Department of Bacteriology and Immunology and Research Programs Unit, Immunobiology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Center for Complement and Inflammation Research, Imperial College London, London, UK.
Scand J Immunol. 2018 Jul;88(1):e12671. doi: 10.1111/sji.12671. Epub 2018 May 23.
Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self-surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full-length mFH, mFH1-5 and mFH18-20 fragments were radiolabelled, and their distribution was examined in WT, FH and FH C3 mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full-length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1-5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18-20 to kidneys was slower, and at tissue level, mFH18-20 was localized at the proximal tubuli in WT and FH C3 mice. No C3-independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such.
因子 H 是人类和小鼠血浆中和细胞表面补体激活的重要调节剂。如果 FH 功能受损，自身表面的补体激活不当可能会产生灾难性的影响，如肾脏疾病非典型溶血尿毒症综合征（aHUS）和 C3 肾小球病。由于已经提出 FH 构建物可用于这些疾病的治疗，我们研究了外源性 FH 片段在小鼠中的分布。全长 mFH、mFH1-5 和 mFH18-20 片段被放射性标记，并在 WT、FH 和 FH C3 小鼠体内研究了它们的分布。全身闪烁显像显示放射性在腹部积聚，但也在甲状腺和膀胱积聚。在 WT 小鼠的器官水平上，一些全长 FH 积聚在内部器官中，但大部分仍在循环中。两种 mFH 片段都积聚在肾脏中，并从尿液中排出。对于 mFH1-5，尿分泌可能是其积聚的原因。mFH18-20 积聚到肾脏的速度较慢，在组织水平上，mFH18-20 定位于 WT 和 FH C3 小鼠的近端肾小管。未检测到与补体 C3 无关的肾小球结合。总之，这些结果表明，肾小球糖胺聚糖和唾液酸本身并不能在肾脏中收集 FH。还需要沉积 C3 片段，这意味着在 aHUS 中，问题是 FH 同时识别 C3 片段和糖胺聚糖或唾液酸，而不仅仅是 FH 无法识别肾小球内皮细胞本身。
