questions 5

Cell-Mediated Immunity

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Topic updated on 09/30/16 4:54pm

Overview
  • Primary function
    • destroy threats arising from within cells
    • infections by viruses, bacteria, and parasites
      • cancerous cells that lack normal cell surface proteins
  • Primary effector cells
    • macrophages
      • kill via oxygen dependent and independent mechanisms
    • cytotoxic T lymphocytes (CTLs)
      • kill via induction of apoptosis
    • natural killer cells (NK cells)
      • kill via induction of apoptosis
Activation of Cell-Mediated Immunity
  • Macrophage activation
    • TH1 cells
      • major orchestrator
      • provides specificity of response
      • produces many activating cytokines
        • IFN-γ
          • increases macrophage killing activity  
          • also produced by cytotoxic T lymphocytes (CD8+)
          • increase MHC I expression on all cells
          • increase MHC II on all antigen presenting cells
          • defective in hyper-IgE syndrome (Job syndrome)
        • TNF-α and -β
          • further increases macrophage killing activity
          • increases general inflammation
          • chemotactic and activating for neutrophils
          • TNF-α blocked pharmacologically by monoclonal antibody infliximab
            • treatment for some autoimmune disorders
              • e.g., rheumatoid arthritis
      • TH1 response responsible for macrophage activation and surrounding of tuberculous lesions   
      • cytokine activation of macrophages by TH1 cells = delayed-type hypersensitivity (type IV)
        • mechanism of PPD test
  • CTL activation
    • three step activation
      • loose attachment
        • non-specific interaction between LFA-1 integrin with ICAM-1
      • recognition (firm attachment)
        • T-cell receptor (TCR) + class I MHC
          • similar mechanism of TCR with class II MHC in TH cell activation
          • must recognize and bind to self MHC as well as bind antigen
            • recognizes non-self class I MHC during non-genotypically identical human transplants due to polymorphisms in structure between individuals
              • activates CTL rejection of transplant tissue
      • activation from TH1 cells
        • via IL-2
          • IL-2 signaling pathway blocked by tacrolimus, cyclosporine, daclizumab, and sirolimus
            • mainly used to prevent transplant rejection
          • severe combined immunodeficiency (SCID) 
    • amplification
      •  can replicate autonomously
        • slow and does not reach high cell concentrations
        • TH1 cells enhance CTL division via IL-2
  • NK cell activation
    • two step activation
      • lack of inhibitory signal 
        • binding to normal cell MHC class I inhibits activation
          • a cell defense in viral infection or cancer is to down-regulate MHC class I expression
      • presence of activation signal
        • lectin surface of pathogen
      • if both criteria are fulfilled the killing can proceed
        • does NOT need activation from lymphocytes
    • activity increased with cytokine activation from other cell-mediated immunity cells e.g., IFN-γ 
      • TNF-α and β release during viral infections
      • IL-12 production by TH1 activated macrophages
        • also stimulated by B cells
        • activates NK cells as well as Th1 cells
Effector Mechanisms
  • Macrophage killing
    • oxygen-dependent mechanisms
      • respiratory burst
        • NADPH oxidase
          • creates superoxide anions which decay into hydroxyl radicals, H2O2
            • microbiocidal
        • myeloperoxidase
          • converts H2O2 + Cl- into hypochlorous acid (bleach)
            • best microbiocidal product
    • oxygen-independent mechanisms
      • degradative lysosomal enzymes
        • hydrolytic enzymes
          • destroy peptides
        • defensins
          • form holes in bacterial membranes
        • lactoferrin
          • bind iron
        • lysozyme
          • cleave bacterial peptidoglycan wall
    • defects in killing
      • chronic granulomatous disease (CGD)
  • CTL killing
    • three mechanisms
      • cytotoxic granules
        • directional exocytosis
          • granzymes
            • serine protease
              • activates apoptotic caspases
          • perforin
            • allows passage of granzyme into target cell
        • detachment from target cell
          • can kill multiple sequential cells
      • Fas ligand
        • binds to Fas receptor on target cell
        • directly induces apoptosis via induction of caspases
      • TNF
        • also induces apoptosis
  • NK cell killing
    • similar mechanism to CTLs
      • apoptosis induction via granzymes and perforin
    • activity does NOT generate memory


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Qbank (3 Questions)

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(M1.IM.21) A 55-year-old Caucasian male presents for a routine colonoscopy. A polyp is found in the patient's transverse colon and is found to be cancerous on histological evaluation. Upon examination, it is found that these cancerous cells have decreased MHC class I expression on their surface. Which immune system cell is most capable of killing these tumor cells? Topic Review Topic

1. Natural killer cells
2. B-cells
3. Macrophages
4. Eosinophils
5. Cytotoxic T-cells

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TAG
(M1.IM.46) A 48-year-old immigrant from Vietnam presents with fever, weight loss, a persistent cough, and malaise. His symptoms began three months ago and have worsened over time. On exam, he is afebrile with BP 140/80, HR 78/minute, and RR 14/min. A sample of the patient's sputum is shown in Figure A, and chest radiograph is shown in Figure B. Which cell type is responsible for the formation of the granuloma? Topic Review Topic
FIGURES: A   B        

1. Neutrophils
2. TH2 lymphocyte
3. CD8 T cell
4. TH1 lymphocyte
5. Natural killer cells

PREFERRED RESPONSE ▶
TAG
(M1.IM.72) A 3-year-old recent immigrant is diagnosed with primary tuberculosis. Her body produces T cells that do not have IL-12 receptors on their surface, and she is noted to have impaired development of Th1 T-helper cells. Which of the following cytokines would benefit this patient? Topic Review Topic

1. IL-4
2. IL-17
3. IL-22
4. Interferon-gamma
5. TGF-beta

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