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.