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Novel mechanisms of nephritogenic antibodies in vascular endothelial injury

致肾炎抗体在血管内皮损伤中的新机制

基本信息

批准号：
08457068
负责人：
NOSE Masato
金额：
$ 3.97万
依托单位：
Ehime University (1997)Tohoku University (1996)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

Lupus nephritis has been considered to be mainly generated by the type II and/or III allergic reactions mediated by autoantibodies. We previously developed nephritogenic antibody-producing hybridoma clones derived from a diseased mouse of an MRL/lpr strain, which can generate glomerulonephritis (GN) when injected into normal mice. One clone induced a wire-loop type of glomerular lesions, characterized by the deposition of osminophilic material in subendothelial and mesangial regions. These glomerular lesions seemed to be generated by active endocytosis of the antibodies by endothelial cells. Actually, aggressive endocytosis of the antibodies by cultured human umbilical vein endothelial cells (HUVEC) in vitro was observed after a short period of cultivation, which was mediated by transendothelial transport and lysosomal system of the HUVEC,but not via Fc receptors and oxidized LDL receptors. Similar phenomena were found when the serum IgG obtained from particular reno-vascular disease patients were reacted. This finding may be important to propose a novel category in reno-vascular diseases. Another clone induced a proliferative type of glomerular lesions, characterized by the accumulation of neutrophils and macrophages, following E-selectin expression on glomerular endothelial cells. This type of antibodies by themselves had a potency to induce the expression of E-selection on HUVEC in vitro, as also confirmed in a transcription level, via endocytotic process. The development of these lesions was not induced in the trainsgenic mice producing E-selectin in a soluble form. Thus, the initial event inducing E-selectin expression by the antibodies on endothelial cells may play a critical role for the development of GN.The mechanisms of such kinds of cell injury by antibody molecules are novel ones which cannot be explained in term of any known form of allergic reaction.

狼疮性肾炎被认为主要是由自身抗体介导的II型和/或III型过敏反应引起。我们之前开发了产生肾炎抗体的杂交瘤克隆，该杂交瘤克隆源自 MRL/lpr 品系的患病小鼠，当注射到正常小鼠体内时，可以产生肾小球肾炎 (GN)。一种克隆诱导了线环型肾小球病变，其特征是嗜嗜酸性物质在内皮下和系膜区域沉积。这些肾小球病变似乎是由内皮细胞主动内吞抗体而产生的。实际上，在体外培养的人脐静脉内皮细胞（HUVEC）经过短时间的培养后，就观察到抗体的侵袭性内吞作用，这是由HUVEC的跨内皮转运和溶酶体系统介导的，而不是通过Fc受体和氧化LDL受体介导的。当对从特定肾血管疾病患者获得的血清IgG进行反应时，也发现了类似的现象。这一发现对于提出肾血管疾病的新类别可能很重要。另一个克隆诱导增殖型肾小球病变，其特征是肾小球内皮细胞上 E-选择素表达后中性粒细胞和巨噬细胞的积累。这种类型的抗体本身具有在体外诱导 HUVEC 上 E-选择表达的效力，这也通过内吞过程在转录水平上得到证实。在产生可溶性E-选择素的转基因小鼠中，没有诱导这些损伤的发生。因此，内皮细胞上的抗体诱导 E-选择素表达的初始事件可能对 GN 的发展起关键作用。抗体分子造成的此类细胞损伤的机制是新颖的，无法用任何已知形式的过敏反应来解释。