What activates the lectin pathway?

Activation of the Lectin Pathway

Mechanism of Activation

The lectin pathway is primarily activated by the binding of pattern recognition molecules, specifically mannose-binding lectin (MBL) or ficolins, to carbohydrate structures on pathogen surfaces. 1, 2

The lectin pathway represents one of the three major activation pathways of the complement system, alongside the classical and alternative pathways. Its activation involves several key steps:

Primary Activators

• Pattern Recognition Molecules:

  • Mannose-binding lectin (MBL)
  • Ficolins (L-ficolin, H-ficolin, and M-ficolin in humans)
  • These molecules recognize specific carbohydrate patterns arranged in particular geometries on microbial surfaces 1

• Target Structures:

  • Mannose, N-acetylglucosamine, and other carbohydrates on pathogen surfaces
  • These carbohydrates are typically arranged in patterns that are not found on healthy human cells 2

Activation Process

1. Recognition Phase:

   • MBL or ficolins bind to carbohydrate structures on pathogen surfaces
   • These pattern recognition molecules are complexed with MBL-associated serine proteases (MASPs) in circulation 3

2. Protease Activation:

   • Upon binding to pathogens, conformational changes occur in the MBL/ficolin-MASP complex
   • This leads to autoactivation of the associated serine proteases 1

3. Complement Cascade Initiation:

   • MASP-2 cleaves complement components C4 and C2
   • MASP-1 activates MASP-2 and can also directly cleave C2
   • This generates the C3 convertase (C4b2a) that activates C3 1, 4

Key Components

Pattern Recognition Molecules

• MBL: Contains collagen-like domains and carbohydrate recognition domains (CRDs)
• Ficolins: Contain collagen-like domains and fibrinogen-like domains that recognize acetylated compounds 3

MBL-Associated Serine Proteases

• MASP-1: Activates MASP-2 and cleaves C2
• MASP-2: Primary enzyme responsible for C4 and C2 cleavage
• MASP-3: Role in lectin pathway unclear, but involved in alternative pathway
• MAp44 and sMAP: Truncated forms of MASPs with regulatory functions 1

Regulation of Activation

The lectin pathway is tightly regulated to prevent excessive activation and potential tissue damage:

• C1-inhibitor (C1-inh): Major physiological inhibitor of MASP-1 and MASP-2
• Antithrombin (AT): Effectively inhibits MASPs, especially in the presence of heparin
• α2-macroglobulin: Forms complexes with MASP-1 but does not effectively inhibit the lectin pathway on activator surfaces 5

Clinical Significance

• Innate Immunity: The lectin pathway serves as a first-line defense against pathogens before adaptive immunity is engaged
• Deficiencies: Deficiencies in components of the lectin pathway are associated with increased susceptibility to infections 1
• Complement Activation: In conditions like sepsis, the lectin pathway can be activated by microbes, contributing to the inflammatory response 6
• Hereditary Angioedema: C1-inhibitor deficiency affects regulation of the lectin pathway, contributing to disease pathophysiology 6

Evolutionary Perspective

The lectin pathway represents an ancient immune mechanism:

• Present in invertebrates and vertebrates
• Predates the evolution of adaptive immunity
• Consists of lectin-protease complexes that function in an opsonic manner in primitive organisms 4

Understanding the activation mechanisms of the lectin pathway is crucial for developing therapeutic approaches targeting complement-mediated diseases and for comprehending the body's response to various pathogens.