Introduction to the immune system: - PowerPoint Presentation

1. Introduction to the immune system:innate immunityProf dr. Ihsan Edan Alsaimarydepartment of microbiology – college of medicine – university of basrah Mobile : 07801410838 - e.mail : ihsanalsaimary@gmail.com

2. ImmunityImmunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells

3. History: what imparts Immunity?Emil von Behring and Kitasato (1890)Serum from vaccinated animals was protective (diptheria)Metchinkoff (1880)Cell based ImmunityMerrill Chase (1940)- Transfer of WBC (immunity to tuberculosis) Both serum and cells contribute to immunity

4. Immunology- nobel prizesSince 1901 there have been 19 Nobel Prizes for immunology-related research.

5. The immune systemA functional system – NOT an organ system:Complex system – includesSkin – physical barrierLining of mucus membranes – physical barrierSecretions – tears, mucus etc - antimicrobialBlood cells and vasculature – WBCsBone marrowLiver – makes complement proteinsLymphatic system and lymphoid organsMost tissues – have resident immune cells

6. Immunity Immunity (immunis- Latin-exempt, state of protection from infectious diseases)Immunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells consists of following activities: Defense against invading pathogens (viruses & bacteria) Removal of 'worn-out' cells (e.g., old RBCs) & tissue debris (e.g., from injury or disease) Identification & destruction of abnormal or mutant cells (primary defense against cancer) Rejection of 'foreign' cells (e.g., organ transplant) Inappropriate responses: Allergies - response to normally harmless substances Autoimmune diseases

7. Overview of the Immune System Interactions between the two systems

8. A typical immune responseINNATE IMMUNITY Rapid responses to a broad range of microbesACQUIRED IMMUNITYSlower responses to specific microbesExternal defensesInternal defensesSkinMucous membranesSecretionsPhagocytic cellsAntimicrobial proteinsInflammatory responseNatural killer cellsHumoral response(antibodies)Cell-mediated response(cytotoxic lymphocytes)Invadingmicrobes(pathogens)Complement

9. Innate immunity vs Adaptive Immunity No memory No time lagNot antigen specificA lag periodAntigen specificDevelopmentof memoryInnate Immunity(first line of defense) Adaptive Immunity(second line of defense)

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11. The innate immune System Interactions between the two systems

12. Innate immune system External defenses

13. Anatomical Barriers - Mechanical FactorsSkin Flushing action of saliva, tears, urine Mucociliary escalator

14. Anatomical Barriers – Chemical factorsAntimicrobial Peptides in sweat Lysozyme in tears /salivaHCl in stomach

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17. Anatomical Barriers – Biological factors Normal flora – microbes in many parts of the bodyNormal flora – competes with pathogensfor nutrients and space Normal flora – > 1000 species of bacteria

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19. Innate immune system internal defenses

20. Innate immune system: components of Blood  Complement proteinsCoagulation proteinsCytokinesWBCsExtracellular

21. White blood cells (WBCs)MacrophagesB-lymphocytesT-lymphocytesNatural killer(NK) cellsMast cells

22. Neutrophils in innate immune responseMost abundant WBCs (~50-60%)Efficient phagocytesMost important cells of the innate immune system

23. PhagocytosisPhago = to eatCyte = cellWBCs (eg. Neutrophils) – find, eat and digest microbes !

24. How do neutrophils eat and digest microbes ?Granules

25. What’s in the granules ?Lysozyme – digests bacterial cell wall; other antimicrobial proteins

26. Additional role of neutrophilsTriggers inflammatory response

27. MonocytesMonocytes (~5% of WBCs)Migrate into the tissues and become Macrophages Lung Bone Liver Brain intestine

28. Macrophages“Big eaters”Phagocytosis of microbes in tissue (neutrophils are present only in blood)Antigen presentation

29. Natural killer cellsNot B-lymphocytes / T-lymphocytesImportant part of the innate immune systemKill virus /bacteria infected cells (Intracellular pathogens)Kills cancer cells

30. NK cells differentiate choose cells to kill ?Uninfected cell / Normal cellMicrobe infected cell / cancer cellSome cell surface proteins are missing

31. How does the killer kill ?Kills both host cells and microbesRelease of granules with perforins and proteases

32. Toll-like receptors (TLRs)Transmembrane proteinsPresent on macrophages / few other cellsConserved across vertebratesImportant part of innate immune system

33. TLRs – What do they do ?They look out for microbes (or their components)They bind to the microbes (or their components)They trigger a cascade of events to kill or protect against pathogens THEY ARE INNATE IMMUNE SENSORS

34. TLRs – look out for microbes

35. TLRs – bind to microbes / components of microbes

36. Which microbial components are recognized by TLRs ?

37. What happens when a TLR bind to a microbe ?TLR binding to microbeInflammationSecretion of Cytokines / InterferonPhagocytosis of infected cellApoptosis of infected cellEnhanced immune responseKilling of infected cell

38. Summary: innate response – internal defenses – Cellular (WBCs)Come into play when the external defenses are breachedNeutrophilsMonocytes /macrophagesNK cellsTLRs

39. Innate immune system: components of Blood  Complement proteinsCoagulation proteinsCytokinesWBCs

40. CytokinesSmall proteins – secreted by cells of the immune systemAffect the behaviour of other cellssignalling moleculesKey players in innate and acquired immunity

41. Which cells release cytokines ?Cells of the immune system:Neutrophils – when they encounter a pathogen Macrophages – when they encounter a pathogenTLRs – bind to microbe / components of a microbeNK cells – on encountering a microbe infected cell /tumour cellLymphocytes – when they are activated

42. Examples of cytokinesInterferonsInterleukinsTumour necrosis factor (TNF)

43. Interferons (IFN)Signalling proteins produced by by virus infected monocytes and lymphocytesSecreted proteins – Key anti-viral proteins“Interfere” with virus replication Warn the neighbouring cells that a virus is around... If we did not have IFNs – most of us may die of influenza virus infection

44. How do interferons inhibit viruses ?Host proteinInductionCascade of eventsVirus ds-RNAActivationInactive host proteinActive host proteinInhibition of host protein synthesis Virus cannot replicate

45. InterleukinsInterleukins – 1-37Not stored inside cellsQuickly synthesized and secreted in response to infectionKey modulators of behaviour of immune cellsMostly secreted by T-lymphocytes & macrophages

46. What to interleukins do ?Interleukins Proliferation of immune cells Activation of immune cellsIncrease antibody production Inflammation

47. Tumour necrosis factor (TNF)TNFKilling of cancer Fever Inflammation

48. Complement (C`) a large number of distinct plasma proteins that react with one another (C1 thro’ C9)Complement can bind to microbes and coat the microbesEssential part of innate immune responseEnhances adaptive immune resposne (taught later)

49. Complement proteins: role in innate immune systemC`proteins Inflammation Facilitates phagocytosis Direct lysis of pathogens

50. How do C` proteins facilitate phagocystosis ? Bacteria coated with C`Neutrophils have C` receptorsInitiation of phagocytosis

51. How do C` proteins lyse pathogens?Membrane attack complex formed by c` proteins

52. Coagulation proteinsCoagulation: mechanism to stop bleeding after injury to blood vesselsComplex pathway involvesPlateletsCoagulation factorsVitamin K

53. How does blood clot ?

54. Coagulation: Delicate balanceCoagulation proteinsAnticoagulantsBlood clottingInflammationApoptosis (prog. Cell death)Prevent blood clottingInhibit inflammationInhibit apoptosisToo much of clotting – Problem Too little clotting - ProblemMaintenance of a balance

55. Coagulation and innate immunityCoagulation proteinsAnticoagulantsPathogens and cytokinesIncreased inflammation and increased apoptosis of infected cells

56. InflammationComplex biological process by which body responds to pathogens and irritantsAssociated with swelling of tissueKey player in innate immune repsone

57. All roads lead to inflammationInflammationNeutrophilsMonocytes /macrophagesNK cellsTLRsCytokines /IFNC` proteinsCoagulation proteinsCellularExtracellular

58. Inflammation and vascular changesVasodilatationIncreased capillary permeabilityNormal blood vesselDilated blood vesselNormal blood vesselLeaky blood vessel

59. Signs of inflammationVascular changesVasodilatationCapillary permeabilityHeat / rednessTemporary loss of functionFeverSwellingPain

60. Inflammation and innate immunityMast cells – similar to basophils in blood; mast cells are present in tissues and release histamines in response to wound / infection /irritantHistamine Pathogen removalAdaptive immune response+ + +

61. Summary: role of Inflammation in innate immunityInitiation of phagocytosis – killing of pathogenLimiting the spread of infectionStimulate adaptive immune responseInitiate tissue repair

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63. Chronic inflammation = tissue damageChronic inflammation - macrophages in the injured tissue. Macrophages release toxins (including reactive oxygen species or ROS) that injure tissueschronic inflammation is almost always accompanied by tissue destruction.Normal tissueTissue : chronic inflammation

64. Chronic inflammation and tissue damageReduced tissue functionTissue damageChronic inflammationActivation of immune cellsKilling of host cells

65. Chronic inflammation and CancerROSO2- OH-DNA MutationCancer

66. Immunogens and antigensImmunogen / antigen: a substance that elicits an immune response [i.e. a humoral (antibody response) or cell-mediated immune response]Immune response generator Though the two terms are used interchangeably – there are differences between the two

67. EpitopeEpitope: the portion of an antigen that is recognized and bound by an antibody (Ab) or a T-cell receptor (TCR)epitope = antigenic determinant

68. EpitopesEpitope: the portion of an antigen that is recognized and bound by an Ab or a T Cell receptorOne protein may have multiple antigenic determinant

69. EpitopesB-cell Epitopes – recognized by B-cells T-cell Epitopes – recognized by T cells

70. ImmunogenicityImmunogencity: is the ability to induce a humoral (antibody) and/or cell-mediated immune response. Weak immunogens Strong immunogens

71. What determines immunogenicity ?Foreignness: essential for immunogenicity (self-responsive immune cells are eliminated during lymphocyte development)Size: Bigger>SmallerChemical composition: Proteins > nucleic acids / polysaccharides / lipidsStructure: Primary /secondary /tertiary structures play a rolePhysical form: Particulate> Soluble

72. Host factors affecting immunogencityDifference across species (interspecies)Differences within a species (intraspecies) - Responders / non-responders to vaccine - differences in disease severity in epidemicsGeneticsAge

73. IsoantigensIsoantigens: Antigens present in some but not all members of a speciesBlood group antigens – basis of blood groupingMHC (major histocompatibility complex)- cell surface glycoproteins

74. AutoantigensAutoantigens are substances capable of immunizing the host from which they are obtained. Self antigens are ordinarily non-antigenicModifications of self-antigens are capable of eliciting an immune response

75. HaptensHaptens are small molecules which are non-immunogenic, thus could never induce an immune response by themselves.

76. Examples of haptensDO NOT ELICIT an immune response by themselves

77. If any invader penetrate the body’s first line defense mechanisms:The second line or the first line immunologic defense  Innate immunityAlways active or nearly activeAdaptive responses devolope usually later (after 96 hours)

78. Innate immunity is prorammed to:To recognize broad range of molecules asscociated with pathogensTo destroy the invaders rapidly: Activation of the phagocytic system and devoloping an inflmmatory response

79. Recognition of the microbes by innate immunityTo recognize those structures, common to the various agent, but bor present in humanPhagocytes have LPS specific receptorsPhagocytes recognize mannose residues which are present only in glycoproteins of mammalian origine

80. Phagocytes recognise and response also to:Ds RNA, unmethylated CpG oligonucleotides

81. The molecules of the microbes targeted by th immune system are -pathogen asscociated molecular patterns (PAMPs)The receptors of the innate immunity for these molecules are “pattern recognition receptors” (PRRs)The targets of the innate immunity are critical regarding the survival and infectivity of the microbes

82. Innate immunity can also recognise those molecules released from demaged or stressed cells of the body  damage asscociated molecular patterns (DAMPs)

83. These receptors are encoded in the germline  Receptors expressed on all cells of a certain type (not clonal)Innate immunity does not reat against the hostİnnate immunity respond in the same way to repeated invasions

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85. The main goals of the innate immunityTo induce inflammationTo achieve antiviral defense

86. Receptors expressed onPhagocytes, DC, lynphocytes, epithelial and endothelial cellsReceptors are expressed on different compartments of these cells

87. Toll like receptors (TLR)

88. TLR activates transcription factors, which stimulate the expression of genes encoding cytokines, enzymes and other proteinsMost important transcription factors are:Nuclear factor-kappaB (NF-kappaB) and interferon response factor -3 (IRF-3)

89. NF-kappaB promotes expression of cytokines and endothelialadhesion factorIRF-3 stimulates type I interferons and cytokines with antiviral activity

90. Soluble defense mechanismsTYpe I interferons: DC (IFN-alfa), fibroblasts (IFN-beta)Microbicidal molecules: Epithelial cells, PMN and macrophages secrete cystein rich peptides (defensines). Others are cathelicdine, lysozyme, DNAase, RNAase

91. Complement

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99. Steps in PhagocytosisAttachmentbacterial carbohydrates (lectins)receptor for opsoninsfibronectin receptorsFc receptorsInternalization (phagocytic vacuole)Digestion (phagosome)

100. Antibacterial compounds of the phagolysosome IOxygen-dependent compoundsHydrogen peroxide: NADPH oxidase and NADHSuperoxideHydroxil radicals (OH)Activated halides (Cl_, I_, Br_): myeloperoxidaseNitrous oxide

101. Antibacterial compounds of the phagolysosome IIOxygen-independent compoundsAcidsLysosome (degrades bacterial peptidoglycan)Lactoferrin (chelates iron)Defensin and other cationic proteins (damage membranes)Proteases, elastase, cathepsin G

102. Phagocytosis & killing of bacteria

103. Macrophages in antibacterial responseImportant antibacterial phagocytic cellsKilling by oxygen-dependent and oxygen-independent mechanismsProduction of IL-1, IL-6, and IL-12; TNF-a and TNF-b, and interferon-aActivation of acute-phase and inflammatory responsesPresentation of antigen to CD4 T cell

104. Expansion of capilaries to increase blood flow (seen as blushing or a rash)Increase in the permeability of the microvasculature structure to allow escape of fluid, plasma proteins, and leukocytes from the circulation edemaExit of leukocytes from the capillaries and their accumulation at the site of injury

105. Acute-Phase Reactantsa1-antitrypsina1-glycoproteinAmyloid A & PAntithrombin IIIC-reactive proteinC1 esterase inhibitorC3 complementCeruloplasminFibrinogenHaptoglobulinOrosomucoidPlasminogenTransferrinLypopolysaccharide-binding proteins

106. What is an antibody?Produced by Plasma cell (B-lymphocytes producing Ab)Essential part of adaptive immunitySpecifically bind a unique antigenic epitope (also called an antigenic determinant)Possesses antigen binding sitesMembers of the class of proteins called immunoglobulins

107. What does an antibody look like ?2 identical heavy chains 2 identical light chainsEach heavy chain – has a constant and a variable regionEach light chain has a constant and a variable regionH HLL Constant region Variable region

108. Antibody: structure and functionFab – fragment antigen bindingFc- Fragment constant

109. Antibody: FabFab regionVariable region of the antibodyTip of the antibody Binds the antigenSpecificity of antigen binding determined by VH and VL

110. Antibody: FcFc regionConstant regionBase of the antibodyCan bind cell receptors and complement proteins

111. Antibodies occur in 2 formsSoluble Ag: secreted in blood and tissueMembrane-bound Ag: found on surface of B-cell, also known as a B-cell receptor (BCR)Antibodies exist in two forms