Complement Pathway

Aka: Complement Pathway, Complement C3, Complement C4, Complement CH50, Complement Activation, Alternative Complement Pathway, Classical Complement Pathway, Mannose-Binding Lectin Complement Pathway, Complement Disorder, Complement Deficiency Disease, Complement Abnormality

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II. Physiology: General

  1. Complement is a group of ~15 Proteins (esp. enzyme precursors)
    1. Hepatic production and secreted into serum
    2. Contribute to immune response when activated
  2. Complement are components of both Innate Immunity and the humoral Immune System
  3. Multiple triggers including Antigen-Antibody complex as well as direct exposure to pathogen (see activation below)
  4. Results in inflammatory response (Chemoattractant), Phagocytosis (as Opsonin on cell surface) and pathogen lysis
  5. Other complement functions
    1. Solubilizes immune complexes to aid in clearance
    2. Attaches Antibody-Antigen complexes to Red Blood Cells for transport to the Spleen and liver
    3. Promotes Bacterial Agglutination
    4. Neutralization of viral pathogens
    5. In some cases, inhibits Antigen-Antibody complex formation (and deposition)

III. Physiology: Complement Pathway

  1. Images
    1. idComplementPathway.jpg
  2. Activation
    1. Classical Pathway (C1, C2, C3, C4)
      1. C1q binds Antigen-Antibody complex
      2. C1r and C1s are activated and bind C1q (and Antigen-Antibody complex)
      3. C1 complex (C1q, C1r, C1s) acts on C2 and C4, resulting in C4b2a which activates C3
      4. Classical Pathway is regulated by C1 Esterase Inhibitor which dissociates C1r/s from C1q
    2. Alternate Pathway (Properdin, Factor B, Factor D, C3)
      1. Activation via Microbe cell surface (Bacterial lipopolysaccharide or LPS)
    3. Lectin Pathway (Mannose Binding Lectin or MBL)
      1. Mannose Binding Lectin (MBL) binds mannose on Microbe surface
      2. Mannose Binding Lectin Associated Proteases (MASP-1, MASP-2) are activated
      3. Classical Pathway (above) is stimulated
  3. Enzyme C3 Convertase (C3bBb or C4b2a) Formation
    1. Enzyme C3 Convertase splits C3 into C3a and C3b
    2. C3a stimulates inflammation (attracts Neutrophils, Histamine release from Mast Cells and Basophils)
    3. C3b results in Opsonization, and stimulates Phagocytosis, and lysis (see below), as well as inflammation (as with C3)
  4. Opsonization
    1. Microbe coated with an Opsonin such as an Antibody or complement (e.g. C3b)
    2. Surface Opsonins target Microbes for Phagocytosis by Neutrophils and Macrophages
  5. Phagocytosis
    1. Phagocytes such as Neutrophils (PMNs) and Macrophages attract and engulf targeted organisms
  6. Inflammation (via C3a, C5a)
    1. Chemoattraction of Neutrophils
    2. Anaphylatoxic activation of Mast Cells and Basophils to degranulate, releasing Histamines and vasoactives
      1. Inflammation occurs when Histamine-induced capillary dilation results in fluid and Protein release
  7. Lysis
    1. C3b splits C5 into C5a and C5b
    2. Membrane attack complex or MAC (C5b, C6, C7, C8, C9) binds Microbe surface
    3. MAC promotes Microbe lysis

IV. Labs

  1. Complement C3
    1. Marker for Intrinsic and Extrinsic Pathway Function
    2. Measured by immunochemical assay
  2. Complement C4
    1. Marker for Intrinsic Pathway Function
    2. Measured by immunochemical assay
    3. Deficient in 1% of population
    4. Deficient in 11% with Systemic Lupus Erythematosus
  3. Complement CH50
    1. Marker for function of entire intrinsic cascade
    2. Measured by serum ability to lyse IgG coated RBCs
      1. Most affected by delay in performing assay

V. Causes: Low Complement levels indicate depletion

  1. Rheumatic causes
    1. Systemic Lupus Erythematosus
    2. Mixed Connective Tissue Disease (MCTD)
    3. Vasculitis (especially cryoglobulinemia)
  2. Non-Rheumatic Causes
    1. Septic Shock
    2. Liver failure
    3. Severe Malnutrition
    4. Pancreatitis
    5. Severe burns
    6. Atheromatous embolization

VI. Indications: Follow rheumatic disease activity

  1. Complement fall 20% below baseline signal exacerbation

VII. Associated Conditions: Complement Disorders (2% of Immunodeficiency disorders)

  1. Autoimmune Condition or Rheumatologic Condition (associated with C1-C4 deficiencies)
    1. Systemic Lupus Erythematosus
  2. Recurrent encapsulated organism, esp. pyogenic infections (manifestations vary depending on missing complement type)
    1. Complement deficiencies include C1q, C2-C9 (except C4), Factor I, Properdin
    2. Neisseria infections are most common including Meningitis, Sepsis and Arthritis (associated with C5-C9 deficiencies)
    3. Recurrent infections with Streptococcus Pneumoniae and HaemophilusInfluenzae (associated with C3 deficiency)
  3. Hereditary Angioedema
    1. C1 Esterase Inhibitor Deficiency

VIII. References

  1. Guyton and Hall (2006) Medical Physiology, p. 419-50
  2. Mahmoudi (2014) Immunology Made Ridiculously Simple, MedMaster, Miami, FL

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