title: Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature.
abstract: Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies--nature's own knockouts--including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1beta and IL-8 were more dependent on complement than IFN-gamma and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-gamma inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to gram-negative bacteria.
authors.affiliation: Department of Medicine, Nordland Hospital, Bodø, and University of Tromsø, Norway. knut.lappegard@nlsh.no
authors.forename: Knut Tore
authors.initials: KT
authors.lastname: Lappegård
authors.forename: Dorte
authors.initials: D
authors.lastname: Christiansen
authors.forename: Anne
authors.initials: A
authors.lastname: Pharo
authors.forename: Ebbe Billmann
authors.initials: EB
authors.lastname: Thorgersen
authors.forename: Bernt Christian
authors.initials: BC
authors.lastname: Hellerud
authors.forename: Julie
authors.initials: J
authors.lastname: Lindstad
authors.forename: Erik Waage
authors.initials: EW
authors.lastname: Nielsen
authors.forename: Grethe
authors.initials: G
authors.lastname: Bergseth
authors.forename: Dag
authors.initials: D
authors.lastname: Fadnes
authors.forename: Tore G
authors.initials: TG
authors.lastname: Abrahamsen
authors.forename: E Arne
authors.initials: EA
authors.lastname: Høiby
authors.forename: Lone
authors.initials: L
authors.lastname: Schejbel
authors.forename: Peter
authors.initials: P
authors.lastname: Garred
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Morten
authors.initials: M
authors.lastname: Harboe
authors.forename: Tom Eirik
authors.initials: TE
authors.lastname: Mollnes
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000276:immunology; D003167:Complement Activation; D003175:Complement C2 / Q000172:deficiency / Q000235:genetics; D003182:Complement C5 / Q000172:deficiency / Q000235:genetics; D003165:Complement System Proteins / Q000172:deficiency* / Q000235:genetics*; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D006090:Gram-Negative Bacteria / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D018448:Models, Immunological; D009000:Monocytes / Q000276:immunology / Q000382:microbiology; D009345:Neisseria meningitidis / Q000276:immunology; D010587:Phagocytosis; D016897:Respiratory Burst / Q000276:immunology; D013925:Thromboplastin / Q000096:biosynthesis
chemical_list: D003175:Complement C2; D003182:Complement C5; D018950:Lipopolysaccharide Receptors; D003165:Complement System Proteins; D013925:Thromboplastin