Mjelle Janne Erikke, Kalaaji Manar, Rekvig Ole Petter
Department of Biochemistry, Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
Autoimmunity. 2009 Feb;42(2):104-11. doi: 10.1080/08916930802375729.
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.
最近的研究表明，抗双链DNA和核小体抗体的致肾炎性取决于其与肾小球膜相关核小体的结合，而非与交叉反应性肾小球抗原的结合。除了对双链DNA/核小体的特异性外，目前尚无已知参数可决定抗体的致病性，系统性红斑狼疮（SLE）患者无论是否患有狼疮性肾炎，都可能有高滴度的抗双链DNA抗体。一个可能的参数是抗体亲和力，因为理论上只有高亲和力抗体才能在体内稳定结合。在患有严重狼疮性肾炎的（NZB×NZW）F1小鼠中对此进行了分析。这些小鼠有抗双链DNA血清抗体，免疫电镜（IEM）检测显示IgG自身抗体原位结合在肾小球膜相关电子致密结构中。通过表面等离子体共振测定纯化的循环和肾小球IgG抗双链DNA抗体的内在亲和力。结果表明，肾小球结合的抗双链DNA抗体的亲和力高于循环中的抗体。然而，来自不同小鼠的肾小球原位结合抗体的亲和力差异很大，解离常数（K(D)）在10^(-8)至10^(-13)范围内。这些结果表明，抗体亲和力不是决定性的致病因素，而染色质片段的可及性可能是决定抗双链DNA抗体是否在肾小球中结合的因素。
