What are the three pathways to activate the complement system?

The Three Pathways of Complement Activation

The complement system is activated through three distinct pathways: the classical pathway, the lectin pathway, and the alternative pathway. 1, 2

1. Classical Pathway

• Initiated by antibody-antigen complexes or direct pathogen binding 1, 2
• The C1 complex (C1q, C1r, C1s) recognizes and binds to immunoglobulin (IgG or IgM) bound to antigens or directly to bacterial surfaces 2, 3
• C1q binding activates C1r, which then activates C1s 3
• Activated C1s cleaves C4 and C2 to form the C3 convertase (C4b2a) 1, 4
• Laboratory assessment: CH50 assay measures classical pathway function; a result of 0 suggests C1, C2, or C4 deficiency 1

Clinical significance: Immunoglobulin-positive patterns on immunofluorescence suggest classical pathway activation and should prompt evaluation for underlying causes including infections (hepatitis B/C, chronic microbial infections), autoimmune disorders (SLE, rheumatoid arthritis), and neoplasms 1

2. Lectin Pathway

• Initiated by pattern recognition molecules binding to carbohydrates on pathogen surfaces 1, 2, 4
• Mannose-binding lectin (MBL) and ficolins (L-ficolin, H-ficolin, M-ficolin) recognize specific carbohydrate patterns 4, 5
• These lectins form complexes with MBL-associated serine proteases (MASP-1, MASP-2, MASP-3) 4, 3
• MASP-2 is the primary activator, cleaving C4 and C2 to generate the same C3 convertase as the classical pathway 4
• MASP-1 activates both C2 and MASP-2, providing amplification 4

Important caveat: MBL deficiency will show normal results on both CH50 and AH50 assays, as standard complement testing does not assess the lectin pathway 1

3. Alternative Pathway

• Continuously activated at low levels through spontaneous C3 hydrolysis ("tick-over") 1
• Does not require antibodies or specific recognition molecules 2, 6
• C3b deposited on surfaces binds Factor B, which is cleaved by Factor D to form the alternative pathway C3 convertase (C3bBb) 1
• Properdin stabilizes the C3 convertase, amplifying activation 1
• Laboratory assessment: AH50 (AP50) assay measures alternative pathway function; defects in Factor B, Factor D, or properdin cause reduced or absent activity 1

Clinical significance: C3-positive but immunoglobulin-negative patterns suggest alternative pathway dysregulation (C3 glomerulopathy), which may result from genetic mutations in complement factors H, I, B, or CD46, or from acquired autoantibodies like C3 nephritic factor 1

Convergence and Amplification

All three pathways converge at C3 activation, forming C3 convertases that cleave C3 into C3a and C3b 1, 4. This leads to:

• Formation of C5 convertase, which cleaves C5 into C5a and C5b 1
• Assembly of the membrane attack complex (C5b-C9), causing cell lysis 5
• Generation of anaphylatoxins (C3a, C5a) that promote inflammation 1

Critical point: The alternative pathway also serves as an amplification loop for all three pathways, as C3b generated by any pathway can trigger additional alternative pathway activation 1, 6