Immunology lecture med t e ch


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Immunology lecture med t e ch

  1. 1. IMMUNOLOGYMary Joyce Saborrido-Teoxon, RMT, MDDept. of Micro & ParaFEU-NRMF Institute of Medicine
  2. 2.  Study of body’s protective and defensive mechanisms against foreign substances Discriminate self vs. non self Eliminate non-self (infectious agents)IMMUNOLOGY
  3. 3.  Collection of organs, tissues, cells and soluble factors that allow individuals to defend against harmful agents such as viruses, bacteria, fungi, parasitic organisms, and tumor cellsImmune System
  4. 4. 1. Provides defense mechanism.2. Identification and destruction of abnormal cells.Two (2) Important Roles of theImmune System
  5. 5. Innate vs. Adaptive
  6. 6.  Non-specific  Specific Natural  Acquired 1st/ 2nd line  3rd line Memory- NO  Memory- YES Rxn time- RAPID  Rxn time- SLOW CELLULAR:  CELLULAR: ◦ Phagocytes, mø, ◦ Specific B (plasma cells) monocytes, NK cells, & T cells Mast cells ◦ APCs HUMORAL:  HUMORAL: ◦ Complement (Alternate) ◦ Abs ◦ Cytokines ◦ Complement (Classic) ◦ CytokinesInnate Adaptive
  7. 7.  Mechanical Defenses 1.) Skin A. Epidermis: Thin outer layer of epithelial tissue. Contains Langerhans cells, dead cells, and keratin (waterproof). B. Dermis: Thick inner layer of connective tissue. Infections are rare in intact skin. Exceptions:  Hookworms can penetrate intact skin  Dermatophytes: “Skin loving” fungiFirst Line of Defense: Skin and Mucous Membranes
  8. 8. • Mechanical Defenses2.) Mucous Membranes:  Lines gastrointestinal, genitourinary, and respiratory tracts.  Two layers: ◦ Outer epithelial ◦ inner connective layer.◦ Epithelial layer secretes mucus which maintains moist surfaces.◦ Although they inhibit microbial entry, they offer less protection than skin.◦ Several microorganisms are capable of penetrating mucous membranes:  Papillomavirus  Treponema pallidum  Enteroinvasive E. coli  Entamoeba histolyticaFirst Line of Defense: Skin and Mucous Membranes
  9. 9. I. Mechanical Defenses 3. Lacrimal apparatus: Continual washing and blinking prevents microbes from settling on the eye surface. 4. Saliva: Washes microbes from teeth and mouth mucous membranes. 5. Mucus: Thick secretion that traps many microbes. 6. Nose Hair: Coated with mucus filter dust, pollen, and microbes. 7. Ciliary Escalator: Cilia on mucous membranes of lower respiratory tract move upwards towards throat at 1-3 cm/hour.First Line of Defense: Skin and Mucous Membranes
  10. 10. I. Mechanical Defenses 8. Coughing and sneezing: Expel foreign objects. 9. Epiglottis: Covers larynx during swallowing. 10. Urination: Cleanses urethra. 11. Vaginal Secretions: Remove microbes from genital tract.First Line of Defense: Skin and Mucous Membranes
  11. 11. ◦ Sebum: Oily substance produced by sebaceous glands that forms a protective layer over skin. Contains unsaturated fatty acids which inhibit growth of certain pathogenic bacteria and fungi. ◦ pH: Low, skin pH usually between 3 and 5. Caused by lactic acid and fatty acids. ◦ Perspiration: Produced by sweat glands. Contains lysozyme and acids. ◦ Lysozyme: Enzyme that breaks down gram-positive cell walls. Found in nasal secretions, saliva, and tears.B. Chemical Defenses:
  12. 12. ◦ Gastric Juice: Mixture of hydrochloric acid, enzymes, and mucus. pH between 1.2 to 3 kills many microbes and destroys most toxins. Many enteric bacteria are protected by food particles.  Helicobacter pylori neutralizes stomach acid and can grow in the stomach, causing gastritis and ulcers. ◦ Transferrins: Iron-binding proteins in blood which inhibit bacterial growth by reducing available iron.B. Chemical Defenses
  13. 13. 1. Phagocytosis: ◦ Derived from the Greek words “Eat and cell”. ◦ Phagocytosis is carried out by white blood cells: macrophages, neutrophils, and occasionally eosinophils. ◦ Neutrophils predominate early in infection. ◦ Wandering macrophages: Originate from monocytes that leave blood and enter infected tissue, and develop into phagocytic cells. ◦ Fixed Macrophages (Histiocytes): Located in liver, nervous system, lungs, lymph nodes, bone marrow, and several other tissues.II. Second Line of Defense
  14. 14. Phagocytic Cells: Macrophages(Monocytes), Neutrophils, and Eosinophils
  15. 15.  These cells have enzymatic constituents in their granules to oxidize, kill, digest, and destroy particulate material that they ingest.Professional Phagocytic cells
  16. 16. A. Monocytes (in the blood) B. Tissue Macrophages A. Liver  Kupffer cells B. Lungs  Alveolar macrophages/ Dust cells C. Kidney  Mesangial macrophages D. CNS  Microglial cells E. Lymph nodes Dendritic cells F. Skin  Langerhan’s cells G. Spleen  Spleenic macrophages H. Connective tissue  Histiocytes I. Bone Osteoclast J. Peyer’s patches K. Tonsils1.) Mononuclear phagocytes(formerly RES)
  17. 17.  Phagocytosis Antigen Presentation Cytokine ProductionFunctions of MØ
  18. 18. A. Neutrophils (most aggressive phagocyte)B. Eosinophils (antiparasitic phagocyte)C. Basophils (secretory cells)2. Polymorphonuclear leukocytes(PMNs)
  19. 19. 1. Chemotaxis: Phagocytes are chemically attracted to site of infection. 2. Adherence: Phagocyte plasma membrane attaches to surface of pathogen or foreign material.  Adherence can be inhibited by capsules (S. pneumoniae) or M protein (S. pyogenes).  Opsonization: Coating process with opsonins that facilitates attachment. ◦ Opsonins include antibodies and complement proteinsStages of Phagocytosis
  20. 20. 3. Ingestion: Plasma membrane of phagocytes extends projections (pseudopods) which engulf the microbe. Microbe is enclosed in a sac called phagosome. 4. Digestion: Inside the cell, phagosome fuses with lysosome to form a phagolysosome. Lysosomal enzymes kill most bacteria within 30 minutes and include:  Lysozyme: Destroys cell wall peptidoglycan  Lipases and Proteases  RNAses and DNAses After digestion, residual body with undigestable material is discharged.Stages of Phagocytosis(Continued)
  21. 21. Stages of Phagocytosis
  22. 22. Triggered by tissue damage due to infection, heat, wound, etc. Four Major Symptoms of Inflammation: 1. Redness 2. Pain 3. Heat 4. Swelling May also observe: 5. Loss of function2. Inflammation
  23. 23. 1. Destroy and remove pathogens 2. If destruction is not possible, to limit effects by confining the pathogen and its products. 3. Repair and replace tissue damaged by pathogen and its products.Functions of Inflammation
  24. 24. I. Complement System: Large group of serum proteins that participate in the lysis of foreign cells, inflammation, and phagocytosis. Three mechanisms of complement activation: 1. Classical Pathway: Initiated by an immune reaction of antibodies. 2. Alternative Pathway: Initiated by direct interaction of complement proteins with microbial polysaccharides. Both pathways cleave a complement protein called C3, which triggers a series of events. 3. Lectin pathwayAntimicrobial Substances:
  25. 25.  Antiviral proteins that interfere with viral multiplication. ◦ Small proteins (15,000 to 30,000 kDa) ◦ Heat stable and resistant to low pH ◦ Important in acute and short term infections. ◦ Have no effect on infected cells. ◦ Host specific, but not virus specific. Interferon alpha and beta: Produced by virus infected cells and diffuse to neighboring cells. Cause uninfected cells to produce antiviral proteins (AVPs). Interferon gamma: Produced by lymphocytes. Causes neutrophils to kill bacteria.II. INTERFERONS
  26. 26.  LGL / Null cells Lack T cell receptor, CD3 proteins, and surface IgM & IgD Thymus are not required for development Activity not enhance by prior exposure Associated w/ ADCC CD56 & CD16NK cells
  27. 27.  Kill virus-infected/ Cancer cells Killing ◦ Non-specific ◦ Not dependent on foreign antigen presentation by class I or II MHC proteins ◦ Activated by the failure of a cell to present self antigen ◦ Produce perforins & granzymes, w/c cause apoptosis of target cellFunctions of NK cells
  28. 28. Adaptive Immunity
  29. 29.  Antigen – Antibody reaction Cells: ◦ B cells ◦ T cellsAdaptive Immunity
  30. 30.  Antigens  molecules that react w/ Abs  compound that does not necessarily elicit an immune response Immunogens  molecules that induce an immune response  at least 2 antigenic determinantAntigens & Immunogens
  31. 31.  IMMUNOGENECITY  ability to induce specific immune response resulting to formation of antibodies or immune lymphocytes ANTIGENECITY/ SPECIFICITY  the ability to react specifically with the antibody or cell that caused it to be produced.Two properties of Antigens:
  32. 32.  CARRIER PORTION ◦ The bigger part that is responsible for the MW of antigen EPITOPE/ ANTIGENIC DETERMINANT ◦ Determines specificity of antigen, therefore, an antigen w/out epitope is said to be nonspecific.Parts of Ag:
  33. 33.  Molecule that is not immunogenic by itself but can react w/ specific antibody ◦ Incomplete Ag ◦ Small molecules (<10,000D) ◦ univalent ◦ HMW nucleic acids ◦ Drugs (e.g. Penicillin) ◦ Cathechol (plant oak)Haptens
  34. 34.  A molecule that when coupled to a hapten, renders hapten immunogenic. E.g: ◦ Albumin ◦ Globulin ◦ Synthetic polypeptidesCARRIER
  35. 35.  Foreignness Molecular size Chemical-Structural Complexity Antigenic Determinants (Epitopes)Features of molecules thatdetermine immunogenicity
  36. 36.  Primary/ Central Secondary/ PeripheralLymphoid System
  37. 37. Central/ Primary Lymphoid organs
  38. 38.  are the sites for generation and early maturation of lymphocytes (B and T cells)Central/ Primary
  39. 39.  Hematopoeisis ◦ RBC ◦ Platelets ◦ Monocytes ◦ Granulocytes Lymphopoeisis ◦ B cells ◦ T cell precursors  NK cells  Dendritic cells  Mast cellsA. Bone Marrow (Bursa of Fabricusequivalent)
  40. 40.  Maturation & Differentiation of T cellsB. Thymus
  41. 41.  T & B cells  Central L.T. Migrate  Peripheral L.T.  Respond to foreign antigens trap antigens are the sites for initiation of most immune response provide signals for recirculation of lymphocytesSecondary/ Peripheral
  42. 42.  Major antigen-trapping sites of the body Filters foreign substances from the tissue fluids and lymph Central organ for lymphocyte traffic and circulationA. Lymph nodes
  43. 43.  PARTS: ◦ CORTEX (Germinal center)  B cells ◦ PARACORTEX (Juxtamedullary)  T cellsLymph Nodes
  44. 44.  Filters foreign substance from the blood Critical line versus blood borne infections Eliminates dead worn-out RBCsB. Spleen
  45. 45.  White pulp ◦ Marginal zone ◦ Germinal center ◦ PALS (mostly T cells) ◦ Primary follicles (mostly B cells)Spleen
  46. 46.  GUT-associated lymphoid tissue (GALT) Bronchus-associated lymphoid tissue (BALT)Mucosa-associated LymphoidTissue (MALT)
  47. 47.  L.T. beneath the respiratory mucosa and the aggregates of nodular lymphatic tissues called Tonsils. Tonsils  nodular aggregates of B cells & diffuse areas that contain mostly of T cells  for airborne and alimentary tract pathogensBALT
  48. 48. Immune Cells
  49. 49.  Fetal liver Yolk sacEmbryonic development
  50. 50.  Bone Marrow lymphocytes .. . .. . . . … natural killer (NK) cellPostnatal life
  51. 51.  T CELLS ◦ Pre T cell  Immature (thymocyte)  Mature T cell  Lymphokines B CELLS ◦ Pro B cell  Pre B cell  Immature  Mature B cell  Plasma cells  AbsHEMATOPOESIS
  52. 52.  Responsible for foreign antigen recognition or cellular immune response, which include: ◦ rejection in organ transplantation ◦ regulation of antibody production ◦ secretion of soluble mediators It has the ability to bind with sheep’s RBC forming rosette.T cells
  53. 53. 1. T helper cell (CD4 marker) • Recognize Ag in association w/ MHC class II • Collaborate w/ B cells to produce Abs • Th1/Th22. T cytotoxic cell (CD8 marker) • Has killer function3. T effector cell • Also called as TdTh cell • Responsible for delayed type of HPS4. T suppressor cell (CD8 marker) ◦ Involved in presenting autoimmunity activated by AgSubsets of T cells
  54. 54.  Have shorter life span (5-7 days) Precursors, regulators, and effectors of immunity. May transform or differentiate into plasma cell to produce immune antibodies. CD19, CD20, CD21, CD22, CD35B cells
  55. 55. Comparison of T & B cells Feature T cells B cellsAntigen receptors Yes YesIgM on surface No YesCD3 proteins on surface Yes NoClonal expansion after contact w/ Yes Yesspecific antigenImmunoglobulin synthesis No YesRegulator of Antibody synthesis Yes NoIL-2, IL-4, IL-5 & Gamma interferon Yes NosynthesisEffector of CMI Yes NoMaturation in Thymus Yes NoMaturation in Bursa or its equivalent No Yes
  56. 56.  Soluble mediators that serves as the language for cell communication. Either immune / non-immuneCYTOKINES/ LYMPHOKINES
  57. 57. 1. InterleukinsIL-1 T cell activation factor (MØ)IL-2 Activates Tc cellIL-3 Stimulates hematopoietic cellsIL-4 Activates B cellIL-5 Activates eosinophilsIL-6 Activates B cellIL-7 Differentiation and Maturation of T & B cellIL-8 Activates NeutrophilsIL-9 Proliferation of T cells, thymocytes, mast cellsIL-10 Inhibition of cytokine synthesisIL-11 Regulates hematopoiesisIL-12 Activates NK cells
  58. 58.  INF α  augments NK cell activity INF β  identical to IL-6 INF   major mØ activator  antagonistic to IL-4  augments NK cell activity2. Interferons
  59. 59.  TNF α  directly cytotoxic to tumor cells TNF β  lymphotoxin3. TUMOR NECROSIS FACTOR
  61. 61. Immunoglobulins
  62. 62.  Globulin proteins (immunoglobulins) that react specifically w/ the antigen that stimulated their production 20% of the protein in the blood plasma Gamma globulins Glycoproteins Part of the adaptive immune response (humoral immunity)Antibodies
  63. 63. 1. Alloantibody - produced after exposure to genetically different or non-self antigens of same species2. Autoantibody - produced in response to self antigenTypes:
  64. 64. Immunoglobulin Structure
  65. 65.  Pepsin ◦ One large F(ab)2 fragment ◦ LMW peptides Papain ◦ Two (2) Fab fragments ◦ One (1) FcIg tx:
  66. 66.  5 classes/ Isotypes (constant heavy chain) ◦ IgG: gamma heavy chain ◦ IgA: alpha heavy chain ◦ IgM: mu heavy chain ◦ IgE: epsilon heavy chain ◦ IgD: Delta heavy chainMajor Ig Classes
  67. 67. Property IgG IgA IgM IgE IgDA. Physiologic % of total Ig in Serum 75 15 9 0.004 0.2 Catabolic rate(1/2 life) 18-23 5-6.5 5-6 2.3 2.8 MW 150 170/ 400 900 190 180 Structure Monomer Mono/di Mono/penta Mono MonoB. Biological + +2 +4 - - Agglutinating Capacity Complement fixing + - +4 - - ADCC + - - - - Mediation of allergic - - - +4 - Response Placental transport + - - - - Present in external + +4 ± +2 - secretion Receptor on B cell - - + - ? Opsonization + - - - - Polymeric form J chain - + + - - Subclasses 4 2 - - -
  68. 68.  Four subclasses: IgG1, IgG2, IgG3 & IgG4 Monomer Highest concentration in plasma Transported across the placenta Activates complement Opsonizes Main Ab in the secondary immune response Mediates Antibody-dependent cellular cytotoxicity (ADCC)1. IgG
  69. 69. Comparison of IgGSubclasses IgG1 IgG2 IgG3 IgG4Serum ~840 ~240 ~70 ~50concentrationPercent of Total ~70 ~20 ~6 ~4Serum IgGHalf-life(days) ~23 ~23 ~7 ~23Complement ++ + +++ --bindingPlacental +++ + +++ +++transfer
  70. 70.  Two subclasses: IgA1 & IgA2 Monomer/ Dimer Main Ig in external secretions such as milk, tears, saliva & respiratory & intestinal mucus Protects mucosal surfaces Major protective factor in colostrum It is present in the secretion as dimer w/ a J (joining) chain & secretory piece. J chain is made by B or plasma cell; Secretory piece made by epithelial cell2. IgA (Secretory)
  71. 71. IgA
  72. 72.  Produced in the primary response Pentamer: serum (held by J chains) Monomer: Ag receptor on B-cell surface 1st antibody that an infant makes Most efficient at activating complement Highest agglutinating capacity3. IgM
  73. 73. IgM
  74. 74.  Monomer Mediates type I hypersensitivity Main host defense against helminth infxn4. IgE
  75. 75.  Monomer Uncertain Present in the membrane of mature B cells5. IgD
  76. 76.  Isotypes Allotypes IdiotypesAntibody Variants
  77. 77.  Antigenic (amino acid) differences in their constant heavy regions Heavy chain isotypes: 9 Total isotypes: 18Isotypes
  78. 78.  additional antigenic features of Ig that vary among individuals Results from the substitution of only one or two amino acids in the constant regions (usually) of heavy or light chains No biological significanceAllotypes
  79. 79.  Antigenic determinants formed by the specific amino acids in the hypervariable region Individual, unique differences between antibodies of different antigen binding specificities Individually specific to each Ig moleculeIdiotype
  80. 80. Complement
  81. 81.  Composed of several proteins found in human serum (other animal serum) Synthesize in the liver (main) Heat labile (inactivated by heating serum at 56 C for 30 mins)Complement
  82. 82.  Classic Alternative Lectin3 Pathways:
  83. 83.  CLASSIC LECTIN ALTERNATIVE (+) Ag-Ab MBP Microbial surfaces C1q,r,s C3 + B MASP C4 C2 D (protease) C4b,2b/ C4b,2a C3 C3 C3b,Bb(C3 CONVERTASE) (C3 CONVERTASE) C4b,2b,3b/ C4b,2a,3b C3b,Bb,C3b (C5 CONVERTASE) C5 (C5 CONVERTASE) C5a + C5b C5b,6,7 C5b,6,7,8,9 (MAC) Lysis, Cytotoxicity
  84. 84.  Anaphylatoxins – C3a, 4a, 5a Chemoattractants- C5a, LTB4, IL-8, bacterial products Opsonins – C3b, IgG Bacterial cell lysis – C5b, 6, 7, 8, 9Functions of complement:
  85. 85. Complement Regulatory ProteinsProtein Regulatory FunctionsC1 INH Binds to C1, thereby preventing it from initiating complement activationProperdin Stabilizes the alternative pathway C convertaseC4bp Accelerates dissociation of C3 convertase (CP)DAF Accelerates the dissociation of both C3 convertaseFactor I Cleaves and inactivates C3b and C4bAI Proteolytically cleaves anaphylotoxinsMIRL/HRF/ S- Inhibits MAC formationprotein
  86. 86.  Plateau Log Lag Decline4 Phases of Ab response
  87. 87.  Primary  Secondary (Anamnestic)  Lag (Shorter) Lag (Longer)  Log (Higher peak) Log  Plateau (Longer) Plateau (Shorter)  Decline Decline (Shorter) (Gradual/Prolonge d)