Myatt E A, Westholm F A, Weiss D T, Solomon A, Schiffer M, Stevens F J
Center for Mechanistic Biology and Biotechnology, Argonne National Laboratory, IL 60439-4833.
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3034-8. doi: 10.1073/pnas.91.8.3034.
The deposition of certain Bence Jones proteins as tubular casts, basement membrane precipitates, or amyloid fibrils results in the human light-chain-associated renal and systemic diseases--myeloma (cast) nephropathy, light-chain deposition disease, and immunocyte-derived (primary or AL) amyloidosis. To determine if light-chain nephrotoxicity or amyloidogenicity is related to the propensity of these components to form high molecular weight aggregates under physiological conditions, we used a size-exclusion chromatographic system to study 40 different Bence Jones proteins. Each samples was tested over a wide range of protein concentration in three different buffers varying in pH, osmolality, and the presence or absence of low concentrations of urea. Thirty-three of the 35 proteins found clinically and/or experimentally to form in vivo pathologic light-chain deposits were shown to undergo high-order self-association and form high molecular weight aggregates. In contrast, of five nonpathologic proteins, one showed polymerization under the chromatographic conditions used. The correlation between the in vivo results achieved by size-exclusion chromatography and that found in vivo provides (i) a rapid diagnostic method to identify potential nephrotoxic or amyloidogenic Bence Jones proteins and (ii) an experimental means to gain new insight into the physicochemical basis of light-chain aggregation and the treatment of those invariably fatal disorders associated with pathologic light-chain deposition.
某些本-周蛋白以管型、基底膜沉淀物或淀粉样纤维的形式沉积，会导致人类轻链相关的肾脏和全身性疾病——骨髓瘤（管型）肾病、轻链沉积病以及免疫细胞源性（原发性或AL型）淀粉样变性。为了确定轻链肾毒性或淀粉样变性是否与这些成分在生理条件下形成高分子量聚集体的倾向有关，我们使用尺寸排阻色谱系统研究了40种不同的本-周蛋白。每个样品在三种不同的缓冲液中，于广泛的蛋白质浓度范围内进行测试，这些缓冲液在pH值、渗透压以及是否存在低浓度尿素方面有所不同。在临床和/或实验中发现会在体内形成病理性轻链沉积物的35种蛋白质中，有33种显示出发生高阶自缔合并形成高分子量聚集体。相比之下，在5种非病理性蛋白质中，有一种在所用的色谱条件下显示出聚合现象。尺寸排阻色谱法获得的体内结果与体内发现的结果之间的相关性提供了：（i）一种快速诊断方法，用于识别潜在的肾毒性或淀粉样变性本-周蛋白；（ii）一种实验手段，以深入了解轻链聚集的物理化学基础以及与病理性轻链沉积相关的那些致命疾病的治疗方法。
