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Membrane Protein Crry Maintains Homeostasis of the Complement System¹

Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110

Complement activation is tightly regulated to avoid excessive inflammatory and immune responses. Crry^–/– is an embryonic lethal phenotype secondary to the maternal complement alternative pathway (AP) attacking a placenta deficient in this inhibitor. In this study, we demonstrate that Crry^–/– mice could be rescued on a partial as well as on a complete factor B (fB)- or C3-deficient maternal background. The C3 and fB protein concentrations in Crry^–/–C3^+/– and Crry^–/–fB^+/– mice were substantially reduced for gene dosage secondary to enhanced AP turnover. Based on these observations, a breeding strategy featuring reduced maternal AP-activating capacity rescued the lethal phenotype. It led to a novel, stable line of Crry SKO mice carrying normal alleles for C3 and fB. Crry SKO mice also had accelerated C3 and fB turnover and therefore reduced AP- activating potential. These instructive results represent an example of a membrane regulatory protein being responsible for homeostasis of the complement system. They imply that there is constant turnover on cells of the AP pathway which functions as an immune surveillance system for pathogens and altered self.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01-AI037618 and R01-AI041592.

² Current address: Clinical Research and Exploratory Development, Roche-Palo Alto, Palo Alto, CA 94304.

³ Address correspondence and reprint requests to Dr. John P. Atkinson, Washington University, 660 South Euclid Avenue, Campus Box 8045, St. Louis, MO 63110. E-mail address: jatkinso{at}im.wustl.edu

⁴ Abbreviations used in this paper: AP, alternative pathway; DAA, decay-accelerating activity; CA, cofactor activity; HUS, hemolytic uremic syndrome; fB, factor B; fH, factor H; fI, factor I; MCP, murine cofactor protein; WT, wild type; ZP, zymosan particle; GVBS, gelatin-veronal-buffered saline; CVF, cobra venom factor; DAF, decay-accelerating factor; MPGN II, membranoproliferative glomerulonephritis type II.