title: Novel blocking human IgG directed against the pentapeptide repeat motifs of Neisseria meningitidis Lip/H.8 and Laz lipoproteins.
abstract: Ab-initiated, complement-dependent killing contributes to host defenses against invasive meningococcal disease. Sera from nonimmunized individuals vary widely in their bactericidal activity against group B meningococci. We show that IgG isolated from select individuals can block killing of group B meningococci by human sera that are otherwise bactericidal. This IgG also reduced the bactericidal efficacy of Abs directed against the group B meningococcal protein vaccine candidates factor H-binding protein currently undergoing clinical trials and Neisserial surface protein A. Immunoblots revealed that the blocking IgG was directed against a meningococcal Ag called H.8. Killing of meningococci in reactions containing bactericidal mAbs and human blocking Abs was restored when binding of blocking Ab to meningococci was inhibited using either synthetic peptides corresponding to H.8 or a nonblocking mAb against H.8. Furthermore, genetic deletion of H.8 from target organisms abrogated blocking. The Fc region of the blocking IgG was required for blocking because F(ab')(2) fragments were ineffective. Blocking required IgG glycosylation because deglycosylation with peptide:N-glycanase eliminated blocking. C4b deposition mediated by an anti-factor H-binding protein mAb was reduced by intact blocking IgG, but not by peptide:N-glycanase-treated blocking IgG, suggesting that blocking resulted from inhibition of classical pathway of complement. In conclusion, we have identified H.8 as a meningococcal target for novel blocking Abs in human serum. Such blocking Abs may reduce the efficacy of select antigroup B meningococcal protein vaccines. We also propose that outer membrane vesicle-containing meningococcal vaccines may be more efficacious if purged of subversive immunogens such as H.8.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Tathagat Dutta
authors.initials: TD
authors.lastname: Ray
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lewis
authors.forename: Sunita
authors.initials: S
authors.lastname: Gulati
authors.forename: Peter A
authors.initials: PA
authors.lastname: Rice
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
mesh_terms: D000595:Amino Acid Sequence; D000907:Antibodies, Bacterial / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001770:Blood Bactericidal Activity / Q000276:immunology*; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D050296:Microbial Viability / Q000187:drug effects / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D009345:Neisseria meningitidis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009842:Oligopeptides / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D001425:Bacterial Outer Membrane Proteins; C055700:H.8 protein (Neisseria); D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D009842:Oligopeptides