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Properdin Can Initiate Complement Activation by Binding Specific Target Surfaces and Providing a Platform for De Novo Convertase Assembly¹

Division of Rheumatology, Department of Medicine, School of Medicine, Washington University, St. Louis, MO 63110

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 AI05143 (to D.E.H.).

² Address correspondence and reprint requests to Dr. Dennis E. Hourcade, Division of Rheumatology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8045, St. Louis, MO 63110. E-mail address: dhourcad{at}im.wustl.edu

³ Abbreviations used in this paper: CP, classical pathway; LP, lectin pathway; AP, alternative pathway; GPA, glycophorin A; E_R, rabbit erythrocyte; E_S, sheep erythrocyte; E_M, mouse erythrocyte; E_HU, human erythrocyte; E_RP, E_R pretreated with properdin; NHS, normal human serum; DAF, decay accelerating factor; CR1, complement receptor 1; scFv, single-chain Ab; WT, wild type.

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