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Molecular biology of anti-DNA autoantibodies with nephritogenic potential in human lupus nephritis

人类狼疮性肾炎中具有肾炎潜能的抗 DNA 自身抗体的分子生物学

基本信息

批准号：
04454238
负责人：
SAKANE Tsuyoshi
金额：
$ 4.42万
依托单位：
St. Marianna University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

Extensive studies in murine models of lupus nephritis have shown that cationic anti-DNA autoantibodies have nephritogenic potential. We have first investigated whether cationic anti-DNA antibodies of lgG class are also produced in vivo in patients with active lupus nephritis. The highly cationic anti-DNA of lgG class were prominent in the sera of patients with active lupus nephritis. Decreased proteinuria after successful treatment with prednisolone was associated with disappearance of the cationic anti-DNA in their circulation. The cationic anti-DNA did bind to heparan sulfate, which is a major glycosaminoglycan in glomerular basement membrane, much better than did neutral anti-DNA.The results indicate that the cationic anti-DNA autoantibodies may play a certain role in the development of lupus nephritis.We next turned our attention to the investigation of underlying mechanisms responsible for the production of pathogenic autoantibodies. We have isolated lg VL genes(SC17) encoding cat … More ionic anti-DNA of human SLE with severe nephritis, which were present at the disease onset but disappeared after disease remission with corticosteroids. We have also cloned a counterpart lg VL germline gene(SG3) from neutrophils of the patient and found the presence of replacement mutations only in the complementarity-determining regions. Surprisingly, predicted isoelectric point of deduced protein encoded by SG3 was the most cationic one among those encoded by previously reported human Vkappa germline genes in the DNA database. Additionally, the SG3 gene existed in almost all of the SLE patients, wherease approximately a half of normal individuals lacked the SG3 gene, when their genomic DNA of the neutrophils were studied by PCR-single strand conformation polymorphism-Southern blotting based techniques. These results raise the possibility that the usage of specific germline gene may confer cationic charge on the anti-DNA, while somatic mutations induce affinity maturation of anti-DNA in human lupus nephritis and that the presence of such germline gene in the genome is associated with the development of the disease. Less

在狼疮性肾炎小鼠模型中的广泛研究表明，阳离子抗DNA自身抗体具有致肾炎的潜力。我们首先研究了IgG类的阳离子抗DNA抗体是否也在活动性狼疮肾炎患者体内产生。活动性狼疮肾炎患者血清中IgG类高阳离子抗DNA抗体显著。泼尼松龙成功治疗后蛋白尿减少与循环中阳离子抗DNA的消失有关。阳离子抗DNA抗体与肾小球基底膜上主要糖胺聚糖硫酸乙酰肝素的结合能力明显强于中性抗DNA抗体，提示阳离子抗DNA抗体在狼疮性肾炎的发生发展中可能起一定作用。我们已经分离了编码猫的Ig VL基因（SC 17）， ...更多信息 SLE伴重症肾炎患者血清中存在离子型抗DNA抗体，在发病时存在，经糖皮质激素治疗缓解后消失。我们还从患者的中性粒细胞中克隆了对应的Ig VL种系基因（SG 3），并发现仅在互补决定区存在置换突变。令人惊讶的是，预测的等电点由SG 3编码的推导蛋白质是最阳离子的一个之前报道的人类Vkappa种系基因的DNA数据库中编码的。此外，应用PCR-单链构象多态性-Southern印迹技术对SLE患者的中性粒细胞基因组DNA进行研究，发现几乎所有SLE患者都存在SG 3基因，而正常人中约有一半缺乏SG 3基因。这些结果提出了这样的可能性，即特定生殖系基因的使用可能赋予抗DNA阳离子电荷，而体细胞突变诱导抗DNA在人类狼疮肾炎中的亲和力成熟，并且基因组中存在这样的生殖系基因与疾病的发展相关。少