What activates the complement system?

Activation Pathways of the Complement System

The complement system is activated through three distinct pathways: the classical pathway, the alternative pathway, and the lectin pathway, each triggered by different molecular mechanisms and converging at the formation of C3 convertase. 1

Classical Pathway Activation

• Triggered by antigen-antibody complexes: The classical pathway is primarily activated when antibodies (IgG or IgM) bind to antigens, forming immune complexes 2
• C1 complex initiation: These immune complexes are recognized by C1q (part of the C1 complex), which then activates C1r and C1s
• Subsequent activation: C1s cleaves C4 and C2, forming C4b2a (C3 convertase)
• Diagnostic indicators: Low CH50 with normal AH50 suggests deficiency in C1, C2, or C4 components 2

Alternative Pathway Activation

• Spontaneous activation: The alternative pathway is continuously activated at a low level through spontaneous hydrolysis of C3 ("tickover")
• Amplification loop: Factor B binds to C3b, followed by Factor D cleavage, forming C3bBb (alternative C3 convertase)
• Properdin stabilization: Properdin stabilizes C3bBb, extending its half-life
• Surface triggers: Microbial surfaces lacking regulatory proteins can trigger this pathway
• Diagnostic indicators: Normal CH50 with low AH50 suggests properdin defect or Factor B/D deficiency 2

Lectin Pathway Activation

• Pattern recognition: Initiated by mannose-binding lectin (MBL) or ficolins binding to carbohydrate patterns on pathogen surfaces 3
• MBL-MASP complex: In humans, MBL and three types of ficolins (L-ficolin, H-ficolin, M-ficolin) form complexes with MBL-associated serine proteases (MASPs) 3
• MASP activation: Upon binding to pathogens, MASP-1 activates MASP-2, which then cleaves C4 and C2 3
• C3 convertase formation: This leads to the formation of C4b2a (C3 convertase), similar to the classical pathway

Common Terminal Pathway

• C3 convertase: All three pathways converge at the formation of C3 convertase (C4b2a or C3bBb)
• C3 cleavage: C3 convertase cleaves C3 into C3a and C3b
• C5 convertase formation: C3b joins with C3 convertase to form C5 convertase
• Membrane attack complex (MAC): C5 convertase cleaves C5, initiating the assembly of C5b-C9 to form MAC, which creates pores in target cell membranes leading to lysis 2, 4

Complement Regulation

• Regulatory proteins: The complement system is tightly regulated by proteins such as Factor H, Factor I, CD46, CD55, and CD59 2
• Dysregulation consequences: Deficiencies in regulatory components can lead to complement consumption and pathological conditions 2
• Diagnostic approach: Measuring levels of factor B and C4 can help identify consumption of complement through alternative or classical pathways, respectively 2

Clinical Implications

• Infection susceptibility: Deficiencies in complement components increase susceptibility to specific infections 3
• Autoimmune diseases: Dysregulation can contribute to autoimmune conditions like atypical hemolytic uremic syndrome 4
• Inflammatory disorders: Complement activation plays a role in inflammatory conditions and tissue damage 4
• Diagnostic testing: CH50 and AH50 assays help identify pathway-specific deficiencies 2

Understanding these activation pathways is crucial for diagnosing complement-related disorders and developing targeted therapeutic approaches that modulate specific parts of the complement cascade.