Innate and adaptive immunity pt1

• Describe Neutrophils

  These are the first immune cells to arrive at the site of infection and there is a large reserve within the bone marrow. They are short lived and multi-lobed cells, with a granular cytoplasm that contains antimicrobial enzymes, .e.g, myeloperoxidases.
• Describe chemotaxis of neutrophils to the site of infection

  TNF-alpha and other early cytokines stimulate the expression of selectins on blood vessel endothelia. This allows endothelial cells to bind to neutrophils to slow them down in the bloodstream. IL-8 causes neutrophils to express integrins on their surface which bind to intracellular adhesion molecules (ICAMs). This leads to margination against the endothelial wall and transmigration into the tissues due to blood vessel dilation as a results of histamine and platelet activating factor (PAF).
• Describe some of the receptors that can recognise PAMPs

  These are known as pattern recognition receptors (PRRs), such as:

  • Mannose receptor
  • LPS receptor (CD14)
  • Glycan receptor
• Describe Toll-like receptors (TLRs)

  These receptor recognise microbial components and lead to:

  • signalling presence of a pathogen
  • triggering expression of co-stimulators molecules and effector cytokines important for the activation of macrophages and development of adaptive immune responses.

  TLR-4 is a transmembrane protein that acts with CD14 to generate a transmembrane signal that results in cytokine release.
• Describe the steps in phagocytosis

  1. PRRs recognise PAMPs, which is aided by opsonisation
  2. The pseudopodia form a phagosome which engulfs the microbe
  3. The lysosome fuses with the phagosome to form the phagolysosome and kills the microbe
  4. The microbial products are released and some of these products may be presented to the adaptive immune system.
• Give examples and describe antimicrobial proteins

  • Myeloperoxidases in neutrophils
  • Lysozyme
  • Defensins- make holes in bacterial walls
  • Acid hydrolases- activated by low pH which occurs when the neutrophil matures
  • Lactoferrin- sequesters iron
  • Siderocalin: binds to siderophores, which are produced by bacteria to sequester iron in response to lactoferrin release
• Describe the respiratory burst

  This is an oxygen-dependent anti-microbial mechanism where membrane-bound NADPH oxidase is activated following phagocytosis. NADPH oxidase donates an electron to oxygen to generate a superoxide. This superoxide ion can form hydrogen peroxide, which can from hydroxyl radical in the presence of iron ions. This is highly toxic and destroys nucleic acids and membranes.

  
• Describe neutrophil extracellular traps

  Neutrophils can produce a web of extracellular fibres made from DNA, histones or antimicrobial proteins. This is activated by a range of mediators, such as IL-8 and can kill extracellular pathogens via:

  • high local concentration of antimicrobial components
  • limits host damage by preventing diffusion of proteases to nearby host tissues
  • serve as a physical barrier that prevents further spread of the pathogen.
• Describe the function of activated macrophages

  Activated macrophages forms in the presence of IFN-gamma and TNF-alpha. These cells have increased killing function; they increase nitric oxide which:

  • increases release of cytokines
  • activates anti-tumour and anti-microbe functions.
• Describe the synthesis of reactive nitrogen intermediates

  INOS catalyses production of NO radicals, which react with superoxideS to form peroxynitrite, which can trigger cellular responses such as apoptosis. Activated macrophages display increased expression of iNOS.