Atkinson John P, Goodship Timothy H J
Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Exp Med. 2007 Jun 11;204(6):1245-8. doi: 10.1084/jem.20070664. Epub 2007 Jun 4.
Immune recognition is coupled to powerful proinflammatory effector pathways that must be tightly regulated. The ancient alternative pathway of complement activation is one such proinflammatory pathway. Genetic susceptibility factors have been identified in both regulators and activating components of the alternative pathway that are associated with thrombotic microangiopathies, glomerulonephritides, and chronic conditions featuring debris deposition. These observations indicate that excessive alternative pathway activation promotes thrombosis in the microvasculature and tissue damage during debris accumulation. Intriguingly, distinct genetic changes in factor H (FH), a key regulator of the alternative pathway, are associated with hemolytic uremic syndrome (HUS), membranoproliferative glomerulonephritis (dense deposit disease), or age-related macular degeneration (AMD). A mouse model of HUS designed to mirror human mutations in FH has now been developed, providing new understanding of the molecular pathogenesis of complement-related endothelial disorders.
免疫识别与必须严格调控的强大促炎效应通路相关联。古老的补体激活替代途径就是这样一种促炎途径。在替代途径的调节因子和激活成分中都已鉴定出与血栓性微血管病、肾小球肾炎以及以碎片沉积为特征的慢性疾病相关的遗传易感性因素。这些观察结果表明，替代途径的过度激活会促进微血管血栓形成以及碎片堆积期间的组织损伤。有趣的是，替代途径的关键调节因子H因子（FH）中的不同基因变化与溶血性尿毒症综合征（HUS）、膜增生性肾小球肾炎（致密物沉积病）或年龄相关性黄斑变性（AMD）相关。现已开发出一种旨在模拟人类FH突变的HUS小鼠模型，这为补体相关内皮疾病的分子发病机制提供了新的认识。
