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    Novel Complement Blocking Antibodies Against Serogroup B <em>N. meningitidis</em>: A Dissertation

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    Authors
    Dutta Ray, Tathagat
    Faculty Advisor
    Peter A. Rice, M.D.; Sanjay Ram, M.D.
    Academic Program
    Immunology and Microbiology
    UMass Chan Affiliations
    Medicine
    Document Type
    Doctoral Dissertation
    Publication Date
    2010-07-23
    Keywords
    Neisseria meningitidis
    Serogroup B
    Meningococcal Vaccines
    Amino Acids, Peptides, and Proteins
    Bacteria
    Bacterial Infections and Mycoses
    Environmental Public Health
    Immunology and Infectious Disease
    Investigative Techniques
    Nervous System Diseases
    Pathological Conditions, Signs and Symptoms
    Therapeutics
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    Abstract
    N. meningitidis is a common commensal of the human upper respiratory tract and a leading cause of bacterial meningitis and septicemia worldwide. The classical pathway of complement (C) is essential for both naturally acquired and vaccine induced immunity against N. meningitidis. Qualitative and/or quantitative differences in anti-meningococcal antibodies (Abs) in serum is one reason for variations in C-dependent bactericidal Ab activity among individuals. I showed that IgG isolated from select individuals could block killing of group B meningococci by Abs that were otherwise bactericidal. Ligand overlay immunoblots revealed that these blocking IgG Abs were directed against a meningococcal antigen called H.8, Killing of meningococci in reactions containing bactericidal mAbs and human blocking Abs was restored when blocking Ab binding to meningococci was inhibited (or competed for) using either synthetic peptides corresponding to H.8 or a non-blocking mAb against H.8. Further, 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 alone generated by pepsin treatment were ineffective. Blocking required IgG glycosylation; deglycosylation of blocking IgG with peptide:N-glycanase (PNGase) eliminated blocking. C4 deposition mediated by a bactericidal mAb directed against a meningococcal vaccine candidate, called factor H-binding protein (fHbp), was reduced by blocking Ab. Anti-fHbp-mediated C4 deposition was unaffected, however, by deglycosylated blocking IgG. Although preliminary, our data suggests blocking of serum bactericidal activity by human anti-H.8 blocking antibody may require mannan-binding lectin (MBL), which itself is a complement activator. Also, whether MBL recruits a complement inhibitor(s) that facilitates blocking remains to be determined. In conclusion, we have identified H.8 as a meningococcal target for novel blocking antibodies that are commonly found in human serum. Blocking Ab may reduce the efficacy of meningococcal vaccines. We propose that outer membrane vesicle-containing meningococcal vaccines may be more efficacious if purged of subversive immunogens such as H.8.
    DOI
    10.13028/kwp1-3r83
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31829
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/kwp1-3r83
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