Tissue response to amyloidogenic light chains

在AL淀粉样变性中，克隆免疫球蛋白轻链在全身组织中形成淀粉样纤维沉积。淀粉样蛋白纤维沉积很少发生在多发性骨髓瘤（另一种克隆性轻链疾病）中，并非全部发生在意义不明的单克隆伽玛病中。负责将一些单克隆轻链转化为淀粉样原纤维的因素尚不清楚。这个项目的假设是，轻链修饰和组织反应导致纤维的形成和沉积。1)利用Project 1推导出的氨基酸序列，本项目将检测淀粉样蛋白轻链蛋白的序列变异和翻译后修饰。来自同一患者组织沉积物的淀粉样蛋白原纤维将被检查大小和可能继发于蛋白质修饰的蛋白水解位点。2)蛋白聚糖作为原纤维在淀粉样轻链沉积的生理机制中发挥关键作用。随着AA（继发性）淀粉样变性的淀粉样纤维沉积，糖胺聚糖（GAGs），特别是硫酸肝素的量增加。初步数据表明，AL淀粉样变也是如此。GAG富集是先于原纤维沉积，还是与原纤维沉积同时发生，还是在原纤维沉积之后发生尚不清楚。糖胺聚糖对组织微环境中轻链的影响将在体内小鼠模型中进行测试。3)组织内淀粉样蛋白沉积导致器官功能障碍。传统的解释是淀粉样蛋白原纤维大量浸润所产生的纯粹机械效应。然而，临床信息和初步数据表明，轻链蛋白对组织的有害作用已被实验发现β -淀粉样蛋白和转甲状腺素淀粉样蛋白。循环单克隆轻链对器官功能的影响将在心脏生理学实验模型中进行测试。将在项目2中观察到的轻链序列修饰与生物物理性质之间建立相关性。两者都将与临床信息数据库相关联。

In AL amyloidosis, clonal immunoglobulin light chains form amyloid fibril deposits in tissues throughout the body. Amyloid fibril deposits occur infrequently in multiple myeloma, another clonal light chain disease, and not all in monoclonal gammopathy of unknown significance. Factors responsible for converting some monoclonal light chains to amyloid fibrils are unknown. The hypothesis of this project is that light chain modifications and a tissue response lead to fibril formation and deposition. 1) Using the deduced amino acid sequence obtained in Project 1, this project will examine amyloidogenic light chain proteins for sequence variations and post-translational modifications. Amyloid fibrils from tissue deposits of the same patients will be examined for size and proteolytic sites that may be secondary to protein modifications. 2) Proteoglycans are expected to play a key role in the physiologic mechanisms leading to amyloidogenic light chain deposition as fibrils. An increased amount of glycosaminoglycans (GAGs), particularly heparan sulfate, occurs with amyloid fibril deposition of AA (secondary) amyloidosis. Preliminary data suggests this is also true for the AL amyloidosis. Whether GAG enrichment precedes fibril deposition, is coincident with, or follows fibril deposition is not known. The influence of glycosaminoglycans on light chains in a tissue microenvironment will be tested in an in-vivo mouse model. 3) Amyloid deposition in tissues leads to organ dysfunction. The traditional explanation for this is a purely mechanical effect produced by massive infiltration of amyloid fibrils. However, clinical information and preliminary data suggest a deleterious effect of the light chain protein on tissue has been found experimentally for the beta-amyloid and transthyretin amyloidogenic proteins. The effect of circulating monoclonal light chains on organ function will be tested in an experimental model testing cardiac physiology. Correlation will be made between light chain sequence modifications and the biophysical properties observed in Project 2. Both will be correlated with the database of clinical information.