Novel mechanisms of nephritogenic antibodies in vascular endothelial injury

狼疮性肾炎被认为主要是由自身抗体介导的II型和/或III型过敏反应引起的。我们以前开发了产生肾炎抗体的杂交瘤克隆，这些杂交瘤来自一种MRL/LPR株的疾病小鼠，当注射到正常小鼠体内时，可以产生肾小球肾炎(GN)。一个克隆诱导了一种线环型的肾小球病变，其特征是内皮下和系膜区域中嗜奥斯胺物质的沉积。这些肾小球病变似乎是由于内皮细胞对抗体的主动内吞而产生的。事实上，体外培养的人脐静脉内皮细胞(HUVEC)在短期培养后即可观察到抗体的侵袭性内吞作用，这种作用是由HUVEC的内皮转运和溶酶体系统介导的，而不是通过Fc受体和氧化型低密度脂蛋白受体。对特定肾血管疾病患者的血清免疫球蛋白进行反应时，也发现类似的现象。这一发现可能对提出肾血管疾病的一个新类别很重要。另一个克隆诱导了以中性粒细胞和巨噬细胞聚集为特征的增生型肾小球病变，随后E-选择素在肾小球内皮细胞上表达。这种类型的抗体本身具有诱导体外培养的人脐静脉内皮细胞表达E-选择素的能力，这一点也在转录水平上得到证实，通过内吞过程。在以可溶性形式产生E-选择素的训练性小鼠中，这些损伤的发展没有被诱导。因此，抗体诱导内皮细胞表达E-选择素的初始事件可能在肾炎的发生发展中起关键作用。抗体分子对细胞的损伤机制是新的，不能用任何已知的变态反应来解释。

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.