title: Central role of complement in passive protection by human IgG1 and IgG2 anti-pneumococcal antibodies in mice.
abstract: Streptococcus pneumoniae is an important cause of morbitity and mortality worldwide. Capsule-specific IgG1 and IgG2 Abs are induced upon vaccination with polysaccharide-based vaccines that mediate host protection. We compared the protective capacity of human recombinant serogroup 6-specific IgG1 and IgG2 Abs in mice deficient for either leukocyte FcR or complement factors. Human IgG1 was found to interact with mouse leukocyte FcR in vitro, whereas human IgG2 did not. Both subclasses induced complement activation, resulting in C3c deposition on pneumococcal surfaces. Passive immunization of C57BL/6 mice with either subclass before intranasal challenge with serotype 6A induced similar degrees of protection. FcgammaRI- and III-deficient mice, as well as the combined FcgammaRI, II, and III knockout mice, were protected by passive immunization, indicating FcR not to be essential for protection. C1q or C2/factor B knockout mice, however, were not protected by passive immunization. Passively immunized C2/factor B(-/-) mice displayed higher bacteremic load than C1q(-/-) mice, supporting an important protective role of the alternative complement pathway. Spleens from wild-type and C1q(-/-) mice showed hyperemia and thrombotic vessel occlusion, as a result of septicemic shock. Notably, thrombus formation was absent in spleens of C2/factor B(-/-) mice, suggesting that the alternative complement pathway contributes to shock-induced intravascular coagulation. These studies demonstrate complement to play a central role in Ab-mediated protection against pneumococcal infection in vivo, as well as in bacteremia-associated thrombotic complications.
authors.affiliation: Immunotherapy Laboratory, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Eirikur
authors.initials: E
authors.lastname: Saeland
authors.forename: Gestur
authors.initials: G
authors.lastname: Vidarsson
authors.forename: Jeanette H W
authors.initials: JH
authors.lastname: Leusen
authors.forename: Evert
authors.initials: E
authors.lastname: Van Garderen
authors.forename: Moon H
authors.initials: MH
authors.lastname: Nahm
authors.forename: Henriette
authors.initials: H
authors.lastname: Vile-Weekhout
authors.forename: Vanessa
authors.initials: V
authors.lastname: Walraven
authors.forename: Annette M
authors.initials: AM
authors.lastname: Stemerding
authors.forename: J Sjef
authors.initials: JS
authors.lastname: Verbeek
authors.forename: Ger T
authors.initials: GT
authors.lastname: Rijkers
authors.forename: Wietse
authors.initials: W
authors.lastname: Kuis
authors.forename: Elisabeth A M
authors.initials: EA
authors.lastname: Sanders
authors.forename: Jan G J
authors.initials: JG
authors.lastname: Van De Winkel
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000008:administration & dosage* / Q000378:metabolism; D000918:Antibody Specificity; D003165:Complement System Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011018:Pneumonia, Pneumococcal / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D011135:Polysaccharides, Bacterial / Q000276:immunology; D017452:Receptors, IgG / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000276:immunology* / Q000472:pathogenicity
chemical_list: D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D011135:Polysaccharides, Bacterial; D017452:Receptors, IgG; C437065:pneumococcal polysaccharide type 6; D003165:Complement System Proteins