11 - Adaptive Immunity


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11 - Adaptive Immunity

  1. 1. Adaptive Immunity
  2. 2. Immunity: Third Line of Defense • Red bone Marrow  Stem cells  T and B cells • Specific reaction to microbial infection Humoral Immunity Cell Mediated Immunity B-cells Recognize Specific Antigens Make Antibodies against them T-cells Recognize Specific Antigens Make Cytokines against them
  3. 3. Antigens & Antibodies • Antigens (Antibody generators) • proteins or large polysaccharides • Components of invading microbes • Non-microbial antigens: • pollen, egg white, serum proteins, blood cells etc • Epitopes = specific region that interacts with Ab. • Antibodies • globulin proteins (immunoglobulins) Y-shaped • Made in response to antigen; bind specifically to Ag • At least two identical sites that bind to epitopes • Bivalent molecule
  4. 4. Bivalent antibodies binding epitopes
  5. 5. Classes of Immunoglobulin IgG: • Y-shaped “Monomer” • readily cross vessel walls into inflammation site • ~80% of serum antibodies • Protects against bacteria and viruses • Neutralizes toxins • Enhances phagocytosis • Triggers complement • Confers immunity to fetus AFM of a bivalent (monomer) antibody
  6. 6. Classes of Immunoglobulin IgM: • Pentamer (can be monomer too) – Too big to cross into tissue from blood • First Antibody response to 1 response • Dominates ABO blood group response • Effective in Complement Activation • Highly effective at Agglutination – Cross-links several Antigens
  7. 7. Classes of Immunoglobulin IgA: • Dimer – Serum IgA (monomer) – Secretory IgA • Mucus membranes and secretions – Mucus, tears, saliva, breast milk – Prevents pathogen attachment to mucosal surface – Colustrum • Decreases infant risk to GI infections Dimeric IgA antibodies
  8. 8. Classes of Immunoglobulin IgD: • Monomer • Blood, lymph, B-cell surface • No defined function – 0.002% serum antibodies IgE: • Monomer • Allergic Reactions, Parasitic Infections • Signals for complement and phagocytes • Binds mast cells/basophils  histamine  allergy
  9. 9. B-cell Activation • Stem Cells  B-cells – Each B-cell has surface Igs against specific Ag • Binding of specific Ag activates THAT B-cell • Activated B-cell  clonal expansion  Plasma cells  Antibodies – Some activated B-cells become Memory cells
  10. 10. Antigen-antibody binding • Antigen-Antibody Complex – Specific interaction • Affinity: strength of bond • Specificity: ability to distinguish minor differences in AA – Binds at epitope – Complex formation tags foreign cells • Destruction by phagocytes and complement
  11. 11. Outcomes of Ab-Ag binding • Agglutination – Clumping of Antigens • Opsonization – Ab coats microbe – Enhances phagocytosis • Neutralization – prevents Ag binding host cell • Antibody-dependent cell-mediated cytotoxicity – Ab coats microbe – Ab binds T-cells/NK cells/other immune cells – Cytokines released  lyse microbe • Complement Activation – IgG, IgM – Binds C1 – C1 C2, C4  C3  complementation cascade
  12. 12. T-cells and cellular immunity • T-lymphocytes • Combat pathogens within host cells – Not exposed to circulating Antibodies • Two Types – T-helper Cells (TH: TH1 and TH2) – Cytotoxic T-cells (Tc) – Surface Receptors • Glycoproteins • CD (clusters of differentiation)
  13. 13. Antigen Presenting Cells • B-cells • Phagocytes – Dendritic cells – Macrophages • Chew up Microbe/ Antigen – Present parts of the Antigen on surface – Presentation involves a phagocytic receptor • MHC (major histocompatibility antigen)
  14. 14. The MHC-antigen complex MHC = major histocompatibility complex • Collection of genes that encode proteins found on all nucleated mammalian cell membranes • Presence of MHC identifies the host - Keeps immune system from making antibodies against host cells Class II – found on APCs like B-cells Class I – found on almost any cell of the host • Makes it possible for cytotoxic T-cells to attack host cells that have been altered
  15. 15. T-Helper Cells (CD4+) - bind to MHC class II molecules Activation of TH cells: 1. TH cell recognizes an antigen in complex with MHC class II presented on the surface of an APC 2. TH cell proliferates and differentiates into TH1 and TH2 cells – secrete cytokines TH1 = cytokines activate macrophages, enhance complement TH2 = cytokines stimulate production of antibodies important for allergic reactions, and eosinophils that protect against extracellular parasites
  16. 16. APC (dendritic cell) and TH cell Antigen fragment Antigen MHC class II moleculesMicrobe T helper cell TH cell receptor contacting MHC- antigen complex
  17. 17. Cytotoxic T-cells (CD8+) • Recognize and kill altered or foreign cells • bind to MHC class I molecules - found on all nucleated cells • Presented in complex with viral/parasitic antigens on surface of infection-altered cells Steps in destruction of target cells: 1. Recognize foreign antigen/MHC class I protein complex on cell 2. Attaches and released perforin  pore • Allows proteases to enter 3. Apoptosis = programmed cell death
  18. 18. Cytotoxic T-cells (CD8+) 1. Virus-infected cell with endogenous viral antigens (inside cell) 2. Abnormal antigen is presented on cell surface in complex with MHC class I molecules - TC cell with receptor for that antigen binds 3. TC cell induces destruction by apoptosis Antigen MHC class I MHC-antigen complex Cytotoxic T-cell
  19. 19. Apoptosis Blebbing = external membranes bulge outward Top: B-cell undergoing apoptosis Bottom: Normal B-cell for reference
  20. 20. Antigen-presenting cells Dendritic cells = Principle APCs to induce immune responses by T-cells • Long extensions = dendrites • Resemble nerve cell dendrites 1. engulf invading microbes 2. degrade them 3. transfer them to lymph nodes for display to T-cells located there
  21. 21. Macrophages = (large eaters) • Innate immunity: important in phagocytosis of apoptotic cells and other debris • Adaptive immunity: become activated macrophages upon ingestion of foreign antigen - Appear larger and “ruffled” 1. Take in antigen 2. migrate to lymph nodes 3. present antigen to T-cells located there Antigen-presenting cells
  22. 22. Extracellular killing Natural killer cells = granular leukocytes that destroy virus- infected cells, tumor cells, and parasites • Part of innate immunity (non-specific) - Not triggered by antigen • Remains external to target cell Mechanism: 1. Contact a target cell 2. Determine if it expresses MHC class I self-antigen (*tumor cells, viral-infected cells don’t) 3. No expression  induces lysis/apoptosis (similar to that of cytotoxic T-cell)
  23. 23. Antibody-dependent-cell-mediated cytotoxicity • Invaders too large to be phagocytized (euks) can be attacked by immune cells • Uses antibodies of humoral system • NK cells, macrophages, neutrophils, and eosinophils respond and kill targeted cells Mechanism: • Target cell coated with antibodies • Immune cells bind to antibodies • Target cell is lysed by secretions
  24. 24. Antibody-dependent-cell-mediated cytotoxicity
  25. 25. Antibody-dependent-cell-mediated cytotoxicity Eosinophils adhering to a parasite for external attack
  26. 26. Cytokines Cytokines = chemical messengers of immune cells • Soluble proteins/glycoproteins • Produced by immune cells after a stimulus • Act only on a cell that has receptors for it - Interleukins = cytokines that serve as communicators between leukocytes (WBCs) - Chemokines = induce migration of leukocytes into areas of infection/tissue damage - Interferons = protect cells from viral infection
  27. 27. Cytokines - Tumor necrosis factor (TNF) = cytokines that act in inflammatory reactions; also target tumor cells - Hematopoietic cytokines = control development of stem cells into red or white blood cells Ex) Granulocyte-colony stimulating factor • Granulocyte precursors  neutrophils Cytokine storm = overproduction of cytokines - Damage to host tissues
  28. 28. Extracellular antigens A B cell binds to the antigen for which it is specific. A T-dependent B cell requires cooperation with a T helper (TH) cell. The B cell, often with stimulation by cytokines from a TH cell, differentiates into a plasma cell. Some B cells become memory cells. Plasma cells proliferate and produce antibodies against the antigen. Intracellular antigens are expressed on the surface of an APC, a cell infected by a virus, a bacterium, or a parasite. A T cell binds to MHC–antigen complexes on the surface of the infected cell, activating the T cell (with its cytokine receptors). Activation of macrophage (enhanced phagocytic activity). The CD8+T cell becomes a cytotoxic T lymphocyte (CTL) able to induce apoptosis of the target cell. B cell Plasma cell T cell TH cell Cytotoxic T lymphocyte CytokinesCytokines Lysed target cell Cytokines activate macrophage. Cytokines from the TH cell transform B cells into antibody-producing plasma cells. Cytokines activate T helper (TH) cell. Memory cell Some T and B cells differentiate into memory cells that respond rapidly to any secondary encounter with an antigen. Humoral (antibody-mediated) immune system Cellular (cell-mediated) immune system Control of freely circulating pathogens Control of intracellular pathogens Figure 17.20 The dual nature of the adaptive immune system.
  29. 29. Vaccines • suspension of organisms/ parts of organism used to INDUCE immunity • Artificial Active Immunity
  30. 30. Vaccine: Types • Live attenuated whole-agent • Inactivated whole-agent • Toxoids • Subunit Vaccines – Recombinant subunit vaccines • Nucleic acid Vaccines
  31. 31. Live attentuated Whole agent • living but attenuated (weakened) microbes – Mutated virus – Related virus • Attenuated viruses replicate in the body – Cell and humoral immunity • Lifelong immunity • Counterindicated – immune compromised – Attenuated microbes: from mutated strains  can back-mutate to virulent form • Viral vaccines: MMR, Sabin polio, Smallpox, Flumist (influenza) • Bacterial vaccines: tuberculosis
  32. 32. Inactivated “Dead” Whole-agent • Killed by formalin or phenol • Immunity not life-long – Boosters may be required – Primarily humoral response • Examples: – Viral: Salk (polio, IPV), Rabies, Flu – Bacterial: Pneumococcal, Cholera
  33. 33. Subunit Vaccines • Highly immunogenic fragments – Cannot replicate in host – Less side-effects/ dangers • Recombinant vaccines – Desired Ag fragment expressed by unrelated, non-pathogenic microbe – Ex. HepB virion protein in GM yeast – Rabies glycoprotein in Vaccinia virus (V-RG) • Toxoids – Tetanus, diphtheria – Several injections required for full immunity – Boosters every 10 years • Conjugated Vaccines – Capsular polysaccharides: poor immunogens; T-independent Ags – Conjugate with Toxoid for maximal immunity – Ex. Hib
  34. 34. Nucleic Acid Vaccines (DNA vaccines) • Newest “promising” vaccines • Plasmid DNA – Containing gene for immunogen of interest – Injected intramuscularly • Gene gun • Conventional needle – Expressed Protein Ag  Red Bone Marrow humoral and cellular immunity • Long lasting immunity • West Nile vaccine (horses) • Human trials underway
  35. 35. Types of Vaccine Gene gun = DNA coated with gold or tungsten nanoparticles are “shot” into dermal cell cytosol • Inserted with glass micropipette - Diameter smaller than cell - Punctures plasma membrane • Eliminates • syringes/needles • refrigeration • lower costs
  36. 36. Recommended Immunization Schedule
  37. 37. Vaccine Development • Whole-agent vaccine – Grow in large amounts for use • Early days – Smallpox scarified onto shaved calf bellies • Cow “junk” – Flu, Polio: grown in Eggs • Egg protein: allergen – Human cells required • First HepB vaccine used Ags from chronically infected as source • Tissue culture Yolk sac Allantoic cavity Amniotic cavity Chorioallantoic membrane
  38. 38. Current Vaccine Development • Tissue Culture – Tissue slice – Digest with enzymes (trypsin) • Breaks down tissue into single cells – Nutritive growth media • Cells adhere and divide to from a “monolayer” – Infect with virus • CPE (cytopathic effect) caused by virus infection
  39. 39. Vaccine Development Advancement in cultivation: cell culture Viruses may be grown in: Primary cell lines = derived from tissue slices; die out after a few generations Diploid cell lines = develop from human embryos; maintained for ~100 generations Continuous cell lines = (aka immortal cell lines) Cancerous cells; can be maintained indefinitely Ex) HeLa cell line • tend to have: - Less round shape - Chromosomal abnormalities
  40. 40. Vaccine Safety: Risks v/s benefits • Disease caused by vaccine – Smallpox • Variolation – Incidence of disease decreased from 25% to 1% – OPV (Sabin) • Poliovirus mutated • Reversion to wt – Poliomyelitis • Risk v/s Benefits – Public reaction • Low perceived risk of contracting disease – Polio, measles • Reports/ rumors of harmful effects – MMR  autism – Flu  Guillain Barre syndrome • Herd immunity
  41. 41. Immune Disorders
  42. 42. Hypersensitivity • Abnormal reaction to Antigen – Allergy – Sensitization to previous exposure to Allergen – Higher exposure to Antigen • Sensitized • Immune response to low levels of Ag – Genetic predisposition
  43. 43. Hypersensitivity Hygiene hypothesis = sterile environments don’t provide enough stimulation for immune system • Higher incidence in developed countries • Eczema and hay fever less likely in children from larger families • Allergies linked to antibiotic use in 1st year of life • Asthma linked to use of household antibacterials
  44. 44. Hypersensitivity Reactions • Type I: Anaphylaxis – Sytemic anaphylaxis (Anaphylactic shock) – IgE response • Type II: Cytotoxic Reactions – IgM, IgG, complement response • Type III: Immune complex reactions – IgG response against soluble Antigen • Type IV: Delayed Hypersensitivity Reaction – Cell mediated response (CTL or ADCC)
  45. 45. Type I: Anaphylactic Reactions • Rapid – 2-30 mins after exposure – Systemic • Shock, breathlessness, can be fatal – Localized • Hives • IgE response – Binds basophils/ mast cells – Degranulation: release mediators • Histamine • Leukotrienes • Prostaglandins – Swelling, inflammation, runny nose, contraction of smooth muscles
  46. 46. Anaphylactic Reactions Mediators: attract neutrophils and eosinophils to site of degranulated cell; and: Histamine • Increase vessel permeability Swelling, redness • Smooth muscle contraction Breathing difficulty Leukotrienes & Prostaglandins • Not preformed in granules • Leukotrienes: prolonged smooth muscle contraction asthmatic bronchial spasms • Prostaglandins: vasodilation, fever, pain
  47. 47. Systemic & Localized Anaphylaxis • Systemic – Shock – Second or subsequent exposure to allergen • Mediators  vasodilation  BP drop (shock) • Injected antigens (insect bites) – Epinephrine • Constricts blood vessels • Localized – Ingested or inhaled allergen • Pollen – Inhalation • Itchy eyes, runny nose, congestion, coughing, sneezing – Antihistamine (blocks histamine receptors) – Ingestion • Food allergies • Hives, systemic anaphylaxis
  48. 48. Systemic & Localized Anaphylaxis SEM of pollen grains, dust mite • common inhaled triggers of localized anaphylaxis Ingestion: 8 foods = 97% food allergies • Eggs, peanuts, tree nuts, milk, soy, fish, wheat, peas - 200 food allergy deaths per year in U.S.
  49. 49. Type II:Cytotoxic Reactions • complement activation by IgG/ IgM with an antigenic cell Ex) Transfusion reactions • RBCs destroyed by circulating antibodies
  50. 50. Type III: Immune Complex Reactions • IgG/ IgM against soluble antigens circulating in serum Immune complexes: • [Ag] > [Ab] • Complexes evade phagocytes • Soluble, circulating • “stuck” on capillaries, joints, organ tissues • Activate complement:  Transient Inflammation  Attract neutrophils  enzymes - tissue destruction Glumerulonephritis = inflammatory damage to kidney glomeruli
  51. 51. Type IV: Delayed Cell-Mediated Reactions • T-cell activation • Development time: longer – Days – T-cell and macrophage migration/ accumulation • Sensitization – Macrophage phagocytoses Ag – Presents to T-cells – T-memory cells formed • Subsequent exposure – Memory cells activated – Cytokines releases • Attract and activate macrophages
  52. 52. Delayed Cell-Mediated Reactions Ex) Allergic contact dermatitis = exposure to substances to which you have become extra sensitive • Fragrances • Metals • Plant oils (poison ivy) • Latex Graft rejection Poison ivy plant Catechols = oils secreted by poison ivy plant • Combine with skin proteins, become antigenic  immune response • First contact: sensitization • Second exposure: contact dermatitis
  53. 53. Comparison of the four types of hypersensitivity
  54. 54. Autoimmune Diseases • Hosts immune response against self – Loss of discrimination between self v/s non-self – Thymic selection – >40 known ds., 75% women • Autoimmune hepatitis – Hepatocytes display MHC-II to APCs • Viral infections (HepC, EBV) • Medications • Genetic predisposition
  55. 55. Autoimmune Diseases • Immune complex reactions – Rheumatoid arthritis • Immune complexes (IgG/ IgM) deposits in joint • Chronic inflammation • Damage to bone/ joint cartilage – SLE (systemic lupus erythematosus) • Abs against cell components – DNA – Tissue breakdown • Cytotoxic autoimmune reactions – Graves Disease • Abs that mimic TSH bind TSH-receptors • Increased production of thyroid hormones – Hyperthyroidism – Goiter, bulging eyes
  56. 56. Immunodeficiencies • Absence/ deficient immune response • Congenital – DiGeorge’s syndrome (22q11.2) • Chromosome 22 • Defective/ missing thymus – No CMI – Frequent/ severe infections • Acquired: drugs, cancer, infectious agents – AIDS • Final stage of HIV • Destruction of T-helper (CD4+) cells – cancer, bacterial, viral, fungal, and protozoan diseases » Pneumocystis pneumonia, Kaposi’s sarcoma • Diagnosis: CD4+ T-cell count below 200 cells/μl • Chemotherapy: inhibit viral enzymes reverse transcriptase inhibitors
  57. 57. Types of Acquired Immunity: Active & Passive Immunity Active immunity = acquired from an immune response to exposure of foreign antigens • Naturally acquired = exposure to antigens leads to illness, recovery • Artificially acquired = vaccination Passive immunity = acquired from transfer of antibodies from one person to another • Naturally acquired = mother to infant - Transplacental, breast milk • Artificially acquired = injection of antibodies