Light chain (AL) amyloidosis is a devastating, complex, and incurable protein misfolding disease. It is characterized by an abnormal proliferation of plasma cells (fully differentiated B cells) producing an excess of monoclonal immunoglobulin light chains that are secreted into circulation, where the light chains misfold, aggregate as amyloid fibrils in target organs, and cause organ dysfunction, organ failure, and death. In this article, we will review the factors that contribute to AL amyloidosis complexity, the findings by our laboratory from the last 16 years and the work from other laboratories on understanding the structural, kinetics, and thermodynamic contributions that drive immunoglobulin light chain-associated amyloidosis. We will discuss the role of cofactors and the mechanism of cellular damage. Last, we will review our recent findings on the high resolution structure of AL amyloid fibrils. AL amyloidosis is the best example of protein sequence diversity in misfolding diseases, as each patient has a unique combination of germline donor sequences and multiple amino acid mutations in the protein that forms the amyloid fibril.

中文翻译：

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免疫球蛋白轻链淀粉样蛋白聚集

轻链（AL）淀粉样变性病是一种破坏性，复杂且无法治愈的蛋白质错误折叠疾病。它的特征是浆细胞（完全分化的B细胞）异常增殖，产生过量的单克隆免疫球蛋白轻链，这些轻链分泌到循环中，其中轻链错折叠，在目标器官中聚集为淀粉样原纤维，并导致器官功能障碍，器官失败和死亡。在本文中，我们将回顾导致AL淀粉样变性病复杂性的因素，我们实验室过去16年的发现以及其他实验室在了解驱动免疫球蛋白轻链相关淀粉样变性病的结构，动力学和热力学贡献方面的工作。我们将讨论辅因子的作用和细胞损伤的机制。最后的，我们将回顾我们有关AL淀粉样蛋白原纤维高分辨率结构的最新发现。AL淀粉样变性病是错误折叠疾病中蛋白质序列多样性的最好例证，因为每个患者都有独特的种系供体序列和形成淀粉样蛋白原纤维的蛋白质中多个氨基酸突变的组合。