Structural properties and mutation patterns of anti-nucleosome monoclonal antibodies are similar to those of anti-DNA antibodies.
Four monoclonal antibodies (mAb) derived from an (NZB x NZW)F1 mouse bound to nucleosomes, total histones and to the H2A-H2B dimers but not to individual histones or DNA. Sequencing of their heavy (H)- and light (L)-chain variable region genes showed that they derived by somatic mutations from the same B cell precursor. The distribution of negatively and positively charged amino acids in the H-chain complementarity-determining regions was very similar to that observed not only in anti-H2A-H2B mAb derived from different lupus-prone mouse strains but also in anti-DNA mAb. Combined analysis of the mAb structures and their interactions with immobilized H2A-H2B dimer or total histones by plasmon resonance allowed us to assign the H-chain mutations a major role in the binding profiles of these anti-nucleosome mAb. Interestingly, four of the five H-chain mutations that distinguished mAb 3F6 from 2E1 generated negatively or positively charged amino acid residues, and two of them occurred at positions 56 and 76, which are frequently involved in the maturation process of anti-DNA antibodies. A modeling study of the 3F6 variable fragment (Fv) predicted that acidic residues occupy the cleft of the Ab combining site and have the potential to participate in electrostatic interactions. Thus, the demonstration that (NZB x NZW)F1-derived anti-H2A-H2B antibodies share certain structural features and mutation patterns with anti-DNA mAb suggest that common selection and maturation processes account for the production of these lupus-related autoantibodies.
Brard
F
F
Groupe de Recherche en Immunopathologie, Faculté Mixte de Médecine et de Pharmacie, Hôpital Charles Nicolle, Rouen, France.
Jovelin
F
F
Petit
S
S
Tron
F
F
Gilbert
D
D
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000737:chemistry* / Q000235:genetics*; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000918:Antibody Specificity; D001483:Base Sequence; D015374:Biosensing Techniques; D003198:Computer Simulation; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology*; D009707:Nucleosomes / Q000276:immunology*; D017422:Sequence Analysis, DNA; D013329:Structure-Activity Relationship
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D009707:Nucleosomes; D004247:DNA