Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation

Martı́nez-Barricarte, Rubén; Heurich, Meike; Valdés-Cañedo, Francisco; Vazquez-Martul, Eduardo; Torreira, Eva; Montes, Tamara; Tortajada, Agustín; Pinto, Sheila; López‐Trascasa, Margarita; Morgan, B. Paul; Llorca, Óscar; Harris, Claire L.; Córdoba, Santiago Rodrı́guez de

doi:10.1172/jci43343

Cited by 195 publications

(205 citation statements)

References 39 publications

(37 reference statements)

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“…Three familial studies, in particular, have provided unique insights into DDD and C3GN. These families include one family described by Martínez-Barricarte et al (11) in which a mother and her two identical twin boys segregated a 2-amino acid deletion in MG7 of C3 (D923-924AspGly). This mutation makes C3 resistant to cleavage by C3 convertase; however, through the normal tick-over process, a hydrolyzed mutant C3 convertase forms that is resistant to factor H regulation but can cleave circulating wild-type C3.…”

Section: Discussionmentioning

confidence: 99%

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Bomback

Smith

Barile

et al. 2012

Clinical Journal of the American Society of Nephrology

309

259

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SummaryBackground and objectives The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial. Design, setting, participants, & measurementsIn this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria .1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark. ResultsThe subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria.Conclusions Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.

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Section: Discussionmentioning

confidence: 99%

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Bomback

Smith

Barile

et al. 2012

Clinical Journal of the American Society of Nephrology

309

259

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“…Nevertheless, attention should be paid because certain mutations in factor B or C3 are resistant to regulation by FH, and C3 nephritic factors may also render the C3 convertase resistant to regulation (61)(62)(63)(64)(65). Mini-FH could likely also be used to protect erythrocytes from complement-mediated damage in patients with paroxysmal nocturnal hemoglobinuria (PNH) (66).…”

Section: Discussionmentioning

confidence: 99%

An Engineered Construct Combining Complement Regulatory and Surface-Recognition Domains Represents a Minimal-Size Functional Factor H

Hebecker

Alba-Domínguez

Roumenina

et al. 2013

The Journal of Immunology

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Complement is an essential humoral component of innate immunity; however, its inappropriate activation leads to pathology. Polymorphisms, mutations, and autoantibodies affecting factor H (FH), a major regulator of the alternative complement pathway, are associated with various diseases, including age-related macular degeneration, atypical hemolytic uremic syndrome, and C3 glomerulopathies. Restoring FH function could be a treatment option for such pathologies. In this article, we report on an engineered FH construct that directly combines the two major functional regions of FH: the N-terminal complement regulatory domains and the C-terminal surface-recognition domains. This minimal-size FH (mini-FH) binds C3b and has complement regulatory functions similar to those of the full-length protein. In addition, we demonstrate that mini-FH binds to the FH ligands C-reactive protein, pentraxin 3, and malondialdehyde epitopes. Mini-FH was functionally active when bound to the extracellular matrix and endothelial cells in vitro, and it inhibited C3 deposition on the cells. Furthermore, mini-FH efficiently inhibited complement-mediated lysis of host-like cells caused by a disease-associated FH mutation or by anti-FH autoantibodies. Therefore, mini-FH could potentially be used as a complement inhibitor targeting host surfaces, as well as to replace compromised FH in diseases associated with FH dysfunction.

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“…For example, fH would be ineffective in C3G patients carrying C3 mutations that render C3 convertase fH resistant or in the presence of autoantibodies to C3 convertase that block regulation by fH. 13,14 Among the non-fH proteins that regulate C3 convertase is soluble CR1. CR1 is a cell-surface glycoprotein expressed on erythrocytes, monocytes, neutrophils, B cells, some T cells, follicular dendritic cells, and podocytes, and modulates the complement cascade at multiple levels (Supplemental Figures 1 and 2).…”

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confidence: 99%

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

Zhang

Nester

Holanda

et al. 2013

Journal of the American Society of Nephrology

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Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are widely recognized subtypes of C3 glomerulopathy. These ultra-rare renal diseases are characterized by fluid-phase dysregulation of the alternative complement pathway that leads to deposition of complement proteins in the renal glomerulus. Disease triggers are unknown and because targeted treatments are lacking, progress to end stage renal failure is a common final outcome. We studied soluble CR1, a potent regulator of complement activity, to test whether it restores complement regulation in C3 glomerulopathy. In vitro studies using sera from patients with DDD showed that soluble CR1 prevents dysregulation of the alternative pathway C3 convertase, even in the presence of C3 nephritic factors. In mice deficient in complement factor H and transgenic for human CR1, soluble CR1 therapy stopped alternative pathway activation, resulting in normalization of serum C3 levels and clearance of iC3b from glomerular basement membranes. Shortterm use of soluble CR1 in a pediatric patient with end stage renal failure demonstrated its safety and ability to normalize activity of the terminal complement pathway. Overall, these data indicate that soluble CR1 re-establishes regulation of the alternative complement pathway and provide support for a limited trial to evaluate soluble CR1 as a treatment for DDD and C3GN. Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are two widely recognized subtypes of C3 glomerulopathy (C3G). 1,2 These ultra-rare renal diseases are caused by fluid-phase dysregulation of the C3 convertase of the alternative pathway (AP) of complement, with variable concomitant dysregulation of the C5 convertase. Consistent with complement-mediated disease acting through the AP, C3G is strongly positive for C3 and notably negative for Igs by immunofluorescence microscopy. 2 Electron microscopy distinguishes DDD from C3GN, with the former characterized by pathognomonic electron-dense transformation of the lamina densa of the glomerular basement membrane (GBM). 3 In C3GN, the electron microscopy deposits are lighter in color, and are more often mesangial and/or subendothelial, intramembranous, and subepithelial in location. 4 In both diseases, mass spectroscopy of laser dissected glomeruli is highly enriched for proteins of the AP and terminal complement cascade. 4,5

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Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation

Cited by 195 publications

References 39 publications

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

An Engineered Construct Combining Complement Regulatory and Surface-Recognition Domains Represents a Minimal-Size Functional Factor H

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

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