The activation of the C3b feedback cycle with human complement components. I. Through the classical pathway

Area of Science:

• Immunology
• Biochemistry

Background:

• The human complement system is crucial for innate immunity.
• Its activation involves complex enzymatic cascades.
• Understanding novel pathways is key to therapeutic development.

Purpose of the Study:

• To investigate the properties and function of a newly generated complement enzyme, C4oxy2.
• To explore the potential for a novel complement activation pathway.

Main Methods:

• In vitro generation of the C4oxy2 enzyme from human complement components.
• Assays for C3 cleavage and complement consumption in human serum.
• Investigation of C3b feedback cycle activation.
• In vivo studies in rats to assess C4oxy2 activity.

Main Results:

• C4oxy2 efficiently cleaved C3 and depleted total complement in human serum.
• C4oxy2 activated the C3b feedback cycle, consuming factor B.
• A 'C-1 tickover' pathway analogous to 'C3b tickover' was proposed.
• In vivo, C4oxy2 induced C3 cleavage, C5 consumption, and altered neutrophil counts in rats.

Conclusions:

• The stable enzyme C4oxy2 demonstrates significant complement-activating potential.
• This suggests a previously unrecognized complement activation pathway ('C-1 tickover').
• C4oxy2 has implications for understanding complement function and potential therapeutic strategies.