Fulpius T, Berney T, Lemoine R, Pastore Y, Reininger L, Brighouse G, Izui S
Department of Pathology, University of Geneva, Switzerland.
Kidney Int. 1994 Apr;45(4):962-71. doi: 10.1038/ki.1994.130.
We have previously shown that murine IgG3 monoclonal autoantibodies with cryoglobulin activity, derived from lupus-prone mice, are able to induce glomerular lesions resembling the "wire-loop" lesion typically described for human lupus nephritis. In the present study, we have further assessed the nephritogenic potential of four IgG3 anti-hapten, trinitrophenyl (TNP), monoclonal antibodies (mAb) obtained from non-autoimmune mice immunized with TNP-conjugated foreign antigens. Our results showed that two of four IgG3 anti-TNP monoclonal cryoglobulins were capable of inducing glomerular lesions, characterized by voluminous intracapillary thrombi and mesangial deposition of PAS-positive materials, which differed from "wire-loop" lesions generated by IgG3 monoclonal cryoglobulins with autoantibody activities. These anti-TNP monoclonal cryoglobulins, however, failed to induce glomerular lesions when mice were kept at 37 degrees C after the mAb administration. This finding formally proves that the cryoglobulin activity is critically involved in the development of glomerular lesions induced by IgG3 anti-TNP mAb. In addition, we have demonstrated a remarkable difference in the nephritogenic activities of two IgG3 anti-TNP mAb, which exhibit a marked sequence homology in the variable regions of their heavy and light chains (91.5% and 99.1% at the amino acid level, respectively) and an identical isoelectric point. Our results indicate first, that IgG3 monoclonal cryoglobulins are able to generate two different kinds of glomerular lesions, and second, that a subtle difference in variable region sequences may determine not only the nephritogenic activities, but also the type of glomerular lesions mediated by IgG3 cryoglobulins.
我们先前已经表明，源自狼疮易感小鼠的具有冷球蛋白活性的鼠源IgG3单克隆自身抗体，能够诱导出类似于典型人类狼疮性肾炎中所描述的“铁丝圈”病变的肾小球病变。在本研究中，我们进一步评估了四种从用三硝基苯基（TNP）偶联的外来抗原免疫的非自身免疫小鼠中获得的IgG3抗半抗原、三硝基苯基（TNP）单克隆抗体（mAb）的致肾炎潜力。我们的结果表明，四种IgG3抗TNP单克隆冷球蛋白中有两种能够诱导肾小球病变，其特征为大量的毛细血管内血栓形成以及PAS阳性物质的系膜沉积，这与具有自身抗体活性的IgG3单克隆冷球蛋白所产生的“铁丝圈”病变不同。然而，在给予mAb后将小鼠饲养在37摄氏度时，这些抗TNP单克隆冷球蛋白未能诱导出肾小球病变。这一发现正式证明冷球蛋白活性在由IgG3抗TNP mAb诱导的肾小球病变发展中起关键作用。此外，我们已经证明了两种IgG3抗TNP mAb在致肾炎活性方面存在显著差异，它们在重链和轻链可变区表现出明显的序列同源性（氨基酸水平分别为91.5%和99.1%）且等电点相同。我们的结果首先表明，IgG3单克隆冷球蛋白能够产生两种不同类型的肾小球病变，其次表明可变区序列的细微差异不仅可能决定致肾炎活性，还可能决定由IgG3冷球蛋白介导的肾小球病变类型。
