11 Activated complement generates three major types of effectors: (i) anaphylatoxins (C3a and C5a), which are potent pro-inflammatory molecules that attract and activate leukocytes through interaction with their cognate G protein-couple receptors, C3a receptor (C3aR) and C5a receptor (C5aR); (ii) opsonins (C3b, iC3b and C3d), which decorate target surface through covalent bonding to facilitate transport and disposal of target cells or immune complexes; (iii) MAC, the terminal assembly of multiple complement proteins that directly lyses targeted (opsonized) pathogens or altered see more self (Fig. 1). These effectors allow the complement system to fulfil its three major biological

functions, i.e. host defence, disposal of immune complexes and cellular ‘wastes’ and priming the adaptive immune systems.2 MK1775 While the complement system is a critical first line of defence against infections, its powerful effector functions also have the potential to harm the host. The activation of classical and lectin pathways is largely dependent on foreign materials, but under certain situations (e.g. tissue ischaemia and reperfusion), both pathways can be activated and cause autologous injury. More relevant to complement-mediated pathologies, deposition of C3b via AP activation and amplification is nondiscriminatory and, if not properly regulated, can rapidly damage host cells.4,12 This is particularly true in the context of pathogenic infection when all three pathways can be activated and bystander injury to host cells may occur more readily. To control unintended complement activation on host cells, humans and mammalian species have developed Liothyronine Sodium a variety

of inhibitory proteins to regulate the location and efficacy of complement activation. Some of these regulatory proteins are localized on the host cell membrane to provide intrinsic protection. Membrane-bound complement regulators include decay-accelerating factor (DAF/CD55), membrane cofactor protein (MCP/CD46), complement receptor 1 (CR1/CD35) and its rodent analogue CR1-related gene/protein y (Crry), and CD59.2,13 Others are present in the plasma to limit fluid-phase complement activation but can also protect host cells using specific recognition mechanisms. Key fluid-phase complement regulators include factor H (fH), factor I (fI), C4-binding protein (C4bp)2 and C1 inhibitor. Some of these regulators with relevance to kidney disease will be discussed in more detail in the sections below. The regulatory proteins work at multiple points along the complement activation cascade (Fig. 2). Given the fact that activation of C3 is the key step in these processes, it is not surprising that several of the regulatory proteins act at the C3 convertase step, often with redundant effects.