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

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