Tissue response to amyloidogenic light chains

在AL淀粉样变性中，克隆性免疫球蛋白轻链在全身组织中形成淀粉样原纤维沉积。淀粉样原纤维沉积在另一种克隆性轻链疾病多发性骨髓瘤中很少见，但并不全出现在意义不明的单克隆性丙种球蛋白病中。负责将一些单抗轻链转化为淀粉样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)利用项目1中推导的氨基酸序列，本项目将研究导致淀粉样变的轻链蛋白的序列变异和翻译后修饰。来自同一患者组织沉淀物的淀粉样纤维将被检查其大小和蛋白分解部位，这些部位可能是蛋白质修饰的次要部位。2)蛋白多糖被认为在导致淀粉样变轻链沉积为纤维的生理机制中发挥关键作用。伴随AA(继发性)淀粉样变性的淀粉样纤维沉积，糖胺多聚糖(GAG)含量增加，尤其是硫酸乙酰肝素。初步数据表明，AL淀粉样变性也是如此。GAG的浓缩是否在纤维沉积之前，与纤维沉积一致，还是在纤维沉积之后尚不清楚。糖胺多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)组织中淀粉样蛋白沉积导致器官功能障碍。对此的传统解释是由大量淀粉样蛋白纤维渗透所产生的纯机械效应。然而，临床信息和初步数据表明，已在实验中发现轻链蛋白对组织的有害影响，即β-淀粉样蛋白和转甲状腺素淀粉样蛋白。循环的单抗轻链对器官功能的影响将在测试心脏生理学的实验模型中进行测试。轻链序列的修改将与项目2中观察到的生物物理性质相关联。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.