Immunology Course Outline - Session 3 Cell Mediated Immunity I Case Presentation: History: A 26 year old woman has exhibited malaise for the past week. She notes that the whites of her eyes appear yellowish. She has nausea and a poor appetite. She does not have diarrhea. On physical examination, she has vital signs of: T 36.6 C, R 16, P 75, and BP 122/82 mm Hg. She has mild right upper quadrant tenderness. A CBC shows WBC count 5930/microliter, Hgb 14.3 g/dL, Hct 42.5%, MCV 88, platelet count 401,000/microliter, and WBC differential count 62 segs, 2 bands, 22 lymphs, 11 monos, 2 eos, and 1 baso. Serum chemistries include: sodium 144 mmol/L, potassium 4.3 mmol/L, chloride 105 mmol/L, CO2 26 mmol/L, creatinine 1.3 mg/dL, urea nitrogen 19 mg/dL, glucose 70 mg/dL, calcium 8.4 mg/dL, phosphorus 4.3 mg/dL, total protein 6.2 g/dL, albumin 3.4 g/dL, total bilirubin 5.4 mg/dL, direct bilirubin 2.8 mg/dL, AST 413 U/L, ALT 484 U/L, alkaline phosphatase 78 U/L, and LDH 493 U/L. Serum hepatitis panel shows: HAV IgM positive, HAV IgG positive, HBsAg negative, HBsAb negative, HBcAb negative, and HCV antibody negative. What is this process? Hepatitis. What type of infectious agent is most likely to be the cause? Hepatitis A virus What findings are characteristic for this kind of infection? The findings are not dramatic, with signs and symptoms developing over days to weeks. Decreased liver function is seen with the lower serum albumin. Jaundice is typical for liver disease. Is this infection acute or chronic? She has an acute infection, because the IgM is positive as well as the IgG, to hepatitis A. The initial immune response of the humoral immune system mainly produces IgM antibody, later switching to IgG. What is the probable course of her disease? Hepatitis A is typically self-limited, with complete recovery in a few weeks. What kind of immune response is involved in controlling this infection? Intracellular infections by organisms such as viruses cannot be "seen" by antibodies or by phagocytic cells directly. There may be an initial innate immune response, and even a humoral response with antibody, but this will not control the infection. Thus, viral infections require adaptive cellular immunity. What is (are) the major cell(s) of the immune system involved in this process? The major players are the T lymphocytes, aided by antigen presenting cells such as macrophages. What is the origin of this arm of the immune system? During development of the cell mediated immune system in fetal life, T lymphocytes are generated in the thymus. The T cells proliferate to be able to recognize millions of potential antigens. Thus, once the immune system is constituted, only a fraction of the body's total lymphocyte population can react to any one specific antigen. The T cells circulate through the vascular system (lymphatics, arteries, veins, capillaries) and organs to give them opportunity to contact antigens. Such a specific T lymphocyte can generally find the antigen within a day. By what mechanism is the immune system prevented from attacking normal cells? The mechanism by which T cells are prevented from attacking normal cells is called MHC restriction. T cells have a receptor (T cell receptor composed of alpha and beta chains) which recognizes MHC molecules. There are two mechanisms for MHC recognition. There are two forms of MHC (major histocompatibility locus) molecules. All nucleated cells of the human body express class I MHC molecules on their surfaces. The T cell can only react to an antigen presenting cell (APC) which presents an antigenic peptide product along with the MHC. The APC processes the antigen, after either phagocytosis or from infection of the APC itself, and processes it in the APC cytoplasm and puts it into a class I MHC molecule that is transported by exocytosis onto the APC cell surface. Animation: antigen processing and presentation by a macrophage. Antigen presenting cells include dendritic cells (Langerhans cells in the epithelia, follicular dendritic cells in lymph nodes) and macrophages that process antigen found in the cytoplasm of nucleated cells. The APC's tend to be brought via lymphatics to lymph nodes where antigens can be concentrated and the circulating T cells can find them. CD8 (suppressor, or cytotoxic) lymphocytes react to such class I molecules with bound peptide. The CD8 cells become cytotoxic and attack and destroy infected cells when a costimulator is present. Animation: antigen presenting cell and CD8 cell interaction. There is a second mechanism within APCs for processing of antigen for presentation. If the antigen originates outside of a host nucleated cell, then the mechanism involves presentation with class II MHC molecules, and the main immune response is formation of antibody effective against extracellular organisms. Expression of class II MHC is normally limited to B lymphocytes, antigen presenting cells, and capillary endothelium. Through endocytosis, antigen in the form of microbial organisms or macromolecules is taken into the APC where fusion with a lysosome produces a phagosome in which antigen is broken down to peptides. The peptides are bound with a CLIP (a peptide that prevents breakdown of the class II molecule) to a class II MHC molecule and transported to the surface. CD4 lymphocytes respond to the class II molecules with bound peptide. Most CD4 cells are T "helper" cells that are activated with a costimulator and help B cells secrete antibody that attaches to the extracellular antigens. How is activation of the immune response achieved? Costimulators are needed to activate T cells. The costimulator is a "second signal" that is a failsafe mechanism to prevent inappropriate T cell activation in the absence of an appropriate stimulus such as an infection. The infectious agent stimulates macrophages to produce costimulator molecules on their surfaces that bind to T cell receptors in conjunction with T cell receptors for MHC molecules with peptide to activate the T cell. The B7 costimulators on APCs attach to T cell receptors. The CD28 receptor on the T cell surface, when contacted by B7, activates the T cell, while contact with the CD152 receptor on the T cell turns off the T cell. Macrophages also secrete the cytokine interleukin 12 which stimulates T cells. CD40 ligand on T cells, when binding with CD40 on APCs, enhances B7 and IL-12 production. Animation: antigen presenting cell and CD8 cell interaction. To combat intracellular organisms such as hepatitis virus that live not within vesicles but within the cytoplasm, cytotoxic T cells, the CD8 cells, are needed. The CD8 cells recognize class I MHC-peptide complexes on infected hepatocytes, binding via both T cell receptor and CD8 coreceptor and adhere via integrins. Costimulators from APCs or interaction with a helper CD4 cell activates the CD8 cell. This antigen recognition and adhesion with activation of the CD8 cell causes release of granules that punch holes (perforations) in the target cells with a granule protein called perforin. Granzymes from the granules enter through the holes and activate target cell caspases to turn on apoptosis. Some viruses have adapted to resist cytotoxic lymphocyte destruction by inhibiting class I molecule production or movement within cells. However, cells deficient in MHC class I molecules can become targets of NK cells. Viruses can also inhibit cytokine production or mimic cytokine receptors. 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