A review of: Xu C, Mao D, Holers VM, Palanca B, Cheng AM, Molina H 2000 A critical role for murine complement regulator Crry in fetomaternal tolerance. Science 287:498–501.

The ability of the fetus to thrive as a semi-allogenic graft in its mother is one of the most enigmatic aspects of reproduction. Suppression of the “acquired” immune system has been proposed to occur by expression of placental products such as immunomodulatory cytokines, non-classical major histocompatability complex (MHC) antigens, and Fas ligand. To date, however, there is little proof that loss of these factors plays a significant role in fetal loss (1–3). The importance of suppressing the “innate” immune system, involving complement-mediated cell killing, in fetoplacental tolerance was suggested by the discovery that the human placenta produces several inhibitors of the complement cascade (4). Several years after this discovery, the importance of this system for pregnancy success has been demonstrated using knockout mice.

Xu et al. tested the function of the complement regulator Crry, by making targeted mutant mice. They found that Crry-deficient embryos die in the early post-implantation period due to local activation of complement and infiltration of maternal inflammatory cells into the conceptus. At this stage of development, Crry is expressed in placental trophoblast cells but not the fetus. To prove that fetal loss was due to complement-mediated events, the authors showed that complement protein C3-deficiency in the mother suppressed the effects of Crry-deficiency in the conceptus. Several complement inhibitors have been described, but the results from the Crry knockout clearly indicate that they do not have redundant functions, at least in mice. This is somewhat surprising because two others, decay accelerating factor (DAF) and membrane co-factor protein (MCP), inhibit complement activation at the same step as Crry. One explanation is that DAF and MCP are not expressed in the placenta of mice.

This work beautifully shows a causal relationship between loss of a placental protective mechanism and induction of maternal immune-mediated fetal loss, and raises questions about the potential importance of this mechanism in spontaneous abortion in humans. The Crry gene is restricted to rodents. Nonetheless, other complement inhibitors (DAF, MCP, and CD59) are expressed in the human placenta (4). It is curious from an evolutionary perspective that different complement inhibitors are expressed in the placenta of different species and that, unlike mice, multiple inhibitory proteins are expressed in the placenta of humans. This may mean that the human placenta is better adapted, compared to mouse, to prevent maternal complement attack during pregnancy. Tissues from first-trimester spontaneous abortions often show considerable signs of inflammation (5), but whether this is secondary to complement activation is not clear as few studies have examined the expression of complement inhibitors in these cases. The provocative results from Xu et al. should renew interest in these questions for understanding fetal loss in humans.