• The innate immune system provides the first line of defense against pathogens
  • It consists of multiple lines of defense including
    • physical barriers such as mucous membranes
    • soluble proteins such as complement
    • specialized cells such as neutrophils
  • The innate immune system is broadly effective but not adaptive because
    • all components are germline encoded (not subject to recombination)
    • components recognize conserved molecular patterns 
  • The innate immune system interacts with the adaptive immune system in important ways such as
    • activation of the adaptive immune system by antigen presenting cells
    • serving as effectors of the adaptive immune system
Innate Immune Activation 
  • The innate immune system recognizes pathogen-associated molecular patterns (PAMPs)
  • PAMPs are structures that are conserved among large pathogen classes including
    • lipopolysaccharides (LPS) in gram-negative bacteria
    • lipoteichoic acids in gram-positive bacteria
    • double stranded RNA in some viruses
  • PAMPs are not present on mammalian cells ensuring that
    • innate immune components do not damage the host
    • detection of PAMPs indicates that pathogens are nearby
  • PAMPs are detected by diverse pattern recognition receptors (PRRs) that
    • are present in all innate immune cells
    • trigger the acute inflammatory response upon being activated
The Acute Inflammatory Reponse
  • The acute inflammatory response is triggered when
    • pathogens have breached the physical barriers of the body
    • PAMPs are released and bind to local PRRs
  • The acute inflammatory response consists of
    • a release of soluble proteins into the bloodstream
    • an early (< 5 hours) mobilization of neutrophils
    • a late (> 5 hours) recruitment of macrophages
  • The soluble protein response is known as the acute phase reaction consisting of
    • C-reactive protein
      • which fixes complement and facilitates phagocytosis
    • ferritin
      • which binds and sequesters iron
    • fibrinogen
      • which promotes endothelial repair
    • hepcidin
      • which decreases iron absorption and iron release
    • serum amyloid A
      • which can accumulate during chronic inflammation
  • Neutrophils are recruited in a coordinated fashion
  • After arrival, neutrophils perform a variety of actions including
    • generation of reactive oxygen species
    • recruitment of macrophages for phagocytosis and antigen presentation
Neutrophil Recruitment
  • Neutrophil recruitment is a key part of the innate immune response because they 
    • phagocytose and damage pathogens
    • recruit additional immune cells
    • create a proinflammatory environment
  • Neutrophil recruitment is a tightly coordinated process
Steps Involved in Neutrophil Recruitment
Stage Purpose
  • Dilates blood vessels around areas of damage
  • Allows blood to flow slowly in potentially infected areas
  • Nitric oxide
  • Other vasoactive substrances
  • Loose attachment of neutrophils to vessel walls
  • Concentrates neutrophils near the endothelial cells of areas that have been previously damaged
  • Selectins
  • Glycoproteins
  • Tight attachment of neutrophils to the epithelium
  • Stops the movement of neutrophils and primes them for further activity
  • LFA integrins
  • ICAM proteins
  • Diapedesis of neutrophils across vessel wall
  • Localization of neutrophils to region of damage
  • Integrins
  • Pseudopodia
  • Extravascular attraction of neutrophils to pathogens
  • Migration of neutrophils to sites of highest pathogen concentration
  • IL-8
  • C5a
  • Leukotriene B
  • Formyl-methionyl peptides
Effector Mechanisms
  • Three key effector mechanisms used by the innate immune system include
    • opsonization of pathogens
    • phagocytosis of pathogens
    • generation of reactive oxygen species
  • Opsonization is the process by which effector mechanisms are enhanced by
    • coating pathogens with C3b and other opsonins
    • recognition of opsonins by specific receptors on macrophages and neutrophils
  • Phagocytosis is the process by which pathogens can be degraded and includes
    • formation of pseudopodia around pathogenic material
    • envelopment of the material by a phagosome
    • fusion of the phagosome to endsomal and lysosomal compartments
    • digestion of the material by degradative enzymes
  • Reactive oxygen species are toxic metabolites that are
    • used to damage pathogenic structures
    • tightly controlled by inactivating enzymes
Enzymes Involved in Reactive Oxygen Species Metabolism
Activators Function
Inhibitors Function
NADPH oxidase
  • Transform oxygen into superoxide radicals
Glutathione peroxidase
  • Inactivation of hydrogen peroxide into water by oxidizing glutathione
Superoxide dismutase
  • Transform superoxide radicals into hydrogen peroxide
Glutathione reductase
  • Reduction of glutathione to original state by oxidizing NADPH to NADP+
  • Transformation of hydrogen peroxide into hypochlorite (bleach)
  • Final toxic compound used to damage pathogens
  • Reduction of NADP+ to original state via the hexose monophosphate shunt

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