Updated: 9/6/2018

Complement

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Overview

Introduction
  • The complement system is a group of circulating proteins that
    • are synthesized by the liver
    • participate in humoral immunity
    • act as proteases and cleave one another in cascade
    • bind to pathogens as well as immune complexes
    • alert phagocytes of the innate immune system
  • The system can be activated in one of three ways including
    • the classical pathway
      • when activated by antibodies
    • the alternative pathway
      • when activated spontaneously
    • the lectin pathway when
      • activated by mannose residues on pathogens
  • Activation of the complement pathway leads to
    • a cascading cleavage of downstream proteins
    • seperation of protein fragments after cleavage where
      • a is the smaller component that is carried by the bloodstream
      • b is the larger component that stays on the pathogen
  • Complement must be closely controlled by inhibitors such as
    • C1 esterase inhibitor
    • CD55 (decay accerating factor)
Activation of Complement
Complement Activation Pathways
Feature Classical
Alternative Lectin
Detects • Surfaces with bound antibodies (IgG and IgM)
• Surfaces not protected by complement inhibitors 
• Surfaces with mannose
Specificity • Conferred by the specific binding of antibodies
• Conferred by inactivation of complement by host inhibitors
• Conferred by lack of mannose on host membranes
Initiating factor • C1q
• C1r
• C1s
• C3 factor turnover
• Factor D
• Mannose binding lectin and associated proteases
C3 convertase • C4b
• C2b
• C3b
• Factor Bb
• C4b
• C2b
 
Functions
  • The complement cascade has many functions including
    • opsonization of invading pathogens mediated by
      • coating of pathogens by C3b and IgG
      • activation of phagocytosis by these fragments
    • clearance of immune complexes and cellular debris
    • chemotaxis of neutrophils mediated by
      • release of C5a into bloodstream after cleavage
      • detection of C5a by innate immune cells
    • direct cytolysis of pathogens through
      • formation of the membrane attack complex (MAC)
      • insertion of the MAC into bacterial membranes
      • rupture of the cell with release of internal contents
    • vascular changes such as dilation that 
      • are caused by immune reaction to C3a, C4a, and C5a
      • can lead to anaphylaxis if released systemically
  • Together these effects of the complement cascade are important in
    • initial activation of the innate immune system
    • clearance of debris such as immune complexes
    • assistance with humoral immunity
Complement Component Deficiencies
 
Complement Component Deficiencies
Missing Factor Presentation
Pathology
Circulating C3
  • Recurrent infection by pyogenic bacteria
  • Increased susceptibility to type III hypersensitivity reactions
  • Failure of C3 convertase formation
  • Lack of immune complex and pathogenic bacterial clearance
C5, C6, C7, C8, or C9
  • Increased susceptibility to recurrent Neisseria infections
  • Failure of membrane attack complex formation
C1 esterase inhibitor
  • Hereditary angioedema 
  • ACE inhibitors are contraindicated
  • Unregulated activation of kallikrein by complement system leading to increased bradykinin activity

Decay accelerating factor (CD55)

  • Paroxysmal nocturnal hemoglobinuria
  • Unregulated activation of complement leads to lysis of red blood cells
 

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Questions (3)
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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