title: Activator-specific requirement of properdin in the initiation and amplification of the alternative pathway complement.
abstract: Properdin is a positive regulator of alternative pathway (AP) complement. The current understanding of properdin function is that it facilitates AP complement activation by stabilizing the C3 convertase C3bBb. Properdin-deficient patients are susceptible to lethal meningococcal infection, but the mechanism of this selective predisposition is not fully understood. By gene targeting in the mouse, we show here that properdin is essential for AP complement activation induced by bacterial lipopolysacharride (LPS) and lipooligosacharride (LOS) and other, but not all, AP complement activators. LPS- and LOS-induced AP complement activation was abolished in properdin-/- mouse serum, and properdin-/- mice were unable to clear Crry-deficient erythrocytes, which are known to be susceptible to AP complement-mediated extravascular hemolysis. In contrast, zymosan- and cobra venom factor-induced AP complement activation, and classical pathway-triggered AP complement amplification were only partially or minimally affected in properdin-/- mice. We further show that the ability of human properdin to restore LPS-dependent AP complement activity in properdin-/- mouse serum correlated with the human properdin-binding affinity of the LPS. These results reveal a novel role of properdin in AP complement initiation and have implications for understanding the selective predisposition of properdin-deficient patients to meningococcal infection.
authors.affiliation: Institute for Translational Medicine and Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Song
mesh_terms: D000818:Animals; D051561:Complement C3 Convertase, Alternative Pathway / Q000235:genetics / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008589:Meningococcal Infections / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011414:Properdin / Q000235:genetics / Q000378:metabolism*; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism; D017463:Receptors, Complement 3b
chemical_list: C482970:CR1L protein, human; C081470:Cr1l protein, mouse; D008070:Lipopolysaccharides; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D011414:Properdin; D051561:Complement C3 Convertase, Alternative Pathway