Regulation of the Alternative Pathway of Complement (APC). The APC, unlike the classical pathway, is in a state of continuous activation. When C3 is activated, an internal thioester bond (brown circle) is exposed that mediates covalent attachment of nascent C3b to a cell-surface constituent (blue curved line). C3b serves as the nidus for formation of a C3 convertase consisting of C3b, activated factor B (Bb, red triangle), and factor P (properdin, green circle). The C3 convertase amplifies the APC by cleaving many molecules of C3 to C3b that then form additional C3 and C5 convertases that eventually lead to generation of the cytolytic membrane attack complex (not shown). The convertase also releases C3a anaphylatoxin [orange triangle] into the fluid phase. Because the APC is continuously primed for attack, elaborate mechanisms for self-recognition and protection of the host against APC-mediated injury have evolved. Both fluid-phase factor H (orange arrow) and factor I (red lightning bolt) and membrane-bound proteins (e.g., MCP, green-brown elbow line) are involved in this process. Those APC regulatory proteins shown to be mutated in patients with aHUS are indicated with an asterisk. Thrombomodulin (green curved line) which was found in this study to be mutated in ~5 percent of patients with aHUS may regulate the APC by acting, in concert with factor H, as a co-factor for factor I-mediated degradation of C3b. Since thrombomodulin does not have the typical structure of factor I co-factor molecules, a question mark was placed next to asterisk.