C5 nephritic factors drive the biological phenotype of C3 glomerulopathies

Marinozzi, Maria-Chiara; Chauvet, Sophie; Quintrec, Moglie Le; Mignotet, Morgane; Petitprez, Florent; Legendre, Christophe; Cailliez, Mathilde; Deschenes, Georges; Fischbach, Michel; Karras, Alexandre; Nobili, François; Piètrement, Christine; Dragon-Durey, Marie-Agnès; Fakhouri, Fádi; Roumenina, Lubka T.; Frémeaux‐Bacchi, Véronique

doi:10.1016/j.kint.2017.04.017

Cited by 85 publications

(109 citation statements)

References 28 publications

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“…According to the authors, binding of FP to C3bBb stabilizes C5 convertase rather than C3 convertase. The prevalence of C5Nef was higher in C3GN (72%), while C3Nef was more frequent in DDD (71%), suggesting that the type of nephritic factors may determine the biological phenotype of C3G [98]. These results are consistent with the previously described role of FP in animal models deficient in CFH gene, where coexisting FP deficiency was associated with C3 depletion, whereas plasma C5 depletion was (at least in part) FP-dependent [91,92].…”

Section: Acquired Ap Abnormalities In C3gsupporting

confidence: 89%

“…However, the activation of MAC occurs only when C3 convertase is stabilized by both C3Nef and FP [96,97]. In a recent study, Marinozzi et al [98] have shown a more detailed insight on the association between FP and autoantibodies to AP components. The authors found IgG to C5 convertase (called C5Nef) in 49% of C3G cases and C3Nef in 68% of cases, including 39% patients positive for both C3 and C5Nefs.…”

Section: Acquired Ap Abnormalities In C3gmentioning

confidence: 99%

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The role of the alternative pathway of complement activation in glomerular diseases

2018

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The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called 'thick-over.' A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.

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Section: Acquired Ap Abnormalities In C3gsupporting

confidence: 89%

Section: Acquired Ap Abnormalities In C3gmentioning

confidence: 99%

The role of the alternative pathway of complement activation in glomerular diseases

2018

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“…Autoantibodies against complement components occur in a significant proportion of cases with C3G or IC-MPGN, although only a few large-scale studies have analyzed their presence in these conditions. Case reports [4,12,16,21,23,24] and case series studies [2], [5,31,32] described the presence of nephritic factors and other complement autoantibodies, but still, approximately 30 to 60% of the C3G cases remain without identified pathogenic factors (autoantibodies to complement components or pathogenic variants of disease-associated complement genes).…”

Section: Discussionmentioning

confidence: 99%

“…These antibodies are routinely measured in complement laboratories all over the world, although their exact contribution to the disease pathomechanism is not entirely known. Interestingly, C5 nephritic factor is a recently described antibody which can bind to the C5-convertase and has a similar function [21]. On the other hand, C4 nephritic factor (C4NeF) is analogous to C3NeF, this autoantibody can stabilize the C3-convertase (C4bC2a) shared by the classical and by the lectin pathways, in a dose-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy

Garam

Prohászka

Szilágyi

et al. 2019

Orphanet J Rare Dis

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Background: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. Results: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF.

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“…The main autoantibodies associated with C3G are the so-called NeFs, which comprise a heterogenous group of antibodies against neoepitopes generated in C3 or C5 convertases with the capacity to stabilize the molecule and prolong its half-life [20]. Two major subtypes of C3 nephritic factors (C3NeFs) have been described: properdin-dependent C3NeFs responsible for the activation of C5 convertase, also called C5NeFs [30], and properdinindependent C3NeFs that target the C3 convertase, as reflected by low C3 levels but normal serum levels of the terminal complement pathway [20]. C3NeFs (properdin-independent) have mainly been associated with DDD, whereas C5NeFs have been associated with C3GN [21].…”

Section: Pathogenesismentioning

confidence: 99%

Update on C3 Glomerulopathy: A Complement-Mediated Disease

Caravaca-Fontán

Lucientes

Cavero

et al. 2020

Nephron

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C3 glomerulopathy (C3G) is a clinicopathologic entity secondary to dysregulation of the alternative complement pathway in plasma and the glomerular microenvironment. The current consensus definition of C3G relies on immunofluorescence staining criteria. However, due to its high clinical variability, these criteria may not be accurate enough in some clinical scenarios. Thus, a new pathogenic classification based on a cluster analysis of clinical, histologic, and genetic data has recently been proposed, which could also help identify patients at higher risk of progression. Several pathogenic abnormalities in complement genes have been described, and the role of autoantibodies in the disease is increasingly recognized, but still the genotype-phenotype correlations in C3G are poorly understood. C3G may be diagnosed in both children and adults. The spectrum of clinical manifestations is wide, although one of the most common clinical presentations is proteinuria with relatively preserved kidney function. In order to standardize the evaluation of kidney biopsies from these patients, a histopathologic index was recently proposed, including both parameters of activity and chronicity. However, this index has not yet been val-idated in independent cohorts. Currently, no targeted therapies are available in clinical settings for the treatment of C3G, although several new molecules are under investigation. Treatment with corticosteroids plus mycophenolate mofetil has been shown to be associated with improved renal outcomes, as compared to other immunosuppressive regimens. Yet, the main determinants of treatment response with this regimen and the influence of the underlying pathogenic drivers have not been extensively studied. The therapeutic response to eculizumab, an anti-C5 monoclonal antibody, has been shown to be highly heterogeneous. Thus, its current clinical indication in C3G is restricted to rapidly progressive forms of the disease. To summarize, in recent years, several important advances have taken place in the understanding of C3G, but still further studies are warranted to elucidate the best therapeutic strategies that could improve prognosis of this entity.

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C5 nephritic factors drive the biological phenotype of C3 glomerulopathies

Cited by 85 publications

References 28 publications

The role of the alternative pathway of complement activation in glomerular diseases

The role of the alternative pathway of complement activation in glomerular diseases

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy

Update on C3 Glomerulopathy: A Complement-Mediated Disease

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