Tuesday, April 20, 2010

Cell Mediated Immunity

CELL-MEDIATED IMMUNITY: Antibody-independent immunity, mediated by TH1 cells.
Examples: Type-IV Hypersensitivity Responses, mycobacterium tuberculosis and other intracellular pathogens.
  • MACROPHAGE ACTIVATION: IFN-gamma, secreted by TH1 cells, activates macrophages. Effects are generally anaphylactic:
    • Increase expression of MHC-II molecules in macrophages, to enhance their roles as APC's.
    • Increase expression of Fc-receptors and CR3-receptors, to enhance opsonization.
    • Increase oxidative-burst ------> reactive O2-intermediates and reactive N2 intermediates (such as NO).
    • Increase synthesis of eicosanoids: PGD2, PGI2, TXA2, LTB4
  • CYTOTOXIC LYMPHOCYTE (CTL) ACTIVATION: IL-2 converts CTL-Precursors ------> Active CTL
    • IL-2 is secreted by TH1 cells.
    • Antigen activation of a CD8 cell causes it to up-regulate its expression of IL-2 Receptors. Subsequent IL-2 activation (by TH1 cells) causes CTL proliferation.
    • After antigen activation, both CTL's and TH-Cells are dependent on IL-2 for their proliferation.
    • TERMINATION: After antigen clearance, the levels of IL-2 decline and CTL's die by apoptosis. This ensures that the immune response is limited and help to prevent excessive tissue damage.
    • CONJUGATE FORMATION: CTL binds to MHC-I of the target cell (which is expressing antigen and is therefore targeted for destruction).
      • TCR-CD3 complex on CD8-Cell binds to HLA-I of target cell
      • Additional binding by LFA-1 of CD8 cell with ICAM-1 of target cell.
    • PERFORIN MONOMERS: After conjugate formation, the CD8 cell releases perforin monomers from storage granules.
      • These monomers polymerize within the membrane to form perforin pores ------> target-cell membrane lysis.
    • DEATH BY APOPTOSIS: Some evidence exists that the CTL cell sends a signal to target cell which causes the target-cell to die by apoptosis.
      • TNF-beta has been a signal that is implicated in this apoptosis signal.
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  • NATURAL KILLER (NK) CELLS: Non-specific (natural) killing of tumors and some virally infected cells.
    • They are believed to derive from null cells. Strange cell lineage.
    • KILLING METHOD: Similar to CTL's.
      • They degranulate perforin-like monomers to cause target-cell lysis.
      • They kill cells by apoptosis (mediated by TNF-alpha)
      • They do not express CD8, CD3 or any other CD lymphocyte markers on their membranes.
      • They have no immunologic memory.
  • ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY (ADCC): Many cytotoxic cells express Fc-receptors on their membranes. They can then kill an antibody(IgG)-coated cell by a non-specific process.
    • Cells involved: Most natural immunity cells have Fc-Receptors and can thus partake in ADCC. Neutrophils, Eosinophils, Macrophages, NK-Cells, Monocytes
    • Cells coated with IgM are not subject to ADCC because IgM has no available Fc region! Primarily IgG is the antibody responsible for ADCC. 

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