Serum C′3 Lytic System in Patients with Glomerulonephritis

Spitzer, Robert J.; Vallota, Enrique H.; Forristal, Judith; Sudora, E; Stitzel, Ann E.; Davis, Neil C.; West, Clark D.

doi:10.1126/science.164.3878.436

Cited by 233 publications

(80 citation statements)

References 7 publications

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“…An anti-factor H miniantibody consisting of lambda light-chains, which inhibited factor H complement regulatory activity, was identified in a DDD patient (Meri et al, 1992;Jokiranta et al, 1999). C3 nephritic factor (C3NeF), an antibody against the C3bBb convertase (Spitzer et al, 1969), is found in 50-80% of DDD patients (Schwertz et al, 2001;Appel et al, 2005). C3NeF binds to a neoepitope on the newly assembled C3bBb, increases the half-life of the convertase against both intrinsic and extrinsic, factor H-mediated, decay and thus enhances C3 consumption (Daha et al, 1976).…”

Section: Introductionmentioning

confidence: 99%

Anti-factor B autoantibody in dense deposit disease

Strobel

Zimmering

Papp

et al. 2010

Molecular Immunology

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Dense deposit disease (DDD), also known as membranoproliferative glomerulonephritis type II, is a rare kidney disorder that is associated with dysregulation of the alternative pathway of complement. Autoantibodies against the C3bBb convertase termed C3 nephritic factor are common in DDD patients. Here we report an autoantibody that binds to complement factor B in a DDD patient who was negative for C3 nephritic factor. This anti-factor B autoantibody recognized an epitope within the Bb fragment and was able to bind to the C3bBb convertase.Upon binding, the anti-factor B autoantibody stabilized the convertase against both intrinsic and factor H-mediated extrinsic decay, and thus enhanced C3 consumption. Functional analyses demonstrated that, in contrast to C3 nephritic factor, the anti-factor B autoantibody inhibited complement-mediated lysis in vitro due to inhibition of the C5 convertase and the terminal complement pathway. Analysis of C5a plasma levels indicated that not all C5 convertases are inhibited by the autoantibodies in the patient in vivo. Antigen array experiments confirmed the presence of anti-factor B autoantibodies and also revealed complement activating anti-C1q antibodies in the patient's plasma. In summary, the present report describes a new autoantibody in DDD that binds to factor B and to the alternative pathway C3 convertase and alters the kinetics of complement activation and regulation.

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Section: Introductionmentioning

confidence: 99%

Anti-factor B autoantibody in dense deposit disease

Strobel

Zimmering

Papp

et al. 2010

Molecular Immunology

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“…Studies in humans further suggest that the generation of C5a is, by itself, insufficient to produce ARDS (58). Similarly, systemic activation of complement in patients with nephritis due to nephritic factor (59) has not been shown to lead to lung injury. Taken together, these data imply the involvement of multiple factors, including the generation of complementderived chemotactic factors, in the pathogenesis of ARDS.…”

Section: Neutrophil-mediated Endothelial Injury 1239mentioning

confidence: 99%

Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase.

Smedly¹,

Tonnesen²,

Sandhaus³

et al. 1986

J. Clin. Invest.

559

204

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The neutrophil has been implicated as an important mediator of vascular injury, especially after endotoxemia. This study examines neutrophil-mediated injury to human microvascular endothelial cells in vitro. We found that neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a, or lipopolysaccharide (LPS) (1-1,000 ng/ ml) alone produced minimal endothelial injury over a 4-h assay. In contrast, neutrophils incubated with endothelial cells in the presence of low concentrations of LPS (1-10 ng/ml) could then be stimulated by FMLP or C5a to produce marked endothelial injury. Injury was maximal at concentrations of 100 ng/ml LPS and 1o-7 M FMLP. Pretreatment of neutrophils with LPS resulted in a similar degree of injury, suggesting that LPS effects were largely on the neutrophil. Endothelial cell injury produced by LPS-exposed, FMLP-stimulated neutrophils had a time course similar to that induced by the addition of purified human neutrophil elastase, and different from that induced by hydrogen peroxide (H202). Further, neutrophil-mediated injury was not inhibited by scavengers of a variety of oxygen radical species, and occurred with neutrophils from a patient with chronic granulomatous disease, which produced no H202. In contrast, the specific serine elastase inhibitor methoxy-succinyl-alanyl-alanylprolyl-valyl-chloromethyl ketone inhibited 63% of the neutrophilmediated injury and 64% of the neutrophil elastase-induced injury. However, neutrophil-mediated injury was not inhibited significantly by 50% serum, 50% plasma, or purified a, proteinase inhibitor. These results suggest that, in this system, chemotactic factor-stimulated human neutrophil injury of microvascular endothelial cells is enhanced by small amounts of LPS and may be mediated in large part by the action of neutrophil elastase.

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“…First identified in 1969 by Spitzer et al (12), C3Nefs were described as a substance in serum that increases AP activity from basal "tick-over" levels. Tick-over is the process by which hydrolysis of a reactive thioester in C3 generates small amounts of an initial C3 convertase called C3(H 2 O)Bb.…”

Section: Introductionmentioning

confidence: 99%

Causes of Alternative Pathway Dysregulation in Dense Deposit Disease

Zhang¹,

Meyer²,

Wang

et al. 2012

Clinical Journal of the American Society of Nephrology

171

160

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SummaryBackground and objectives This study was designed to investigate the causes of alternative pathway dysregulation in a cohort of patients with dense deposit disease (DDD).Design, setting, participants, & measurements Thirty-two patients with biopsy-proven DDD underwent screening for C3 nephritic factors (C3Nefs), factor H autoantibodies (FHAAs), factor B autoantibodies (FBAAs), and genetic variants in CFH. C3Nefs were detected by: ELISA, C3 convertase surface assay (C3CSA), C3CSA with properdin (C3CSAP), two-dimensional immunoelectrophoresis (2DIEP), and immunofixation electrophoresis (IFE). FHAAs and FBAAs were detected by ELISA, and CFH variants were identified by Sanger sequencing.Results Twenty-five patients (78%) were positive for C3Nefs. Three C3Nef-positive patients were also positive for FBAAs and one of these patients additionally carried two novel missense variants in CFH. Of the seven C3Nef-negative patients, one patient was positive for FHAAs and two patients carried CFH variants that may be causally related to their DDD phenotype. C3CASP was the most sensitive C3Nef-detection assay. C3CASP and IFE are complementary because C3CSAP measures the stabilizing properties of C3Nefs, whereas IFE measures their expected consequence-breakdown of C3b.Conclusions A test panel that includes C3CSAP, IFE, FHAAs, FBAAs, and genetic testing for CFH variants will identify a probable cause for alternative pathway dysregulation in approximately 90% of DDD patients. Dysregulation is most frequently due to C3Nefs, although some patients test positive for FHAAs, FBAAs, and CFH mutations. Defining the pathophysiology of DDD should facilitate the development of mechanism-directed therapies.

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Serum C′3 Lytic System in Patients with Glomerulonephritis

Cited by 233 publications

References 7 publications

Anti-factor B autoantibody in dense deposit disease

Anti-factor B autoantibody in dense deposit disease

Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase.

Causes of Alternative Pathway Dysregulation in Dense Deposit Disease

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