Update on C3 glomerulopathy

Abstract

C3 glomerulopathy refers to a disease process in which abnormal control of complement activation, degradation or deposition results in predominant C3 fragment deposition within the glomerulus and glomerular damage. Recent studies have improved our understanding of its pathogenesis. The key abnormality is uncontrolled C3b amplification in the circulation and/or along the glomerular basement membrane. Family studies in which disease segregates with structurally abnormal complement factor H-related (CFHR) proteins demonstrate that abnormal CFHR proteins are important in some types of C3 glomerulopathy. This is currently thought to be due to the ability of these proteins to antagonize the major negative regulator of C3 activation, complement factor H (CFH), a process termed 'CFH de-regulation'. Recent clinicopathological cohort studies have led to further refinements in case definition, culminating in a 2013 consensus report, which provides recommendations regarding investigation and treatment. Early clinical experience with complement-targeted therapeutics, notably C5 inhibitors, has also now been published. Here, we summarize the latest developments in C3 glomerulopathy.

Keywords: C3 glomerulopathy; complement; dense deposit; factor H.

FIGURE 1:

The CFH–CFHR protein family. (A) CFH consists of 20 SCR domains. Those at the C-terminus (depicted in yellow) mediate surface recognition and are common to the five CFHR proteins (CFHR4 has two isoforms, CFHR4A and CFHR4B). In contrast, N-terminal SCR domains mediating CFH complement regulatory function (red) are not found on CFHR proteins. The N-terminal SCR domains 1 and 2 are highly conserved on CFHR1, CFHR2 and CFHR5 (blue) but not CFHR3 and CFHR4A/B, with very high sequence homology (B).

FIGURE 2:

Family studies have identified abnormal CFHR proteins associated with C3 glomerulopathy. These include duplication of N-terminal SCR domains and formation of a hybrid CFHR protein containing two domains from CFHR3 (depicted in purple) linked to the whole of CFHR1.

FIGURE 3:

Schematic representation of potential homodimers and heterodimers within the CFHR1, CFHR2 and CFHR5 protein family. The dimerization motif is located within N-terminal SCR domains 1 and 2 of CFHR1, -2 and -5 (depicted in blue) enabling head-to-tail dimer formation. Potential homo- and heterodimers are shown. The combined deletion of the CFHR1 and CFHR3 genes (ΔCFHR3/1) would, in homozygosity, result in a complete loss of CHFR1-containing species. In this setting, the potential species comprise: CFHR2 and CFHR5 homodimers and a CFHR2–CFHR5 heterodimer (inset).

FIGURE 4:

Schematic representation of pathogenesis of C3 glomerulopathy. Triggers of C3 activation (depicted at the centre) may be exogenous (e.g. infection) or endogenous (C3 tickover). C3 activation generates C3b molecules for attachment to surfaces including the GBM. In health (upper panel), C3b amplification is tightly controlled by factor H (CFH) in the circulation. Thus minimal C3b becomes available for attachment to surfaces, where amplification is further regulated by CFH on the GBM. In theory, any surface-attached C3b is then metabolised, leaving C3 fragments (iC3b, C3d) attached to the GBM, and releasing CFH back into the circulation. In practice, neither C3 nor CFH are detected along the GBM in normal glomeruli. In the setting of abnormal CFH (bottom left panel), uncontrolled C3 activation leads to excessive C3 fragments (iC3b, C3d) in the circulation, which later accumulate along the GBM. Some C3b amplification/metabolism may also occur on the GBM. Enhanced CFH de-regulation due to abnormal CFHR proteins (bottom right panel) has been proposed as one mechanism by which C3 accumulates along the GBM despite intact CFH. Competitive inhibition of CFH by abnormal CFHR proteins along the GBM would facilitate C3b surface amplification/metabolism. Increased C3b amplification in plasma due to an abnormal CFHR protein that stabilizes the C3 convertase has also been demonstrated (see the text).