Crry deficiency in complement sufficient mice: C3 consumption occurs without associated renal injury

The rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry) is critical for complement homeostasis. Gene deletion is 100% embryonically lethal; Crry-deficient (Crry^-/-) mice were rescued by back-crossing onto C3 deficiency, confirming that embryo loss was complement mediated. In order to rescue viable Crry^-/- mice without deleting C3, we have tested inhibition of C5 during gestation. Crry^+/- females were given neutralizing anti-C5 mAb immediately prior to mating with Crry^+/- males and C5 inhibition maintained through pregnancy. A single, healthy Crry^-/- female was obtained and mating with Crry^+/- males yielded healthy litters containing equal numbers of Crry^+/- and Crry^-/- pups. Inter-crossing Crry^-/- mice yielded healthy litters of expected size. Although the mice were not anemic, exposure of Crry^-/- erythrocytes to normal mouse serum caused C3 deposition and lysis, while transfusion into normal or C6^-/- mice resulted in rapid clearance. Complement activity and C3 levels in Crry^-/- mice were markedly reduced. Comparison with factor H deficient (CfH^-/-) mice revealed similar levels of residual C3; however, unlike the CfH^-/- mice, Crry^-/- mice showed no evidence of renal injury, demonstrating distinct roles for these regulators in protecting the kidney.