Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, United Kingdom.
Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):16115-20. doi: 10.1073/pnas.1306621110. Epub 2013 Aug 19.
Systemic amyloid A (AA) amyloidosis is a serious complication of chronic inflammation. Serum AA protein (SAA), an acute phase plasma protein, is deposited extracellularly as insoluble amyloid fibrils that damage tissue structure and function. Clinical AA amyloidosis is typically preceded by many years of active inflammation before presenting, most commonly with renal involvement. Using dose-dependent, doxycycline-inducible transgenic expression of SAA in mice, we show that AA amyloid deposition can occur independently of inflammation and that the time before amyloid deposition is determined by the circulating SAA concentration. High level SAA expression induced amyloidosis in all mice after a short, slightly variable delay. SAA was rapidly incorporated into amyloid, acutely reducing circulating SAA concentrations by up to 90%. Prolonged modest SAA overexpression occasionally produced amyloidosis after long delays and primed most mice for explosive amyloidosis when SAA production subsequently increased. Endogenous priming and bulk amyloid deposition are thus separable events, each sensitive to plasma SAA concentration. Amyloid deposits slowly regressed with restoration of normal SAA production after doxycycline withdrawal. Reinduction of SAA overproduction revealed that, following amyloid regression, all mice were primed, especially for rapid glomerular amyloid deposition leading to renal failure, closely resembling the rapid onset of renal failure in clinical AA amyloidosis following acute exacerbation of inflammation. Clinical AA amyloidosis rarely involves the heart, but amyloidotic SAA transgenic mice consistently had minor cardiac amyloid deposits, enabling us to extend to the heart the demonstrable efficacy of our unique antibody therapy for elimination of visceral amyloid.
系统性淀粉样 A (AA) 淀粉样变性是慢性炎症的严重并发症。血清 AA 蛋白 (SAA) 是一种急性相血浆蛋白，可在外周组织中沉积为不溶性淀粉样纤维，从而破坏组织结构和功能。临床 AA 淀粉样变性通常在出现之前有多年的活跃炎症，最常见的是肾受累。我们使用 SAA 的剂量依赖性、强力霉素诱导的转基因表达在小鼠中，表明 AA 淀粉样沉积可以独立于炎症发生，并且淀粉样沉积前的时间取决于循环 SAA 浓度。高浓度 SAA 表达在所有小鼠中诱导淀粉样变性，潜伏期短，略有变化。SAA 迅速掺入淀粉样物中，急性降低循环 SAA 浓度高达 90%。长期适度的 SAA 过表达偶尔会在长时间延迟后产生淀粉样变性，并在随后 SAA 产生增加时使大多数小鼠对爆发性淀粉样变性产生致敏。内源性致敏和大量淀粉样沉积是可分离的事件，每个事件都对血浆 SAA 浓度敏感。在用强力霉素停药后，淀粉样沉积物缓慢消退，同时恢复正常的 SAA 产生。重新诱导 SAA 过度产生表明，在淀粉样物消退后，所有小鼠均被致敏，尤其是在 SAA 产生后迅速发生肾小球淀粉样沉积导致肾衰竭，这与炎症急性加重后临床 AA 淀粉样变性迅速发生肾衰竭非常相似。临床 AA 淀粉样变性很少涉及心脏，但淀粉样变性 SAA 转基因小鼠始终有轻微的心脏淀粉样沉积，使我们能够将我们独特的抗体治疗消除内脏淀粉样物的疗效扩展到心脏。
