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。淀粉样原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，而不是所有的单克隆丙种球蛋白病的意义不明。负责将一些单克隆轻链转化为淀粉样纤维的因素尚不清楚。该项目的假设是轻链修饰和组织反应导致原纤维形成和沉积。1)利用项目1中获得的推导氨基酸序列，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。将检查来自相同患者的组织沉积物的淀粉样原纤维的大小和蛋白水解位点，其可能继发于蛋白质修饰。2)蛋白聚糖在淀粉样蛋白轻链沉积成纤维的生理机制中起关键作用。AA（继发性）淀粉样变性的淀粉样原纤维沉积会导致糖胺聚糖（GAG），特别是硫酸乙酰肝素的量增加。初步数据表明，AL淀粉样变性也是如此。GAG富集是否先于原纤维沉积，与原纤维沉积同时发生，还是在原纤维沉积之后尚不清楚。将在体内小鼠模型中检测糖胺聚糖对组织微环境中轻链的影响。3)组织中的淀粉样蛋白沉积导致器官功能障碍。对此的传统解释是淀粉样纤维大量浸润产生的纯机械效应。然而，临床信息和初步数据表明，对于β-淀粉样蛋白和甲状腺素运载蛋白淀粉样蛋白，已通过实验发现轻链蛋白对组织的有害作用。将在测试心脏生理学的实验模型中测试循环单克隆轻链对器官功能的影响。将在轻链序列修饰和项目2中观察到的生物物理特性之间建立相关性。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.