces IL-2 B-cells stimulated by IL-2, makes Antibodies. 2. 2.T C Cytotoxic - CD8- kill tumor cells. Stimulated by IL-2, attacks cellular invaders. 3. 3.T D hypersensitivity -cause allergic responses. 4. 4.T S Suppressor - CD 8 - turn off immune response. 5. 5.Null Killer Cell = Rogue Cell finds aberrant and initiates apoptosis = Kervorkian Cell

35. Since antibodies are useless against intracellular antigens, cell-mediated immunity is needed Since antibodies are useless against intracellular antigens, cell-mediated immunity is needed Two major populations of T cells mediate cellular immunity Two major populations of T cells mediate cellular immunity CD4 cells (T4 cells) are primarily helper T cells (T H ) CD4 cells (T4 cells) are primarily helper T cells (T H ) CD8 cells (T8 cells) are cytotoxic T cells (T C ) that destroy cells harboring foreign antigens CD8 cells (T8 cells) are cytotoxic T cells (T C ) that destroy cells harboring foreign antigens Other types of T cells are: Other types of T cells are: Suppressor T cells (T S ) Suppressor T cells (T S ) Memory T cells Memory T cells Cell-Mediated Immune Response

36. Major Types of T Cells Figure 21.14

37. T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells T cells are best suited for cell-to-cell interactions, and target: T cells are best suited for cell-to-cell interactions, and target: Cells infected with viruses, bacteria, or intracellular parasites Cells infected with viruses, bacteria, or intracellular parasites Abnormal or cancerous cells Abnormal or cancerous cells Cells of infused or transplanted foreign tissue Cells of infused or transplanted foreign tissue Importance of Cellular Response

38. Immunocompetent T cells are activated when the V regions of their surface receptors bind to a recognized antigen Immunocompetent T cells are activated when the V regions of their surface receptors bind to a recognized antigen T cells must simultaneously recognize: T cells must simultaneously recognize: Nonself (the antigen) Nonself (the antigen) Self (a MHC protein of a body cell) Self (a MHC protein of a body cell) Antigen Recognition and MHC Restriction

39. Both types of MHC proteins are important to T cell activation Both types of MHC proteins are important to T cell activation Class I MHC proteins Class I MHC proteins Always recognized by CD8 T cells Always recognized by CD8 T cells Display peptides from endogenous antigens Display peptides from endogenous antigens MHC Proteins

40. Endogenous antigens are: Endogenous antigens are: Degraded by proteases and enter the endoplasmic reticulum Degraded by proteases and enter the endoplasmic reticulum Transported via TAP (transporter associated with antigen processing) Transported via TAP (transporter associated with antigen processing) Loaded onto class I MHC molecules Loaded onto class I MHC molecules Displayed on the cell surface in association with a class I MHC molecule Displayed on the cell surface in association with a class I MHC molecule Class I MHC Proteins

41. Figure 21.15a

42. Class II MHC proteins are found only on mature B cells, some T cells, and antigen- presenting cells Class II MHC proteins are found only on mature B cells, some T cells, and antigen- presenting cells A phagosome containing pathogens (with exogenous antigens) merges with a lysosome A phagosome containing pathogens (with exogenous antigens) merges with a lysosome Invariant protein prevents class II MHC proteins from binding to peptides in the endoplasmic reticulum Invariant protein prevents class II MHC proteins from binding to peptides in the endoplasmic reticulum Class II MHC Proteins

43. Class II MHC proteins migrate into the phagosomes where the antigen is degraded and the invariant chain is removed for peptide loading Class II MHC proteins migrate into the phagosomes where the antigen is degraded and the invariant chain is removed for peptide loading Loaded Class II MHC molecules then migrate to the cell membrane and display antigenic peptide for recognition by CD4 cells Loaded Class II MHC molecules then migrate to the cell membrane and display antigenic peptide for recognition by CD4 cells Class II MHC Proteins

44. Figure 21.15b

45. Provides the key for the immune system to recognize the presence of intracellular microorganisms Provides the key for the immune system to recognize the presence of intracellular microorganisms MHC proteins are ignored by T cells if they are complexed with self protein fragments MHC proteins are ignored by T cells if they are complexed with self protein fragments Antigen Recognition

46. T cell antigen receptors (TCRs): T cell antigen receptors (TCRs): Bind to an antigen-MHC protein complex Bind to an antigen-MHC protein complex Have variable and constant regions consisting of two chains (alpha and beta) Have variable and constant regions consisting of two chains (alpha and beta) T Cell Activation: Step One – Antigen Binding

47. MHC restriction – T H and T C bind to different classes of MHC proteins MHC restriction – T H and T C bind to different classes of MHC proteins T H cells bind to antigen linked to class II MHC proteins T H cells bind to antigen linked to class II MHC proteins Mobile APCs (Langerhans’ cells) quickly alert the body to the presence of antigen by migrating to the lymph nodes and presenting antigen Mobile APCs (Langerhans’ cells) quickly alert the body to the presence of antigen by migrating to the lymph nodes and presenting antigen T Cell Activation: Step One – Antigen Binding

48. T C cells are activated by antigen fragments complexed with class I MHC proteins T C cells are activated by antigen fragments complexed with class I MHC proteins APCs produce co-stimulatory molecules that are required for T C activation APCs produce co-stimulatory molecules that are required for T C activation TCR that acts to recognize the self-antiself complex is linked to multiple intracellular signaling pathways TCR that acts to recognize the self-antiself complex is linked to multiple intracellular signaling pathways Other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition) Other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition) T Cell Activation: Step One – Antigen Binding

49. Figure 21.16

50. Before a T cell can undergo clonal expansion, it must recognize one or more co-stimulatory signals Before a T cell can undergo clonal expansion, it must recognize one or more co-stimulatory signals This recognition may require binding to other surface receptors on an APC This recognition may require binding to other surface receptors on an APC Macrophages produce surface B7 proteins when nonspecific defenses are mobilized Macrophages produce surface B7 proteins when nonspecific defenses are mobilized B7 binding with the CD 28 receptor on the surface of T cells is a crucial co-stimulatory signal B7 binding with the CD 28 receptor on the surface of T cells is a crucial co-stimulatory signal Other co-stimulatory signals include cytokines and interleukin 1 and 2 Other co-stimulatory signals include cytokines and interleukin 1 and 2 T Cell Activation: Step Two – Co-stimulation

51. Depending on receptor type, co- stimulators can cause T cells to complete their activation or abort activation Depending on receptor type, co- stimulators can cause T cells to complete their activation or abort activation Without co-stimulation, T cells: Without co-stimulation, T cells: Become tolerant to that antigen Become tolerant to that antigen Are unable to divide Are unable to divide Do not secrete cytokines Do not secrete cytokines T Cell Activation: Step Two – Co-stimulation

52. T cells that are activated: T cells that are activated: Enlarge, proliferate, and form clones Enlarge, proliferate, and form clones Differentiate and perform functions according to their T cell class Differentiate and perform functions according to their T cell class T Cell Activation: Step Two – Co-stimulation

53. Primary T cell response peaks within a week after signal exposure Primary T cell response peaks within a week after signal exposure T cells then undergo apoptosis between days 7 and 30 T cells then undergo apoptosis between days 7 and 30 Effector activity wanes as the amount of antigen declines Effector activity wanes as the amount of antigen declines The disposal of activated effector cells is a protective mechanism for the body The disposal of activated effector cells is a protective mechanism for the body Memory T cells remain and mediate secondary responses to the same antigen Memory T cells remain and mediate secondary responses to the same antigen T Cell Activation: Step Two – Co-stimulation

54. Mediators involved in cellular immunity, including hormonelike glycoproteins released by activated T cells and macrophages Mediators involved in cellular immunity, including hormonelike glycoproteins released by activated T cells and macrophages Some are co-stimulators of T cells and T cell proliferation Some are co-stimulators of T cells and T cell proliferation Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to: Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to: Release interleukin 2 (IL-2) Release interleukin 2 (IL-2) Synthesize more IL-2 receptors Synthesize more IL-2 receptors Cytokines

55. IL-2 is a key growth factor, which sets up a positive feedback cycle that encourages activated T cells to divide IL-2 is a key growth factor, which sets up a positive feedback cycle that encourages activated T cells to divide It is used therapeutically to enhance the body’s defenses against cancer It is used therapeutically to enhance the body’s defenses against cancer Other cytokines amplify and regulate immune and nonspecific responses Other cytokines amplify and regulate immune and nonspecific responses Cytokines

56. Examples include: Examples include: Perforin and lymphotoxin – cell toxins Perforin and lymphotoxin – cell toxins Gamma interferon – enhances the killing power of macrophages Gamma interferon – enhances the killing power of macrophages Inflammatory factors Inflammatory factors Cytokines

57. Regulatory cells that play a central role in the immune response Regulatory cells that play a central role in the immune response Once primed by APC presentation of antigen, they: Once primed by APC presentation of antigen, they: Chemically or directly stimulate proliferation of other T cells Chemically or directly stimulate proliferation of other T cells Stimulate B cells that have already become bound to antigen Stimulate B cells that have already become bound to antigen Without T H, there is no immune response Without T H, there is no immune response Helper T Cells (T H )

58. Figure 21.17a

59. T H cells interact directly with B cells that have antigen fragments on their surfaces bound to MHC II receptors T H cells interact directly with B cells that have antigen fragments on their surfaces bound to MHC II receptors T H cells stimulate B cells to divide more rapidly and begin antibody formation T H cells stimulate B cells to divide more rapidly and begin antibody formation B cells may be activated without T H cells by binding to T cell–independent antigens B cells may be activated without T H cells by binding to T cell–independent antigens Most antigens, however, require T H co- stimulation to activate B cells Most antigens, however, require T H co- stimulation to activate B cells Cytokines released by T H amplify nonspecific defenses Cytokines released by T H amplify nonspecific defenses Helper T Cell

60. Helper T Cells Figure 21.17b

61. T C cells, or killer T cells, are the only T cells that can directly attack and kill other cells T C cells, or killer T cells, are the only T cells that can directly attack and kill other cells They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized Their targets include: Their targets include: Virus-infected cells Virus-infected cells Cells with intracellular bacteria or parasites Cells with intracellular bacteria or parasites Cancer cells Cancer cells Foreign cells from blood transfusions or transplants Foreign cells from blood transfusions or transplants Cytotoxic T Cell (T c )

62. Bind to self-antiself complexes on all body cells Bind to self-antiself complexes on all body cells Infected or abnormal cells can be destroyed as long as appropriate antigen and co-stimulatory stimuli (e.g., IL-2) are present Infected or abnormal cells can be destroyed as long as appropriate antigen and co-stimulatory stimuli (e.g., IL-2) are present Natural killer cells activate their killing machinery when they bind to MICA receptor Natural killer cells activate their killing machinery when they bind to MICA receptor MICA receptor – MHC-related cell surface protein in cancer cells, virus-infected cells, and cells of transplanted organs MICA receptor – MHC-related cell surface protein in cancer cells, virus-infected cells, and cells of transplanted organs Cytotoxic T Cells

63. In some cases, T C cells: In some cases, T C cells: Bind to the target cell and release perforin into its membrane Bind to the target cell and release perforin into its membrane In the presence of Ca 2+ perforin causes cell lysis by creating transmembrane pores In the presence of Ca 2+ perforin causes cell lysis by creating transmembrane pores Other T C cells induce cell death by: Other T C cells induce cell death by: Secreting lymphotoxin, which fragments the target cell’s DNA Secreting lymphotoxin, which fragments the target cell’s DNA Secreting gamma interferon, which stimulates phagocytosis by macrophages Secreting gamma interferon, which stimulates phagocytosis by macrophages Mechanisms of T c Action

64. Figure 21.18a, b

65. Suppressor T cells (T S ) – regulatory cells that release cytokines, which suppress the activity of both T cells and B cells Suppressor T cells (T S ) – regulatory cells that release cytokines, which suppress the activity of both T cells and B cells Gamma delta T cells (T gd ) – 10% of all T cells found in the intestines that are triggered by binding to MICA receptors Gamma delta T cells (T gd ) – 10% of all T cells found in the intestines that are triggered by binding to MICA receptors Other T Cells

66. Summary of the Primary Immune Response Figure 21.19

67. Cellular Immunity Relationship between APC, MHC and Immune Response Mac (APC) digests organisms, presents antigens to T H. T H recruits T C and B-cells.

70. Cellular Immunity Cell Mediated Cytotoxicity. T C recognizes invader cell. Makes and releases perforin. Cell lyses.

71. Immunity - Dual Systems

72. Types of Immune Responses Primarily Humoral, B-Cells Most common bacteria, free viruses, soluble antigens (like toxins, proteins) Primarily Cellular, T-Cells Mycobacteria, tumor cells, virus-infected cells, protozoans, large parasites