Updated: 5/24/2020

Innate Immune Response

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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
Margination
  • 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 B
  • 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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Questions (7)
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(M1.IM.17.4754) A researcher is studying how arachidonic acid metabolites mediate the inflammatory response in rats. She has developed multiple enzyme inhibitors that specifically target individual proteins in the arachidonic acid pathway. She injects these inhibitors in rats who have been exposed to common bacterial pathogens and analyzes their downstream effects. In one of her experiments, she injects a leukotriene B4 inhibitor into a rat and observes an abnormal cell response. Which of the following interleukins would most closely restore the function of one of the missing products?

QID: 108949
1

Interleukin 1

19%

(62/333)

2

Interleukin 2

21%

(71/333)

3

Interleukin 4

16%

(53/333)

4

Interleukin 5

7%

(22/333)

5

Interleukin 8

33%

(109/333)

M 1 C

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(M1.IM.15.74) A 2-year-old boy has a history of recurrent bacterial infections, especially of his skin. When he has an infection, pus does not form. His mother reports that, when he was born, his umbilical cord took 5 weeks to detach. He is ultimately diagnosed with a defect in a molecule in the pathway that results in neutrophil extravasation. Which of the following correctly pairs the defective molecule with the step of extravasation that molecule affects?

QID: 106654
1

ICAM-1; margination

9%

(10/107)

2

LFA-1 (integrin); margination

11%

(12/107)

3

LFA-1 (integrin); tight adhesion

53%

(57/107)

4

E-selectin; tight adhesion

7%

(8/107)

5

E-selectin; transmigration

10%

(11/107)

M 1 C

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Evidence (1)
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EXPERT COMMENTS (5)
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