Pathway Analysis
The following sections summarize key functional steps of the complement cascade that may be suggested by the measured analytes. The complement system is a coordinated network of proteins involved in immune defense, inflammation, and clearance of pathogens and immune complexes.
Activation may occur through multiple pathways (classical, lectin, and alternative), which converge on central effector mechanisms and terminal pathway activation. These pathway-level interpretations reflect potential sites of complement activity or regulation and should be interpreted in the context of clinical findings and other laboratory data.
Classical Pathway Initiation
The classical complement pathway is typically initiated by antigen–antibody complexes, linking adaptive immune recognition to complement activation. This pathway plays a key role in immune complex clearance and host defense.
Core Initiation Marker
- C1q – The recognition component of the classical pathway that binds to immune complexes, apoptotic cells, and certain pathogens, triggering downstream complement activation.
Lectin Pathway Initiation
The lectin pathway is activated through recognition of carbohydrate patterns on microbial surfaces, providing an antibody-independent mechanism of complement activation.
Core Initiation Marker
- Mannose-Binding Lectin (MBL) – Binds to mannose and related sugars on pathogens, initiating complement activation via MBL-associated serine proteases.
Classical and Lectin Pathway C3 Convertase Formation or Function
Following initiation, both the classical and lectin pathways converge to form the C3 convertase (C4b2a), a key enzymatic complex that amplifies complement activation.
Core Convertase Components
- C2 – Combines with C4b to form the C3 convertase.
- C4, C4b – Cleavage products that bind to pathogen surfaces and participate in convertase assembly.
Alternative Pathway C3 Convertase Formation or Function
The alternative pathway provides continuous low-level complement activation (“tick-over”) and amplifies activation initiated by other pathways.
Core Alternative Pathway Components
- Factor B – Binds to C3b to form the alternative pathway convertase.
- Factor D – Cleaves Factor B to activate the convertase complex.
- Properdin – Stabilizes the alternative pathway C3 convertase, prolonging its activity.
Central Effector Activity
C3 is the central hub of the complement system, integrating signals from all activation pathways and driving downstream immune effects.
Core Effector Components
- C3 – Cleavage generates C3a (inflammatory mediator) and C3b (opsonin).
- C3b / iC3b – Key opsonins that tag pathogens for phagocytosis and amplify complement activation.
Terminal Pathway Activation
Activation of the terminal pathway leads to formation of the membrane attack complex (MAC), which can directly lyse target cells.
Core Terminal Components
- C5 – Cleavage produces C5a and initiates MAC formation.
- C5a – A potent anaphylatoxin that drives inflammation, chemotaxis, and immune activation.
C9 – Final component of the MAC that forms pores in target cell membranes.
Regulation of Complement Activation
Complement activity is tightly regulated to prevent damage to host tissues. Dysregulation can lead to excessive inflammation or impaired immune defense.
Core Regulatory Factors
- Factor H – Inhibits alternative pathway activation and promotes degradation of C3b.
- Factor I – Cleaves C3b and C4b, helping terminate complement activation.