Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly.
Complement promotes the rapid recognition and elimination of pathogens, infected cells, and immune complexes. The biochemical basis for its target specificity is incompletely understood. In this report, we demonstrate that properdin can directly bind to microbial targets and provide a platform for the in situ assembly and function of the alternative pathway C3 convertases. This mechanism differs from the standard model wherein nascent C3b generated in the fluid phase attaches nonspecifically to its targets. Properdin-directed complement activation occurred on yeast cell walls (zymosan) and Neisseria gonorrhoeae. Properdin did not bind wild-type Escherichia coli, but it readily bound E. coli LPS mutants, and the properdin-binding capacity of each strain correlated with its respective serum-dependent AP activation rate. Moreover, properdin:single-chain Ab constructs were used to direct serum-dependent complement activation to novel targets. We conclude properdin participates in two distinct complement activation pathways: one that occurs by the standard model and one that proceeds by the properdin-directed model. The properdin-directed model is consistent with a proposal made by Pillemer and his colleagues >50 years ago.
Division of Rheumatology, Department of Medicine, School of Medicine, Washington University, St. Louis, MO 63110, USA.
Dirk
D
Spitzer
Lynne M
LM
Mitchell
John P
JP
Atkinson
Dennis E
DE
Hourcade
D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051561:Complement C3 Convertase, Alternative Pathway / Q000737:chemistry* / Q000378:metabolism; D003170:Complement Pathway, Alternative; D004927:Escherichia coli Infections / Q000235:genetics / Q000378:metabolism; D048168:Escherichia coli K12 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006069:Gonorrhea / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000378:metabolism; D009154:Mutation; D009344:Neisseria gonorrhoeae / Q000737:chemistry* / Q000378:metabolism; D011414:Properdin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012756:Sheep; D020298:U937 Cells; D015054:Zymosan / Q000737:chemistry* / Q000378:metabolism
D000906:Antibodies; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins; D011414:Properdin; D015054:Zymosan; D051561:Complement C3 Convertase, Alternative Pathway