Rekvig O P, Moens U, Fredriksen K, Traavik T
Department of Immunology and Transfusion Medicine, University Hospital of Tromsø, Norway.
Methods. 1997 Jan;11(1):44-54. doi: 10.1006/meth.1996.0386.
Although the origin of autoimmune antibodies to double-stranded DNA (dsDNA) is not known, the variable-region structures of such antibodies indicate that they are produced in response to antigen-selective stimulation. In accordance with this, results from experiments using artificial complexes of DNA and DNA-binding polypeptides for immunizations have indicated that DNA may induce these antibodies. The immunogenicity of DNA in vivo may therefore depend upon structures, or processes, that render DNA immunogenic. It is therefore crucial to determine the nature of the antigen(s) recognized by anti-DNA antibody-inducing Th cells. We describe here the results of a series of experiments using polyomavirus BK (BKV) inoculation as a model system for initiation of antibodies to DNA, including dsDNA, in animals. From the early observation that BKV had the potential to induce the linked production of antibodies to DNA and histones, we have investigated and described the molecular bases for how this virus may do so. The minimum requirement for DNA to act as an immunogen is the in vivo expression of the BKV early gene encoding the DNA-binding large T-antigen. In the context of in vivo expression of this gene, IgG antibodies to dsDNA, histones, and T-antigen were produced. Monoclonal anti-dsDNA antibodies derived from BKV immunized mice demonstrated variable-region structures highly similar to those of spontaneous anti-DNA antibodies in murine lupus. These results represent a conceptual advance in understanding a potential molecular basis for initiation of autoimmunity in systemic lupus erythematosus and establish a precedent for further studies on polyomavirus expression as one biological origin for anti-dsDNA antibodies in human lupus.
尽管针对双链DNA（dsDNA）的自身免疫抗体的起源尚不清楚，但此类抗体的可变区结构表明它们是在抗原选择性刺激下产生的。与此一致的是，使用DNA与DNA结合多肽的人工复合物进行免疫的实验结果表明，DNA可能诱导这些抗体。因此，DNA在体内的免疫原性可能取决于使其具有免疫原性的结构或过程。因此，确定诱导抗DNA抗体的Th细胞所识别的抗原的性质至关重要。我们在此描述了一系列实验的结果，这些实验使用多瘤病毒BK（BKV）接种作为动物体内引发包括dsDNA在内的DNA抗体的模型系统。从早期观察到BKV有可能诱导DNA和组蛋白抗体的连锁产生开始，我们就研究并描述了这种病毒可能如何做到这一点的分子基础。DNA作为免疫原的最低要求是体内表达编码DNA结合大T抗原的BKV早期基因。在该基因的体内表达背景下，产生了针对dsDNA、组蛋白和T抗原的IgG抗体。源自BKV免疫小鼠的单克隆抗dsDNA抗体表现出与小鼠狼疮中自发抗DNA抗体高度相似的可变区结构。这些结果代表了在理解系统性红斑狼疮自身免疫起始潜在分子基础方面的概念性进展，并为进一步研究多瘤病毒表达作为人类狼疮中抗dsDNA抗体的一种生物学起源奠定了先例。
