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The activation of the C3b feedback cycle with human complement components. I. Through the classical pathway
Insights
A novel complement enzyme, C4oxy2, cleaves C3 and activates the C3b feedback cycle in human serum. This finding suggests a new
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.
Abstract:
Reaction between the fourth, the oxidized second and the activated first components of human complement generated the stable enzyme C4oxy2 capable of cleaving the third component and depleting total complement in human serum. This enzyme was shown further to activate the C3b feedback cycle as shown by its ability to consume factor B in serum and the reduction in the extent of complement consumption in the presence of EDTA. OxyC2 on its own gave rise to C3 cleavage in normal human serum by a pathway needing classical pathway components. This unexpected finding suggests that there may be a 'C-1 tickover' in serum analogous to the 'C3b tickover'; the presence of oxyC2 allowing the 'capture' of the trivial amounts of C42 normally formed. In preliminary experiments in the rat, C4oxy2 was successfully formed in vivo, where it gave rise to cleavage of C3, consumption of C5, depletion of cobra venom factor cofactors and a biphasic change in the neutrophil count.