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Updated: May 24 2020

Innate Immune Response

  • Introduction
    • 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
      • stimulated by interleukin-6 release
    • The protein components of the acute phase reaction consist 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
      • Mediators
      • Magination
      • Dilates blood vessels around areas of damage
      • Allows blood to flow slowly in potentially infected areas
      • Nitric oxide
      • Other vasoactive substrances
      • Rolling
      • Loose attachment of neutrophils to vessel walls
      • Concentrates neutrophils near the endothelial cells of areas that have been previously damaged
      • Selectins
      • Glycoproteins
      • Adhesion
      • Tight attachment of neutrophils to the epithelium
      • Stops the movement of neutrophils and primes them for further activity
      • LFA integrins
      • ICAM proteins
      • Extravasation
      • Diapedesis of neutrophils across vessel wall
      • Localization of neutrophils to region of damage
      • Integrins
      • Pseudopodia
      • Chemotaxis
      • Extravascular attraction of neutrophils to pathogens
      • Migration of neutrophils to sites of highest pathogen concentration
      • IL-8
      • C5a
      • Leukotriene B4
      • 5-HETE
      • 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+
      • Myeloperoxidase
      • Transformation of hydrogen peroxide into hypochlorite (bleach)
      • Final toxic compound used to damage pathogens
      • G6PD
      • Reduction of NADP+ to original state via the hexose monophosphate shunt
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