MMI 133 Part 2.2

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MMI 133 Part 2.2
2013-02-22 21:56:43
Part Lecture

Lecture 6, last before second quiz
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  1. Adaptive/Acquired Immunity (specific responses)
    • 3 rd Line (specialized lymphocytes)
    • 1. B cells (antibodies)
    • 2. T cells (helper and killer cells)
  2. What's so special about the adaptive immune system?
    • -Takes time to develop (5-7 days) Secondary response occurs more rapidly
    • -Mediated by B and T lymphocytes
    • -Adaptive immunity has two branches
    • 1. B cell mediated (antibody or humoral immunity)
    • 2. T cell mediated (cell-mediated immunity)
  3. Special about the adaptive immune system:
    • Learning self vs. foreign
    • Specificity recognizes very small differences between antigens (ie. single amino acid changes)
    • Diversity many pathogens, therefore must have broad coverage
    • Memory for future reference
  4. B Cells and T Cells
    • Antibody (humoral) response  Cell mediated response
    • Best against extracellular pathogens  Best against intracellular pathogens
    • Produce antibodies that neutralize bacteria, toxins and free virus  T cells recognize and kill altered self-cells (eg. virally infected or cancer cells)
  5. B cells
    • Originate and mature in the Bone marrow
    • Can act as an APC (Antigen Presenting Cell)
    • Possess special B-cells antigen binding receptors (aka BCR) that recognize specific antigens
  6. Antigen:
    A substance, usually foreign, capable of provoking an immune response (eg. bacteria, virus, protozoa, pollen, transplanted tissue, etc)
  7. Epitope:
    The specific site on an antigen recognized by immune cells or antibodies
  8. Antibody
    (aka immunoglobulin or IG): Protein produced by B-cells that recognizes a specific epitope on an antigen: leads to clearance of that antigen
  9. B cell Activation
    • Antigen binds BCR (B cell receptor)
    • Rapid B cell division and proliferation
    • Antigen-specific antibody production by plasma cells

    Plasma cell: B cell that produces antibody
  10. Plasma cell:
    B cell that produces antibody
  11. B cell differentiation and clonoal expansion
    • Step #1: B cell differentiation
    • Stem cells differentiate into mature B cells each bearing a unique surface immunoglobulin (BCR) against a specific antigen
    • Step #2: Antigen recognition
    • B cell encounters and recognizes it's specific antigen in peripheral lymphoid tissue (ie. spleen and lymph nodes)
    • Step # 3: Clonal Expansion
    • B cells proliferate in an antigen specific manner
    • All cells produced are CLONES of the original B cell and have the SAME antigen specificity (same BCR)
    • Step #4: B cell differentiation
    • B cells differentiate into one of two specialized cell types:
    • 1. Antibody producing plasma cell
    • 2. Long-lived memory cells
  12. More about B cells and antibodies
    • Each B cell can make antibodies with specificity for ONLY ONE kind of antigen
    • Antibody = immunoblobulin (Ig)
    • Antibodies can be found in TWO forms
    • 1. Stuck to the surface of a B cell as the BCR
    • 2. Secreted and circulating in the blood and lymph or patrolling mucosal surfaces
  13. Antibody Structure
    • Antibodies have 2 main structural sites:
    • 1. The variable region or Fab, are the antigen binding sites
    • 2. The constant region or Fc, is recognized by different components of the immune system (ie. Complement, other immune cells with receptors for the Fc region like macrophages
  14. 2 main Antibody functions:
    • 1. Bind specifically to pathgoens
    • via variable region
    • Huge variability: antibody repertoire is so large that there will be an antigen available to recognize virtually ANY structure
    • 2. Recruitment of other cells and immune system components to destroy the pathogen
    • Via constant region
    • Minimal variability
  15. Antibody Isotypes
    • Each type of antibody is called an isotype, and each isotype specializes in a certain biological activity
    • IgM, IgG, IgA, IgE, nd IgD
    • A single B cell can express each isotype at different times in the immune response
    • *** antigen specificity of the antibodies produced from a single B cell remains the SAME regardless of isotype!***
  16. IgM
    • 5-10% of serum antibody
    • 1% Ig produced during the primary exposure to antigen and is short lived (great for diagnostic purposes)
    • When in its membrane bound form (monomeric), it forms the BCR
    • In its pentameric form, it is serum IgM
    • Highly efficient, binds numerous antigens simultaneously (has 10 Fab regions)
    • Excellent for activating complement
    • The J-chain, or joining chain, allows for secretion across mucosal surfaces
    • In is blood, lymph, B cell
  17. IgG
    • 80% of serum Ig
    • Long-lived and may indicate immunity to a pathogen was acquired in distant past
    • Capable of crossing the placenta (fetus and newborn protection)
    • Complement activation
    • The opsonizing antibody (Binds to Fc receptors on phagocytes by the Fc region)
    • Is in blood, lymph, gut
  18. IgA
    • 10-15% of serum Ig
    • Monomer in serum, dimer in secretions (J-chain)
    • The predominant Ig is in external secretions (breast milk, saliva, tears, mucous)
    • Prevents attachment of pathogens to mucosa (inhibits colonization)
    • Protects newborns during the 1st month of life
    • Is in secretions, blood and lymph
  19. IgE
    • VERY low serum concentration (0.00025 of serum antibodies)
    • Binds Fc receptors on mast cells and eosinophils
    • Important role in the neutralization of parastises
    • Mediates hypersensitivity reactions (eg. hay fever, asthma, hives, anaphylactic shock, prevents attachment of pathogens to mucosa)
    • Is bound to mast cells and basophils
  20. IgE and Hypersensitivey
    • In those afflicted by allergies:
    • IgE specific for allergen binds the Fc receptors on mast cells or basophils
    • Upon antigen encounter, the mast cell or basophil is activated
    • Activation results in the release of histamines
  21. IgD
    • 0.2% of serum Ig
    • Membrane-bound Ig on mature B cells (along with IgM)
    • Unknown biological function
    • Is on B cell
  22. Serology (disease diagnosis by analyzing antibodies)
    • Based on the premise that most individuals produce specific antibodies when exposed to an infectious agent.  We can measure the levels of these antibodies to find out if they are present and/o increased.
    • The antibody concentration will increase if the patient has an active infection, sometimes referred to as "titre rise". (titre rise is how many times you have to dilute it in order to be able to count it)
  23. Type of specimens tested for antibodies
    • Serum: blood is allowed to clot, then the tube centrifuged.  Fibrin has been removed.  Use the liquid.
    • Plasma: Blood exposed to an anticoagulant (prevents clotting). Centrifugation of the tube results in the red cells ending up in the bottom half of the tube.  Plasma is the top half - a clear yellowy liquid
    • Secretions: eg. sputum, tears, ejaculate
  24. Biological activity of antibodies (4)
    • 1. Opsonization
    • 2. Activation of complement
    • 3. Neutralization
    • 4. Agglutination
  25. Opsonization
    • Antibodies coat the exterior of antigens to facilitate their phagocytosis
    • Essentially antibodies act as bid EAT ME signs that coat bacteria
  26. Complement Activation
    • Immune complex or Antibody binding to bacteria is an activating step for complement
    • Complement activation with production of C3a, C5a and C3b leads to: 1. Inflammation, 2. Opsonization, 3. Lysis of the bacterial cell wall by formation of MAC (OIL)
  27. Neutralization
    • Antibodies can bind the surface of a pathogen to lock pathogen's adhesion
    • No adherence -> no infection
    • Antibodies may also bind toxins to block their activity
  28. Agglutination
    • Each antibody has more than one binding site, therefore one antibody can "clump" antigens together
    • Facilitation of phagocytosis
  29. Antibodies in the neonate
    • Neonates are born with their mothers' IgG and do not produce their own until ~6-12 mo. of age (this is the only kind of antibody that can cross the placenta)
    • Neonates can only produce IgM
    • Neonates receive IgA from mom's breast milk
  30. General things to remember about antibodies
    • Not all antibodies are protective against disease (there are many epitope that induce non-protective antibodies)
    • Many antibodies that arise during a given infection are only useful as markers for infection in lab tests (Don't have a significant effect on the pathogen)
  31. Application of antibodies in biotechnology
    • Monoclonal antibodies!
    • Monoclonal antibody-producing cells are made in a lab by fusing a specific antibody-secreting plasma cell with a cancer cell
    • Eg. Herceptin, for certain breast cancers
  32. T cells
    • T cells respond to specific pathogens
    • Two Kinds of T cells:
    • 1. CD4+ Helpter T (TH) cells: send signals to activate other parts of the immune system
    • 2. CD8+ Cytotoxic T (CTL or Tc) cells: directly kill altered-self cells (eg. virally-infected cells, tumour cells)
  33. T cell antigen Recognition
    • Specially cells called antigen presenting cells (APCs) present foreign antigen to Th cells to induce their activation.  Activated Th cells produce cytokines that affect other cells like T cytotoxic cells and B cell
    • APC's process antigen and present the antigen to Th cells on a molecule called MHC
    • MHC = Major Histocompatibility Complex
    • T cells recognize the antigen through their surface T Cell Receptor (TCR)
    • **TCR can only recognize antigen if presented (bound) on MHC***
  34. Limits of TCR
    Can only recognized antigen if is it presented (bound) on MHC
  35. Major Histocompatibility Complex (MHC)
    • MHC molecules are the warning signs of the immune system
    • When there is no infection, MHC molecules present self-peptides to T cells to show them there is no danger
    • When there is an infection, MHC molecules present foreign peptides and let T cells know they may have a problem
    • Note: In humans, MHC = HLA (human leukocyte antigen)
  36. Antigen Presenting Cells (APCs)
    • Cell that can process and present antigen on MHC and provide a co-stimulatory signal that is crucial for T cell activation
    • APCs phagocytose antigens and breakdown their proteins into small peptide fragments for presentation to T cells
    • Macrophages, dendritic cells, and B cells are the "profession" APCs of the immune system
  37. The T cell receptor (TCR)
    • Like B cells, T cells also recognize foreign antigen
    • Recognition of foreign antigen is mediated by the TCR found on the surface of all T cells
    • Like antibodies, the TCR also has a variable region for antigen recognition and a constant region
    • The TCR however can only recognize foreign antigen if it is presented bound to MHC
    • Like B cells, antigen recognition by T cells also results in clonal expansion and eventual memory cell production!!!!
  38. TCR/MHC-peptide complexes
    • Remember that the TCR of T cells can only recognize antigen that is presented bound to MHC
    • Immune system must recognize incredible array to antigens (facilitated by genetic diversity in both the TCR and MHC)
  39. 2 types of MHC molecules
    MHC Class I            MHC Class II
    • Found on all nucleated cells (self-marker)   Found only on APCs
    • Presents endogenous peptides  Presents exogenous peptides
    • Activates CD8+ cytotoxic cells   Activates CD4+ helper T cells
  40. TC = CTL = cytotoxic T lymphocyte = CD8+ cell
    • Directly kills infected cells
    • TC = CTL: recognize antigen presented on MHC class I (antigen within cytoplasm of the cell)
  41. TH = T helper cell = CD4+ cell
    • Important for initiation of adaptive immune response
    • TH= T helper cell: recognize antigen present on MHC class II (antigen outside the cytoplasm)
  42. Antigen Processing and Presentation for MHC Class I
    • MHC I presents endogenous peptides (peptides that are produced inside the cell, including viral and some bacterial peptides)
    • When there is not infection, normal self peptides will be loaded on MHC I
    • Foreign peptide on MHC I indicates an intracellular infection (virus infection, tumor cell)
    • 1. Virus infects cell
    • 2. Endogenous peptide is loaded onto MHC I in the endoplasmic reticulum
    • 3. MHC I with peptide is transported to cell surface
    • 4. CTL will recognize the foreign peptide complexed with MHC I and will KILL the infected cell directly.
  43. Natural Killer (NK) cells
    • MHC class I - marker of "self"
    • Expressed on all nucleated cells
    • Provides a way for T cells to scan and detect intracellular infection
    • Many viruses decrease MHC class I expression to avoid detection by T cells
    • NK cells then detect these cells that lack MHC class I and kill them
  44. Antigen Processing and Presentation for MHC Class II
    • MHC II presents exogenous antigen (ie. bacteria, toxins, etc. that have been phagocytosed and processed by APCS)
    • 1. Phagocytic APC take up bacteria or toxin
    • 2. Formation of phagosome
    • 3. Lysosomes fuses with the phagosome
    • 4. Bacteria are digested
    • 5. Peptides from bacterial digestion are loaded onto MHC II
    • 6. MHC II/Peptide complex is transported to the cell surface
    • 7. MHC II/peptide complex can be recognized by TH cells
    • 8. Foreign peptide + MHC II -> tells TH cell that an APC has encountered and phagocytosed an antigen (usually bacteria or toxin)
    • 9. Specific TH activated -> CONSEQUENCES
    •   The activated TH cell secretes special chemical messengers called cytokines that go on to :
    • I. Provide help to activated B cells -> antibodies
    • ii. Help macrophages to become better phagocytes
    • iii. Help CTL to become better killers
  45. Cytokines
    • Are secreted by activated TH cells
    • Go on to:
    • i. Provide help to activated B cells -> antibodies
    • ii. Help macrophages to become better phagocytes
    • iii. Help CTL to become better killers
  46. DEATH
    2 kinds of cell death
    • 1. Necrosis: whole cell is destroyed at once.  Cellular debris contaminates the extracellular environment, and this can lead to inflammation
    • 2. Apoptosis: programmed cell death.  A clean, contained way to go as this death program prevents the release of inflammatory cellular elements (no inflammation)
    • Death the tidy way
  47. CTL kill infected cells by apoptosis
    • Foreign peptide presented in MHC I indicated that the cell is either infected or cancerous
    • Since a cell infected by a virus is no benefit and may even harm surrounding cells, that cell must be destroyed
    • Killing of such "altered" self cells in mediated by CTL
    • CTL kill infected cells by apoptosis through 2 mechanisms:
    • 1. Pore-forming protein called perforin (punches holes in cell membrane)
    • 2. Proteases called granzymes (enzymes that chop up protein in the cell - > apoptosis
  48. Perforin
    • Pore-forming proteins in CTL
    • Essentailly "punch holes" in cell membranes
    • First mechanism that CTL uses to kill infected cells
  49. Granzymes
    • Proteases that chop up proteins in the cell ->apoptosis
    • Second mechanism that CTL uses to kill infected cells
  50. The immunology of cancer
    • In cancer, apoptosis is inhibited thus allowing cells to proliferate without any sort of control
    • Eg. Epstein-Barr virus prevents apoptosis
  51. Looking at adaptive immunity in a new way
    • Naturally acquired active immunity:
    • individual exposed to antigens in course of daily life where sub-clinical infections can confer immunity (eg. unimmunized child gets chickenpox and develops immunity after infection)
    • Naturally acquired passive immunity:
    • The natural transfer of antibodies
    • Maternal transfer of IgG antibodies over placenta
    • IgA antibodies in mother's breast milk
    • Eg. baby is protected from Haemophilus influenza until ~6mo of life by mothers IgG antibodies
    • Artificially acquired active immunity:
    • Result of vaccination, where specially prepared antigens (vaccines) are introduced into the body
    • These substances are altered so that they can no longer cause disease, but can stimulate an immune response
    • Ig. Immunity after a mumps vaccine
    • Artifically acquired passive immunity:
    • Involves the introduction of antibodies from an animal or person who is already immune to the disease
    • Eg. varicella immunoglobulin given after exposure of unimmunized person to varicella (Ig or antibodies pooled from blood donor sera)
  52. Adaptive immunity
    Humoral Immunity   Cell mediated Immunity
    • B cells          CD4+ TH cells      CD8+ TC cells
    • Plasma cells    Cytokines     Perforin + Granyme
    • Antibodies
    • IgM
    • IgG
    • IgA
    • IgE
    • IgD
  53. Hypersensitivity = Allergy
    Four major types
    • Type 1: Immediate IgE mediated (anaphylactic)
    • Localized (hives, hay fever, asthma)
    • General anaphylaxis --> SHOCK
    • Type 2: Cytotoxic
    • Transfusion reactions, HDN
    • Type 3: Immune complex-mediated
    • Serum sickness, Arthus reaction
    • Type 4: Delayed cell-mediated
    • Tuberculin test, contact hypersensitivity
  54. Hypersensitivity
    • Immune reactions that can cause tissue damage
    • All Hypersensitivity reactions require previous exposure to the antigen (allergen)
  55. Common allergens
    • Ingested: Peanuts, shellfish
    • Inhaled: Pollen, dustmites, pet dander
    • Injected: Drugs, insect venom
    • Contact: Latex, poison ivy, nickel
  56. Type 1 reactions
    • Localized (hives, urticarial, allergic rhinitis, hay fever)
    • Systemic (results in shock, need to carry Epi-pen, eg. peanut allergies)
  57. Type 1
    3 phases
    • Sensitization, activation and effector phases
    • Sensitization: result of classical antigen presentation with T helper cell involvement and B cell activation.
    • Activation: cross linking of at least two high affinity IgE Fc receptors (and bound IgE) - triggers mast cell (and basophil) degranulation.
    • Effector: 2 phases
    • Primary mediators released: histamine, eosinophil chemotactic factor, neutrophil chemotactic factor, proteases
    • Secondary mediators released: Leukotrienes and prostaglandins
  58. Type 1 Systemic Reactions
    • Immediate reaction
    • Life-threatening impaired breathing due to swelling of the airways
    • Uterine cramps, involuntary urination and defecation are additional symptoms.  All due to smooth muscle contraction.
    • Edema may result from fluid leaking into tissue spaces.
    • Blood pressure may also drop dramatically, leading to life-threatening anaphylactic shock
  59. Mediators released from Mast Cells and Basophils:
    • Histamine and other lipid molecules and cytokines
    • Collectively they act to:
    • 1. Increase permeability and distension of blood vessels leading to edema and erythema (redness)
    • 2. Increase mucus secretion, smooth muscle contraction
  60. Treatment of Anaphylaxis
    • Antihistamine: block action of histamine
    • Epinephrine (Epi-pen): constricts blood vessels; raises blood pressure
  61. Type II (cytotoxic)
    Mother is Rh- and baby is Rh+ (becomes a problem with the second pregnancy)
  62. Prevention of Rh sensitization
    Rhogam (anit-Rh antibodies) administered soon after delivery (to mom), prevents fetal red blood cells from entering maternal blood
  63. Type II
    • Mediated by antibody-dependent cell-mediated cytotoxicity or by complement fixing IgG or IgM antibodies
    • Other Transfusion reaction:
    • ABO incomparibilities
    • Eg. Type A blood - RBC have A antigen on them and individuals produce anti-B antibodies.  If Type A blood type is transfuse with B or AB blood then there will be an antigen-antibody reaction which with the aid of complement leads to lysis of the red cells
  64. Type III (Immune complex mediated)
    • Immune complex circulates in blood
    • Immune complex deposits on e.g. skin, joints and kidney (glomerulr basement membrane)
    • Complement is activated by immune complex (classical pathway)
    • "Arthus reaction" local reaction (eg. Schick test for diphtheria)
    • Generalized reaction: systemic dissemination of AG-AB complexes eg. poststreptococcal glomerulonephritis or SLE, or serum sickness
    • Activated complement attracts neutrophils that release their granules and enzymes to damage tissue
  65. Type IV (delayed cell mediated)
    • Slower response (2-3 days)
    • Activated macrophages are the principal effector cell
    • Lytic enzymes that leak from activated macrophages cause local tissue destruction. CTL induced by Th1 cells may also participate in tissue destruction
    • DTH responses can cause allergic responses such as contact dermatitis, e.g. skin reaction to poison oak and poison ivy where an oil from the plant complexes with skin proteins that are then presented by skin dendritic cells to Th1 cells
    • Other types IV reaction: tuberculin test, transplant rejection
    • Treatment: corticosteroids for contact dermatitis
    • Immunosuppressive drugs for transplant rejection
  66. 6 types of vaccines
    • 1. Attenuated whole-agent
    • 2. Inactivated whole-agent
    • 3. Toxoids
    • 4. Subunit
    • 5. Conjugated
    • 6. Nucleic Acid
  67. Attenuated whole agent vaccines
    • Living but changed (weakened) microbes: antigen intact but virulence diminished
    • Closely mimics real infection: vaccine strain replicates in host cells
    • 95% effectiveness, often life-long immunity: stimulates both humoral and cell mediated immunity; memory cells
    • E.g. Sabin (polio), MMR (measles, mumps, rubella), BCG (TB), nasal influenza vaccine (Flumist)
    • Disadvantage:
    • If the microbe mutates back to the virulent form it may cause disease
    • Cannot use for people with compromised immunity
  68. Inactivated whole-agent vaccines
    • Use whole microbes that have been killed, usually by formalin or phenol: eg. rabies, Salk (polio), some influenza vaccines
    • No replication in host; safe for immunocompromised: even pregnant women (so this is why they can be immunized against influenza!)
    • Immunity does not last as long as attenuated vaccine
  69. Toxoids
    • Toxin isolated and chemically treated to preserve the antigenicity but make the toxin non-functional
    • Toxoid then used as vaccine to produce antibodies to toxin, not the microbe
    • Requires boosters for full immunity: eg. diphtheria, tetanus
  70. Subunit vaccines
    • Only the antigenic fragments of a microorganism that will best stimulate an immune response (no living organism)
    • Usually produced by genetic engineering: recombinant vaccines, other microbes are programmed to produce the antigen
    • Eg. Hepatitis B vaccine, Gardasil: Both of these are made in yeast cells
  71. Conjugated vaccines
    • Used for organisms that have polysaccharide capsules (poor antigens)
    • Children <2 yrs can't respond t polysaccharides as antigen
    • Polysaccharides are combined with a protein which is highly immunogenic (eg. diphtheria toxoid) (fooling the immune system to react to the protein, and at the same time get immunity to the carbohydrate)
    • eg. Haemophilus influenza type b
    • Neisseria meningitidis
    • Streptococcus pneumoniae
  72. Nucleic Acid Vaccines
    • DNA vaccines
    • Introduce a gene for an organism into human host cells, hope that it will persist there and get transcribed
    • Induce cells to produce organism specific proteins that linger and keep the immune system activated to the organisms
    • Still in stage of R + D (research and development)
    • Hold promise but there are many problems yet to solve
  73. Tuberculin Skin Test
    • Test to determine the immune status of an individual
    • Widely used to detect TB in North America because most people are not immunied
    • Small amount of PPD (purified protein derivative) - proteins from M. tuberculosis are injected into the skin of the forearm. Positive test is indicated by reddening and thickening of skin 48-72 hours after inoculation.  (this is caused by the infiltration of lymphocytes and macrophages)
    • Cell-mediated reaction (type IV)
  74. Mantoux Test
    • Quantitative:
    • A type of tuberculin test where different concentrations of PPD are injected and the area that reacts on the skin is measured
  75. Restrictions in usefulness of tuberculin tests:
    • Cannot be used in people that are anergic (unresponsive) or patients that are immunosuppressed as they do not react predictably to an immune stimulus (eg. AIDS patients)
    • Tuberculin test is not specific for M. tuberculosis, -other Mycobacteria can also give a positive test
  76. QuantiFERON - TB Gold Test
    • New blood test for diagnosing TB
    • Can be used to help confirm or rule out a latent or active tuberculosis infection
    • Does not require the patient to return in 48 to 72 hours to have their results read
    • Blood - separate T lymphocytes, stimulate with PPD, then measure the interferon produced by the lymphocytes
    • Limited data on the usefulness of this test in children, immunosuppressed
  77. Allergies
    Hypersensitivity (Immune system going "wrong"
  78. Vaccine:
    Different types with different activities for different bugs
  79. Tuberculin Test:
    Not a vaccine, but a diagnostic test using the Type IV hypersensitivity reaction to gauge patient exposure