Introduction 1 2 3 4 Overview of the complement pathways 1 Fig. 1 Schematic overview of the three pathways of complement activation  The first component in the activation of the classical pathway is C1. Binding of at least two bindings sites of C1q to antigen-bound IgG or IgM, acute phase proteins such as CRP or dead cells leads to conformational changes that result in the activation of the associated serine proteases C1r and C1s. Activated C1s cleaves C4 into C4a and C4b. C4b then covalently binds to nearby structures. The bound C4b then binds C2 whereupon the smaller C2b fragment is cleaved off, resulting in the formation of the C4bC2a complex, which is the classical pathway C3 convertase. The lectin pathway is related to the classical pathway and uses the same C3 convertase, C4bC2a. The initiation molecules of the lectin pathway, mannose-binding lectin (MBL) and the ficolins, recognise carbohydrate ligands present on a wide range of microorganisms in a pattern-like fashion. The interaction of MBL with its ligand leads to the activation of the MBL-associated serine proteases (MASP-1, MASP-2 and MASP-3). MASP-2 then cleaves C4 and subsequently C2 leading to the formation of the C3 convertase which is identical to the classical route C3 convertase, C4bC2a. MBL-2 2 2 5 7 The early activation steps of the classical, lectin and alternative route of complement activation converge in a common terminal pathway. The addition of a further C3b molecule to the C3 convertase complex leads to the formation of C3bBbC3b in the case of the alternative pathway and to the formation of C4bC2aC3b in the case of both the classical and lectin pathways. These C5 convertases then initiate the assembly of the membrane attack complex by cleavage of C5 to C5a and C5b. C5a can then function as a potent anaphylotoxin. The newly formed C5b forms a tri-molecular complex by binding C6 and C7. After inserting into a cell membrane, this complex binds C8 and multiple C9 molecules. This results in the completion of the pore-forming membrane attack complex (C5b-9). This complex can lead to cell lysis and, in the absence of complete lysis, to cell activation. Regulation of complement activation The complement system consists of numerous regulatory molecules that protect the host from uncontrolled tissue destruction and activation by the complement system. Recently, defective complement regulation has been shown to play an important role in the pathogenesis of some forms of the haemolytic uremic syndrome (HUS) and membranoproliferative glomerulonephritis (MPGN). The role of complement in these diseases will be discussed in more detail below. 8 Factor I is a circulating serine protease that proteolytically degrades C3b and C4b in the presence of the co-factors fH and C4-binding protein (C4bp). Next to its function as a co-factor, fH also inhibits activation of the alternative pathway by binding to C3b and displacing Bb from the C3 convertase complex. Similarly, C4bp regulates activation of the classical and lectin pathway by displacing C2a from C4b. Both fH and C4bp promote the degradation of the C3 and C5 convertases of the respective pathways. Cell-membrane-bound inhibitors of complement activation also contribute to the defence against inappropriate tissue damage by homologous complement. Decay-accelerating factor (CD55) exerts its effect early in the complement cascade by inhibiting the activation of C3 by preventing the formation and accelerating the decay of both the alternative and classical pathway C3 and C5 convertases. Membrane co-factor protein (MCP, CD46) serves as a co-factor for the cleavage of C3b and C4b by factor I. CD59 interacts with the final section of the complement activation pathway by inhibiting the formation of C5b-9. 9 10 11 Immune-complex-mediated glomerulonephritis Immune complex glomerulonephritis is a good example for the dual role of the complement system. Immune complexes can either be deposited in the glomerulus by passive deposition from the circulation or by in situ formation via binding of antibody to local antigens. Alternatively, local formation of immune complexes may occur when a circulation antigen is recognised by antibodies after deposition in the glomerulus (planted antigen). Subepithelial complement deposition as found in membranous nephropathy leads to a non-inflammatory complement-mediated damage because the anaphylotoxins produced during the local activation do not reach circulating leucocytes. Subendothelial deposition of complement factors is associated with a brisk inflammatory response because the produced anaphylotoxins easily come into contact with circulating cells. Subendothelial immune complex deposition is typical of proliferative lupus nephritis. 12 13 14 15 16 17 It is interesting to note that many of the complement-deficient models of renal disease show spontaneous or worsened renal disease. This is compatible with the observation that the complement system plays an important role in the clearance of immune complexes from the circulation and in the solubilisation of deposited immune complexes. Immune complexes are rapidly opsonised with C4b and C3b. These complement components mediate the binding of the immune complexes to CR1 on erythrocytes. The complexes are then stripped off the erythrocytes when they pass through the liver or spleen. Thus, CR1-mediated clearance plays an important role in the handling of immune complexes and in keeping soluble immune complexes away from the endothelial surface thereby preventing vascular injury. 18 19 20 21 The important role of the complement system in immune complex clearance is underscored by the finding that humans with complement deficiency are prone to immune-complex-mediated disease. Systemic lupus erythematosus (SLE) is a highly relevant example for this dual role of the complement system as will be discussed in the next section. Role of complement in lupus nephritis 22 23 24 25 27 28 29 Taken together, it seems that, in lupus, the early components of the classical pathway of complement activation are beneficial due to their role in the clearance of immune complexes and apoptotic cells. Probably, the damage caused by Fc-receptor-mediated mechanisms in the presence of an increased deposition of immune complexes overrides the benefit of complement inhibition in these models. However, the inhibition of complement activation downstream of C3 may be a promising therapeutic approach. 30 31 32 33 34 IgA nephropathy 35 36 37 39 40 41 42 43 Membranoproliferative glomerulonephritis 44 45 46 47 48 49 50 A chronic serum sickness model of immune complex disease demonstrated increased deposition if IgG immune complexes with increased C3 deposition in fH-deficient mice compared to wild-type mice. The fH-deficient mice developed diffuse proliferative glomerulonephritis, while the wild-type mice were protected against glomerular pathology. These findings indicate a role of fH in processing immune complexes and protecting the glomerulus against immune-complex-mediated disease. 51 54 55 These observations suggest that anti-C5 treatment could serve as a treatment option in MPGN type II. Complement and the atypical haemolytic uremic syndrome Escherichia coli 56 57 58 59 60 61 http://www.FH-HUS.org 62 62 63 65 66 67 62 61 68 Taken together, the clinical and experimental findings clearly point towards an important role of complement regulation in the pathogenesis of aHUS. However, until now, mutations of complement-regulatory proteins are only found in about 50% of the affected patients and family members of affected patients can share the mutations without manifesting aHUS. It seems that both additional predisposing factors and triggering circumstances, e.g. infections, are necessary to initiate the full-blown microangiopathy of aHUS. 69 62 70 71 72 74 Complement and progressive renal damage 75 77 78 81 82 83 84 85 86 87 88 89 90 91 92 Conclusions Increasing knowledge about the complement system has taught us about both the protective and harmful roles of complement in renal disease. In the course of this review, it has repeatedly become clear that complement inhibition early on in both the classical and alternative pathways is associated with the risk of increased deposition of immune complexes and the resulting damage may outweigh the benefit. On the other hand, it seems that complement inhibition distal of the formation of the C3 convertases is safe and offers more promising therapeutic options for renal diseases for which no satisfying treatment has been established until now. Independently of these promising therapeutic prospects, complement has become an invaluable tool in the diagnosis and monitoring of renal disease and results of complement studies have a strong impact on day-to-day decision making in the care of our patients with renal disease.