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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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The 3 complement activation pathways. Bold text denotes complement-regulatory molecules; red text, proteins with genetic defects that have been associated with atypical hemolytic uremic syndrome (aHUS) and/or membranoproliferative glomerulopathy (MPGN)/C3 glomerulopathy (C3G). Abbreviations and definitions: C3(H2O)Bb, alternative pathway initiation convertase; C1inh, C1 inhibitor (inactivates C1r and C1s, MASP-1, and MASP-2); FB, complement factor B; FD, complement factor D; FH, complement factor H (binds C3b, exerts cofactor activity for FI-mediated C3b cleavage, prevents the formation of the alternative pathway C3 convertase, and destabilizes (decay accelerating activity) the alternative pathway C3 and C5 convertases); C4BP, C4b-binding protein (binds to C4b and has decay accelerating activity for the classical pathway C3 convertase and cofactor activity for FI-mediated C4b cleavage); CD59, protectin (with vitronectin and clusterin, prevents C5b-9 formation); CR1, complement receptor 1 (has decay accelerating activity as well as cofactor activity for FI-mediated C3b and C4b cleavage); DAF, decay accelerating factor (has decay accelerating activity on C3/C5 convertases of the classical and alternative pathways); FI, complement factor I (degrades C3b and C4b, aided by cofactors); Ig, immunoglobulin; MASP, MBL-associated serine proteases; MBL, mannose binding lectin; MCP, membrane cofactor protein (exerts cofactor activity for FI-mediated C3b cleavage); P, properdin.
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fig1: The 3 complement activation pathways. Bold text denotes complement-regulatory molecules; red text, proteins with genetic defects that have been associated with atypical hemolytic uremic syndrome (aHUS) and/or membranoproliferative glomerulopathy (MPGN)/C3 glomerulopathy (C3G). Abbreviations and definitions: C3(H2O)Bb, alternative pathway initiation convertase; C1inh, C1 inhibitor (inactivates C1r and C1s, MASP-1, and MASP-2); FB, complement factor B; FD, complement factor D; FH, complement factor H (binds C3b, exerts cofactor activity for FI-mediated C3b cleavage, prevents the formation of the alternative pathway C3 convertase, and destabilizes (decay accelerating activity) the alternative pathway C3 and C5 convertases); C4BP, C4b-binding protein (binds to C4b and has decay accelerating activity for the classical pathway C3 convertase and cofactor activity for FI-mediated C4b cleavage); CD59, protectin (with vitronectin and clusterin, prevents C5b-9 formation); CR1, complement receptor 1 (has decay accelerating activity as well as cofactor activity for FI-mediated C3b and C4b cleavage); DAF, decay accelerating factor (has decay accelerating activity on C3/C5 convertases of the classical and alternative pathways); FI, complement factor I (degrades C3b and C4b, aided by cofactors); Ig, immunoglobulin; MASP, MBL-associated serine proteases; MBL, mannose binding lectin; MCP, membrane cofactor protein (exerts cofactor activity for FI-mediated C3b cleavage); P, properdin.

Mentions: The complement system is organized in 3 activation pathways (the alternative, classical, and lectin pathways) and a common terminal pathway (Fig 1). Activation of the 3 pathways leads to the formation of protease complexes (C3 convertases) that cleave C3 into C3a and C3b.


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)

The 3 complement activation pathways. Bold text denotes complement-regulatory molecules; red text, proteins with genetic defects that have been associated with atypical hemolytic uremic syndrome (aHUS) and/or membranoproliferative glomerulopathy (MPGN)/C3 glomerulopathy (C3G). Abbreviations and definitions: C3(H2O)Bb, alternative pathway initiation convertase; C1inh, C1 inhibitor (inactivates C1r and C1s, MASP-1, and MASP-2); FB, complement factor B; FD, complement factor D; FH, complement factor H (binds C3b, exerts cofactor activity for FI-mediated C3b cleavage, prevents the formation of the alternative pathway C3 convertase, and destabilizes (decay accelerating activity) the alternative pathway C3 and C5 convertases); C4BP, C4b-binding protein (binds to C4b and has decay accelerating activity for the classical pathway C3 convertase and cofactor activity for FI-mediated C4b cleavage); CD59, protectin (with vitronectin and clusterin, prevents C5b-9 formation); CR1, complement receptor 1 (has decay accelerating activity as well as cofactor activity for FI-mediated C3b and C4b cleavage); DAF, decay accelerating factor (has decay accelerating activity on C3/C5 convertases of the classical and alternative pathways); FI, complement factor I (degrades C3b and C4b, aided by cofactors); Ig, immunoglobulin; MASP, MBL-associated serine proteases; MBL, mannose binding lectin; MCP, membrane cofactor protein (exerts cofactor activity for FI-mediated C3b cleavage); P, properdin.
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fig1: The 3 complement activation pathways. Bold text denotes complement-regulatory molecules; red text, proteins with genetic defects that have been associated with atypical hemolytic uremic syndrome (aHUS) and/or membranoproliferative glomerulopathy (MPGN)/C3 glomerulopathy (C3G). Abbreviations and definitions: C3(H2O)Bb, alternative pathway initiation convertase; C1inh, C1 inhibitor (inactivates C1r and C1s, MASP-1, and MASP-2); FB, complement factor B; FD, complement factor D; FH, complement factor H (binds C3b, exerts cofactor activity for FI-mediated C3b cleavage, prevents the formation of the alternative pathway C3 convertase, and destabilizes (decay accelerating activity) the alternative pathway C3 and C5 convertases); C4BP, C4b-binding protein (binds to C4b and has decay accelerating activity for the classical pathway C3 convertase and cofactor activity for FI-mediated C4b cleavage); CD59, protectin (with vitronectin and clusterin, prevents C5b-9 formation); CR1, complement receptor 1 (has decay accelerating activity as well as cofactor activity for FI-mediated C3b and C4b cleavage); DAF, decay accelerating factor (has decay accelerating activity on C3/C5 convertases of the classical and alternative pathways); FI, complement factor I (degrades C3b and C4b, aided by cofactors); Ig, immunoglobulin; MASP, MBL-associated serine proteases; MBL, mannose binding lectin; MCP, membrane cofactor protein (exerts cofactor activity for FI-mediated C3b cleavage); P, properdin.
Mentions: The complement system is organized in 3 activation pathways (the alternative, classical, and lectin pathways) and a common terminal pathway (Fig 1). Activation of the 3 pathways leads to the formation of protease complexes (C3 convertases) that cleave C3 into C3a and C3b.

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