Effect of gangliosides on activation of the alternative pathway of human complement.
Liposomes as defined model membranes were used to quantitatively study the effects of specific sialic acid containing glycolipids on activation of the alternative pathway of human C. Liposomes containing dimyristoylphosphatidylethanolamine, cholesterol, and cerebrosides at molar ratios of 1.0/0.75/0.33 activated the alternative pathway in human serum treated with MgEGTA. Activation was measured by C3 conversion and the deposition of total C3 and functional C3b on the liposome surface. The monosialoganglioside GM1, when incorporated into the activating liposome membrane at molar ratios between 10(-5) and 10(-2), inhibited activation in a dose-dependent manner. Sialosylparagloboside also inhibited activation in human serum, and inhibition was completely reversed after neuraminidase treatment. The degree of inhibition by GM1 correlated with the relative amount of GM1 exposed on the liposome surface. Sialic acid did not directly inhibit the binding of C3b when liposomes containing gangliosides were incubated with the purified components C3, B, D, and P. GM1 did inhibit activation when liposomes were incubated with a mixture of purified C3, B, D, P, H, and I. Binding assays with radiolabeled H showed increased binding of H to liposome-bound C3b in the presence of GM1. These results establish the ability of sialic acid on glycolipids to promote H binding to C3b and thereby regulate alternative pathway activation on a defined lipid membrane.
Michalek
M T
MT
Department of Immunology/Microbiology, Rush University, Chicago, IL 60612.
Bremer
E G
EG
Mold
C
C
D001667:Binding, Competitive; D003167:Complement Activation / Q000187:drug effects*; D003176:Complement C3 / Q000378:metabolism; D003180:Complement C3b Inactivator Proteins / Q000494:pharmacology*; D011415:Complement Factor B / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000187:drug effects*; D005677:G(M1) Ganglioside / Q000494:pharmacology; D005732:Gangliosides / Q000494:pharmacology*; D005915:Globosides / Q000494:pharmacology; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D008081:Liposomes; D008954:Models, Biological; D009439:Neuraminidase / Q000494:pharmacology
D003176:Complement C3; D003180:Complement C3b Inactivator Proteins; D005732:Gangliosides; D005915:Globosides; D008051:Lipid Bilayers; D008081:Liposomes; D005677:G(M1) Ganglioside; C014812:sialosylparagloboside; D009439:Neuraminidase; D011415:Complement Factor B