Background Properdin (P) is a positive regulator of the alternative pathway of complement activation. Although P inhibition is expected and has been shown to ameliorate the alternative pathway of complement-mediated tissue injury in several disease models, it unexpectedly exacerbated renal injury in a murine model of C3 glomerulopathy. The role of P in atypical hemolytic uremic syndrome (aHUS) is uncertain.

Methods We blocked P function by genetic deletion or mAb-mediated inhibition in mice carrying a factor H (FH) point mutation, W1206R (FH^R/R), that causes aHUS and systemic thrombophilia with high mortality.

Results P deficiency completely rescued FH^R/R mice from premature death and prevented thrombocytopenia, hemolytic anemia, and renal disease. It also eliminated macrovessel thrombi that were prevalent in FH^R/R mice. All mice that received a function-blocking anti-P mAb for 8 weeks survived the experimental period and appeared grossly healthy. Platelet counts and hemoglobin levels were significantly improved in FH^R/R mice after 4 weeks of anti-P mAb treatment. One half of the FH^R/R mice treated with an isotype control mAb but none of the anti-P mAb-treated mice developed stroke-related neurologic disease. Anti-P mAb-treated FH^R/R mice showed largely normal renal histology, and residual liver thrombi were detected in only three of 15 treated mice.

Conclusions These results contrast with the detrimental effect of P inhibition observed in a murine model of C3 glomerulopathy and suggest that P contributes critically to aHUS pathogenesis. Inhibition of P in aHUS may be of therapeutic benefit.

背景备解素（P）是补体激活的另一种途径的积极监管者。尽管在某些疾病模型中P抑制作用是预期的并且已显示出可以改善补体介导的组织损伤的替代途径，但在C3肾小球病的小鼠模型中，它出乎意料地加剧了肾脏损伤。P在非典型溶血性尿毒症综合征（aHUS）中的作用尚不确定。

方法我们通过基因缺失或mAb介导的抑制作用来阻断小鼠的P功能，该小鼠携带H因子（FH）点突变W1206R（FH ^{R / R}），该突变导致aHUS和系统性血友病，死亡率高。

结果磷缺乏症完全使FH ^{R / R}小鼠免于过早死亡，并预防了血小板减少症，溶血性贫血和肾脏疾病。它还消除了FH ^{R / R}小鼠中普遍存在的大血管血栓。接受功能阻断性抗P mAb达8周的所有小鼠均在实验期间幸存下来，并表现出总体健康状况。抗P mAb治疗4周后，FH ^{R / R}小鼠的血小板计数和血红蛋白水平显着提高。用同种型对照mAb治疗的FH ^{R / R}小鼠中有一半，但抗P mAb治疗的小鼠均未发生中风相关的神经系统疾病。抗P mAb处理的FH ^{R / R} 小鼠显示出基本正常的肾脏组织学，并且在15只经治疗的小鼠中只有3只检测到残留的肝血栓。

结论这些结果与在C3肾小球病小鼠模型中观察到的P抑制的有害作用相反，并表明P在aHUS发病机理中起关键作用。抑制aHUS中的P可能具有治疗益处。