Stringent regulation of complement lectin pathway C3/C5 convertase by C4b-binding protein (C4BP)

Area of Science:

• Immunology
• Innate Immunity
• Complement System

Background:

• The complement lectin pathway rapidly recognizes infections.
• C4b deposition is crucial for forming C3/C5 convertases in this pathway.

Purpose of the Study:

• To investigate the role of C4b-binding protein (C4BP) in regulating the lectin pathway's C3/C5 convertase.
• To compare C4BP regulation of lectin pathway convertases versus classical pathway convertases.

Main Methods:

• Examined C4BP's inhibition of C3/C5 convertase assembly on zymosan and mannan-coated erythrocytes (E(Man)).
• Assessed C4BP binding interactions with surface-bound C4b and C4b/C3b complexes.
• Investigated the effect of C4b density on C4BP binding stoichiometry.

Main Results:

• C4BP required higher concentrations to inhibit C5 convertase assembly on zymosan and E(Man) compared to C3 convertase.
• C4BP binding stoichiometry varied with C4b density on zymosan but remained constant on E(Man).
• C4BP exhibited significantly greater affinity for C4b deposited via the lectin pathway than the classical pathway.

Conclusions:

• C4BP effectively regulates the lectin pathway's C3/C5 convertase assembly and decay.
• C4BP's higher affinity for lectin pathway C4b contributes to controlling pro-inflammatory product generation.
• This regulation is vital for balancing infection defense and preventing pathological inflammation.