Updated: 2/13/2019

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 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
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
  • 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 (5)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.IM.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? Review Topic

QID: 108949
1

Interleukin 1

18%

(46/249)

2

Interleukin 2

24%

(61/249)

3

Interleukin 4

15%

(37/249)

4

Interleukin 5

8%

(19/249)

5

Interleukin 8

29%

(71/249)

M1

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(M1.IM.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? Review Topic

QID: 106654
1

ICAM-1; margination

13%

(6/47)

2

LFA-1 (integrin); margination

15%

(7/47)

3

LFA-1 (integrin); tight adhesion

34%

(16/47)

4

E-selectin; tight adhesion

9%

(4/47)

5

E-selectin; transmigration

15%

(7/47)

M1

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