Molecular analysis of anti- N-propionyl Neisseria meningitidis group B polysaccharide monoclonal antibodies

• Published in: Molecular Immunology 2006-03, Vol.43 (9), p.1424-1431
• Main Authors: Moe, Gregory R., Dave, Apurva, Granoff, Dan M.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies, Bacterial - chemistry; Antibodies, Bacterial - genetics; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - genetics; Antigens, Bacterial - chemistry; Autoantibodies; Autoantibodies - chemistry; Autoantibodies - genetics; Autoantigens; Cloning, Molecular; Crystallography, X-Ray; Humans; Immunoglobulin Variable Region - genetics; Meningococcal vaccine; Meningococcal Vaccines - immunology; Mice; Models, Molecular; Molecular Sequence Data; Neisseria meningitidis; Neisseria meningitidis, Serogroup B - immunology; Polysaccharides, Bacterial - chemistry; Polysaccharides, Bacterial - immunology; Protein Conformation; Sequence Homology, Amino Acid; Sialic Acids - chemistry; Sialic Acids - immunology; Structural models; V region genes
• ISSN: 0161-5890; 1872-9142; 1365-2567
• DOI: 10.1016/j.molimm.2005.07.033

The capsular polysaccharide of Neisseria meningitidis group B (MBPS) is a polymer of alpha (2 → 8) N-acetyl neuraminic acid, which is chemically identical to polysialic acid (PSA) expressed in human tissues. Antibodies from mice immunized with a MBPS-protein conjugate vaccine in which N-acetyl groups have been replaced by propionyl groups (N-Pr MBPS) can be bactericidal and show minimal or no cross-reactivity with human PSA. To investigate the molecular basis for antigen recognition, we cloned and sequenced the variable region (V) genes of five bactericidal anti-N-Pr MBPS murine mAbs and produced computer models of the combining sites. The results were compared to those reported in the literature for two autoreactive anti-MBPS. The V region genes of the anti-N-Pr MBPS mAbs and the anti-MBPS autoreactive mAbs are derived from a limited set of germline V, J, and D genes. However, the anti-N-Pr MBPS mAbs are more mutated than the anti-MBPS mAbs and the former use V–D–J editing that introduces arginine in H-CDR3. Models of the respective combining sites indicate that the anti-MBPS or anti-N-Pr MBPS mAbs that react with host PSA have relatively wide and shallow grooves with a high overall positive charge, consistent with recognition of extended helical polysaccharide structures recognized by the autoreactive mAbs. In contrast, anti-N-Pr MBPS mAbs that do not react with host PSA contain pockets and deep clefts that are consistent with recognition of discrete structural features of individual residues.