Exam IV

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Exam IV
2010-11-06 23:44:43

Med Foundations I
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  1. What is the Classical Complement Pathway?
    • activated by Ag-Ab complexes
    • 1. C1 binds to the Fc region of the antibody bound to antigen
    • 2. C1q, C1r, and C1s clump together on the Fc region to become the C1 esterase
    • 3. C1 esterase cleaves C4 into C4a (which is released) and C4b (which binds to the complex on the antibody)
    • 4. C14b binds and cleaves C2 into C2a and C2b (which binds to the complex)
    • 5. C14b2b becomes the C3 convertase which cleaves C3 into C3a and C3b
    • 6. C14b2b3b cleaves C5 into C5a and C5b which forms the Membrane Attack Complex (MAC)
  2. What is the MAC?
    • C5b initiated the complex of C6, C7, C8, and many molecules of C9
    • incoporation of many molecules of C9 causes further penentration of the lipid bilayer and results in the formation of a transmembrane channel that disturbs the cell's osmotic equilibrium that results in cell lysis
  3. What are the functions of the complement system?
    • 1. Opsonization: phagocytes have a cell surface receptor called the CRI that binds C3b when it is bound to and Ag-Ab complex; this assists in phagocytosis
    • 2. Inflammation: C3a and C5a are chemo attractants which direct the migration of phagocytes towards the site of complement activation; these are also called anaphylatoxins because they cause degranulation of mast cells and basophils whic release histamine and other things that increase capillary permeability
    • 3. Lysis of pathogens: via the MAC; particularly important in destroying Neisseria organisms
    • 4. Viral neutralization
    • 5. Clearance of Immune-Complexes
  4. What is the alternative complement pathway?
    • activate dby bacterial or viral particles, such as LPS
    • 1. Free-floating C3b binds to foreign microbial products
    • 2. serum factors B and D, as well as properdin (aka Factor P) combine witht he C3b to form C3BbBP which is a C3 convertase
    • 3. This complex splits C3 and continues the complement cascade

    this pathway is primed and ready to go, and it is inhibited by Factor H and Factor I which bind C3b to inactivate it.
  5. What is the Lectin Pathway of Complement Activation?
    • Activated by mannose resiudes found on the surface of many bacteria
    • Mannose-binding-lectin (MBL) binds lectin, then Mannose-associated serine proteases 1 and 2 bind
    • This complex cleaves C4 and C2 to make the C4b2b which cleaves C3 and activates the cascade
  6. What is C1 esterase inhibitor (C1 INH)?
    • a protein that inhibits the first step in the activationof the classical complement pathway
    • binds C1r and C1s so they dissociate from C1q to prevent complement activation
    • absence of this protein results in Hereditary Angioedema
  7. Complement Deficiencies
    • C1q, C1r, C2, C4: SLE possibly due to the inability to clear immune complexes
    • C3: recurrent bacterial infection; rare, life-threatening
    • C5: bacterial infection, but not as severe as the above deficincy
    • C6, C7, or C8: Neisserial Infection
    • Alternative pathway proteins: recurrent pyogenic infections
    • MBL pathway: recurrent infection in childhood
    • C1 INH: Hereditary angioedema (HAE)
  8. What is HAE?
    • deficient C1 INH
    • characterized by localized edema in the skin and mucosa
    • recurrent attacks of swollen face and limbs, pain in the abdomen, and swelling of the larynx
    • can be aggrivated by trauma or menses
    • can be treated with pure C1 INH or with certain androgens that can stimulate the liver to make more
  9. What is an adjuvant?
    • substances distinct from antigen that enhance T-cell activiation by promoting the accumulation of APCs at the site of antigen exposure
    • might increase cytokine production and expression of co-stimulator molecules by APCs
    • significantly increases antibody response
  10. What is CD40?
    • a co-stimulator molecule on B-cells that binds to the CD40 ligand on T-cells
    • needed to induce antibody isotype switching
  11. How are T-cells regulated?
    • 1. CTLA-4: molecule expressed on the surface of t-cells that is also a receptor for B7 and it competes with CD28 for binding to B7; when bound to B7 it delivers an inhibitory signal to the T-cell
    • 2. Activation Induced Cell Death: repeated activation of T-cells leads to the co-expression of a death receptor; they normally have Fas ligand but they will begin to express Fas which induced apoptosis
    • 3. T-regulator Cells (Tregs): CD25+CD4+ cells that develop during positive selection in the thymus; express CTLA-4; may also secrete supressive cytokines such as IL-10 and TNF-beta
    • 4. Cytokine Mediated Regulation: INF-gamma produced by TH1 cells inhibits proliferation of TH2 cells; IL-4 from TH2 cells inhibits the proliferation of TH1 cells
  12. What is anergy?
    the inactivation of t cells that occurs when these cells recognize antigens without adequate levels of costimulators that are needed for full T cell activation
  13. What is central tolerance?
    • un-responsiveness to self-antigens
    • the self-tolerance that occurs in the thymus during negative selection
  14. What is peripheral tolerance?
    • when t-cells with central tolerance escape the thymus and migrate to the periphery
    • they are dealt with by clonal deletion (antigen-specific cells are removed by apoptosis) or clonal anergy (antigen-specific cells are present but unable to respond
  15. What is fetal tolerance?
    if you implant something foreign into a fetus, it wll not react because its thymus is still developing and it will treat the donor tissue as self
  16. What are the ways that adult tolerance may be produced?
    • interaction of T cells with antigen in the absence of thew co-stimulatory signals; administer anti-B& and anti-CD28
    • high dose tolerance by administering proteins systemically in high doses
    • oral tolerance by introducing protein antigens administered orally
  17. What are the immunological factors that may contribute to autoimmunity?
    • 1. Exposure of Hidden/Sequestered Antigen: certain tissues antigens are sequestered from the thymus during devlopment so they are not recognized as self; exposure of mature t cells to such normally sequestered antigens at a later date could result in their activation, ex. sympathetic ophthalmia (arrow to the eye)
    • 2. Polyclonal Lymphocyte Activation: some viruses and bacteria can activate B-cells non-specifically; super-antigens over-activate t-cells
    • 3. Abnormal Lymphocyte Regulation/ Excessive cytokine production: may abnormally activate lymphocytes; ex. IL-2 may activate a lot of T-cells and CD28 and B7 may activate many B-cells
    • 4. Defective Fas-Fas L Interaction: mature peripheral T cells do not die and they can continue to proliferate and produce autoimmune disease
    • 5. Defective TREGS: inability to turn down the t-cell response
    • 6. Balance between CTLA-4 and CD28: inability to terminate the immune response may lead to overactive t-cells
  18. What evidence is there that there may be genetic factor for autoimmune disease?
    • 1. autoimmune diseases are more common in certain families; in-bred strains of mice have been developed that spontaneoulsy develop autoimmune disease
    • 2. certain auto-immune diseases occur in individuals with certain HLA alleles
    • 3. increased incidence in twins
  19. What are the microbial factors that lead to autoimmunity?
    • 1. Molecular Mimicry: some microbes share similar or identical antigens with humans, so onfection leads to production of cross-reactive antibodies or t-cells that attack self tissue; ex. rheumatic fever after strep throat
    • 2. Abnormal activation of Lymphoid Cells: microbes and their superantigens may inappropriately activate B cells or T cell that are not specific; also may stimulate them to secrete cytokines which induces inappapropriate class II MHC expression
    • 3. Release of Hidden Antigens: microbes may cause tissue damage that release hidden antigens
    • 4. Microbes may function as adjuvants: usually when the APC process and present tissue proteins with bacteria; the bacteria induce the formation of MHC class II molecules but the T-cells recognize the self protein with it then begin to attack it
  20. What evidence is there for the presence of a hormonal factor to autoimmune disease?
    they are much more common in females
  21. What are the four types of grafts?
    • Autograft: one person to the same person
    • Syngraft: onre person to a genetically identically recipient, ie a twin
    • Allograft: one person to a genetically different recipient
    • Xenograft: donor and recipient are of different species
  22. Cancer Immunotherapy options
    • Imiquimod: activates TLR7 to cause a localized inflammatory response for HPV and basal cell carcinomas
    • BCG: induces a localized inflammatory response for superficial bladder cnacer
    • Cytokine treatment: IL-2 and IFN-gamma have been used to treat advanced melanoma and renal cell carcinoma; the network is complex
    • Immunization: vaccinate against cancer causing viruses; or immunize with whole tumor cells; problem is that tumors are weakly immunogenic so they may not activate a response; may introduce a co-stimulator like B7 to make them more immunogenis
    • Monoclonal antibodies: target tumor associated antigens; examples include anti-CD20 for B cell lymphoma, anti EGFR for colo-rectal cancers and anti-HER2/neu for breast and ovarian cancer
    • Immunotoxins: attach a plant or bacterial toxin to a tumor directed antibody
    • Radioimmunoconjugates: carry a raditation source to the tumor site for therapy or diagnosis
  23. Immediate Hypersensitivity (Type I)
    • aka allergic reaction; IgE-mediated release of histamine from mast cells and basophils
    • examples: allergic rhinitis (hayfever), asthma, food allergies, insect venom allergy and atopic dermatitis (eczema)
    • Sensitization: when atopic individuals (someone genetically capable of making IgE) are exposed to a specific antigen; APCs process it and present it to TH1 or TH2 cells; in the presence of IL-4 TH2 cells will be activated and will make more IL-4 and IL-13 which acts on B cells to make IgE; the Fc region binds to mast cells and basophils and they are primed and move into the mucosa and submucosa
    • Early Phase: Allergen binds to the IgE on the surface of the cell and the cells degranulate and release inflammaotry mediators
    • Late Phase: the things release in the early phase recruit leukocytes to the area; IL-3 for basophils, IL-4 makes more IgE and TH2 cells, IL-5 stimulate proliferation and recruitment of eosinophils and basophils, TNF-alpha starts the complement cascade, GM-CSF makes more granulocytes and PAF increases vascular permeability; all of this results in a recurrence of symptoms; eosinophils release chemicla mediators, toxic oxygen products and cytolytic enzymes that damage airways; they also make leukocyte attractants and endothelial cell adhesion molecules
    • Test: Skin prick tests
    • Treatment: eliminate antigen from environment, inhibit degranulation and reduce inflammation; antihistamines, bronchodialators, corticosteroids; monoclonal anticodies against IgE (Omalizumab); desensitization (raise the level of IgG antibodies in the serum)
  24. What are the imflammatory mediators released from Mast cells during Type I hypersensitivity and what do they do?
    • Histamine: bronchioconstriction, vasodilation, increase vascular permeability, stimulate nerve endings, and stimulate mucous secretions in airway
    • Platelet Activating Factor: constrict bronchial airways and vasodilation
    • Leukotrienes: constrict bronchial airways; dilate blood vessels
    • Prostaglandin D: constrict airways
    • All leads to wheezing and difficulty breathing, local redness, swelling, itching, congestion
  25. Cytotoxic Hypersensitivity (Type II)
    • IgG and IgM antibodies bind to antigens which are structural components of circulating cells or fixed tissues
    • Can cause cell destruction via:
    • 1. Complement pathway: the antibodie sinteract with antigen on host cell membranes and the classical complement pathway is activated, MAC kills the cell
    • 2. C3a and C5a are released from complement activation and they are chemoattractants for inflammation
    • 3. Binding of IgG and C3b to cells enhance phagocytosis (opsonization)
    • 4. Antibody coated cells are targetted by NK cells
  26. What are some clinical examples of Cytotoxin hypersensitivity reactions?
    • Autoimune Hemolytic Anemia: autoantibodies against RBCs; destroyed via complement or phagocytosis
    • Autoimmune thrombocytopenia: autoantibodies againts platelets; when bound to IgG they are removed from circulation by macrophages in the spleen and liver
    • Hyperacute Graft Rejection: pre-formed antibodies in the circulation against antigens on the transplanted tissue; triggers the blood clotting cascade leading to ischemia and necrosis of the graft
    • Goodpasture's Syndrome: autoantibodies against glomerular and alveolar basement membranes; damage to the kidneys and the lungs
    • Myasthenia Gravis: autoantibodies against the AChR at neuromuscular joints; antibody attaches to the receptors and is taken into the muscle cell; leads to sever muscle weakness; can be treated with plasmaphoresis
    • Graves Disease: Autoantibodies against the TSH receptor; acts as an agonist and constitutively turns on the thryoid gland and results in hyperthryoidism
  27. Immune Complex Hypersensitivity (Type III)
    • antigen bound to antibody (immune complexes) circulate throughout the body and deposit in tissues
    • they can bind complement leading to inflammation; the C3a and C5a also attarct neutrophils to the site which release degredative enzymes that damage tissues
  28. Clinical examples of systemic immune complex disease
    • Systemic Lupus Erythematosus (SLE): involves antibodies to several nuclear components including DNA; immune complexes deposit in many tissue and affect many organ systems; test for antinuclear antibodies in the serum
    • Post-streptococcal glomerulonephritis: anti-strep antibodies complex with strep antigens in the blood and get stuck in the glomerular capillary wall
    • Serum sickness: make antibodies to foreign serum after treatment with horse anitbodies for something else (like snake venom); immune complexes deposit in various tissue but especially in the joints, arteries, and glomeruli
    • Drug reactions: antibodies are commonly produced against drugs and when they combine with the drug they form an immmune complex that deposits in the arteries causin vasculitis; NOTE: penecillin cna cause Type I, II and IV reactions
  29. Clinical examples of localized immune complex diseases
    Also known as the Arthus Reaction: localized inflammation mediated by IgG bound to antigen

    • 1. Inoculation sites: usually for booster shots; there is already IgG present so it binds to the antigen and recruits neutrophils that damage vessels
    • 2. Farmer's lung: repeated exposure to moldy hay causes a farmer to make IgG to the mold spores; later inhalation of the spores causes inflammation; it can also result in delated hypersensitivity
  30. Delayed Hypersensitivity (Type IV)
    • a form of cell-mediated immunity (used T cells activated my macrophages); can be damaging to host when the t cells release inappropriately large amounts of cytokines
    • Sensitization Phase: APCs process antigen and present it to TH1 cells which causes an increase in the circulating TH1 cells specific to that antibody
    • Effector Phase: when exposed to antigen, the TH1 cells release cytokines that recruit and activate macrophages and other inflammatory cells; CD8 T cells also get activated and all of these things combined cause tissue damage
    • The effector response is mediated by : IL-2 (promotes T cell proliferation), IFN-gamma (activated macrophages; release other inflammatory factors), IL-1 and TNF (uregulate endothelial cell adhesion and cause them to release IL-8 to attract more leukocytes)
  31. Clinical examples of Type IV Hypersensitivity
    • 1. Contact Dermatitis: poison ivy, cosmetics, foreign chemicals, latex/rubber, metals in jewelry
    • 2. Mantoux reaction: TB PPD skin test; bump full of monocytes and macrophages, not neutrophils
    • 3. Chronic Infections: lesions from tuberculosis, leprosy, or syphilis; skin rashes in smallpox, measles, lesions caused by herpes, fungal disease, or parasitic disease like leishmania
    • 4. Autoimmune disease: T cells specific for iselt cells in IDDM, specific for unknown antigens in joint synovium in rheumatoid arthiritis, specific for myelin in MS, infiltration fo t cells in Crohn's disease, hyperproliferation of keratinocytes in psoriasis due to cytokines released by TH1 cells; t cells specific for wheat in Celiac's disease
  32. Congenital defects in neutrophil response
    • 1. Neutropenia: inadequate numbers to mount an immune response
    • 2. Defective opsinization: can be caused from a defect in IgG or C3b
    • 3. Chronic granulomatous disease (CGD): X-linked condition; defect in cytochrome b and NADPH oxidase makes them unable to generate superoxide in their phagosomes; results in granulomas in the skin, lymph nodes and other organs (accumulationg of monocytes, macrophages, and neutrophils)
    • 4. Leokocyte Adhesion Deficiency (LFA-1 deficiency): failure of neutrophils to migrate out of vessels at the site of antigen exposure; causes recurrent bacterial infections and inability to heal wounds such as the umbilical cord
    • 5. Cediak Higashi Syndrome: giant lysosomal granules that can't move; affects every organ
  33. Primary Humoral immunodeficiency disorders
    • 1. X-linked/Bruton's Agammaglobulinemia: Pre-B cells are in the bone marrow but they do not mature or make IgG, IgA, or IgM; absent or very small tonsils and lymph nodes becuase they do not have germinal centers of b cells; mutation of the Burton's tyrosine kinase gene needed fo rlight chain rearrangement; use antibody to CD19 to test for B cells; recurrent infections with extracellular pathogens; treatment: avaoid pathogens, use antibiotics, IVIG every three weeks
    • 2. IgA deficiency: very common and often undiagnosed; when combined with IgG2 or IgG4 deficiency it is more serious; IVIG doesn't help because IgA cant get into the serum; common symptoms include diarrhea and cough
    • 3. Hyper-IgM Syndrome: mutation of the CD40 ligand that is on T cells and needed for B cells to do isotype switching; patients do not have IgG, IgA or IgE so they get recurrent infections; dont have germinal centers
    • 4. Transient Hypogammaglobulinemia of infancy: delay in the normal production of antibodies and maternal ones only last 3-6 months; B-cells are present; cause is unknown
    • 5. Common Variable Immunodeficiency: low serum levels of all immunoglobulins; cuase unknown; recurrent infections of all types; example is honeymoon cystitis
  34. Primary T cell immunodeficiencies
    • 1. DiGeorge Syndrome: deletion on chromosome 22 that causes defective development of the thymus; C (cardiac abnormalities); A (abnormal facial features); T (thumic aplasia); C (cleft palate); H (hypoglycemia); recurrent infections with intracellular bacteria, fungi, and large viruses because of the dampered CD8 t cell response; recurrent pyogenic infections too because t cells are needed to stimulate b cells
    • 2. T cell activation defects: can be caused by abnormal CD3 expression, abnormal signal transduction, defective cytokine production or defective IL-2 receptor expression
  35. SCID
    • numerous forms of the disease and many causes; all aspects of the immune system are affected so patients are susceptible to all types of infection
    • most common form is a defect in the IL-2 receptor; this is X-linked SCID
    • ADA deficiency: accumulation of metabolites is toxic to proliferatoin of B and T cells
    • bare lymphocyte syndrome: they are missing MHC molecules
    • Abnormal signal trandsuction: can be mutations of protein kinases like JAK and ZAP or RAG1 or 2 so there is no isotype switching
    • Missing CD3: no signal transduction
    • Treatment: stem cell transplants but must be exact HLA match
    • Wiskott Aldridge Syndrome: leads to thrombocytopenia; X-linked; increased IgE leads to eczema; treated by stem cell transplant
    • Ataxia Telangiectasia: ataxia (drunken walk) and telangiactasia (little spider-looking patterns of vessels); no treatment
  36. Secondary immunodeficiency
    • Humoral: lymphoma, myeloma and burns
    • Cell mediaited: people on immunosuppresive durgs; protein malnutrition; viral infections (like HIV: has gp120 which binds CD4 and gp41 which binds CCR5 to enter the cell)
    • Aging: decreased numbers of neutrophils, APCs, NK cells, and t cells