PHRD5015 Lecture 16 (Ju) - Regulation of the Immune System

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PHRD5015 Lecture 16 (Ju) - Regulation of the Immune System
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2013-10-30 05:55:30
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PHRD5015 Regulation Immune System
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Regulation of the Immune System
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  1. humoral immunity
    Ab specificity and diversity
  2. Ab/Ig site for attachment to phagocytic cells
    constant region (Fc)
  3. Ab/Ig site for attachment to Ag
    variable region (Fab)
  4. types of bonds holding Ig's together
    disulfide bonds
  5. CDR
    • complementary-determining region
    • location of Ag binding 
    • determines specificity
  6. Ab structure
    • 2 heavy chains, 2 light chains
    • variable (V) domain located at N-terminus
  7. goodness of fit
    affinity between antigenic determinant/epitope & Ab
  8. Instruction Theory
    • Ag tells the immune system to make Ab of appropriate conformation 
    • ("tailor made dress")
  9. Clonal Selection Theory
    • each cell of immune system is programmed to make only 1 Ab - entire population preexists before Ag contact
    • choice of which Ab to make is RANDOM
    • ("store bought dress")
  10. 5 ways to maximize Ab diversity
    • 1) multiple germ line V genes
    • 2) V-J & V-D-J recombination
    • 3) combinatorial diversity (recombinational inaccuracies)
    • 4) somatic point mutation
    • 5) pairing of heavy & light chains
  11. segments in light-chain DNA
    V-J-C
  12. how many genes encode each constant region?
    ONE
  13. segments in heavy-chain DNA
    V-D-J-C
  14. enzyme responsible for VDJ splicing
    RAG recombination enzyme
  15. recombinational inaccuracies
    VDJ joins are sloppy, with some nucleotides lost/added (by TdT) at random without a template -> increased diversity
  16. TdT
    • terminal deoxynucleotide transferase
    • replaces lost nucleotides during VDJ recombination
  17. types of cells expressing class I MHC
    all nucleated cells
  18. types of cells expressing class II MHC
    • B cells
    • APCs (DCs)
    • macrophages
  19. what do cells expressing class I MHC present Ag to?
    CD8+ cells (CTLs)
  20. what do cells expressing class II MHC present Ag to?
    CD4+ cells (Th1 & Th2)
  21. describe the MHC region presented to T cells
    •  and  chains are folded to form a groove
    • groove base is a beta sheet, and sides are 2 alpha helices
    • Ag peptide is in groove & presented to T cells
  22. 3 requirements for a successful T cell
    • 1) not recognize or bind too tightly to self 
    • 2) recognize Ag-selfMHC complex
    • 3) not recognize free Ag
  23. negative selection
    cells are eliminated through apoptosis if they recognize self peptides with too high affinity or don't recognize self MHC at all
  24. where does T cell development/maturation occur
    thymus
  25. positive selection
    • selection of T cells with low (but real) affinity for self MHC
    • low affinity for self may = high affinity for self+Ag
  26. 3 stages of central tolerance
    • 1) negative selection
    • 2) rescue from programmed cell death
    • 3) lineage determination (based on low affinity to specific MHC class)
  27. 3 mechanisms of peripheral tolerance
    • 1) anergy
    • 2) activation-induced cell death
    • 3) suppression by regulatory T cells
  28. example of costimulatory molecule binding during T cell activation
    B7 on APC binds to CD28 on T cell
  29. anergy
    • incomplete activation
    • absence of sensitivity to substances that would normally elicit an antigenic response
  30. 2 causes of T cell anergy
    • 1) lack of costimulatory molecule
    • 2) inhibition of/competition with costimulatory molecule for B7 binding
  31. CTLA-4
    • cytotoxic T lymphocyte associated molecule
    • competes with CD38 for binding to B7 -> T cell anergy/suppression of activation
  32. how are costimulatory molecules expressed?
    TLR binding activates NF-B pathway -> costimulatory molecules expressed
  33. type of cell death important in preventing autoimmunity
    activation-induced T cell death
  34. T cells express what 2 molecules that lead to cell death?
    Fas & FasL
  35. immunosuppressive cytokines secreted by Tregs (2)
    • 1) IL-10
    • 2) TGF-
  36. 2 ways Tregs can inhibit activation/effector fcn of other T cells
    • 1) acts as an IL-2 "sink"
    • 2) secrete IL-10 & TGF

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