Department of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee.
Webb School of Knoxville, Knoxville, Tennessee.
Am J Pathol. 2019 May;189(5):989-998. doi: 10.1016/j.ajpath.2019.01.011. Epub 2019 Feb 6.
Light chain-associated amyloidosis is characterized by the extracellular deposition of amyloid fibrils in abdominothoracic organs, skin, soft tissue, and peripheral nerves. Phagocytic cells of the innate immune system appear to be ineffective at clearing the material; however, human light chain amyloid extract, injected subcutaneously into mice, is rapidly cleared in a process that requires neutrophil activity. To better elucidate the phagocytosis of light chain fibrils, a potential method of cell-mediated dissolution, amyloid-like fibrils were labeled with the pH-sensitive dye pHrodo red and a near infrared fluorophore. After injecting this material subcutaneously in mice, optical imaging was used to quantitatively monitor phagocytosis and dissolution of fibrils concurrently. Histologic evaluation of the residual fibril masses revealed the presence of CD68, F4/80, ionized calcium binding adaptor molecule 1 macrophages containing Congo red-stained fibrils as well as neutrophil-associated proteins with no evidence of intact neutrophils. These data suggest an early infiltration of neutrophils, followed by extensive phagocytosis of the light chain fibrils by macrophages, leading to dissolution of the mass. Optical imaging of this novel murine model, coupled with histologic evaluation, can be used to study the cellular mechanisms underlying dissolution of synthetic amyloid-like fibrils and human amyloid extracts. In addition, it may serve as a test bed to evaluate investigational opsonizing agents that might serve as therapeutic agents for light chain-associated amyloidosis.
轻链相关性淀粉样变性的特征是在腹胸部器官、皮肤、软组织和周围神经中外源性沉积淀粉样纤维。先天免疫系统的吞噬细胞似乎无法有效清除该物质；然而，人类轻链淀粉样提取物被皮下注射到小鼠体内后，在需要中性粒细胞活性的过程中迅速被清除。为了更好地阐明轻链纤维的吞噬作用，即细胞介导溶解的一种潜在方法，将 pH 敏感染料 pHrodo red 和近红外荧光团标记在淀粉样纤维上。将这种物质皮下注射到小鼠体内后，使用光学成像技术同时定量监测纤维的吞噬作用和溶解作用。对残留纤维团块的组织学评估显示，存在 CD68、F4/80、离子钙结合接头分子 1 巨噬细胞，其中含有刚果红染色的纤维以及中性粒细胞相关蛋白，没有完整中性粒细胞的证据。这些数据表明，早期有中性粒细胞浸润，随后巨噬细胞大量吞噬轻链纤维，导致纤维团块溶解。这种新型小鼠模型的光学成像与组织学评估相结合，可用于研究合成淀粉样纤维和人类淀粉样提取物溶解的细胞机制。此外，它可能成为评估潜在调理剂的试验台，这些调理剂可能成为轻链相关性淀粉样变性的治疗药物。
