Complement system

• Complement


  The innate immune killing mechanism of blood
• Free bacteria in blood are unusual because they engage a key immediate innate response
• Complement and humoral defenses

  • Facilitated by antibody, but does not require specific antibody; some bacteria are resistant
• Complement protein names


  • C1-C9 are classical complement components; B, D, H, I are regulatory factors that also play key roles
  • When complement factors are cleaved, the products get a letter appended: so C3 is cleaved to C3a and C3b
  • Complexes are often described by putting these names together: so C3bBb is a complex of a fragment of C3 and a fragment of B
• The "alternative" complement pathway: complement component C3 is present at high concentration in serum
• The "alternative" complement pathway

  1. Internal thioester bond in C3 is hydrolysed

  2. C3(H2O) binds a circulating serine protease zymogen, factor B

  3. C3(H2O)B is cleaved by another serine protease, factor D, to generate C3(H2O)Bb and Ba

  4. C3(H2O)Bb is able to cleave and other molecules of C3 ("C3 convertase")
• Conversion (cleavage) of C3


  The critical event in complement activation
• Conversion of C3


  1. C3 is cleaved into C3a and C3b

  2. C3a is a signalling molecule: it drives smooth muscle contraction, macrophage recruitment, mast cell degranulation, vascular permeabilization (an anaphylotoxin)

  3. In C3b, the thioester bond is exposed and reactive—it will react with water, or with local hydroxyl or amine groups
• Biological surfaces react with the thioester
• Amplification


  1. C3b binds factor B

  2. Factor B is cleaved by factor D to form C3bBb, the alternative pathway C3 convertase

  3. C3bBb cleaves more C3 to C3b, amplifying the process
• C3b


  An opsonin: surfaces covered with C3b are recognized as foreign by phagocytes and targeted for phagocytosis
• Formation of the membrane attack complex (MAC)

  1. C3b recruits C5

  2. C5 is cleaved into C5a and C5b

  3. C5b nucleates the membrane attack complex (C5bC6C7C8C9)

  4. C9 multimerizes to form a pore in biological membranes—directly lysing foreign bodies
• Phagocytosis by macrophages requires recognition by phagocytic receptors
• The "classical" complement pathway

  1. Antibodies (mainly IgG) bind a bacterium in serum

  2. Fc region of antibody is bound by C1

  3. C1q binds Fc and activates C1r and C1s serine proteases

  4. C1s cleaves C4

  5. C4b binds the bacterium and recruits C2, which is cleaved by C1s to form the C3 convertase C4bC2a
• The "classical" pathway affords a mechanism for complement to be activated by specific antibodies
• The MBL (mannose-binding lectin) pathway

  1. MBL binds mannose on microbial surfaces

  2. MBL recruits MASP1 and MASP2 serine proteases

  3. MASP1/2 cleave and activate C4, then C2, as in the classical pathway
• Mechanisms that funnel into the complement effector cassette

  • C5 - membrane attack complex
  • C3 - opsonization/phagocytosis
  • Antibody
  • C1 - C4bC2a
  • MBL - MASP1/2
  • C3 spontaneous activation
• C3a


  A signalling molecule that drives smooth muscle contraction, macrophage recruitment, mast cell degranulation, vascular permeabilization (an anaphylotoxin)
• C3b


  The thioester bond is exposed and reactive—it will react with water, or with local hydroxyl or amine groups
• Complement regulatory factors


  • H binds glycosaminoglycans and recruits factor I
  • CD46 is a transmembrane protein that recruits factor I
  • I cleaves and inactivates C3b and C4b—prevents opsonization and kills the amplification step
  • P (Properdin) binds biological surfaces and increases the half-life of C3bBb—only known positive regulator of complement activity. Released by neutrophils.
• People who lack C1q or C2 have autoimmune disease (due to failure to clear complexes of cell debris with antibodies?)
• People who lack C3 are susceptible to infections with many pyogenic bacteria, mostly gram-negative
• People who lack MAC components (C5-C9) are similar, slightly weaker phenotype, particularly susceptible to Neisseria meningitidis
• How bacteria evade complement-mediated killing

  • Polysaccharide capsules
  • Inhibition of antibody binding
  • Mimickry of host cell surfaces
  • Hiding inside host cells
• Bacteria with capsules that impair complement-mediated killing

  • Streptococcus pneumoniae
  • Klebsiella pneumoniae
  • Haemophilus influenzae
• How capsules impair complement-mediated killing

  • Capsule excludes efficient diffusion of C3 to bacterial surface
  • C5 convertase is bound at capsule surface, reducing efficiency of membrane attack
  • Diffusion within the capsule is inefficient, reducing effectiveness of amplification
  • Capsule also inhibits phagocytosis
• Capsular polysaccharides are recognized as non-host (because there are antibodies)
• Capsular polysaccharides are diverse, even within very tight bacterial groupings (indicating a selective pressure)
• Mechanisms used by specific bacteria to evade complement


  • Streptococcus pyogenes mimics the host capsule: glycosaminoglycan (binds host factor H)
  • Streptococcus pyogenes M protein recruits factor H
  • Neisseria meningitidis LPS is sialylated, recruiting factor H and facilitating its interaction with C3
  • Neisseria meningitidis NalP binds and degrades C3
  • Staphylococcus aureus Protein A binds Fc, inhibiting C1q binding
  • Staphylococcus aureus SdrE binds C4BP to recruit H
  • Staphylococcus aureus Efb directly binds and inhibits C3