Immuno Transplant, Tumor, Hypersen I (12/13/14)

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mse263
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244630
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Immuno Transplant, Tumor, Hypersen I (12/13/14)
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2013-11-09 19:00:49
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Immunology
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Exam 4
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  1. Immuno 12
  2. Autoimmunity
    • the response of the immune system against self-components due to a LOSS of self-tolerance
    • results in immune reactions against autologous (one's own) antigens
    • eg. Lupus, ulcerative colitis, multiple sclerosis, Crohn's disease, Sjogren's disease, rheumatoid arthritis, psoriasis, scleroderma, autoimmune hemolytic anemia
    • Fundamental Problem: there's an imbalance between immune activation & immune control
  3. To develop an autoimmune disease, often there are problems in what components of the body systems?
    • 1. Immune Regulation
    • 2. Genes
    • 3. Environment (eg. smoking increases risk of rheumatoid arthritis)
  4. What are some immunological factors that could cause autoimmunity?
    • 1. exposure of hidden antigens (sympathetic ophthalmia)
    • 2. polyclonal lymphocyte activation
    • 3. abnormal lymphocyte regulation
    • 4. defective Fas-FasL interactions: T cell has FasL, most cells have Fas
    • 5. imbalance between CTLA-4 & CD28 (no CTLA-4 = overactive T cells)
    • 6. defective Treg cells (CD4 & CD25)
  5. How can hidden antigens cause autoimmunity?
    • any tissue antigens normally hidden from circulation and not seen by the developing immune system won't be exposed to developing T cells and induce self-tolerance
    • if these hidden antigens are later exposed to mature T cells an immune response will be generated
    • this could occur after tissue destruction by infections or trauma or other means
    • eg. autoantibodies to sperm after vasectomy or testicular trauma, antibodies to heart muscle after myocardial infarction, or antibodies to lens protein after eye damage (sympathetic ophthalmia)
  6. Abnormal Lymphocyte Regulation
    • excessive or uncontrolled cytokine may cause abnormal lymphocyte activation, including autoreactive B and T cells
    • could happen following preferential activation of TH1 cells (the main producers of IL-2)
    • cytokines may produce tissue damage by upregulating adhesion molecules, or they may upregulate costimulatory molecules B7 & CD28 causing increased B cell activity
    • EBV (viral) infection stimulates B cells non-specifically; might activate B cells against themselves
    • Similarly super antigens stimulate T cells non specifically --> may activate a T cell that is anti-self
  7. HLA associated with Autoimmunity
  8. Molecular Mimicry
    • there are certain antigens present on foreign pathogenic organisms that are ALSO present within our bodies
    • eg. the rheumatic fever antigen looks similar to heart valve proteins
    • the proliferation of anti-rheumatic fever antibodies targets the bacteria 1st & then damages (heart murmur) the patients heart after a streptococcal infection
  9. autoimmunity is 9x ____ common in women than in men
    • more common in women
    • could potentially be due to female hormonal influences
  10. What causes diseases like Crohn’s, IDDM, psoriasis, or multiple sclerosis?
    • T-cells hitting a target
    • can treat these patients by turning down T cell reaction (interrupt immunological synapse)
  11. immuno 13
  12. Autograft
    • from one person to the same person
    • usually done with skin from one part of the body to another, i.e. in order to heal a burn: skin from thigh to wherever is damaged
  13. Syngraft
    • person to a genetically identical recipient
    • rare occurrence: need to have identical HLA; usually happens between twins
  14. Allograft
    • person to a genetically different recipient
    • common: kidney, bone marrow, liver, heart
  15. Xenograft
    • graft to a different species
    • pig --> man
    • worry about this is that you can pass animal viruses to human receiving the transplant
  16. How do my body's T cells recognize a graft as foreign?
    • 1. my antigen presenting cells process & present the graft's (donor) MHC peptides to my T-cells [same way we always recognize foreign molecules]
    • 2. my T-cells recognize unprocessed donor MHC molecules directly on graft antigen presenting cells (our T cells can recognize donor HLA on antigen presenting cells from the graft)
    • #2 is the ONE exception to T cells only recognizing peptides in our OWN MHC molecules; unique aberration to know about

  17. Hyperacute rejection
    • happens within minutes or hours as a result of pre-formed antibodies in the recipient against the donor
    • instigated by complement binding to said pre-formed antibody and initiating powerful destruction of the tissue
  18. Why might hyperacute rejection of a transplanted organ occur?
    • could occur due to antibodies having been previously made against HLAs/WBCs in transfusion blood that had previously occurred
    • why blood banks wash their blood and only give RBCs now
    • coud also occur to a mother who's been exposed to her baby's cells during birth, leaving her resistant to her child's and her husband's HLA
    • before transplant is done need to make sure recipient doesn't have an antibody against the donor
  19. Acute rejection
    • happens after about 10-14 days as a result of mainly cell mediated immunity but you also make some antibody to the foreign tissue
    • the recipient's T cells rejects the foreign HLA types
    • takes 10-14 days because the graft antigen has to be presented/activate T cells, T cells proliferate, make cytokines, etc. there's a build up to the immune response
  20. Chronic rejection
    • can happen months or years after the transplant as a result of antibody, T-cell, & NK cell attack on the graft
    • due mainly to antibody made against the graft --> humoral immune response
    • natural killer and T cells also attack the graft
    • occurs after an extended period of immunosuppression
  21. What is the main way a recipient's body acutely rejects an allograft?
    • *direct contact between CD8+ cells and the graft*
    • CD8+ cells recognizes an MHC class I molecule on the graft's APC
    • T cell's FasL binds to the APC's Fas --> induces apoptosis
    • T cell releases perforin & granzyme into the APC, killing it
    • acute rejection takes 10-14 days to occur

  22. What are other ways a recipient's body acutely rejects an allograft?
    • 1. locally released cytokines & chemokines cause inflammation, macrophage activation, & infiltration of phagocytic cells at graft
    • 2. antibody may be made against donor HLA: induces destruction via complement (holes punched in cell membranes) or ADCC
    • 3. or natural killer cells can attack & destroy graft cells
    • acute rejection takes 10-14 days to occur
  23. Antibody-dependent cellular cytotoxicity (ADCC)
    • 1. antibody binds antigens on the surface of target cells
    • 2. Fc receptors on NK cell surface recognize bound antibody
    • 3. cross-linking of Fc receptors signal NK cells to kill target cell
    • 4. target cell dies --> apoptosis
  24. Stem cell transplantation
    used with patients who lack some component of immune response (eg. children with no B cells, DiGeorge Syndrome, or SCID) & Cancer
  25. When can we get stem cells for stem cell transplantation?
    • 1. the peripheral blood (after treatment with colony stimulating factors)
    • 2. umbilical cord blood
    • 3. bone marrow
  26. What is the major problem with bone marrow transplantation?
    • competent T-cells from the donor may be transplanted giving rise to graft versus host disease
    • aka donor T cells & APCs that were injected along with the stem cells start rejecting the recipient from inside because the host molecules' MHCs they detect are 'foreign' to them
    • these donor proliferate and cause graft versus host disease
  27. graft versus host disease (GVH)
    • a reaction of donor T cells against recipient MHC
    • CD4+ T cells in the graft are activated by allogeneic [foreign] host molecules and produce a “cytokine storm”
    • this recruits other HOST/NATIVE T cells, macrophages and NK cells to create the severe inflammation characteristic of GVH
  28. What three conditions must be satisfied in order for graft versus host disease (GVH) to occur?
    • 1. graft must contain live donor T cells (eg. bone marrow or thymus graft; no T cells on a kidney [washed])
    • 2. recipient MUST be immunosuppressed - would be rejected immediately upon transplantation; cancer patients/kids with immunodeficiency ARE immunosuppressed
    • 3. donor and recipient must have DIFFERENT HLA types (can't happen in identical twins)
  29. cyclosporine A is fungal metabolite used to prevent graft/transplantation rejection. How does it accomplish this?
    • it complexes with calcineurin, INHIBITING T cell activation & preventing cytokine synthesis that activates effector cells to reject the foreign tissue --> IMMUNOSUPPRESSES
    • FK506 (tacrolimus) is a drug that accomplishes the same thing
    • calcineurin: phosphatase that ACTIVATES T cells
  30. Besides cyclosporine & FK506, how else might one immunosuppress somebody receiving a graft transplant? (3)
    • 1. corticosteroids: inhibit cytokine production & are anti-inflammatory
    • 2. anti-CD3 monoclonal antibody: knocks out T cells, impossible for them to be activated, proliferate, & cause an immune response
    • 3. anti-IL-2 receptor antibody
    • interfering w/ any of this would cause immunosuppression
  31. Why aren't tumors perceived as foreign and destroyed?
    while tumors DO have foreign antigens on their surface that can be recognized by the immune system, we don't know why they aren't they rejected
  32. What are the types of antigens seen on the surface of tumor cells?
    • 1. virally controlled antigens
    • 2. oncofetal antigens
    • 3. abnormal peptides made by tumor cells
    • 4. mutant antigens (eg. Her2/neu)
    • 5. tissue specific differentiation antigens
  33. viral antigens
    • viruses such as Hepatitus B & HPV cause cancer in that they instigate uncontrolled cell proliferation
    • such cells present viral proteins in their MHC molecules on their surface
    • Hepatitus B causes liver cancer, & HPV causes cervical cancer
  34. oncofetal antigens
    some antigens that are found on fetal but not adult cells are ALSO expressed by cancerous cells, such as alpha-fetoprotein on tumor cells of primary hepatocellular carcinoma (liver cancer) and carcino-embryonic antigen on tumor cells of colon cancer
  35. alpha-fetoprotein
    • an antigen found on the liver of fetuses but NOT in adults
    • patients that develop primary liver cancer start making alpha-fetoprotein & all their cells express it
    • condition: primary hepatocellular carcinoma
  36. carcino-embryonic antigen (CEA)
    • an antigen found on the colon of fetuses but not in adults
    • patients that develop colon cancer have CEA on their cell surfaces
    • condition: colon carcinoma
  37. Her2/neu protein
    • mutated (of normal proteins) peptide made by breast tumor cells
    • if the tumor expresses Her2/neu, a monoclonal antibody called Herceptin can treat the cancer by binding to the surface peptide & killing cells that produce this mutated protein
  38. tissue specific differentiation antigens
    • different tissues make different proteins, and sometimes cancerous cells produce above average levels of certain proteins; can also simply test a tumor for what proteins are present & the findings can be used to determine what the disease is (markers)
    • eg. PSA made by prostate cells, B-cells' CD19, CD20, & T-cell markers such as CD3, CD4 or CD8
  39. prosatte-specific antigen (PSA)
    • made by prostate cells but made much MORE by prostate cancer cells
    • as soon as you see the levels increase, it's like the person has prostate cancer
  40. Normal B-lymphocytes have CD__, CD__, and _____ & ______ light chains in their antibodies. However B-cell lymphomas (malignancy of a single B-cell clone) have CD__, CD__, and ONLY _____ light chains in their antibodies.
    • normal B-cell: CD19, CD20, kappa OR lambda light chains
    • B-cell lymphomas: CD19, CD20, and ONLY kappa light chains
  41. What is an additional change on the surface of malignant cells involving MHC/HLA Class I molecules?
    • tumor cells may lose HLA Class I
    • this prevents such cells from interacting with CD8+ T cells --> therefore CD8+ cells can't kill them but NK cells that recognize & are cytotoxic to HLA Class I negative cells CAN kill them
  42. Natural Killer Cells (NK cells)
    • recognize and eliminate cancerous (malignant) or diseased (virally infected) cells that fail to exhibit class I MHC protein
    • are large granular lymphocytes (LGL's)
    • have Fc RECEPTORS that bind to IgG --> ADCC
    • can be activated by cytokines such as IL-2, 12, & IFN-γ
    • and themselves produce cytokines (eg. TNFα, IFNγ, & IL-10)
  43. What are the two ways an NK cell destroys tumor cells?
    • 1. it recognizes that the cell lacks an MHC class I surface molecule, docks on the cell, & pumps in perforin & granzyme to kill the cell
    • 2. ADCC: if an IgG antibodies are made to the tumor cell & bind, NK cell Fc receptors can bind IgG --> using this connection to pump in & perforin & granzyme to kill the tumor cell
  44. Immune mechanisms of tumor rejection: the main ways in which a healthy person kills any aberrant cancer
    • #1 cytotoxic CD8+ T cells (CTL’s) - using granzyme + perforin, TNF, & expression of FasL
    • #2 activated macrophages
    • #3 NK cells
  45. How do tumors evade a host's immune system?
    • 1. by releasing immunosuppressive factors (eg. IL-10, TGF-β)
    • 2. by releasing factors that activate Treg cells
    • 3. by selecting antigen-negative variants: they change their antigens and become resistant to lymphocytes responsible for recognition (new & different T cells must be made specific to the tumor cells NEW adapted antigen)
  46. How can we boost the immune response to get rid of cancer?
    • 1. stimulate innate immune mechanisms (eg. imiquimod & BCG)
    • 2. cytokines (eg. IL-2, IFNγ) - hasn't worked mostly*
    • 3. immunization against oncogenic viruses (eg. Hep B, HPV)
    • 4. increase immunogenicity of tumors
    • 5. monoclonal antibodies
  47. Imiquimod
    • a drug which increases the expression of toll like receptor 7 (TLR7)
    • when applied to the skin causes massive inflammation & skin to slough off
    • useful for skin cancer
  48. BCG
    • vaccine against tuberculosis in other countries but here used for bladder cancers because it causes inflammation in bladder wall
    • it causes such inflammation that superficial bladder and cancer sloughs off
  49. increase immunogenicity of tumors
    • by putting into tumors/cancer cells more immunogenic proteins, will help the immune system find, bind to, & incapacitate malignant cells
    • not as successful as hoped
    • eg. adding B7 ---> to bind to CD28 [activate antibody production]
    • MHC Class II ---> to activate and proliferate CD4+ T cells
    • cytokine genes
  50. immunotoxins
    • monoclonal antibodies attached to toxins such as ricin or radioactive isotopes that are delivered specifically to the malignant cells to initiate direct killing
    • eg. Rituximab targets CD20 on B-cell lymphomas
    • Erbitux targets growth factor receptors in colon cancer
    • Herceptin (anti Her2/Neu) blocks growth factor signaling on breast cancer cells

  51. immuno 14
  52. hypersensitivity implies:
    damage; when elements of the immune system goes wrong
  53. Type I Hypersensitivity
    • also called IgE-mediated Hypersensitivity or Immediate Hypersensitivity
    • reaction occurs within minutes ("allergic reaction")
    • 1. upon 1st exposure to an antigen, IgE antibodies stick to mast cells through their Fc portion (mast cells & basophils have receptors for IgE Fc regions)
    • 2. upon 2nd exposure to the antigen, it cross-links 2 molecules of IgE on the surface of a mast cells causing it to degranulate
    • *it's the granules released which cause the allergic reaction
  54. Why do some individuals preferentially make IgE antibodies as opposed to IgG antibodies?
    • it is unclear why some people turn on TH1 T cell production (IgG) versus TH2 T cell production (IgE)
    • could be due to an unknown genetic component
    • if an antigen is internalized through the skin or mucus membrane, IgE production is favored over IgG
    • if an APC preferentially presents antigen to TH2 cells, resulting in production of IL-4 and IL-13
    • if Treg cells fail to proliferate & control TH2 cells
  55. Inhibiting which cytokines helps alleviate the symptoms of an allergic response, notably asthma?
    • IL-4 & IL-13
    • APC presents antigen fragment to TH2 T cell
    • TH2 T cell replicates and makes *IL-4 & IL-13
    • IL-4 & IL-13 bind to their receptors on the B cell surface
    • induce the B cell to make IgE
    • inhibiting IL-4 & IL-13 (by binding them to a complementary antibody that immobilizes them) improves asthma

  56. Will you ever get an allergic reaction on 1st exposure to a foreign antigen?
    • NO
    • you will never get an allergic reaction to FIRST exposure; 1st exposure sensitizes you to the allergen
    • 2nd exposure may cause the allergic reaction

  57. Upon degranulation of mast cells - triggered by an antigen binding & cross-linking IgE receptors on the cell surface - what is released?
    • early phase pro-inflammatory mediators: released in minutes
    • Histamine
    • Proteases
    • Leukotrienes
    • Prostaglandins
    • Platelet Activating Factor (PAF)
    • Chemotactic Factors for neutrophils & eosinophils
    • *generally cause vessels to open & cells to move into where the reaction is taking place
  58. Histamine
    • responsible for acute inflammatory symptoms that occur within minutes after allergen exposure in sensitized individuals
    • local effects: vasodilation, increased vascular permeability, increased mucus secretion, bronchiolar smooth muscle contraction
  59. Histamine symptoms in allergic rhinitis
    • itching, edema, nasal congestion, sneezing, rhinorrhea (runny nose)
    • ocular itchiness and tearing (due to vasodilation)
  60. Histamine symptoms in asthma
    bronchial constriction and bronchial hyperresponsiveness (due to activation of neuronal reflexes)
  61. Proteases
    cause tissue degradation and increased mucus production
  62. Leukotrienes
    • increase vascular permeability, mucus production & bronchoconstriction
    • leukotriene B4 is a chemoattractant for neutrophils & eosinophils
  63. Platelet Activating Factor (PAF)
    • activates platelets to release serotonin, another inflammatory mediator
    • causes bronchoconstriction & massive vasodilatation responsible for anaphylactic shock*
    • is the MOST potent vasodilator
  64. What are late phase mediators of the acute allergic reaction?
    • cytokines from mast cells, TH2 cells, macrophages, & eosinophils released in the late phase
    • the reason they come later is because they're present/released from eosinophils and neutrophils that are BROUGHT to the site of the hypersensitivity reaction by initially released chemokines
  65. FEV-1
    • a means of chest expansion; if high can take in a big breath
    • if low = bronchoconstriction, airway is compromised
  66. How can the late phase reaction be controlled?
    • by corticosteroids that INHIBIT cytokine production
    • cytokines from mast cells, TH2 cells, macrophages, & eosinophils don't receive the signal to come to an area of inflammation --> no late phase reaction
  67. Which phase takes longer to recover from, the early or late phase?
    • the LATE PHASE
  68. What are some causes of allergic rhinitis?
    • allergic rhinitis = IgE mediated allergic reactions (type I)
    • hay fever: specifically caused by grass pollens (most common; active during summer)
    • tree pollens: April/May
    • ragweed pollen: Sept/Oct
    • cat hair
    • dog hair
    • house dust mite: allergies flare up at night
    • moulds
  69. Bronchial asthma
    another type of type I hypersensitivity reaction that results in bronchial constriction
  70. Examples of IgE mediated allergic reactions (Type I Hypersensitivity Reactions)
    • allergic rhinitis (hay fever)
    • bronchial asthma: results in bronchial constriction
    • acute drug reactions
    • food allergies
    • insect stings: lots of insects from same family have similar venom - all cause allergic reactions
    • acute urticaria (hives): itchy, angioedema
  71. How do you treat Type I hypersensitivity allergic reactions?
    • *epinephrine (adrenaline): treats acute anaphylactic reactions
    • remove the antigen (eg. house dust mite, moulds, cats, peanuts etc)
    • can treat symptomatically with antihistamines, anti-leukotrienes, corticosteroids
    • omalizumab
    • hyposensitization therapy (shots)
  72. omalizumab
    • a monoclonal antibody that inhibits IgE binding to mast cells
    • used to treat type I hypersensitivity allergic reactions
  73. hyposensitization therapy
    • shots are given containing tiny doses of whatever the person is allergic to (eg. eg. bee venom, cat hair antigen, grass pollen antigen
    • the treatment consists of multiple exposures to increasing concentrations of the antigen, which results in an INCREASE of IgG antibodies, and a decrease in IgE antibodies (because antigen is injected deeply into skin)
    • when the allergen is there, IgG reacts with the it before IgE can

  74. Why might there be an increase in IgG and a decrease in IgE during hyposensitization therapy? (2)
    • 1. hyposensitization activates the TH1 cells
    • 2. hyposensitization activates Treg cells that INHIBITS the TH2 cells
  75. How else can mast cells be degranulated BESIDES an IgE mediated type I hypersensitivity reaction?
    • C5a and C3a (anaphylatoxins)
    • CNS effects via the vagus nerve - seeing a cat and getting bronchoconstriction
    • direct effect of drugs on mast cells
    • heat
    • cold
    • pressure (eg. dermatographism)
    • exercise
  76. hygiene hypothesis
    hypothesis that states that a lack of early childhood exposure to infectious agents, symbiotic microorganisms (eg. gut flora or probiotics), & parasites increases susceptibility to allergic diseases by SUPPRESSING the natural development of the immune system

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