Exposure of chromatin and not high affinity for dsDNA determines the nephritogenic impact of anti-dsDNA antibodies in (NZBxNZW)F1 mice.
Recent studies have demonstrated that the nephritogenicity of antibodies to dsDNA and nucleosomes confers to binding of glomerular membrane-associated nucleosomes, and not to cross-reacting glomerular antigens. There is no known parameter that determines antibody pathogenicity aside from specificity for dsDNA/nucleosomes, and systemic lupus erytheomatosus (SLE) patients may have high titer anti-dsDNA antibodies irrespective whether they have lupus nephritis or not. One parameter may be antibody affinity, as theoretically only high affinity antibodies may bind in vivo in a stable way. This was analyzed in (NZB x NZW)F1 mice with full-blown lupus nephritis. These mice had serum antibodies to dsDNA, and IgG autoantibodies bound in situ in glomerular membrane-associated electron dense structures as determined by immune electron microscopy (IEM). Intrinsic affinity of purified circulating and glomerular IgG anti-dsDNA antibodies was determined by surface plasmon resonance. The results demonstrate that affinity of glomerular-bound anti-dsDNA antibodies was higher than for those in circulation. However, affinity of glomerular in situ-bound antibodies from different mice varied considerably, from K(D) in the range from 10(- 8) to 10(- 13). These results indicate that antibody affinity is not a decisive pathogenic factor, but rather that availability of chromatin fragments may be the factor that determines whether an anti-dsDNA antibody binds in glomeruli or not.
Mjelle
Janne Erikke
JE
Department of Biochemistry, Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
Kalaaji
Manar
M
Rekvig
Ole Petter
OP
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D000915:Antibody Affinity / Q000276:immunology; D002843:Chromatin / Q000276:immunology*; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D007668:Kidney / Q000276:immunology* / Q000648:ultrastructure; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008814:Mice, Inbred NZB; D016253:Microscopy, Immunoelectron; D009707:Nucleosomes / Q000276:immunology / Q000648:ultrastructure; D020349:Surface Plasmon Resonance
D000974:Antibodies, Antinuclear; D002843:Chromatin; D009707:Nucleosomes; D004247:DNA