Molecular Otolaryngology and Renal Research Laboratories, and.
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
JCI Insight. 2020 May 7;5(9):135758. doi: 10.1172/jci.insight.135758.
Therapeutic complement inhibition is a major focus for novel drug development. Of upstream targets, factor D (FD) is appealing because it circulates in plasma at low concentrations and has a single function: to cleave factor B to generate C3 convertase of the alternative pathway (AP). Mice with a targeted deletion of factor H (FH; Cfh-/- mice) develop C3 glomerulopathy (C3G) due to uncontrolled AP activity. To assess the impact of FD inhibition, we studied Cfh-/- Cfd-/- mice. We show that C3G in Cfh-/- mice is not rescued by removing FD. We used serum from Cfh-/- Cfd-/- mice to demonstrate that residual AP function occurs even when both FD and FH are missing and that hemolytic activity is present due to the action of C3(H2O). We propose that uncontrolled tick-over leads to slow activation of the AP in Cfh-/- Cfd-/- mice and that a minimal threshold of FH is necessary if tissue deposition of C3 is to be prevented. The FD/FH ratio dictates serum C3 level and renal C3b deposition. In C3G patients with chronic renal disease, the FD/FH ratio correlates inversely with C3 and C5 serum levels, suggesting that continuous AP control may be difficult to achieve by targeting FD.
治疗性补体抑制是新药开发的主要关注点。在上游靶点中，因子 D (FD) 很有吸引力，因为它在血浆中浓度较低，且仅有一个功能：裂解因子 B 生成替代途径 (AP) 的 C3 转化酶。靶向缺失因子 H (FH; Cfh-/- 小鼠) 会导致 AP 活性失控，从而引发 C3 肾小球病 (C3G)。为了评估 FD 抑制的影响，我们研究了 Cfh-/- Cfd-/- 小鼠。我们发现，Cfh-/- 小鼠中的 C3G 并未因 FD 的缺失而得到挽救。我们利用 Cfh-/- Cfd-/- 小鼠的血清证明，即使 FD 和 FH 均缺失，仍存在残余的 AP 功能，并且由于 C3(H2O) 的作用存在溶血活性。我们提出，不受控制的持续激活导致 Cfh-/- Cfd-/- 小鼠中 AP 的缓慢激活，并且如果要防止 C3 在组织中的沉积，则需要有最小阈值的 FH。FD/FH 比值决定了血清 C3 水平和肾脏 C3b 沉积。在患有慢性肾脏疾病的 C3G 患者中，FD/FH 比值与 C3 和 C5 血清水平呈负相关，这表明通过靶向 FD 可能难以实现持续的 AP 控制。
