Fig. 4

Mechanisms-of-action driving SLE pathogenesis via impairing debris clearance machinery. There are three mechanisms to initiate the complement cascade for debris clearance, i.e., the classical, lectin, and alternative pathways. In the classical and lectin pathways, the complement system is triggered by the binding of the antibody complexes to C1q of the C1 complex and the binding of foreign carbohydrate moieties to mannose binding lectin (MBL) or ficolin, respectively, which converge to the cleavage of C4 to C4b and C4a followed by the generation of one C3 convertase, i.e., C4b2a. In the alternative path, the complement system is activated via spontaneous hydrolysis of C3 into C3b and C3a by the convertase C3(H2O)Bb followed by the formation of another C3 convertase, i.e., C3bBb. Under the cleavage of C4b2a or C3bBb, C3 becomes C3b and C3a. Following this, C3b binds to C4b2a or C3bBb to form C4b2a3b or C3bBbC3b which are C5 convertases capable of hydrolyzing C5 into C5b and C5a; and C5b can initiate the cascade of forming the membrane attack complex (MAC) capable of generating pores in the membranes of pathogens or targeted cells. While C3 activation fragments such as C3b participate in the cleaning of cellular debris to avoid overt activation of the immune system that is favorable for halting SLE pathogenesis, overt production of MAC may promote SLE pathogenesis via causing cell death and generating more immunoreactants