questions 2

Complement

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Topic updated on 05/22/17 6:53pm

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 C5b
      • 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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