Chapter 15

1. Chapter 15 The Immune System 15-1

2. Chapter 15 Outline • Innate Immunity • Adaptive Immunity • Complement System • T Cells • Histocompatibility Antigens • Interactions Between Antigen-Presenting Cells and Lymphocytes • Active Immunity • Passive Immunity • Immune System and Cancer • Diseases Caused By Immune System 15-2

3. Defense Mechanisms • Against pathogens constitute the immune system • Can be grouped into 2 categories: • Innate (nonspecific) immunity is inherited as part of structure of each organism • Adaptive (specific) immunity is a function of lymphocytes and changes with exposure 15-3

4. Innate Immunity 15-4

5. Innate Immunity • Distinguishes between “self” and “non-self” • Is 1st line of defense against invading pathogens • Includes epithelial barriers, high acidity of gastric juice, phagocytosis, and fever 15-5

6. Phagocytosis • Is triggered in response to pathogen-associated molecular patterns (PAMPs) produced only by microorganisms • Best known are lipopolysaccharide (LPS) from gram-bacteria and peptidoglycan from gram+s • Some immune cells have receptors for PAMPs (called Toll receptors) 15-6

7. Phagocytosis continued • Is performed by 3 classes of phagocytic cells: • Neutrophils - 1st to arrive at infection sites • Mononuclear phagocytes - macrophages and monocytes • Organ-specific phagocytes in liver, spleen, lymph nodes, lungs, and brain • Fixed phagocytes line sinusoids of liver, spleen, and lymph nodes and remove pathogens 15-7

8. Phagocytosis continued • Connective tissue and blood contain mobile leukocytes (WBCs) • These are attracted to infection (chemotaxis) by chemokines • WBCs from blood exit capillaries by extravasation (diapedesis) and ingest pathogens 15-8

9. Phagocytosis continued • Pseudopods from phagocyte surround pathogen • Forming a vacuole • Vacuole fuses with lysosomes which digest pathogen 15-9

10. Fever • Appears to be component of innate immunity • Occurs when hypothalamic thermostat is reset upwards by IL1- and other cytokines (endogenous pyrogens) • Pyrogens are released by WBCs in response to endotoxin from gram– bacteria 15-10

11. Interferons • Are polypeptides produced by cells infected with virus that provide short-acting, non-specific resistance to viral infection in nearby cells • 3 types: a, b, g, interferon 15-11

12. 15-12

13. 15-13

14. Adaptive Immunity 15-14

15. Adaptive Immunity • Is acquired ability to defend against specific pathogens by prior exposure to those pathogens • Is mediated by production of specific antibodies by lymphocytes 15-15

16. Antigens • Are molecules that elicit production of antibodies that specifically bind those antigens • Are usually large molecules that are foreign to the body • Immune system can distinguish “self” molecules from non-self antigens • Normally makes antibodies only against non-self antigens • Large, complex molecules can have a number of antigenic determinant sites (different sites that stimulate production of, and bind to, different antibodies) 15-16

17. Haptens • Are small non-antigenic molecules that become antigens when bound to proteins (form an antigenic determinant site) • Useful for creating antibodies for research and diagnosis 15-17

18. Immunoassays • Are tests that use specific antibodies to identify a particular antigen • The binding of antibody to antigen causes clumping (agglutination) which can be visualized 15-18

19. Lymphocytes • Are derived from stem cells in bone marrow • Which replace selves by cell division so are not depleted • Lymphocytes produced by this process seed thymus, spleen, and lymph nodes with self-replacing colonies 15-19

20. T Lymphocytes (T cells) • Develop from lymphocytes that seed thymus • Do not secrete antibodies • Attack infected host cells, cancer cells, and foreign cells • Thus they provide cell-mediated immunity • Supply 65 – 85% of lymphocytes for blood and most of lymphocytes in germinal centers of lymph nodes and spleen 15-20

21. B Lymphocytes (B cells) • Fight bacterial infections by secreting antibodies into blood and lymph • Thus provide humoral immunity 15-21

22. Thymus • Is located below the thyroid gland • Grows during childhood, gradually regresses after puberty • Contains T cells that supply other tissues • T cells can be depleted, e.g. by AIDs or chemotherapy • These can only be replenished up to late childhood • After that, repopulation is accomplished by production in secondary lymphoid organs 15-22

23. Secondary Lymphoid Organs • Consist of lymph nodes, spleen, tonsils, and Peyer’s patches • Located in areas where antigens could gain entry to blood or lymph • Lymphocytes migrate constantly through blood and lymph from one lymphoid organ to another • Enhances chance that antibody will encounter its antigen • Spleen filters blood; other lymphoid organs filter lymph 15-23

24. Local Inflammation • Occurs when bacteria enter a break in the skin • Inflammatory reaction is initiated by nonspecific mechanisms of phagocytosis and complement activation • Complement activation attracts phagocytes to area 15-24

25. Local Inflammation continued • As inflammation progresses, B cells produce antibodies against bacterial antigens • Attachment of antibodies to antigens amplifies nonspecific responses because of complement activation • And promotes phagocytic activity of neutrophils, macrophages, and monocytes (= opsinization) 15-25

26. Local Inflammation continued • In inflamed area, leukocytes attach to surface of endothelial cells • Move by chemotaxis to inflamed site • Neutrophils arrive 1st, then monocytes, then T cells • Undergo extravasation 15-26

27. Local Inflammation continued • Mast cells secrete heparin, histamine, prostaglandins, leukotrienes, cytokines, and TNF-a • These produce redness, warmth, swelling, pus, and pain • Recruit more leukocytes • If infection continues, endogenous pyrogens are released 15-27

28. B Lymphocytes (B cells) • Have antibodies on surface that are receptors for antigens • When bound to antigen, are stimulated to divide and secrete antibodies 15-28

29. B Lymphocytes (B cells) continued • When B cells divide, some progeny become memory cells • Others become plasma cells that produce about 2000 antibodies/sec that are specific for original antigen • This provides active immunity 15-29

30. B Lymphocytes (B cells) continued • Binding of B cells to antigen also triggers a cascade of reactions that activate complement proteins • Complement proteins can kill antigen-bearing cells and promote phagocytosis 15-30

31. Antibodies • Are proteins called immunoglobulins • Part of gamma globulin class of plasma proteins • Antibodies have same basic structure but their differences provide for antibody specificity 15-31

32. 15-32

33. Antibody Structure • Is in shape of “Y” • 2 long heavy (H) chains are joined to 2 shorter light (L) chains • When cleaved, stalk of Y becomes crystallizable fragment (Fc) • Fc is constant among different antibodies • Arms of Y contain antigen-binding fragment (Fab) • Fab contains a variable region that confers antibody specifity 15-33

34. Antibody Diversity • Each person has about 1020 antibody molecules • With a few million different specificities • Likely there is an antibody specific for any antigen a person might encounter 15-34

35. Antibody Diversity continued • 2 mechanisms might account for diversity • If a few hundred genes code for Hs and a few hundred for Ls, different combinations could lead to millions of different antibodies • Recombination of these in developing lymphocytes of marrow produces antigen-independent diversity • Diversity further increases via somatic hypermutation • Occurs as B cells undergo antigen dependent proliferation in 2o lymphoid tissues in response to foreign antigens 15-35

36. Complement System 15-36

37. The Complement System • Is part of nonspecific defense system • Activity is triggered by binding of antibodies to antigens (classic pathway) and by bacterial coat polysaccharides (alternative pathway) • Binding of antibodies to antigens does not by itself destroy antigens or pathogens • Antibodies label targets for complement system attack and also stimulate opsonization 15-37

38. The Complement System continued • Is a series of proteins whose activation forms a membrane attack complex which perforates a cell causing it to lyse • Complement proteins can be subdivided into 3 functional groups: • C1 - recognition • C4, C2, C3 - activation • C5-C9 - attack (complement fixation) • These form the membrane attack complex 15-38

39. The Complement System continued • In classic pathway, antibody-antigen binding activates C1 • C1 hydrolyzes C4 into C4a and C4b • C4b binds to cell membrane and becomes active, splitting C2 into C2a and C2b • C2a attaches to C4b and cleaves C3 into C3a and C3b • Alternate pathway also cleaves C3 (and so converges with classic pathway at this step) • C3b converts C5 to C5a and C5b 15-39

40. Fixation of Complement Proteins 15-40

41. Membrane Attack Complex • C5b and C6 - C9 are inserted into bacterial cell membrane, forming membrane attack complex • This creates large pore in membrane, causing osmotic influx of H2O, lysis, and cell death 15-41

42. Complement Fragments • That are liberated during activation have a number of effects, including • Attracting phagocytes (chemotaxis) • Phagocytes have receptors for C3b which can serve as bridge to victim cell • C3a and C5a stimulate mast cells to secrete histamine • Which increases blood flow and capillary permeability, bringing in more phagocytes 15-42

43. T Cells 15-43

44. Killer or Cytotoxic T Cells • Carry CD8 cell surface marker • Destroy body cells that possess foreign antigens • Usually from a pathogen, but can be from malignancy or self cells never seen by immune system • Kill by cell-mediated destruction • That is, must be in contact with victim cell • Kill by secreting perforins which create a pore in victim's membrane and cause lysis • Also secrete granzymes which cause destruction of victim's DNA 15-44

45. Helper and Suppressor T Cells • Helper Ts carry CD4 surface marker • Indirectly participate by enhancing responses of both killer T cells and B cells • Regulatory Ts decrease responses of killer Ts and B cells • Carry CD25 surface marker (and CD4) • Help protect against autoimmune responses 15-45

46. Lymphokines • Are cytokines secreted by lymphocytes • Usually called interleukin-1, 2, 3 . . . or IL-1, IL-2 . . . 15-46

47. T Cell Receptor Proteins • Only protein antigens are recognized by most T cells • T cell receptors cannot bind to free antigens • T cells respond to foreign antigens when they are presented on surface of antigen-presenting cells • Chief antigen presenting cells are macrophages and dendritic cells 15-47

48. Dendritic Cells • Originate in marrow, then migrate to most tissues • Prominent where pathogens might enter body • Engulf protein antigens, partially digest them, and display polypeptide fragments on surface for T cells to "see" 15-48

49. Dendritic Cells continued • Fragments are associated on surface with histocompatibility antigens which are necessary to activate Ts • To increase chance of interacting with correct T cells, dendritics migrate to secondary lymphoid organs • Where secrete chemokines to attract Ts 15-49

50. Histocompatibility Antigens 15-50