Ch 45

• Three lines of defense against pathogens in mammals

  • Physical barriers
  • Innate immune system
  • Adaptive immune system

  
• Every organism is constantly exposed to pathogens
• Physical barriers

  • Tight junctions between epithelial cells of the body surface keep most pathogens and toxins from entering the body
  • Mucus layer secreted by many epithelial cells protects against pathogens, toxins and other chemicals
  • In the respiratory tract, ciliated cells sweep away mucus, trapped bacteria, and other foreign matter
  • Some mucus layers produce chemicals (e.g., acids, digestive enzymes, lysozyme) that are hostile to pathogens
  • Not considered a part of the immune system

  
• Innate immunity


  • Provides an immediate, nonspecific response to cellular pathogens such as bacteria and viruses
  • No memory of prior exposure to the pathogen
  • Inherited mechanisms that protect the body from pathogens in a nonspecific way

  
• Adaptive (acquired) immunity


  • Specific - it recognizes individual pathogens and mounts an attack that directly neutralizes or eliminates them
  • Retains a cellular memory of a pathogen and reacts quickly upon second exposure
  • Inherited mechanisms leading to the synthesis of molecules that target pathogens in a specific way

  
• White blood cells (leukocytes) and their derivatives, along with several types of plasma proteins, are responsible for the activities of the two immune systems

  
• Some white blood cells are phagocytes that engulf foreign particles (phagocytosis)
• Most leukocytes originate from stem cells in bone marrow, and are released into the blood. Lymphocytes form in the bone marrow and then migrate to the thymus
• Innate immunity: nonspecific defenses


  • When a pathogen is encountered for the first time, the body needs 7 to 10 days to develop an effective specific response
  • Meanwhile, innate immunity holds off invading pathogens killing or containing them until adaptive immunity is developed
  • Innate immunity has both molecular and cellular components
  • Cellular pathogens (such as bacteria) and viral pathogens elicit different innate responses

  
• Defense against cellular pathogens

  1. Specific cell-surface receptors in the host recognize various type of molecules on microbial pathogens

  2. Depending on the receptor, the response may: Secrete antimicrobial peptides that kill the microbe, Trigger the host cell to engulf and destroy the pathogen, initiating inflammation, Activate the complement system

  
• Pathogen recognition

  • The innate immune system recognizes pathogen-associated molecular patterns that are associated with pathogenic organisms but are absent in the host
  • The patterns are recognized by pattern recognition receptors of phagocytic cells
  • Mammals have several classes of pattern recognition receptors, one of which is the Toll-like receptors
  • Toll-like receptors are found on the cell surface and within the cell on various membrane-bound compartments

  
• Antimicrobial peptides

  • All our epithelial surfaces, inside and out, are protected by antimicrobial peptides called defensins
  • Epithelial cells secrete defensins when attacked by a microbial pathogen
  • Defensins attack the plasma membranes of pathogens, eventually disrupting them, thereby killing the cells
  • Defensins play a significant role in innate immunity of the mammalian intestinal tract

  
• Inflammation

  1. Infection by most pathogens involves inflammation - the heat, pain, redness, and swelling that initially or exclusively occur at the site of an infection

  2. Cell-surface receptors on macrophages recognize and bind to pathogen, activating the macrophage

  3. Activated macrophages secrete cytokines, which bind host cells and trigger a response

  4. Tissue damage activates mast cells, which release histamine, an inflammatory signaling molecule

  5. Histamine and cytokines dilate local blood vessels and increase their permeability

  6. Cytokines make the blood vessel wall stickier, causing circulating neutrophils and monocytes to attach to it

  7. Neutrophils and monocytes are attracted to the infection site by chemokines secreted by activated macrophages

  8. Monocytes differentiate into macrophages and work with neutrophils to engulf the pathogens

  9. Engulfed pathogens are destroyed

  10. When pathogens are too large to be engulfed, macrophages, neutrophils, and eosinophils cluster around the pathogen and kill it by secreting large amounts of lysosomal enzymes and defensins

  11. If tissue damage is extensive, or infection spreads to the blood, a systemic inflammation (inflammation throughout the body) may occur

  
• Inflammation - fever

  1. Macrophages release pyrogens that stimulate the hypothalamus to release locally-acting prostaglandins

  2. Prostaglandins signal the hypothalamic thermostat that regulates body temperature to produce the fever

  3. Fever may fight infection by enhancing phagocytosis, or by interfering with bacterial propagation
• The complement system

  • Includes more than 30 interacting plasma proteins that circulate in blood and interstitial fluid, and are activated by molecules on the surfaces of pathogens
  • Some assemble into membrane attack complexes, which insert into the plasma membrane of bacterial cells and create pores that allow ions and small molecules to pass through
  • As a result, the bacteria can no longer maintain osmotic balance, and they swell and lyse

  
• Defense against viral pathogens

  • The innate immune system uses two main strategies against viral pathogens: Interferon, natural killer cells
  • For viral pathogens, the innate immune system is unable to detect the virus as it is contained inside host cells

  
• Interferon


  • When a virus infects a cell, the cell synthesizes cytokines called interferons
  • Interferons act on the infected cell that produces them and on neighboring uninfected cells
  • Interferons bind to cell-surface receptors, triggering a signal transduction pathway that changes the gene expression pattern of the cells
  • Interferon activates genes for RNA nuclease and inhibits protein synthesis in the cell
  • These effects on RNA and protein synthesis inhibit replication of the viral genome, while putting the cell in a weakened state from which it may or may not recover
• Natural killer cells - perforins

  • Circulate in the blood and kill host cells that are infected with a virus or have become cancerous
  • Can be activated by cell-surface receptors or by interferons secreted by virus-infected cells
  • Secrete granules containing perforin, a protein that creates pores in the target cell's membrane
  • Unregulated diffusion of ions and molecules through the pores causes osmotic imbalance, swelling, and rupture of the infected cell
  • Also kill target cells indirectly by secreting proteases that pass through the pores and trigger apoptosis

  
• Natural killer cells - MHC

  • The surfaces of most vertebrate cells have self-identifying major histocompatibility complex (MHC) proteins on them
  • An NK cell monitors the level of MHC proteins to distinguish a target cell from a normal cell
  • A high level of these "self" tags, as on normal cells, inhibits the killing activity of NK cells
  • A low level, as on virus-infected cells (or cancer cells) targets the cell for destruction

  
• Major Histocompatibility Complex (MHC) proteins

  Self-identifying proteins on the surface of most vertebrate cells
• NK cell

  Monitors the level of MHC proteins to distinguish a target cell from a normal cell
• High level of MHC 'self' tags on normal cells

  Inhibits the killing activity of NK cells
• Low level of MHC 'self' tags on virus-infected or cancer cells

  Targets the cell for destruction

  
• Innate immunity


  Nonspecific, retains no memory of exposure to the pathogen
• Adaptive immunity

  Specific, retains a memory of the foreign molecule, enabling a rapid, more powerful response if that pathogen is encountered again

  
• Four key characteristics of the adaptive immune response

  • Specificity
  • Diversity
  • Memory
  • Self/non-self recognition

  
• Antibody-mediated immunity

  1. cell derivatives called plasma cells secrete antibodies that circulate in the blood and lymph, recognizing and binding to antigens and clearing them from the body

  
• Cell-mediated immunity


  A particular type of T cell becomes activated and, with other cells of the immune system, attacks foreign cells directly and kills them

  
• Examples of Antigens

  • Large proteins (glycoproteins or lipoproteins)
  • Polysaccharides (lipopolysaccharides)
  • Some nucleic acids
  • Various large, artificially synthesized molecules
• Antigen


  A foreign molecule that triggers an adaptive immune response
• Lymphocytes

  • B cells: differentiate from stem cells in the bone marrow and are carried in blood to capillary beds serving the tissues and organs of the lymphatic system
  • T cells: differentiate from stem cells in bone marrow and are carried in blood to the thymus – two types of T cells (helper T cells and cytotoxic T cells) are involved in adaptive immunity
• Four steps of the adaptive immune response

  1. Antigen encounter and recognition: lymphocytes encounter and recognize an antigen

  2. Lymphocyte activation: lymphocytes are activated by binding to the antigen and divide to produce clones

  3. Antigen clearance: large clones of activated lymphocytes clear the antigen from the body

  4. Development of immunological memory: memory cells circulate in blood and lymph, prepared for a rapid response

  
• B-cell receptor

  Consists of four polypeptide chains, with two identical antigen-binding sites at one end and transmembrane domains at the other end
• T-cell receptor

  Consists of a protein made up of two different polypeptides, with an antigen-binding site at one end and transmembrane domains at the other end
• The shapes of an antigen and its matching receptor fit together (like an enzyme and its substrate)
• A B-cell receptor or T-cell receptor does not bind to the whole antigen molecule, but to small regions of it called epitopes or antigenic determinants
• Several different B cells and T cells, each with different receptors, may bind to the population of a particular antigen encountered in the lymphatic system

  
• Ten steps in the antibody-mediated immune response

  1. Engulfment of bacterium

  2. Degradation of bacterium and release of antigens

  3. Presentation of antigens on dendritic cell surface

  4. Interaction of antigen-presenting cell with lymphocyte

  5. Activation of T cell

  6. Production of helper T cells

  7. Presentation of antigens on B cell surface

  8. Interaction of B cell with helper T cell

  9. Activation of B cell

  10. 10. Production of plasma cells and memory B cells

  
• Antigen-presenting cell (APC)


  A cell that presents an antigen to a lymphocyte
• Clonal selection

  The process by which a particular lymphocyte is specifically selected for cloning when it recognizes a particular foreign antigen