Zhu L, Herrera G A, Murphy-Ullrich J E, Huang Z Q, Sanders P W
Department of Pathology, University of Alabama at Birmingham 35233-7331, USA.
Am J Pathol. 1995 Aug;147(2):375-85.
The glomerulopathy of monoclonal immunoglobulin light chain deposition disease is a progressive disorder characterized by accumulation of monoclonal light chains and matrix proteins in the mesangium. To define the role of light chains in this process, cultured rat mesangial cells were exposed to different light chains and human albumin. Two light chains were purified from the urine of patients who had biopsy-proven light chain deposition disease. These proteins inhibited mesangial cell proliferation and increased production of matrix proteins, including type IV collagen, laminin, and fibronectin. By immunocytochemistry and bioassay, transforming growth factor-beta (TGF-beta) production and activity increased when mesangial cells were exposed to these proteins. Furthermore, anti-TGF-beta antibody abolished the inhibition of cell proliferation and the increase of extracellular matrix protein production caused by these light chains. These findings were not observed in mesangial cells exposed to human albumin and two other light chains previously characterized to be tubulopathic. We concluded that the glomerulopathic light chains increased TGF-beta, which inhibited mesangial cell proliferation and increased matrix protein production. Together with overexpression of TGF-beta in affected glomeruli of light chain deposition disease, light chain-mediated stimulation of mesangial cells to produce TGF-beta appears to be a key pathological mechanism of this disease.
单克隆免疫球蛋白轻链沉积病的肾小球病是一种进行性疾病，其特征是单克隆轻链和基质蛋白在系膜中积聚。为了确定轻链在此过程中的作用，将培养的大鼠系膜细胞暴露于不同的轻链和人白蛋白中。从经活检证实为轻链沉积病的患者尿液中纯化出两种轻链。这些蛋白质抑制系膜细胞增殖，并增加包括IV型胶原、层粘连蛋白和纤连蛋白在内的基质蛋白的产生。通过免疫细胞化学和生物测定，当系膜细胞暴露于这些蛋白质时，转化生长因子-β（TGF-β）的产生和活性增加。此外，抗TGF-β抗体消除了这些轻链对细胞增殖的抑制作用以及细胞外基质蛋白产生的增加。在暴露于人白蛋白和另外两种先前被鉴定为肾小管病变的轻链的系膜细胞中未观察到这些发现。我们得出结论，肾小球病变轻链增加了TGF-β，后者抑制系膜细胞增殖并增加基质蛋白产生。连同TGF-β在轻链沉积病受累肾小球中的过度表达，轻链介导的系膜细胞产生TGF-β的刺激似乎是该疾病的关键病理机制。
