1. Introduction to Immunology By Dr. Nabil El Aila Assistant Professor of Medical Microbiology Medical Technology Department Al -Aqsa University

2. Immunity 1.Immunity: : Meaning the state of protection from infectious disease. In 430BC, a plaque in Athens, Those who recovered from the plaque would not contact the disease a second time. 2. Agents: microorganisms (viruses, bacteria etc) and their products, foods, chemicals, pollen, tumor cells, etc. 3.Immune system: immune tissues and organs, immune cells, immune molecules 4.Immune response: collective and coordinated response to the introduction of foreign substances. 5.Immunology: study the structure of immune system and its functions.

3. Immune Response  I nnate immune response natural immune response non-specific immune response  Adaptive immune response acquired immune response specific immune response

4. CharacteristicsCellsMolecules Innate immunity Responds rapidly No memory No or low specificity Physical barriers Phagocytes (PMNs and macrophages) Natural killer cells Humoral factors Complement Acute phase Proteins Cytokines Adaptive immunity Responds Slowly Memory Highly specific T cells B cells Dendritic cells Antibodies Cytokines Granzymes The innate and adaptive immune response

5. Adaptive immune response

6. Innate vs. Adaptive Immune Innate: structural defenses; responds to nonspecific foreign substances  First line: external surface epithelium & membranes  Second line: internal defenses: inflammatory processes – antimicrobial proteins, phagocytes, etc.

7. Innate vs. Adaptive Immune Adaptive: responds to specific foreign substances Innate & adaptive mechanisms work together

8. Innate, Defenses

9. Innate, Surface Defenses Skin  physical barrier to microbes  Keratin resistant to most bacterial enzymes & toxins  secretions are acidic pH 3-5 Mucosa  physical barrier & produces a variety of protective chemicals Gastric mucosa  very acidic & produces proteolytic enzymes Saliva & lacrimal fluid contain lysozyme Mucous  traps bacteria & moves them away from epithelial surface

11. LACRIMAL APPARATUS.

12. CILIARY ESCALATOR.

13. Innate, Defenses

14. Innate, Internal Defenses Based on recognition of surface carbohydrates (glycocalyx)  Glycocalyx is recognized as “self” or “non-self”

15. Innate, Internal Defenses Phagocytes  Macrophages: derived from monocytes Free Macrophages: roam through tissues Fixed Macrophages: Kupffer cells (liver) & microglia cells (brain) Ingest cellular debris, foreign material, bacteria, fungi  Neutrophils: ingest pathogens  Eosinophils: weakly phagocytic of pathogens. Attack parasites (degranulation)  Mast Cells: phagocytic of various bacteria

16. Innate, Internal Defenses Phagocytic mechanisms:  Adherence: cell binds to invader Aided by opsonization (a chemical process that enhances binding via complement & antibodies)  Ingestion: formation of phagolysosomes Respiratory Bursts: merge phagosome with lysosome & flood phagolysosome with free radicals (macrophage) Defensins: proteins that crystallize out of solution & pierce pathogen membranes (neutrophils)

17. Mechanism of Phagocytosis Figure 21.2

18. Innate, Defenses

19. Innate, Internal Defenses Natural Killer Cells:  Small population of large granular lymphocytes  Non specific for “non-self”  Not phagocytic: attack is by release of perforins that perforate the target cell plasma membrane. Shortly after perforation the target nucleus disintegrates.  Release chemicals that enhance the inflammatory response

20. Innate, Defenses

21. Innate, Internal Defenses: Inflammation tissue response to injury Triggered by injury – trauma, heat, chemical irritation, infection, etc. Beneficial effects  Prevents spread of injury  Disposes of cellular debris & pathogens  Promotes repair

22. Innate, Internal Defenses: Inflammation cardinal signs of inflammation  Redness  Heat  Swelling  Pain  (functional impairment Rigon)

23. Innate, Internal Defenses: Inflammation Inflammatory response: signs are associated with vasodilation & increased vascular permeability  Dilation: redness, heat  Permeability: edema, (increased pressure) pain  Pain also associated with bacterial toxins & some mediators (kinins, PGs)

24. Innate, Internal Defenses: Inflammatory Response Mechanisms causing vasodilation & vascular permeability  Injured cells release inflammatory mediators Histamines Kinins Prostaglandins Complement Cytokines (also activated by receptors on macrophages in response to microbial glycocalyx)

25. Innate, Internal Defenses: Inflammatory Response Edema  Dilutes harmful substances repair  Provides nutrients (& O 2 ) for repair  Enhances entry of clotting protein Epithelial breaches also stimulate b-defensin release from epithelial cells

26. Events in Inflammation Figure 21.3

27. Innate, Internal Defenses: Inflammatory Response Phagocyte mobilization: infiltration of damaged area by neutrophils & macrophages

28. Innate, Internal Defenses: Inflammatory Response Leukocytosis: leukocytosis inducing factors released by injured cells promote rapid release of WBCs from marrow CAMs Margination: increased vascular permeability causes decreased fluid in vessels; blood flow slows & neutrophils are able to move to vessel margins. Here endothelial markers (CAMs) allow neutrophils to cling to vessel walls (pavementing).

29. Innate, Internal Defenses: Inflammatory Response Diapedesis: neutrophils migrate through capillary walls Chemotaxis – inflammatory chemicals attract neutrophils to move up the chemical concentration gradient (neutrophils respond first) As the process continues, monocytes diapedes into the area & become macrophages. With chronic inflammation, macrophages predominate

30. Inflammatory Response: Phagocytic Mobilization Figure 21.4

31. Innate, Internal Defenses: Inflammatory Response Macrophages clean up cellular debris & pathogens If pathogens were associated with the injury, activation of the complement cascade occurs & elements of adaptive immunity join the process

32. Innate, Internal Defenses Viral replication – (viruses lack metabolic processes) Viruses release nucleic acid (RNA or DNA) into cytoplasm. The information on the nucleic acid is incorporated into the cell’s DNA. Normal cellular mechanisms then produce viral structural components. Multiple new viral particles are produced & released from the cell (sometimes killing the cell)

33. Innate, Internal Defenses Antiviral proteins: interferon & complement Interferon: some cells produce & release interferons (IFNs) when invaded by virus Released interferons stimulate nearby cells to produce proteins (PKR) that interfere with viral replication by disrupting protein synthesis & the ribosome Not virus specific.

34. Interferon (IFN) Figure 21.5

35. Innate, Internal Defenses Complement – a group of plasma proteins (20) that are activated in the presence of foreign substances Complement activation enhances & amplifies inflammation Bacteria & some other cell types are lysed by complement activation Complement activation enhances both innate & adaptive defenses

36. Innate, Internal Defenses Complement activation pathways  Classical pathway: requires antibodies Antibodies bind to target (antigen) Complement protein C1 binds to the antibody- antigen complex (complement fixation)  Alternative pathway: complement factors interact with microorganism glycocalyx Both pathways lead to a cascade of protein activation, leading to activation of C3

37. Innate, Internal Defenses; Complement Figure 21.6

38. Innate, Internal Defenses C-reactive proteins (CRP) produced by the liver in response to inflammatory molecules can activate the classical pathway by binding to membrane & activating C1. Also participates in opsonization. Fever – a systemic response to infection. Leukocytes & macrophages release pyrogens that raise the hypothalamic “set point” for temperature

39. ADAPTIVE DEFENSES  Innate & adaptive mechanisms work together in a cohesive fashion

40. Adaptive Defenses: Characteristics Specificity: directed at specific targets Systemic: not restricted to initial site of infection / invasion Memory: after initial exposure & activation, a more rapid & more vigorous response is made to subsequent exposures to pathogens  (secondary response)

41. Adaptive Defenses: Components Humoral Immunity: (antibody mediated immunity) provided by antibodies floating free in body fluids Cell mediated immunity:  lymphocytes directly attack specific invaders by lysis or indirect attack by initiating inflammation and/or activating other lymphocytes & macrophages

42. Adaptive, Humoral Immunity Antigen = any substance that can mobilize the immune system & provoke an immune response* *Humoral and/or cell mediated

43. Adaptive, Humoral Immunity Complete antigens (proteins, nucleic acids, lipids, polysaccharides):  Immunogenicity: the ability to stimulate specific lymphocytes & specific antibodies  Reactivity: the ability to react with activated lymphocytes & antibodies Hapten (an incomplete antigen): a smaller molecule that is not immunogenic until attached to proteins

44. Adaptive, Humoral Immunity Antigenic determinants: sites on an antigenic molecule that are immunogenic  Epitope Major Histocompatibility Complex (MHC): cell surface glycoproteins associated with self recognition

45. Adaptive Immune System: Cells Lymphocytes  T-cells  B-cells Antigen Presenting Cells (APCs)

46. Adaptive Immune System: Cells Lymphocytes: initially uncommitted T-cells: are sorted in the Thymus  Positive selection: recognize MHC survive  Negative selection: react against to self-antigens on MHC killed  2% of initial T-cell precursors  T-cells manage the immune response B-cells: are sorted in the marrow by an incompletely understood process

48. Adaptive Immune System: Cells Immunocompetence: as T- or B-cells mature they become immunocompetent, they display receptors on their cell membrane for a specific antigen. All of the receptors on one cell are identical; immunity depends upon genetic coding for appropriate receptors.

49. Adaptive Immune System: Cells Antigen Presenting Cells (APCs) APCs ingest foreign material, then present antigenic fragments on their cell surface where they are recognized by T-cells  T-cells: respond to antigen only if it is displayed on plasma membrane. APCs: Macrophages & B lymphocytes Interactions between APCs & lymphocytes & lymphocyte-lymphocyte interactions are critical to immune response

50. Adaptive, Humoral response Humoral response (clonal selection) B-cells: Antigen challenge to naïve immunocompetent B-cell Antigen binds to B-cell receptors & form cross-links between receptors Cross linked antigen-receptor complex undergoes endocytosis; B-cell presents to T-cell

53. Humoral Immunity Active humoral immunity:  B-cells encounter & respond to antigen to produce an antibody Passive humoral immunity:  Introduced “non-native” antibody

54. Active Humoral Immunity Naturally acquired: natural exposure to antigen (i.e. infection) Artificially acquired: vaccines; dead/attenuated or fragmented pathogen injected to elicit an immune response  Bestow immunity without disease; primary response  Booster shots (secondary response); intensify response  Shortcomings – adverse reactions & the immunity is less durable (poor memory) & has less cell mediated component

55. Passive Humoral Immunity Natural: maternal antibody crosses the placental barrier conferring temporary immunity to the baby (degrades after a few months) Artificial: antibodies harvested from an outside source given by injection protect from immediate threat but no memory is formed (antitoxins, antivenins, gamma globulin, etc.)

56. Antibodies A.K.A Immunoglobulins & gamma globulins Structure  variable  hypervariable  constant

57. Antibodies Constant (C) region defines antibody class determines chemical & cellular interactions determines how class functions to eliminate antigens

58. Antibody Classes Antibody Classes: IgM, IgG, IgA, IgD, IgE (Ig = immunoglobulin)

59. Antibody Classes IgG: the most abundant circulating Ig. The dominant circulating Ig of the primary & the secondary response. Crosses the placenta. Complement binding (Monomer). IgA: the Ig of secretions. Helps prevent antigen penetration of membranes (Dimer). IgD: the Ig of B-cell activation. Found on B-cell surface (Monomer).

60. Antibody Classes IgM: occurs as a monomer & a pentamer  Occurs on the B-cell surface (Monomer).  The Ig of early primary plasma cell response, circulating antibody; a potent agglutinator. Complement binding (Pentamer).

61. Antibody Classes IgE: the Ig associated with allergies.  Stem binds to mast cells & basophils.  Receptor binding results in histamine release & inflammation.  Found mostly in mucosa of respiratory & GI tract (Monomer).

62. Antibody Targets & Functions Immune complex formation = antigen-antibody binding. All the following events are initiated by antigen-antibody binding. Complement fixation: Neutralization: Agglutination: Precipitation: Inflammation & phagocytosis prompted by debris

63. Antibody Targets & Functions Complement fixation: cells & bacteria.  Immune complex formation exposes a complement binding site on the C region of the Ig.  Complement fixation results in cell lysis. Neutralization: immune complex formation blocks specific sites on virus or toxin & prohibit binding to tissues Agglutination: cells are crosslinked by immune complexes & clump together Precipitation: soluble molecules (such as toxins) are crosslinked, become insoluble, & precipitate out of the solution Inflammation & phagocytosis prompted by debris

65. Antibody Targets & Functions Monoclonal antibodies: antibodies produced by descendants of a single cell  Pure antibody preparations that are specific for a single antigenic determinant  Research / diagnostic / therapeutic use

66. Cell Mediated Immune Response T-cell activation: involves recognition of PM surface antigens only  Antigen is combined with MHC & displayed on PM  T-cell receptors: bind to the MHC & are stimulated by the associated antigen  The addition of a co-stimulator (cytokines, interleukins, etc) prompts the T-cell to form a clone  In the absence of a co-stimulator the T-cell becomes tolerant to antigen (anergy)

67. Cell Mediated: MHC MHC occurs as two classes  MHC I on virtually all tissue cells  MHC II only on PM some immune system cells

68. Cell Mediated: MHC display properties MHC I on virtually all tissue cells  Display only proteins produced inside the cell  Endogenous antigens = foreign proteins produced by the cell (viral / cancer)  Stimulate the CD8* cell population form cytotoxic T-cells (Killer T, TC) *formerly T8 cells

70. Cell Mediated: MHC display properties MHC II found only on PM of B-cells, some T-cells & APCs  Display proteins derived from a phagocytized target  Exogenous antigen: foreign protein from outside the cell – presented to PM surface  Stimulates the CD4* cell population form Helper T-cells (T H ) *formerly T4 cells

72. Cell Mediated: T-cell roles Helper T-cells (T H ) stimulate B-cells & other T-cells to proliferate

73. Cell Mediated: T-cell roles Activated T H cells interact with B-cells displaying antigen & produce cytokines that prompt the B-cell to mature & form antibody

74. Cell Mediated: T-cell roles T H cells also produce cytokines that promote T C cells T H cells recruit other WBCs & amplify innate defenses (inflammatory) Subpopulations of T H cells specialize in specific sets of activations

75. Cell Mediated: T-cell roles Cytotoxic T-cells (T C, Killer T): directly attack & kill cells with specific antigen Activated T C cells are co-stimulated by T H cells

76. Cell Mediated: T-cell roles T C mechanism (Cytotoxic T-cells, Killer T)  T C binds to cell & releases perforin & granzymes  In the presence of Ca 2+ perforin forms pores in target cell PM  Granzymes enter through pores & degrade cellular contents  T C then detaches & moves on  Macrophages clean up

77. Cells, tissues and organs of the immune system n Immune cells are bone marrow-derived, & distributed through out the body n Primary lymphoid organs: – Thymus: T cell maturation – Bone marrow (bursa of Fabricius in birds): B cell maturation n Secondary lymphoid organs: – Lymph nodes – Spleen – Mucosal lymphoid tissues (lung, gut)

78. Cells of the Immune system: FORMED ELEMENTS IN BLOOD n Many cells of the immune system derived from the bone marrow n Hematopoetic stem cell differentiation

79. COMPONENTS OF THE LYMPHATIC SYSTEM.

81. The bursa of Fabricius in birds

82. Types of Acquired Immunity Figure 21.11

83. Major Types of T Cells Figure 21.14

84. T Cell Activation: Step One – Antigen Binding Figure 21.16

85. Helper T Cells (T H ) Figure 21.17a

86. Helper T Cells Figure 21.17b

88. Summary of the Primary Immune Response Figure 21.19