Complement System

Overview & Pathways Intro - Cascade Crew

• System of ~30 plasma proteins (mainly liver-derived) acting sequentially in a cascade.
• Key component of innate immunity; bridges to adaptive immunity.
• Key Functions (📌 O-I-L-C):
  • Opsonization (e.g., C3b) to enhance phagocytosis.
  • Inflammation (anaphylatoxins: C3a, C5a).
  • Lysis of pathogens (Membrane Attack Complex: C5b-C9).
  • Clearance of immune complexes.
• Three Main Activation Pathways: Classical, Alternative, Lectin. All converge on C3 activation.

⭐ The complement system acts as a crucial bridge between innate and adaptive immunity, enhancing both pathogen clearance and antibody responses.

Activation Pathways - Triple Ignition

• Classical Pathway: (Adaptive immunity link)
  • Trigger: Ag-Ab complexes (IgM is most efficient; also IgG1, IgG2, IgG3). C1q binds Fc of Ab.
  • Initiation: C1 complex (C1q, C1r, C1s) activates. C1s (serine protease) cleaves C4 $\rightarrow$ C4b; C2 $\rightarrow$ C2b.
  • C3 Convertase: $C4b2a$.
• Alternative Pathway: (Innate immunity; Antibody-independent)
  • Trigger: Spontaneous C3 hydrolysis ($C3(H_2O)$ "tick-over"); direct C3b binding to pathogen surfaces (LPS, zymosan).
  • Key Factors: C3b binds Factor B; Factor D cleaves Factor B (bound to C3b) $\rightarrow$ Bb. Properdin (P) stabilizes $C3bBb$.
  • C3 Convertase: $C3bBb$.
  • 📌 Alternative: Always active at low levels, rapid response.
• Lectin Pathway: (Innate immunity; Antibody-independent)
  • Trigger: Mannose-Binding Lectin (MBL) or Ficolins bind specific microbial carbohydrates (e.g., mannose, N-acetylglucosamine).
  • Initiation: MBL-Associated Serine Proteases (MASPs: MASP-1, MASP-2) activate. MASP-2 cleaves C4 and C2 (like C1s).
  • C3 Convertase: $C4b2a$.

⭐ The generation of C3 convertase (e.g., $C4b2a$ for classical/lectin, $C3bBb$ for alternative) is the central and most critical amplification step in all complement pathways, cleaving many C3 molecules.

Effector Functions & Regulation - Power & Control

• Effector Functions (CRITICAL Outcomes):
  • Opsonization & Phagocytosis: C3b (major), C4b.
  • Inflammation: Anaphylatoxins C5a (potent), C3a, C4a → histamine release, ↑vascular permeability. C5a: neutrophil chemotaxis.
  • Cell Lysis: Membrane Attack Complex (MAC) C5b-9 → pores, lysis.
  • Immune Complex Clearance: C3b binds complexes → splenic/hepatic removal.
• Regulation (Preventing Host Damage):
  • C1 Inhibitor (C1-INH): Serpin; dissociates C1r/C1s from C1q. Deficiency → Hereditary Angioedema (HAE).
  • Factor H: Cofactor for Factor I → cleaves C3b to iC3b.
  • Decay-Accelerating Factor (DAF/CD55): Dissociates C3 convertases (C4b2a, C3bBb).
  • Protectin (CD59): Blocks C9 binding, prevents MAC assembly on host cells.
  • S-protein (Vitonectin): Binds fluid-phase C5b-7, prevents bystander lysis.
  • Carboxypeptidase N: Inactivates C3a, C5a.

⭐ C3b is the primary opsonin of the complement system, facilitating phagocytosis, while C5a is a potent anaphylatoxin and chemoattractant for neutrophils.

Clinical Significance - System Under Siege

• Deficiencies & Disease:
  • Early (C1q, C2, C4): SLE-like, pyogenic infections.
  • C3: Severe pyogenic infections, GN.
  • Properdin: ↑ Neisseria risk.

  ⭐ Deficiencies in terminal complement components (C5-C9) lead to a significantly increased susceptibility to recurrent infections by Neisseria species (e.g., N. meningitidis, N. gonorrhoeae).

• Dysregulation & Disease:
  • PNH (CD55/CD59↓): IV hemolysis.
  • HAE (C1-INH↓): Angioedema (bradykinin↑).
  • aHUS (Factor H/I/MCP↓): TMA.
• Diagnostics:
  • CH50: Classical/terminal screen.
  • AH50: Alternative pathway screen.

High‑Yield Points - ⚡ Biggest Takeaways

• Three pathways activate complement: Classical (antibody-driven), Alternative (pathogen surfaces), and Lectin (mannose-binding lectin).
• All pathways converge to form C3 convertase; C3b is crucial for opsonization and forming C5 convertase.
• C5a is a potent anaphylatoxin and neutrophil chemoattractant; C3a is a weaker anaphylatoxin.
• The Membrane Attack Complex (MAC), C5b-C9, forms pores that lyse target cells, especially gram-negative bacteria.
• Key regulators like DAF (CD55) and CD59 (Protectin) prevent complement activation on host cells.
• C3 deficiency leads to severe, recurrent pyogenic infections and immune-complex disease.
• C5-C9 deficiencies (MAC defects) cause recurrent infections with Neisseria species (e.g., meningitis, gonorrhea).