Extrahepatic C6 is as effective as hepatic C6 in the generation of renal C5b-9 complexes

Abstract

In order to study the contribution of extrahepatic C6 to anti-Thy1.1 nephritis, C6 deficient PVG/c- livers were grafted in C6 sufficient PVG/c+ rats (Tx-L). Infusion of anti-Thy1.1 antibodies in Tx-L and PVG/c+ rats resulted in generation of C5b-9 complexes and subsequent glomerular injury, while infusion of anti-Thy1.1 antibodies in PVG/c- rats revealed no detectable C6 deposition. Because C6 mRNA was expressed in both liver and kidney tissue of PVG/c+ rats, we assessed whether production of C6 in the kidney alone was sufficient for glomerular injury. One kidney of a PVG/c- rat was replaced with a PVG/c+ kidney (Tx + K) followed by administration of anti-Thy1.1 antibodies. C6 deposits were detectable neither in PVG/c+ kidneys nor in PVG/c- kidneys of Tx + K rats, indicating that C6 production in PVG/c+ kidneys alone is not sufficient to contribute to renal injury. That C6 production had occurred was suggested by the presence of equal amounts C6 mRNA in control PVG/c+ kidneys and in grafted PVG/c+ kidneys of Tx + K rats. C6 mRNA expression in kidney tissue of PVG/c+ rats is presumably derived from peritubular sites. In conclusion, we have demonstrated that extrahepatic, but not renal synthesis of, C6 is sufficient to contribute to glomerular injury during anti-Thy1.1 nephritis.

The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injury

“…Hepatic biosynthesis is responsible for the majority of circulating C6,20 although human endothelial cells, monocytes, and macrophages may also contribute to its production 21. In fact, macrophage‐derived C6 can be a significant factor in tissue injury, as exemplified by graft rejection,22 whereas both extrahepatic production and intrahepatic production of C6 are equally effective in the generation of renal C5b‐9 complexes 23…”

C6 Produced by Macrophages Contributes to Cardiac Allograft Rejection

“…4,18,19 The assessment of macrophage production of complement components in normal animals is complicated by the fact that numerous extrahepatic sites of biosynthesis have been identified for individual complement components. In fact, endothelial cells, fibroblasts, and myocytes are among the cells that are capable of synthesizing several complement components.…”

Complement C6 and C2 Biosynthesis in Syngeneic PVG/c− and PVG/c+ Rat Strains

“…Therefore, extrahepatic C6 may not only be derived from circulating bone marrow derived cells such as monocytes [19] but also from tissues such as lung and kidney. By immunohistochemistry we demonstrated that the C6 synthesizing cell-type in the kidney is of renal origin and not of bone marrow origin [32]. Thus, not only bone marrow derived cells contribute to the amount of C6 in the circulation but also tissue specifc cells.…”

“…370 J. J Timmerman et al ᭧ 1997. Blackwell Science Ltd, Scandinavian Journal of Immunology, 46, 366-372 Anti-rat C6 antibodies in serum of Txþl rats.…”