Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2.

Area of Science:

• Immunology
• Complement System Biology

Background:

• Lectin pathway activation of complement C3 involves mannan-binding lectin (MBL) or ficolins.
• Classical pathway C3 convertase is generated via cleavage of C4 and C2 by MBL-associated serine protease 2 (MASP-2).

Purpose of the Study:

• To investigate C3 activation mechanisms involving MBL.
• To assess MBL's role in complement recruitment in C2-deficient human sera.
• To identify alternative pathways for MBL-mediated complement activation.

Main Methods:

• ELISA was used to examine C3 deposition on microtiter plates coated with Salmonella O antigen oligosaccharides (BO, CO, DO).
• Experiments utilized C2-deficient sera and sera with other complement defects.
• MBL binding and C3 deposition were assessed in the presence and absence of complement components (C2, C4, MASP-2).

Main Results:

• MBL bound to CO oligosaccharides but not BO or DO.
• MBL efficiently supported C3 deposition in the absence of C2, C4, or MASP-2.
• A MBL-dependent C2 bypass mechanism for alternative pathway C3 activation was demonstrated.
• MASP-1 showed a potential contribution but was not essential.
• Antibody-dependent C3 deposition occurred via classical and alternative pathways, independent of MBL.

Conclusions:

• MBL can mediate C3 activation through a C2 bypass mechanism, independent of classical lectin pathway components.
• This MBL-dependent C2 bypass pathway is significant for complement activation in individuals with complement deficiencies.
• Understanding these alternative pathways is vital for managing inherited and acquired complement disorders.