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Abstract
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 × 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 KD 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.
| Abbreviations | ||
| EDS | = | electron dense structures |
| SLE | = | systemic lupus erythematosus |
| SPR | = | surface plasmon resonance |
| RU | = | response units |
| IEM | = | immune electron microscopy |
| Abbreviations | ||
| EDS | = | electron dense structures |
| SLE | = | systemic lupus erythematosus |
| SPR | = | surface plasmon resonance |
| RU | = | response units |
| IEM | = | immune electron microscopy |
Acknowledgements
Dr Tony N. Marion kindly provided us with the anti-dsDNA monoclonal antibodies 163p64 and 163p77 used in this study. Randi Olsen (Department for Electron Microscopy, Institute of Medical Biology, University of Tromsø) is acknowledged for her highly competent technical help. This study was supported by grants from the Northern Norway Regional Health Authority Medical Research Program (OPR) and from the University of Tromsø as a Milieu Support given to OPR.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.