The Journal of Experimental Medicine BRIEF DEFINITIVE REPORT JEM © The Rockefeller University Press $15.00 Vol. 204, No. 6, June 11, 2007 1319–1325 www.jem.org/cgi/doi/10.1084/jem.20070432 1319 The complement system is required to mount an appropriate innate immune response to path- ogens. It acts by facilitating phagocytosis of immune complexes and apoptotic cells and by forming a membrane attack complex resulting in cell lysis (1). Particles and pathogens in serum initiate complement activation either through the classical pathway (CP), mannose-binding lectin (MBL) pathway, or alternative pathway (AP; reference 2). Central to complement acti- vation are the convertases, enzyme complexes that cleave the substrates C3 and C5 into their biologically active fragments, C3a, C3b, C5a, and C5b. The C3bBb dimer and C3bC3bBb mul- timers form the convertases of the AP and are required for ampliication of complement acti- vated through any of the three pathways, whereas C4bC2a and C3bC4bC2a are convertases of the CP and MBL pathway. To prevent unwanted complement activa- tion, most mammalian cells are equipped with regulators that block complement ampliication on host self cells (3). In the absence of these in- trinsic regulators, serum exposure results in the generation of complement split product that in turn facilitates inlammation and tissue damage (4, 5). Noncellular surfaces that lack intrinsic complement regulators are therefore especially prone to complement attack and are fully de- pendent on protection by soluble complement regulators in serum. Uncontrolled complement activation due to the lack of appropriate comple- ment regulation has been associated with various chronic inlammatory diseases. Dominant in this inlammatory cascade are the complement split products C3a and C5a that function as chemo- attractant and activators of neutrophils and in- lammatory macrophages via the C3a and C5a receptors (6). Properdin, released from neutro- phils, further ampliies the inlammatory cascade A novel inhibitor of the alternative pathway of complement reverses inlammation and bone destruction in experimental arthritis Kenneth J. Katschke Jr., 1 Karim Y. Helmy, 1 Micah Stefek, 2 Hongkang Xi, 1 JianPing Yin, 5 Wyne P. Lee, 1 Peter Gribling, 1 Kai H. Barck, 3 Richard A.D. Carano, 3 Robin E. Taylor, 4 Linda Rangell, 4 Lauri Diehl, 4 Philip E. Hass, 2 Christian Wiesmann, 5 and Menno van Lookeren Campagne 1 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 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 inlammation 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 inlammation 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 induc- tion, 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. CORRESPONDENCE Menno van Lookeren Campagne: menno@gene.com The online version of this article contains supplemental material.