title: Increased severity of respiratory infections associated with elevated anti-LPS IgG2 which inhibits serum bactericidal killing.
abstract: Although specific antibody induced by pathogens or vaccines is a key component of protection against infectious threats, some viruses, such as dengue, induce antibody that enhances the development of infection. In contrast, antibody-dependent enhancement of bacterial infection is largely unrecognized. Here, we demonstrate that in a significant portion of patients with bronchiectasis and Pseudomonas aeruginosa lung infection, antibody can protect the bacterium from complement-mediated killing. Strains that resist antibody-induced, complement-mediated killing produce lipopolysaccharide containing O-antigen. The inhibition of antibody-mediated killing is caused by excess production of O-antigen-specific IgG2 antibodies. Depletion of IgG2 to O-antigen restores the ability of sera to kill strains with long-chain O-antigen. Patients with impaired serum-mediated killing of P. aeruginosa by IgG2 have poorer respiratory function than infected patients who do not produce inhibitory antibody. We suggest that excessive binding of IgG2 to O-antigen shields the bacterium from other antibodies that can induce complement-mediated killing of bacteria. As there is significant sharing of O-antigen structure between different Gram-negative bacteria, this IgG2-mediated impairment of killing may operate in other Gram-negative infections. These findings have marked implications for our understanding of protection generated by natural infection and for the design of vaccines, which should avoid inducing such blocking antibodies.
authors.affiliation: Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Wells
authors.affiliation: Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK Lung Investigation Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, England, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Whitters
authors.affiliation: Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: Yanina R
authors.initials: YR
authors.lastname: Sevastsyanovich
authors.affiliation: Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Heath
authors.affiliation: Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: John
authors.initials: J
authors.lastname: Pravin
authors.affiliation: Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Goodall
authors.affiliation: Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Browning
authors.affiliation: The University of Oxford, The Jenner Institute, Oxford OX3 7DQ, England, UK.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: O'Shea
authors.affiliation: Sir William Leech Centre for Respiratory Research Newcastle upon Tyne Hospitals Trust, Newcastle NE7 7DN, England, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Cranston
authors.affiliation: Institute of Cellular Medicine, Newcastle University and Adult Bronchiectasis service Freeman Hospital, Newcastle NE7 7DN, England, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: De Soyza
authors.affiliation: Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
authors.affiliation: Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: Calman A
authors.initials: CA
authors.lastname: MacLennan
authors.affiliation: Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK Institute of Microbiology and Infection, School of Immunity and Infection, School Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, England, UK I.R.Henderson@bham.ac.uk.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Henderson
authors.affiliation: Lung Investigation Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, England, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stockley
mesh_terms: D019138:Antibodies, Blocking / Q000097:blood; D019067:Antibody-Dependent Enhancement / Q000276:immunology*; D001770:Blood Bactericidal Activity / Q000276:immunology*; D001987:Bronchiectasis / Q000097:blood / Q000276:immunology / Q000503:physiopathology; D003165:Complement System Proteins / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology*; D019081:O Antigens / Q000276:immunology*; D011552:Pseudomonas Infections / Q000097:blood* / Q000276:immunology / Q000503:physiopathology; D011550:Pseudomonas aeruginosa / Q000276:immunology; D012141:Respiratory Tract Infections / Q000097:blood* / Q000276:immunology* / Q000503:physiopathology
chemical_list: D019138:Antibodies, Blocking; D007074:Immunoglobulin G; D019081:O Antigens; C095976:O antigen, Pseudomonas; D003165:Complement System Proteins
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