Complement catalyzing glomerular diseases

Abstract

Complement is an evolutionarily conserved system which is important in the defense against microorganisms and also in the elimination of modified or necrotic elements of the body. Complement is activated in a cascade type manner and activation and all steps of cascade progression are tightly controlled and regulatory interleaved with many processes of inflammatory machinery. Overshooting of the complement system due to dysregulation can result in the two prototypes of primary complement mediated renal diseases: C3 glomerulopathy and thrombotic microangiopathy. Apart from these, complement also is highly activated in many other inflammatory native kidney diseases, such as membranous nephropathy, ANCA-associated necrotizing glomerulonephritis, and IgA nephropathy. Moreover, it likely plays an important role also in the transplant setting, such as in antibody-mediated rejection or in hematopoietic stem cell transplant associated thrombotic microangiopathy. In this review, these glomerular disorders are discussed with regard to the role of complement in their pathogenesis. The consequential, respective clinical trials for complement inhibitory therapy strategies for these diseases are described.

Keywords: C3 Convertase testing; C3 glomerulopathy; Complement; Complement diagnostics; Glomerular diseases; Thrombotic microangiopathy.

Fig. 1

Different action of autoantibodies in glomerular diseases. Autoantibodies can influence complement by at least three mechanisms. Immune complexes activate the classical complement pathway. For this step the antibodies subtype is relevant. Autoantibodies of the IgM, IgG1, and IgG3 subtype activate the classical pathway of complement. However, IgE and IgA antibodies do not, or activate complement to a much lesser extent. Autoantibodies binding to single complement proteins or protein complexes influence protein function. The influence on protein function depends on the type of autoantigen, region to which the antibody binds and can cause different pathologies. In DEAP-HUS most autoantibodies bind to the C-terminal recognition region of Factor H and block Factor H surface binding. In C3 glomerulopathy autoantibodies bind to an anther region, the N-terminal regulatory region of the Factor H protein. Autoantibodies can also bind to neoepitopes in assembled protein complexes, like the AP C3 convertase C3bBb stabilized by properdin. In C3 glomerulopathy, many autoantibodies bind to neoepitopes of the alternative pathway C3 convertase, C3bBb and affect the stability of the enzymatic complex, block access of stabilizers or destabilizers and thereby alter the half-life of the active enzyme. Other antibodies bind directly to C3b, to Factor H or to Factor B. Thereby the antibodies influence the activity of this central complement activating enzyme in multiple ways

Fig. 2

Complement activation and effector levels. The complement cascade is activated via three separate pathways: the alternative pathway (AP), the lectin pathway (LP), or the classical pathway (CP). The AP is activated by default, for 24 h, all day long and at a low level and in default setting further progression is blocked by inhibitors. The “decision” activation vs inhibition by the many regulators or inhibitors aims for activation on target surfaces. The AP pathway also forms a potent amplification loop at the C3 convertase level. The LP in initiated broadly speaking by carbohydrates and the CP by antibodies and immune complexes. The three pathways form C3 convertases that target C3 the central component of complement. C3 is activated and cleaved to C3a and C3b. C3a as anaphylatoxin drives inflammation and cell recruitment, C3b makes the fluid phase, surface transition and upon deposition on surfaces can form a surface bound C3 convertase. C3b deposition on target surfaces is termed opsonization and prepares the target for interaction and uptake by professional phagocytes. Deposited C3b can be processed further. C3b is inactivated to C3b (iC3b), and then processed to fragments C3dg or C3d. The processed forms of C3 can interact with specific cell receptors. Alternatively, C3b on the surface can form a C3 convertase, be involved in the amplification loop or trigger the conversion of a C3 convertase to a C5 convertases. This new enzyme C3bBbC3b targets C5 and splits C5 into the soluble anaphylatoxin C5a and the surface bound C5b. C5a drives inflammatory complement and C5b deposited on the target surface attracts the plasma proteins C6, C7, C8, and C9, thus allows assembly the C5b-9 and polymeric C9 which generate the terminal complex and the lytic pore

Fig. 3

Targets of autoantibodies and genetic variations in complement catalyzed glomerular Diseases. a Several complement catalyzed glomerular diseases have autoimmune and genetic causes. These autoantibodies bind to multiple complement components and in some cases also attach to non-complement targets. Similarly, many complement genes and in some cases also non complement genes are altered in the diseases. The affected targets include complement convertases, convertase components and in particular various regulators. b Integration of the target components of the various autoantibodies in the complement cascade. c Targets of autoantibodies in glomerular disorders which are not directly linked to complement. d The spectrum of tissue reaction patterns to local complement activity: sublytic damage with proliferation and influx of inflammatory cells lead to the picture of membranoproliferative glomerulonephritis (MPGN, left), whereas lytic damage lead to the loss of endothelial cells followed by thrombus formation and the picture of thrombotic microangiopathy (TMA, right)

Fig. 4

Alternative vs classical complement pathway activation in C3 glomerulopathy and in systemic lupus erythematosus. In situ visualization of complement convertases using proximity ligation assays detecting proximity of the single components reveal high densities of signals (brown dots) for the alternative convertase C3bBb in C3 glomerulopathy (a), but only very few signals for the classical/lectin convertase C4bC2b (b). In contrast, in lupus nephritis (class IV) few signals for C3bBb (d), but a very high signal density for C4bC2b (e) is seen. These results indicate, as expected for these disorders, a predominant activation of the alternative complement pathway in C3 glomerulopathy (c) and a predominant activation of the classical pathway in lupus nephritis (f)