A new screening test for C3 nephritis factor based on a stable cell bound convertase on sheep erythrocytes

Rother, U.

doi:10.1016/0022-1759(82)90386-6

Cited by 57 publications

(49 citation statements)

References 12 publications

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“…APH50 was 89% whereas the CH50 was 32%. The patient was tested negative for C3NeF by a hemolytic assay (Rother, 1982).…”

Section: Patient Descriptionmentioning

confidence: 99%

“…However, C3NeF is also found in patients with partial lipodystrophy and even in healthy individuals; therefore, its pathogenic role is unclear (Appel et al, 2005;Mathieson et al, 1993). In addition, C3NeF is usually identified by hemolysis assays (Rother, 1982) or by C3 breakdown products (Davies and Norsworthy, 2000), but not by measuring autoantibody binding to the C3 convertase directly, which brings uncertainty into the interpretation of literature data.…”

Section: Introductionmentioning

confidence: 99%

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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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“…APH50 was 89% whereas the CH50 was 32%. The patient was tested negative for C3NeF by a hemolytic assay (Rother, 1982).…”

Section: Patient Descriptionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti-factor B autoantibody in dense deposit disease

Strobel

Zimmering

Papp

et al. 2010

Molecular Immunology

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“…fH, fI, and fB levels were measured by sandwich ELISA as previously described (31)(32)(33). Anti-fH and C3Nef autoantibodies were detected as described previously (34,35). Their concentrations in plasma were calculated by reference to the appropriate calibration curve prepared from purified proteins and expressed as mg/dl plasma, or percent of control for fI concentration.…”

mentioning

confidence: 99%

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

Martı́nez-Barricarte¹,

Heurich²,

et al. 2010

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Dense deposit disease (DDD) is a severe renal disease characterized by accumulation of electron-dense material in the mesangium and glomerular basement membrane. Previously, DDD has been associated with deficiency of factor H (fH), a plasma regulator of the alternative pathway (AP) of complement activation, and studies in animal models have linked pathogenesis to the massive complement factor 3 (C3) activation caused by this deficiency. Here, we identified a unique DDD pedigree that associates disease with a mutation in the C3 gene. Mutant C3 923ΔDG , which lacks 2 amino acids, could not be cleaved to C3b by the AP C3-convertase and was therefore the predominant circulating C3 protein in the patients. However, upon activation to C3b by proteases, or to C3(H 2 O) by spontaneous thioester hydrolysis, C3 923ΔDG generated an active AP C3-convertase that was regulated normally by decay accelerating factor (DAF) but was resistant to decay by fH. Moreover, activated C3b 923ΔDG and C3(H 2 O) 923ΔDG were resistant to proteolysis by factor I (fI) in the presence of fH, but were efficiently inactivated in the presence of membrane cofactor protein (MCP). These characteristics cause a fluid phase-restricted AP dysregulation in the patients that continuously activated and consumed C3 produced by the normal C3 allele. These findings expose structural requirements in C3 that are critical for recognition of the substrate C3 by the AP C3-convertase and for the regulatory activities of fH, DAF, and MCP, all of which have implications for therapeutic developments. IntroductionComplement is a major component of innate immunity, with crucial roles in microbial killing, apoptotic cell clearance, immune complex handling, and modulation of adaptive immune responses. Complement is activated by 3 independent activation pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). The critical steps in complement activation are the formation of unstable protease complexes, named complement factor 3-convertases (C3-convertases; specifically, C3bBb for AP and C4b2a for CP and LP), and the cleavage of C3 by the convertases to generate C3b. Convertase-generated C3b can form more AP C3-convertase, providing exponential amplification to the initial activation. Binding of C3b to the C3-convertases generates the C5-convertases with the capacity to bind and cleave C5, initiating formation of the lytic membrane attack complex (MAC). In contrast to the CP and the LP, whose activation is triggered by immune complexes and bacterial mannose groups, respectively, the AP is intrinsically activated. Spontaneous activation of C3 in plasma occurs through the tick-over mecha-

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“…The following three methods based on different principles were used an alternative pathway-dependent sheep erythrocyte (ShE) haemolytic assay [27], an assay for fluid-phase C3 cleavage as assessed by crossed immunoelectrophoresis (CIE) [ 1 1, 2 61, and isoelectric focusing (IEF) combined with alternative pathway-mediated haemolysis of guinea-pig erythrocytes (GpE) [4]. Ethylene diamine tetra-acetic acid (EDTA) was used in buffers for blocking of complement activation, and ethyleneglycol tetra-acetic acid (Sigma Chemical Co., St Louis, MO, USA) with MgL+ added (Mg" EGTA) for selective blocking of classical pathway activation.…”

Section: Nef Assaysmentioning

confidence: 99%

Hypocomplementaemia caused by C3 nephritic factors (C3 NeF): clinical findings and the coincidence of C3 NeF type II with anti‐C1q autoantibodies

Skattum

Mårtensson

Sjöholm

1997

Journal of Internal Medicine

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Objectives. The main purposes were to document manifestations associated with prolonged or clinically unexplained C3 deficiency and to approximate how often hypocomplementaemia of this kind is caused by C3 nephritic factors (C3 NeF), i.e. autoantibodies to alternative pathway C3 convertases. We also wished to distinguish between C3 NeF types I and I1 and to assess coincident autoantibody responses to the collagen-like region of C l q (ClqCLR). Setting. The investigation was based on serum Samples referred to a specialized laboratory for complement analysis in the course of several years. Subjects. Twenty-five persons with C3 concentrations lower than 0.43 g L-', a third of the normal, were included in the study, Results. Analysis using three methods provided evidence of C3 NeF in 20 persons with equal frequencies of C3 NeF types I and 11. We also gave evidence of antibody specificity differences for the two types of C3 NeF. Six patients with C3 NeF type I1 showed antibodies to C 1 qCLR. Membranoproliferative glomerulonephritis was the predominant diagnosis and two patients had partial lipodystrophy reflecting the wellknown association between these diseases and C3 NeF. Anaphylactoid purpura, systemic lupus erythematosus, and severe infection, mainly meningococcal disease, were also observed. Conclusions. The study group was probably fairly representative of C3 deficiency syndromes as encountered in clinical practice. The findings emphasize the heterogeneity of C3 NeF, and that acquired C3 deficiency syndromes caused by C3 NeF should perhaps be considered more often in diagnostic work.

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A new screening test for C3 nephritis factor based on a stable cell bound convertase on sheep erythrocytes

Cited by 57 publications

References 12 publications

Anti-factor B autoantibody in dense deposit disease

Anti-factor B autoantibody in dense deposit disease

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

Hypocomplementaemia caused by C3 nephritic factors (C3 NeF): clinical findings and the coincidence of C3 NeF type II with anti‐C1q autoantibodies

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