PubMed · 8619739
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R H Seder, V P Berardi. 1996. Proficiency testing program for Lyme disease.. https://pubmed.ncbi.nlm.nih.gov/8619739/
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MN12H2 is a bactericidal antibody directed against outer membrane protein PorA epitope P1.16 of Neisseria meningitidis. Binding of MN12H2 to PorA at the meningococcal surface activates the classical complement pathway resulting in bacterial lysis. We have determined the crystal structure of the unliganded MN12H2 Fab fragment in two different crystal forms and compared it with the structure of the Fab in complex with a P1.16-derived peptide. The unliganded Fabs have elbow bend angles of 155 degrees and 159 degrees, whereas the liganded Fab has a more closed elbow bend of 143 degrees. Substantial differences in quaternary and tertiary structure of the antigen binding site are observed between the unliganded and liganded MN12H2 Fab structures that can be attributed to peptide binding. The variable light and heavy chain interface of the liganded Fab is twisted by a 5 degrees rotation along an axis approximately perpendicular to the plane of the interface. Hypervariable loops H1, H2, and framework loop FR-H3 follow this rotation. The hypervariable loop H3 undergoes conformational changes but remains closely linked to hypervariable loop L1. In contrast with the binding site expansion seen in other Fab-peptide structures, the MN12H2 binding site is narrowed upon peptide binding due to the formation of a "false floor" mediated by arginine residue 101 of the light chain. These results indicate that PorA epitope P1.16 of N. meningitidis is recognized by the complement-activating antibody MN12H2 through induced fit, allowing the formation of a highly complementary immune complex.
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Immunoglobulin G (IgG)-mediated phagocytosis by polymorphonuclear leukocytes (PMNL) constitutes the main defense against Streptococcus pneumoniae. Two leukocyte IgG receptors, FcgammaRIIa and FcgammaRIIIb, are constitutively expressed on PMNL. Blocking experiments showed FcgammaRIIa is crucial for opsonophagocytosis of serum-opsonized S. pneumoniae. The biallelic, genetically determined FcgammaRIIa polymorphism (FcgammaRIIa-R131 vs. IIa-H131) determines the capacity of IgG2-mediated phagocytosis via this receptor. Comparative studies with PMNL from donors either homozygous for FcgammaRIIa-R131 or IIa-H131 showed the latter had higher phagocytic capacity. These results were confirmed in FcgammaRIIa-R131- and FcgammaRIIa-H131-transfected IIA1.6 cells. The performance of FcgammaRIIa-transfected cells in S. pneumoniae phagocytosis was validated using sera from adults and children. Serum-induced phagocytic activity depended mainly on anti-pneumococcal IgG2 antibodies. Results obtained with PMNL and IIA1.6 cells showed high correlation (r=0.94; P<.001), and support that FcgammaRIIa transfectants are a good alternative to PMNL as effector cells in opsonophagocytosis assays.