Immunity — Complement

Definition

• Proteolytic enzyme amplification cascade system; forms part of innate + acquired immune response
• Components circulate as inactive precursors
• Activation amplifies as a cascade; regulated by regulator proteins e.g. C1 esterase inhibitor
• Proteins produced by liver
• 9 complements: C1(q, r, s), C2, C3, C4, C5, C6, C7, C8, and C9
  • Also B, D, H, I and properdin

Main functions

• cell lysis of bacteria (MAC)
• opsonisation → ↑phagocytosis
• release of mediators via mast cell degranulation
• local vasodilation
• neutrophil aggregation
• chemotaxis

Components (7 functional)

Pathways

1. Classical – activation by Ag-Ab complex
   • system of 11 enzymes
   • pathway activated by formation of Ag-ab complexes, CRP, aggregated Ig (IgM or certain IgG)
   • activates C1 → reactions involving C4+C2 → formation of enzymatic complex C4b-C2a → cleaves C3a and C3b → common pathway
2. Alternate – activation by lipopolysaccharides
   • C3 undergoes slow, spontaneous conversion to hydrolysed C3
   • Multiple steps leading to complex ith C5 convertase → activation of common pathway
   • Nil ab required
3. Lectin – activation by mannose on surface of parasites, candida, viruses etc

Mechanism

following activation → triggers final common pathway → C3 activation → C3b acts as C5 convertase → C5b binds C6-C9 → forms membrane attack complex → inserted into target cell membrane → leakage of cellular material → cell lysis + destruction

Regulation

• Half of all complement proteins serve regulatory function
• goal
  • to prevent complement damage to normal host tissue (inappropriate / wrong target)
  • fluid-phase activation (no target)
• deficiencies lead to excessive complement activation
• Regulatory proteins inhibit system by destabilizing activation complexes and mediating specific proteolysis of actication-derived fragments
• Complement pathways are regulated at the following critical steps
  • Activation (initiation) – C1 inhibitor (C1inh) in classic and lectin pathways
  • Amplification (convertase formation) – e.g. binding proteins to C3 convertases
  • Membrane attack (lysis) – S-protein prevents insertion of Membrane attack complex (MAC) into membrane, CD 59 (protectin) bind C8 and C9 inhibiting final steps of Membrane attack complex
  • Anaphylactoids – carboxypeptidases inactivate C3a,C4a,C5a

Sources: Kerr’s notes, biosciencenotes.com