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Glomerular Diseases Dependent on Complement Activation, Including Atypical Hemolytic Uremic Syndrome, Membranoproliferative Glomerulonephritis, and C3 Glomerulopathy: Core Curriculum 2015.

Noris M, Remuzzi G - Am. J. Kidney Dis. (2015)

View Article: PubMed Central - PubMed

Affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Italy.

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Interest in the complement system has been boosted in the past 15 years by the discovery that rare devastating kidney diseases, including atypical hemolytic uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN), are disorders of complement regulation... More recently, a novel nonallelic homologous recombination event that forms a reverse hybrid gene consisting of the first 5 exons of CFHR1 and the last exon of CFH has been reported in 2 patients with familial aHUS... Overall, hybrid genes account for 3% to 5% of patients with aHUS (Table 2) and result in gene products with decreased complement-regulatory activity on endothelial surfaces... An acquired CFH defect due to anti-CFH immunoglobulin G (IgG) autoantibodies accounts for 5% to 10% and 25% to 50% of adult and pediatric aHUS cases, respectively (Table 2)... Ninety percent of patients with anti-CFH antibodies have a complete deficiency of CFHR1 and CFHR3 associated with a homozygous deletion of CFHR1 and CFHR3, a polymorphism also observed in 4% of healthy individuals of European ancestry who do not develop anti-CFH antibodies... Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32... A second type of C3Nef was found to display slower C3 activation and dependence on properdin for convertase stabilization... Properdin-independent C3Nefs have been found to have no effect on C5 cleavage and terminal pathway activity, whereas properdin-dependent C3Nef enhances C5 convertase activity... C3Nefs are found in >80% of patients with DDD and 40% to 50% of patients with C3 glomerulonephritis or immune-complex–mediated MPGN... However, in most studies, the presence of C3Nefs has not been found to correlate with disease outcome... However, it forms the alternative pathway initiation C3 convertase (C3[H2O]Bb; Fig 1) through the normal “tick-over” process... This convertase is capable of cleaving circulating wild-type C3 produced from the normal allele, but is resistant to CFH-mediated regulation, resulting in a dominant gain-of-function effect of the mutation... The paradigm of the distinct pathogenetic mechanisms of complement activation (cell surface vs fluid phase) leading to aHUS versus MPGN has been recently thrown into question by a number of findings... At variance with the almost universal response to eculizumab that is observed in aHUS, case reports and a small trial have shown a clinical response (reduction in serum creatinine and/or proteinuria and histopathologic improvement) in some but not all patients with C3G or immune-complex–mediated MPGN either in native kidneys or recurring in the kidney transplant... The last decade has seen great advances in the knowledge of the pathophysiologic role of complement activation in aHUS, immune-complex–mediated MPGN, and C3G and has led to the discovery of an effective therapy, at least in aHUS.

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Model for mechanisms leading from fluid-phase impaired regulation of the alternative pathway to C3 glomerulopathies. Mutations in the factor H (FH) gene causing very low FH levels or impaired FH cofactor activity, or C3 nephritic factor (C3NeF) and C3 gain-of-function mutations that render the alternative pathway C3 convertase resistant to FH-mediated dissociation; all result in uncontrolled fluid-phase alternative pathway activation and finally in the formation of the fluid-phase terminal complement pathway complex (with vitronectin or clusterin bound; sC5b-9). The injury likely develops upon deposition in the subendothelial space of C3 activating products and the terminal complement complex after transfer through the fenestrated endothelium (dashed line). Abbreviations: FB, factor B; FI, factor I; MCP, membrane cofactor protein.
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fig7: Model for mechanisms leading from fluid-phase impaired regulation of the alternative pathway to C3 glomerulopathies. Mutations in the factor H (FH) gene causing very low FH levels or impaired FH cofactor activity, or C3 nephritic factor (C3NeF) and C3 gain-of-function mutations that render the alternative pathway C3 convertase resistant to FH-mediated dissociation; all result in uncontrolled fluid-phase alternative pathway activation and finally in the formation of the fluid-phase terminal complement pathway complex (with vitronectin or clusterin bound; sC5b-9). The injury likely develops upon deposition in the subendothelial space of C3 activating products and the terminal complement complex after transfer through the fenestrated endothelium (dashed line). Abbreviations: FB, factor B; FI, factor I; MCP, membrane cofactor protein.

Mentions: Upregulated activity of the complement alternative pathway can be caused by autoantibodies targeted at either C3 convertase or its components or at regulatory proteins. The first described autoantibody was C3Nef, which binds to a neoepitope on the C3 convertase of the alternative pathway component C3bBb, stabilizing it against CFH-mediated decay and prolonging its C3 cleaving action (Fig 7). A second type of C3Nef was found to display slower C3 activation and dependence on properdin for convertase stabilization. Properdin-independent C3Nefs have been found to have no effect on C5 cleavage and terminal pathway activity, whereas properdin-dependent C3Nef enhances C5 convertase activity. C3Nefs are found in >80% of patients with DDD and 40% to 50% of patients with C3 glomerulonephritis or immune-complex–mediated MPGN. However, in most studies, the presence of C3Nefs has not been found to correlate with disease outcome. In a family with MPGN and partial lipodystrophy, C3Nef was detected in all members with lipodystrophy but did not segregate with the renal phenotype. In addition, C3NeFs have been also found in patients with meningococcal meningitis, lupus nephritis, and even healthy individuals and asymptomatic family members of patients with DDD, indicating that the presence of C3NeFs alone is not sufficient for the development of C3G. Whether C3Nefs are the primary causes of the disease or are secondarily formed as consequences of the disease process is still unclear. Additional studies are needed to define the significance of C3NeFs in the pathophysiology of immune-complex–mediated MPGN and C3G and their relationship to disease course and treatment.


Glomerular Diseases Dependent on Complement Activation, Including Atypical Hemolytic Uremic Syndrome, Membranoproliferative Glomerulonephritis, and C3 Glomerulopathy: Core Curriculum 2015.

Noris M, Remuzzi G - Am. J. Kidney Dis. (2015)

Model for mechanisms leading from fluid-phase impaired regulation of the alternative pathway to C3 glomerulopathies. Mutations in the factor H (FH) gene causing very low FH levels or impaired FH cofactor activity, or C3 nephritic factor (C3NeF) and C3 gain-of-function mutations that render the alternative pathway C3 convertase resistant to FH-mediated dissociation; all result in uncontrolled fluid-phase alternative pathway activation and finally in the formation of the fluid-phase terminal complement pathway complex (with vitronectin or clusterin bound; sC5b-9). The injury likely develops upon deposition in the subendothelial space of C3 activating products and the terminal complement complex after transfer through the fenestrated endothelium (dashed line). Abbreviations: FB, factor B; FI, factor I; MCP, membrane cofactor protein.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528072&req=5

fig7: Model for mechanisms leading from fluid-phase impaired regulation of the alternative pathway to C3 glomerulopathies. Mutations in the factor H (FH) gene causing very low FH levels or impaired FH cofactor activity, or C3 nephritic factor (C3NeF) and C3 gain-of-function mutations that render the alternative pathway C3 convertase resistant to FH-mediated dissociation; all result in uncontrolled fluid-phase alternative pathway activation and finally in the formation of the fluid-phase terminal complement pathway complex (with vitronectin or clusterin bound; sC5b-9). The injury likely develops upon deposition in the subendothelial space of C3 activating products and the terminal complement complex after transfer through the fenestrated endothelium (dashed line). Abbreviations: FB, factor B; FI, factor I; MCP, membrane cofactor protein.
Mentions: Upregulated activity of the complement alternative pathway can be caused by autoantibodies targeted at either C3 convertase or its components or at regulatory proteins. The first described autoantibody was C3Nef, which binds to a neoepitope on the C3 convertase of the alternative pathway component C3bBb, stabilizing it against CFH-mediated decay and prolonging its C3 cleaving action (Fig 7). A second type of C3Nef was found to display slower C3 activation and dependence on properdin for convertase stabilization. Properdin-independent C3Nefs have been found to have no effect on C5 cleavage and terminal pathway activity, whereas properdin-dependent C3Nef enhances C5 convertase activity. C3Nefs are found in >80% of patients with DDD and 40% to 50% of patients with C3 glomerulonephritis or immune-complex–mediated MPGN. However, in most studies, the presence of C3Nefs has not been found to correlate with disease outcome. In a family with MPGN and partial lipodystrophy, C3Nef was detected in all members with lipodystrophy but did not segregate with the renal phenotype. In addition, C3NeFs have been also found in patients with meningococcal meningitis, lupus nephritis, and even healthy individuals and asymptomatic family members of patients with DDD, indicating that the presence of C3NeFs alone is not sufficient for the development of C3G. Whether C3Nefs are the primary causes of the disease or are secondarily formed as consequences of the disease process is still unclear. Additional studies are needed to define the significance of C3NeFs in the pathophysiology of immune-complex–mediated MPGN and C3G and their relationship to disease course and treatment.

View Article: PubMed Central - PubMed

Affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Italy.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Interest in the complement system has been boosted in the past 15 years by the discovery that rare devastating kidney diseases, including atypical hemolytic uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN), are disorders of complement regulation... More recently, a novel nonallelic homologous recombination event that forms a reverse hybrid gene consisting of the first 5 exons of CFHR1 and the last exon of CFH has been reported in 2 patients with familial aHUS... Overall, hybrid genes account for 3% to 5% of patients with aHUS (Table 2) and result in gene products with decreased complement-regulatory activity on endothelial surfaces... An acquired CFH defect due to anti-CFH immunoglobulin G (IgG) autoantibodies accounts for 5% to 10% and 25% to 50% of adult and pediatric aHUS cases, respectively (Table 2)... Ninety percent of patients with anti-CFH antibodies have a complete deficiency of CFHR1 and CFHR3 associated with a homozygous deletion of CFHR1 and CFHR3, a polymorphism also observed in 4% of healthy individuals of European ancestry who do not develop anti-CFH antibodies... Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32... A second type of C3Nef was found to display slower C3 activation and dependence on properdin for convertase stabilization... Properdin-independent C3Nefs have been found to have no effect on C5 cleavage and terminal pathway activity, whereas properdin-dependent C3Nef enhances C5 convertase activity... C3Nefs are found in >80% of patients with DDD and 40% to 50% of patients with C3 glomerulonephritis or immune-complex–mediated MPGN... However, in most studies, the presence of C3Nefs has not been found to correlate with disease outcome... However, it forms the alternative pathway initiation C3 convertase (C3[H2O]Bb; Fig 1) through the normal “tick-over” process... This convertase is capable of cleaving circulating wild-type C3 produced from the normal allele, but is resistant to CFH-mediated regulation, resulting in a dominant gain-of-function effect of the mutation... The paradigm of the distinct pathogenetic mechanisms of complement activation (cell surface vs fluid phase) leading to aHUS versus MPGN has been recently thrown into question by a number of findings... At variance with the almost universal response to eculizumab that is observed in aHUS, case reports and a small trial have shown a clinical response (reduction in serum creatinine and/or proteinuria and histopathologic improvement) in some but not all patients with C3G or immune-complex–mediated MPGN either in native kidneys or recurring in the kidney transplant... The last decade has seen great advances in the knowledge of the pathophysiologic role of complement activation in aHUS, immune-complex–mediated MPGN, and C3G and has led to the discovery of an effective therapy, at least in aHUS.

Show MeSH
Related in: MedlinePlus