C3 glomerulopathy: a kidney disease mediated by alternative pathway deregulation

Abstract

C3 glomerulopathy (C3G) is an ultra-rare complement-mediated kidney disease caused by to the deregulation of the alternative pathway (AP) of proximal complement. Consequently, all effector loops of the complement are active and can lead to pathologies, such as C3a- and C5a-mediated inflammation, C3b opsonization, surface C3b-mediated AP C3 convertase assembly, C3 cleavage product deposition in the glomerulus, and lytic C5b-9/MAC cell damage. The most common pathologic mechanisms are defective chronic alternative pathway deregulation, mostly occurring in the plasma, often causing C3 consumption, and chronic complement-mediated glomerular damage. C3G develops over several years, and loss of renal function occurs in more than 50% of patients. C3G is triggered by both genetic and autoimmune alterations. Genetic causes include mutations in individual complement genes and chromosomal variations in the form of deletions and duplications affecting genes encoding complement modulators. Many genetic aberrations result in increased AP C3 convertase activity, either due to decreased activity of regulators, increased activity of modulators, or gain-of-function mutations in genes encoding components of the convertase. Autoimmune forms of C3G do also exist. Autoantibodies target individual complement components and regulators or bind to neoepitopes exposed in the central alternative pathway C3 convertase, thereby increasing enzyme activity. Overactive AP C3 convertase is common in C3G patients. Given that C3G is a complement disease mediated by defective alternative pathway action, complement blockade is an emerging concept for therapy. Here, we summarize both the causes of C3G and the rationale for complement inhibition and list the inhibitors that are being used in the most advanced clinical trials for C3G. With several inhibitors in phase II and III trials, it is expected that effectice treatment for C3G will become availabe in the near future.

Keywords: C3 glomerulopathy; alternative pathway (AP); complement; complement inhibitors; therapy.

Figure 1

The physiological complement. The complement is activated through three pathways: the alternative pathway, the lectin pathway, and the classical pathway. The C3 convertase of the alternative pathway, which is composed of C3b and Bb, is shown and is at the center of the pathophysiology of C3G. C3 convertases cleave C3 into the anaphylatoxins C3a and C3b. C3a also has antimicrobial activity. C3b decorates, opsonizes target surfaces, and allows phagocytosis of the decorated particle. Complement activation proceeds to the level of C5 convertases, which cleave C5 to the potent anaphylatoxin and inflammatory mediator C5a and to C5b, which can assemble C6, C7, C8, and C9 to form the lytic pore, C5b-9. The triggers for each activation pathway are shown on the left side. The major effector functions of the complement are shown on the right.

Figure 2

Genetic mutations in Factor H and FHR hybrid proteins associated with C3G. (A) Mutation in the Factor H gene in C3G patients and in Factor H-deficient pigs. The structure of Factor H and the alternatively spliced product FHL1 is shown. The functional protein regions are shown below the two proteins. ?? indicates that the function of this region is not understood at the moment. Patients #2 and #3 (see Section 3.4.2 below) have a homozygous deletion of residue K224 in SCR4. This K224 deletion results in defective regulation of both Factor H and FHL1 proteins. The two compound heterozygous Factor H mutations in SCR9 and SCR16 identified in the 13-month-old Sioux boy are shown in black. The compound heterozygous exchanges in SCR9 and SCR20 in the Factor H-deficient pigs are shown in gray. (B) FHR hybrid proteins identified in familial C3G. The FHR gene cluster represents a region of chromosomal instability and is frequently affected by non-homologous recombination. The lower panel shows examples of hybrid proteins, all of which contain an intact FHR1 backbone protein, shown in yellow. In the different scenarios, either N-terminal domains are duplicated or N-terminal SCRs from FHR2 (red) or FHR3 (green color) have been added. The upper panel shows three familial cases in which two or three SCRs were added to the N-terminus of FHR5 (orange). The added domains were the dimerization region of FHR2 (red), FHR5 itself (dashed line), or FHR1 (yellow). The scenario at the bottom is a reverse genetic situation where the N-terminal FHR5 dimerization domain (blue) is attached to the FHR2 protein. Index patients #3 and #4 are shown in the bottom panel in row 1 and row 4, respectively. All scenarios involving FHR gene variations occur in the context of an intact Factor H gene and in the presence of Factor H and FHL1 in the plasma.

Figure 3

Autoimmune present targets of C3G. (A) Autoantibodies identified in C3G bind to different targets. Autoantibodies C3G bind to distinct complement proteins that either regulators of the AP C3 convertase or the elements of this enzyme. C3G-associated autoantibodies that bind single proteins, the regulators Factor H and FHL1, or the components that make up the convertase Factor B or C3. PLEASE add this after the elements of this enzyme. (B) The middle image shows the structure of the properdin-stabilized AP C3 convertase C3bBbP (structure by Gregers Anderson Aarhus, Denmark). These autoantibodies bind to neoepitopes exposed on the assembled convertase in the form of anti-C3 convertase antibodies and C3Nephritic Factor (C3NeF), as well as C5NeF. (C) Binding of nephritogenic λ light-chain dimers within the regulatory region of FHL1 and Factor H.

Figure 4

AP C3 convertase and AP amplification loop dysregulation trigger C3G pathogenesis and target profiles of complement inhibitors. The tick-over, the AP C3 convertase, and the AP-mediated amplification loop are deregulated in C3G as presented for selected and well-characterized cases in Chapter 3.4. AP overactivation induces strong complement activation shown by the red arrows and induces all effector levels of the complement. Consequently, C3a- and C5a-mediated cell recruitment and inflammation, C3b-assisted opsonization, and C5b-9-mediated lysis are turned on and are overactive. On the top and bottom, major complement inhibitors are evaluated in phase II or III clinical trials, including their corresponding targets.