Complement regulation in human atherosclerotic coronary lesions. Immunohistochemical evidence that C4b-binding protein negatively regulates the classical complement pathway, and that C5b-9 is formed via the alternative complement pathway.
OBJECTIVE
The complement system is activated in human atherosclerotic lesions and may hence aggravate local inflammation. We studied the presence and localization of C4b-binding protein (C4bp), the major inhibitor of the classical complement pathway, in human atherosclerotic lesions in relation to complement activation products and protein S, which circulates in complex with C4bp.


RESULTS
Immunohistochemistry of human coronary arteries showed C4bp to be virtually absent in normal arteries but present in early and advanced atherosclerotic lesions. In the lesions, C4bp is associated with proteoglycans, and affinity chromatography showed that C4bp interacts with human arterial proteoglycans. Areas containing C4bp also contained IgM and C4 suggesting that C4bp is involved in the regulation of the classical complement pathway. However, C5b-9 was virtually absent in these areas but, instead, colocalized with properdin deeper in the intima, suggesting that C5b-9 is formed by the alternative complement pathway. A fraction of C4bp was associated with protein S and apoptotic cells.


CONCLUSIONS
The results indicate that C4bp regulates the classical complement pathway in human atherosclerotic lesions. Thus, unlike the alternative pathway, the classical complement pathway does not generate C5b-9, but is likely to be involved in the clean-up of apoptotic cells and cell debris in the arterial intima.
Oksjoki
Riina
R
Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland.
Kovanen
Petri T
PT
Mäyränpää
Mikko I
MI
Laine
Petri
P
Blom
Anna M
AM
Meri
Seppo
S
Pentikäinen
Markku O
MO
D017209:Apoptosis; D050716:Complement C4b-Binding Protein / Q000276:immunology*; D015938:Complement Membrane Attack Complex / Q000276:immunology / Q000378:metabolism*; D003170:Complement Pathway, Alternative; D003171:Complement Pathway, Classical; D003324:Coronary Artery Disease / Q000276:immunology*; D003331:Coronary Vessels / Q000276:immunology* / Q000473:pathology; D006651:Histocytochemistry; D006801:Humans; D017539:Tunica Intima / Q000276:immunology / Q000473:pathology
D050716:Complement C4b-Binding Protein; D015938:Complement Membrane Attack Complex