Factor H–Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy

Abstract

BackgroundC3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H–related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear.MethodsUsing in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant’s association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population.ResultsDuplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome.ConclusionsOur findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G.

The Factor H protein family: The switchers of the complement alternative pathway

“…Evidences supporting this include in vitro experiments showing that surface-bound FHR-1 binds to C3b and serves as a platform for the assembly of the AP C3 convertase, and hemolytic assays where the addition of FHR-1 increases the cell lysis through the AP. 28,29,41 Additional structural and functional findings have recently described the interaction between FHR-1 and native C3. This unexpected finding suggests that surface-bound FHR-1 promotes AP activation through the recruitment of native C3 from the fluid phase (or C3b), increasing the local concentration of C3 that may then be activated either spontaneously or through proteases, and hence, enriching of substrates to form the AP C3 convertase 42 (Figure 4).…”

Genetic variability shapes the alternative pathway complement activity and predisposition to complement‐related diseases

“…and FHR-1(1-2)-FHR-1. 64 Different studies have tried to explain why these peculiar FHR variants associate with C3G. It was initially though that by forming multimeric complexes these variants would outcompete binding of FH to surface-bound C3b (FH de-regulation), promoting complement activation.…”

“…The classic example is an FHR‐5 protein encoded by a CFHR5 gene with an internal duplication resulting in a duplication of SCR1 and SCR2 (FHR‐5[1–2]‐FHR‐5) that was identified in several Greek Cypriot patients with C3GN and a common ancestry (often called CFHR5 nephropathy) 62 . Other FHR proteins with duplicated dimerization domains have been identified associated with C3G in small families and include: FHR‐2(1–2)‐FHR‐5, 65 FHR‐5(1–2)‐FHR‐2, 68 FHR‐1(1–3)‐FHR‐5, 67 FHR‐1(1–4)‐FHR‐1, 63 and FHR‐1(1–2)‐FHR‐1 64 . Different studies have tried to explain why these peculiar FHR variants associate with C3G.…”

“…However, a competition with FH would justify better an association with aHUS than with C3G 26 . Notably, recent data generated for the FHR‐1(1–2)‐FHR‐1 variant suggest these FHRs variants dysregulate complement at C3‐opsonized surfaces by promoting complement activation and further deposition of C3‐activated fragments without interfering the binding of FH to C3b 64 . In summary, variants that confer to FHR‐1 the capacity to bind sialic acids dysregulate complement at endothelial surfaces and result in aHUS, whilst FHR mutant proteins with duplicated dimerization domains exacerbate complement activation at C3 opsonized surfaces and cause C3G.…”

Physiology and pathology of the C3 amplification cycle: A retrospective

“…74 Even more subtle variations in local control of C3 amplification have been revealed by the findings of mutations in complement FH-related (CFHR) proteins in a familial nephropathy first described in Cypriot families, where the resulting dimerization of the CFHR5 protein confers avidity for tissue bound complement fragments, increasing their capacity to compete with FH for ligand binding, thereby enhancing local complement activation. [75][76][77] Thus, there is an impressive body of evidence to indicate that complement dysregulation of the amplification cycle is the major predisposing factor in this group of diseases. Against a background of gross deregulation of the C3bBb amplification cycle, otherwise minor inflammatory events such as transient immune complex deposition, or minor degrees of endotoxinemia, can induce persistent renal inflammation, maybe with the participation of locally synthesized complement proteins.…”