Biology 151 lecture 4 2012 2013 (part 2 hi)

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Biology 151 lecture 4 2012 2013 (part 2 hi)

  1. 1. HUMORAL IMMUNITYThursday, July 19, 2012
  2. 2. HUMORAL IMMUNITY • RECALL: mediated by antibodies AND functions to neutralize and eliminate extracellular microbes and microbial toxins • e.g. microbes with capsules rich in polysaccharides and lipid toxins • B-cells respond to and produce antibodies specific for many types of molecules (vs T cells = only protein antigens) • WHAT ARE WE TO KNOW: process and mechanisms of B-cell activation and antibody production • How are receptor-expressing B-lymphocytes activated and converted to antibody-secreting cells • How is the process of B-cell activation regulated so that the most useful types of antibodies are produced in response to different types of microbesThursday, July 19, 2012
  3. 3. PHASES OF HUMORAL IMMUNE RESPONSESThursday, July 19, 2012
  4. 4. TD & TI ANTIGENSThursday, July 19, 2012
  5. 5. TD and TI ANTIBODY RESPONSES • RECALL: based on the requirement for T-cell help • T-dependent antibody response: Protein antigens are processed in antigen- presenting cells and recognized by helper T-lymphocytes, which play an important role in B cell activation PLUS powerfuI inducers of heavy chain class switching and affinity maturation • In the absence of T cell help, protein antigens elicit weak or no antibody responses • T-independent antibody response: Polysaccharides, lipids, and other nonprotein antigens stimulate antibody production without the involvement of helper T cells • Antibodies show relatively little heavy chain class switching and affinity maturationThursday, July 19, 2012
  6. 6. PRIMARY & SECONDARY IMMUNE RESPONSEThursday, July 19, 2012
  7. 7. PRIMARY & SECONDARY IMMUNE RESPONSEThursday, July 19, 2012
  8. 8. So how do antigens stimulate B- lymphocytes?Thursday, July 19, 2012
  9. 9. ANTIGEN RECEPTOR-MEDIATED SIGNAL TRANSDUCTION IN B-LYMPHOCYTES • RECOGNITION & INITIATION: antigen-specific B-cells in the lymphoid follicles of the spleen, lymph nodes and mucosal lymphoid tissues recognize antigens • membrane-bound Ig receptors recognize antigen in their “native conformation” (without a need for processing) • SIGNAL TRANSDUCTION: Antigen-induced clustering of membrane Ig receptors trigger biochemical signals that are transduced by receptor-associated signaling moleculesThursday, July 19, 2012
  10. 10. THR ROLE OF COMPLEMENT PROTEINS IN B-CELL ACTIVATION: C3d (“second signals”) B-cells express a receptor for a protein of the complement system that provides signals for the activation of the cells (NOTE: C3d = analogous to co-stimulators of T-cells)Thursday, July 19, 2012
  11. 11. FUNCTIONAL CONSEQUENCES OF Ig- MEDIATED B-CELL ACTIVATIONNote: antigen stimulation induces theearly phase of the humoral immuneresponse= response is reatest when: ga) antigen is multivalentb) antigen cross-links many antigenreceptorsc) antigen activates complementstrongly= typical of polysaccharides andother TI antigensThursday, July 19, 2012
  12. 12. The Function of Helper T-lymphocytes in Humoral Immune Responses to Protein AntigensThursday, July 19, 2012
  13. 13. T-CELLS IN B-CELLS FUNCTIONING •Efficiency: protein antigens elicit excellent antibody responses within 3-7 days of antigen exposure •Helper T-cells that have been activated to differentiate into effector cells interact with antigen-stimulated B-lymphocytes at the edges of lymphoid follicles in the peripheral lymphoid organsThursday, July 19, 2012
  14. 14. INTERACTIONS OF T-CELLS & B-CELLS IN LYMPHOID TISSUESThursday, July 19, 2012
  15. 15. ANTIGEN PRESENTATION BY B-LYMPHOCYTES TO HELPER T-CELLS B-cells act as APCThursday, July 19, 2012
  16. 16. HELPER T-CELL-MEDIATED ACTIVATION OF B-LYMPHOCYTESThursday, July 19, 2012
  17. 17. ISOTYPE SWITCHING Helper T-cells stimulate the progeny of IgM+ IgD expressing B-lymphocytes to produce antibodies of different heavy chain classes (isotypes) initiated by CD40L-mediated signals and other cytokinesThursday, July 19, 2012
  18. 18. CLINICAL IMPORTANCE OF CLASS SWITCHING: •In the absence of CD40 or CD40L, B-cells secrete only IgM and fail to switch to other isotypes • X-linked hyper-IgM syndrome: inactivating mutations in the CD40L gene, located in the X chromosome • much of the serum antibody is IgM • defective heavy chain class switching • Patients with defective CMI versus intracellular microbesThursday, July 19, 2012
  19. 19. MECHANISM OF HEAVY CHAIN CLASS SWITCHING WHAT YOU NEED TO KNOW: IgM-producing B-cells, which have not undergone switching contain a rearranged VDJ gene adjacent to the first constant region cluster (Cu) in their heavy chain locus Splicing of VDJ RNA to Cu RNA = heavy chain mRNA heavy chain mRNA = translated to u heavy chain = combines with a light chain producing IgM ***IgM antibody (1st antibody produced)Thursday, July 19, 2012
  20. 20. MECHANISM OF HEAVY CHAIN CLASS SWITCHING WHAT YOU NEED TO KNOW: a) constant region downstream of Cu: where stimulation of transcription via signals from CD40 and cytokine receptors occurs b) switch region: conserved region within the constant region except for C-theta SWITCH RECOMBINATION: 3’ of Cu recombines with 5’ of switch region = all intervening DNA is deletedThursday, July 19, 2012
  21. 21. MECHANISM OF HEAVY CHAIN CLASS SWITCHING WHAT YOU NEED TO KNOW: RESULT OF SWITH RECOMBINATION B-cells begins to produce a new heavy chain class (depending on C region of the antibody) - IgG, IgE Same specificity as the original B-cellThursday, July 19, 2012
  22. 22. CYTOKINES & HEAVY CHAIN CLASSES • Cytokines produced by helper T-cells determine which heavy chain class is produced by influencing which heavy chain constant region gene participates in switch recombination (T-cells as master controllers of immune responses) • e.g. OPSONIZING ANTIBODIES: effect of IFN-g on B-cells complement the actions of this cytokine on phagocytes • their role: bind to phagocyte Fc receptors & promote phagocytosis • stimulated by: IFN-g of TH1 cells • e.g. IgE • stimulated by IL-5, a TH2 cytokineThursday, July 19, 2012
  23. 23. SITE OF IMMUNE RESPONSE & HEAVY CHAIN CLASSES • nature of antibody class may also be influenced by site of immune response • e.g. IgA: major isotype produced in mucosal lymphoid tissues • RATIONALE: mucosal tissues contain large number of B-cells able to switch to IgA and helper T-cells whose cytokines stimylate switching to IgA • NOTE: IgA is the principal antibody class that can be actively secreted through mucosal epitheliaThursday, July 19, 2012
  24. 24. AFFINITY MATURATION • process by which the affinity of antibodies produced in response to a protein antigen increases with prolonged or repeated exposure to that antigen • advantage: ability of antibodies to bind to a microbe or microbial antigen increases if the infection is persistent or recurrent • occurs in the germinal centers of lymphoid follicles • result of somatic hypermutation of Ig genes in dividing B-cells followed by the selection of high-affinity B-cells by antigen displayed by follicular dendritic cells (FDC)Thursday, July 19, 2012
  25. 25. STAGES OF TD ANTIGENS HUMORAL IMMUNE RESPONSE (note different anatomic compartments)Thursday, July 19, 2012
  26. 26. REGULATION: ANTIBODY FEEDBACK MECHANISM SECRETED ANTIBODIES FORM IMMUNE COMPLEXES WITH RESIDUAL ANTIGEN AND SHUT-OFF B- CELL ACTIVATION BY ENGAGING AN INHIBITORY Fc RECEPTOR ON B- CELLSThursday, July 19, 2012
  27. 27. EFFECTOR MECHANISMS OF HUMORAL IMMUNITYThursday, July 19, 2012
  28. 28. SIGNIFICANCE OF HUMORAL IMMUNITYThursday, July 19, 2012
  29. 29. SIGNIFICANCE OF HUMORAL IMMUNITY • RECALL: mediated by antibodies and important for protection against extracellular microbes and their toxins = PREVENTION • only antibodies can mediate this function • by blocking the ability of microbes to bind to and infect host cells • by binding to microbial toxins and prevent them from damaging host cellsThursday, July 19, 2012
  30. 30. SIGNIFICANCE OF HUMORAL IMMUNITY • RECALL: mediated by antibodies and important for protection against extracellular microbes and their toxins = PREVENTION • only antibodies can mediate this function • by blocking the ability of microbes to bind to and infect host cells • by binding to microbial toxins and prevent them from damaging host cells • ADDITIONAL FUNCTIONS: eliminate microbes, toxins and infected cells from the body • NOTE: even if they cannot KILL intracellular microbes, they can bind to these microbes even before they can enter the host cells and thus preventing infectionsThursday, July 19, 2012
  31. 31. SIGNIFICANCE OF HUMORAL IMMUNITY • RECALL: mediated by antibodies and important for protection against extracellular microbes and their toxins = PREVENTION • only antibodies can mediate this function • by blocking the ability of microbes to bind to and infect host cells • by binding to microbial toxins and prevent them from damaging host cells • ADDITIONAL FUNCTIONS: eliminate microbes, toxins and infected cells from the body • NOTE: even if they cannot KILL intracellular microbes, they can bind to these microbes even before they can enter the host cells and thus preventing infections • most VACCINES: STIMULATES ANTIBODY PRODUCTIONThursday, July 19, 2012
  32. 32. PROPERTIES OF ANTIBODIES THAT DETERMINE EFFECTOR FUNCTIONS • antibodies may function distant from their sites of production (so that they perform their functions throughout the body) • protective antibodies are produced during the first response and in larger amounts during subsequent responses • antibodies use their antigen-binding region (Fab) to bind to and block the harmful effects of microbes and toxins while their Fc region is used to activate diverse mechanisms that elimante these antigens and toxins • heavy chain class switching and affinity maturation enhance the protective functions of antibodiesThursday, July 19, 2012
  33. 33. IMPORTANT TO KNOW •What are the mechanisms used by circulating antibodies to combat different types of infectious agents and their toxins? •What is the role of complement system in defense against microbes? •How do antibodies combat microbes that enter via the GIT and RT? •How do antibodies protect the fetus and newborn from infections?Thursday, July 19, 2012
  34. 34. EFFECTOR FUNCTIONS OF ANTIBODIESThursday, July 19, 2012
  35. 35. EFFECTOR FUNCTIONS OF ANTIBODIESThursday, July 19, 2012
  36. 36. NEUTRALIZATION OF MICROBES & TOXINS BY ANTIBODIES Antibodies bind to and block (NEUTRALIZE) the infectivity of microbes and the interactions of microbial toxins with host cells Neutralization does not allow an infection to take holdThursday, July 19, 2012
  37. 37. ANTIBODY-MEDIATED OPSONIZATION & PHAGOCYTOSIS opsonization: antibodies coat microbes and promote their ingestion by phagocytes opsonins: molecules that coat microbesThursday, July 19, 2012
  38. 38. ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY (ADCC) • natural killer cells (NK) and other leukocytes may bind to antibody- coated cells and destroy these cells • important in helminth infections • helminths are too large to be phagocytosed • thick teguments resistant to substances released by phagocytes (neutrophils and macrophages • IgE and eosinophil tandemThursday, July 19, 2012
  39. 39. COMPLEMENT ACTIVATIONThursday, July 19, 2012
  40. 40. COMPLEMENT ACTIVATIONThursday, July 19, 2012
  41. 41. LATE STEPS IN COMPLEMENT ACTIVATIONThursday, July 19, 2012
  42. 42. FUNCTIONS OF COMPLEMENTThursday, July 19, 2012
  43. 43. REGULATION OF COMPLEMENT ACTIVATION • mammalian cells express regulatory proteins that inhibit complement activation, thus preventing complement-mediated damage of host cells (adaptation of mammals) • a) decay accelerating factor (DAF); disrupts the binding of Factor B to C3b or the binding of C4b2a to C3b thus terminating compelemnt activation by both the alternative and the classical pathways • b) membrane cofactor protein (MCP): serves as cofactor for the proteolysis of C3b into inactive fragments (mediated by Factor 1) • c) Type 1 complement receptor: same functions as MCP • d) C1 inhibitor (C1 INH): stops complement activation early (at stage of C1) • ABSENCE OF REGULATION: hypersensitivities; immunodeficiencies, etcThursday, July 19, 2012
  44. 44. REGULATION OF COMPLEMENT ACTIVATIONThursday, July 19, 2012
  45. 45. REGULATORY PROTEINSThursday, July 19, 2012
  46. 46. Thursday, July 19, 2012
  47. 47. Thursday, July 19, 2012
  48. 48. HYPERSENSITIVITY TYPE 1: Anaphylactic hypersensitivityThursday, July 19, 2012
  49. 49. HYPERSENSITIVITY TYPE 1: Anaphylactic hypersensitivity IgG antibodies against the Fc portions of IgE that binds to mast cells has been approved for treatment of certain allergies, as it can block mast cell sensitizationThursday, July 19, 2012
  50. 50. Thursday, July 19, 2012
  51. 51. Thursday, July 19, 2012
  52. 52. Thursday, July 19, 2012
  53. 53. Thursday, July 19, 2012
  54. 54. MUCOSAL IMMUNITY • immunity when IgA produced in mucosal lymphoid tissues are actively transported across epithelia and binds to and neutralizes microbes that enter through mucosal organs • IgA: 60-70% of 3g of antibody produced by a health adult in his intestines • ORAL POLIO VACCINEThursday, July 19, 2012
  55. 55. EVASION OF HUMORAL IMMUNITYThursday, July 19, 2012

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