Timing and mechanism of conceptus demise in a complement regulatory membrane protein deficient mouse

Abstract

Problem: Crry is a widely expressed type 1 transmembrane complement regulatory protein in rodents which protects self-tissue by downregulating C3 activation. Crry^-/- concepti produced by Crry^+/- × Crry^+/- matings are attacked by maternal complement system leading to loss before day 10. The membrane attack complex is not the mediator of this death. We hypothesized that the ability of C3b to engage the alternative pathway's feedback loop relatively unchecked on placental membranes induces the lesion yielding the demise of the Crry^-/- mouse.

Method of study: We investigated the basis of Crry^-/- conceptus demise by depleting maternal complement with cobra venom factor and blocking antibodies. We monitored their effects primarily by genotyping and histologic analyses.

Results: We narrowed the critical period of the complement effect from 6.5 to 8.5 days post-coitus (dpc), which is immediately after the conceptus is exposed to maternal blood. Deposition by 5.5 dpc of maternal C3b on the placental vasculature lacking Crry^-/- yielded loss of the conceptus by 8.5 dpc. Fusion of the allantois to the chorion during placental assembly did not occur, fetal vessels originating in the allantois did not infiltrate the chorioallantoic placenta, the chorionic plate failed to develop, and the labyrinthine component of the placenta did not mature.

Conclusion: Our data are most consistent with the deposition of C3b being responsible for the failure of the allantois to fuse to the chorion leading to subsequent conceptus demise.

Keywords: C3b deposition; Crry; alternative pathway; complement membrane regulatory activity deficiency; complement system; conceptus demise; fusion of the allantois to the chorion.