The Complement System and Its Different Types
The complement system is a complex network of over 50 proteins that function as a tightly regulated proteolytic cascade in the innate immune system, leading to pathogen elimination through cell lysis, inflammation, and opsonization. 1
Activation Pathways
The complement system can be activated through three distinct pathways:
1. Classical Pathway
- Trigger: Antibody-antigen complexes (immune complexes)
- Initial components: C1q, C1r, C1s, C4, C2
- Function: Links adaptive and innate immunity
- Mechanism: Activated when C1q binds to antibodies (primarily IgG and IgM) attached to antigens
- Leads to: Formation of C3 convertase (C4b2a)
2. Alternative Pathway
- Trigger: Spontaneous hydrolysis of C3 ("tickover") or pathogen surfaces
- Initial components: C3, Factor B, Factor D, Properdin
- Function: Continuous low-level surveillance
- Mechanism: C3b binds to pathogen surfaces, followed by Factor B, which is cleaved by Factor D
- Leads to: Formation of C3 convertase (C3bBb)
3. Lectin Pathway
- Trigger: Mannose-binding lectin (MBL) or ficolins binding to carbohydrate patterns
- Initial components: MBL, ficolins, MBL-associated serine proteases (MASPs)
- Function: Recognition of pathogen-associated molecular patterns
- Mechanism: MBL or ficolins bind to carbohydrates on pathogen surfaces, activating MASPs
- Leads to: Formation of C3 convertase (C4b2a)
Convergence and Terminal Pathway
All three pathways converge at the formation of C3 convertase, which cleaves C3 into C3a and C3b:
- C3b contributes to further activation and opsonization
- C3a acts as an anaphylatoxin (inflammatory mediator)
- C5 convertase forms (C4b2a3b or C3bBb3b)
- C5 is cleaved to C5a (anaphylatoxin) and C5b
- C5b initiates the assembly of the membrane attack complex (MAC, C5b-9)
- MAC creates pores in cell membranes, leading to cell lysis 1, 2
Complement Regulators
The complement system is tightly regulated by several proteins to prevent excessive activation and host tissue damage:
Fluid-phase regulators:
- Factor H (regulates alternative pathway)
- C1 inhibitor (regulates classical and lectin pathways)
- Factor I (cleaves C3b and C4b)
- C4-binding protein (regulates classical pathway)
Membrane-bound regulators:
- CD55 (Decay Accelerating Factor)
- CD46 (Membrane Cofactor Protein)
- CD35 (Complement Receptor 1)
- CD59 (Protectin, inhibits MAC formation) 2
Complement-Mediated Disorders
Dysregulation of the complement system contributes to various pathological conditions:
Immune Complex-Mediated Disorders
- Membranoproliferative glomerulonephritis (MPGN): Characterized by immunoglobulin and C3 deposits, indicating classical pathway activation 3
- Systemic lupus erythematosus (SLE): Immune complexes activate complement, leading to tissue damage 3
Alternative Pathway Dysregulation
- C3 glomerulopathy: Characterized by C3 deposits without immunoglobulins 3
- Atypical hemolytic uremic syndrome (aHUS): Caused by mutations in complement regulators 4
Other Complement-Related Disorders
- Paroxysmal nocturnal hemoglobinuria (PNH): Deficiency of GPI-anchored complement regulators 5
- Age-related macular degeneration: Associated with polymorphisms in complement genes 6
- Myasthenia gravis: Complement activation contributes to neuromuscular junction damage 4
Diagnostic Approaches
Laboratory evaluation of complement function includes:
- CH50 assay: Measures classical pathway function
- AH50 assay: Measures alternative pathway function
- Complement component levels: C3, C4, Factor B, etc.
- Genetic testing: For inherited complement disorders
- Autoantibody testing: C3 nephritic factor, anti-Factor H antibodies 3
Therapeutic Targeting of Complement
Complement inhibitors are increasingly used to treat complement-mediated disorders:
- Eculizumab/Ravulizumab: Monoclonal antibodies that inhibit C5 activation, preventing formation of MAC and C5a 5, 4
- Preventive measures: Vaccination against Neisseria meningitidis is essential before initiating complement inhibitor therapy due to increased infection risk 5, 4
Recent Advances
Recent research has identified the "complosome" - an intracellular complement system that plays crucial roles in:
- Cell metabolism regulation
- Mitochondrial activity
- Cell survival and proliferation
- Gene regulation in immune and non-immune cells 7
Understanding the complement system's complexity continues to evolve, with new insights into its role in viral diseases, cancer, and other conditions beyond traditional complement-associated disorders 8, 6.