The Journal of Experimental Medicine
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Published online June 4, 2007
doi:10.1084/jem.20070432
The Journal of Experimental Medicine, Vol. 204, No. 6, 1319-1325
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Katschke et al.
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BRIEF DEFINITIVE REPORT

 A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritis

Kenneth J. Katschke, Jr.1, Karim Y. Helmy1, Micah Steffek2, Hongkang Xi1, JianPing Yin5, Wyne P. Lee1, Peter Gribling1, Kai H. Barck3, Richard A.D. Carano3, Robin E. Taylor4, Linda Rangell4, Lauri Diehl4, Philip E. Hass2, Christian Wiesmann5, and Menno van Lookeren Campagne1

1 Department of Immunology, 2 Department of Protein Chemistry, 3 Department of Tumor Biology and Angiogenesis, 4 Department of Pathology, and 5 Department of Protein Engineering, Genentech, Inc., San Francisco, CA 94080

CORRESPONDENCE Menno van Lookeren Campagne: menno{at}gene.com

Complement is an important component of the innate and adaptive immune response, yet complement split products generated through activation of each of the three complement pathways (classical, alternative, and lectin) can cause inflammation and tissue destruction. Previous studies have shown that complement activation through the alternative, but not classical, pathway is required to initiate antibody-induced arthritis in mice, but it is unclear if the alternative pathway (AP) plays a role in established disease. Previously, we have shown that human complement receptor of the immunoglobulin superfamily (CRIg) is a selective inhibitor of the AP of complement. Here, we present the crystal structure of murine CRIg and, using mutants, provide evidence that the structural requirements for inhibition of the AP are conserved in human and mouse. A soluble form of CRIg reversed inflammation and bone loss in two experimental models of arthritis by inhibiting the AP of complement in the joint. Our data indicate that the AP of complement is not only required for disease induction, but also disease progression. The extracellular domain of CRIg thus provides a novel tool to study the effects of inhibiting the AP of complement in established disease and constitutes a promising therapeutic with selectivity for a single complement pathway.


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