Comparison of pathogenic and non-pathogenic murine antibodies to DNA: antigen binding and structural characteristics.
Three pathogenic and two non-pathogenic NZB/NZW F1 mAbs to DNA were compared. Pathogenicity was defined as the ability to induce nephritis in BALB/c mice. All mAbs were IgG2a or 2b, had high avidity for double-stranded DNA and fixed complement well. All three pathogens expressed idiotype IdGN2. Mice receiving pathogenic mAbs (compared with non-pathogenic) had more glomerular IgG deposits. The unique properties of two of the pathogens were: strong homogeneous staining of Hep-2 nuclei and the ability to bind (i) nucleosomes, (ii) histone (after mAb complexed with DNA), (iii) heparan sulfate in renal basement membranes (after complexing with DNA/histone) and (iv) nuclei in vivo. Comparison of nucleotide and amino acid sequences of the V regions of heavy and light Ig chains showed use of multiple VHDJH and V kappa J kappa gene families, with representation of several anti-DNA 'families' described by others. Arginine (R) occurred in the CDR2 or CDR3 of VH chains in all pathogens; R was absent in the CDRs of VH chains of non-pathogens. Positively and negatively charged AA were more frequent in VH CDR of pathogens than of non-pathogens. We hypothesize that the tertiary structure of mAbs determined by VH CDR regions permits stronger binding to negatively charged antigens (DNA and heparan sulfate) and to positively charged molecules (histone) in pathogens compared with non-pathogens.
Ohnishi
K
K
Department of Medicine, University of California Los Angeles 90024.
Ebling
F M
FM
Mitchell
B
B
Singh
R R
RR
Hahn
B H
BH
Tsao
B P
BP
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D000911:Antibodies, Monoclonal; D000915:Antibody Affinity; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001483:Base Sequence; D003176:Complement C3 / Q000276:immunology; D004247:DNA / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006657:Histones / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009393:Nephritis / Q000276:immunology*
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D003176:Complement C3; D006657:Histones; D004247:DNA