Factor H Autoantibodies and Membranous Nephropathy

Seikrit, Claudia; Ronco, Pierre; Dębiec, Hanna

doi:10.1056/nejmc1805857

Cited by 36 publications

(23 citation statements)

References 4 publications

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“…Bally et al reported that PLA2R1-associated MN could develop in patients with IgG3 kappa anti-PLA2R1 antibodies having a complete MBL deficiency but capable of residual complement activation mainly due to the alternative pathway [30]. Moreover, Seikrit et al described a case of rapidly progressive renal failure in a patient with membranous nephropathy, related to the appearance of antibodies against the complement regulatory protein, factor H. Inhibition of factor H led to hyperactivation of the alternative complement pathway [39]. This mechanism could explain the alternative pathway activation in some MN patients.…”

Section: Discussionmentioning

confidence: 99%

Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation

Lateb

Ouahmi

Payré

et al. 2019

Journal of Immunology Research

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The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy (MN). However, the pathogenic role of anti-PLA2R1 autoantibodies is unclear. Our aim was to evaluate the in vitro cytotoxicity of anti-PLA2R1 antibodies mediated by complement. Forty-eight patients with PLA2R1-related MN from the prospective cohort SOURIS were included. Anti-PLA2R1 titer, epitope profile, and anti-PLA2R1 IgG subclasses were characterized by ELISA. Cell cytotoxicity was evaluated by immunofluorescence in HEK293 cells overexpressing PLA2R1 incubated with patient or healthy donor sera in the presence or absence of rabbit complement or complement inhibitors. Mean cytotoxicity of anti-PLA2R1 sera for HEK293 cells overexpressing PLA2R1 was 2±2%, which increased to 24±6% after addition of rabbit complement (p<0.001) (n=48). GVB-EDTA, which inhibits all complement activation pathways, completely blocked cell cytotoxicity, whereas Mg-EGTA, which only inhibits the classical and lectin pathways, highly decreased suggesting a limited role of the alternative pathway. A higher diversity of IgG subclasses beyond IgG4 and high titer of total IgG anti-PLA2R1 were associated with increased cytotoxicity (p=0.01 and p=0.03 respectively). In a cohort of 37 patients treated with rituximab, high level of complement-mediated cytotoxicity was associated with less and delayed remission at month 6 after rituximab therapy (5/12 vs. 20/25 (p=0.03) in 8.5 months±4.4 vs. 4.8±4.0 (p=0.02)). Kaplan-Meier analysis demonstrated that high level of cytotoxicity (≥40%) (p=0.005), epitope spreading (defined by immunization beyond the immunodominant CysR domain) (p=0.002), and high titer of anti-PLA2R1 total IgG (p=0.01) were factors of poor renal prognosis. Anti-PLA2R1 antibodies containing sera can induce in vitro cytotoxicity mediated by complement activation, and the level of cytotoxicity increases with the diversity and the titer of anti-PLA2R1 IgG subclasses. These patients with high level of complement-mediated cytotoxicity could benefit from adjuvant therapy using complement inhibitor associated with rituximab to induce earlier remission and less podocyte injury.

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Section: Discussionmentioning

confidence: 99%

Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation

Lateb

Ouahmi

Payré

et al. 2019

Journal of Immunology Research

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“…Membranous nephropathy is grouped into primary cases (80% of cases) without causative autoimmune disease (56, 57). In primary membranous nephropathy cases about 70% show autoantibodies directed against phospholipase A 2 receptor 1 (PLA 2 R1), display antibodies directed against thrombospondin type 1 containing 7A (THSD7A) in serum (1–2%) and to complement Factor H (3%) (57–63). PLA 2 R and THSDA7 are podocyte antigens.…”

Section: Diseasesmentioning

confidence: 99%

“…Most scenarios of primary membranous nephropathy are mediated by autoantibodies to M type Phosphoplipase A 2 receptor (PLA 2 R) (95%) and Thrombospondin type 1 domain containing 7a (THSD7a) receptor, a podocyte antigen (3–5%). Recently an additional third autoimmune form was described, where autoantibodies developed which target complement Factor H (3%) (63).…”

Section: Diseasesmentioning

confidence: 99%

“…About 3% of MN patients have Factor H binding antibodies which target the C terminal recognition region of the human regulator and block surface binding (63). In the autoimmune form DEAP-HUS a related pathologic principle, with autoantibodies targeting the C -terminal binding region Factor H block Factor H surface action (64, 65), These features indicate that complement regulation and furthermore cell damage mediated by the terminal complement pathway is a disease relevant mechanisms at the podocyte surface.…”

Section: Diseasesmentioning

confidence: 99%

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Complement Inhibitors in Clinical Trials for Glomerular Diseases

et al. 2019

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Defective complement action is a cause of several human glomerular diseases including atypical hemolytic uremic syndrome (aHUS), anti-neutrophil cytoplasmic antibody mediated vasculitis (ANCA), C3 glomerulopathy, IgA nephropathy, immune complex membranoproliferative glomerulonephritis, ischemic reperfusion injury, lupus nephritis, membranous nephropathy, and chronic transplant mediated glomerulopathy. Here we summarize ongoing clinical trials of complement inhibitors in nine glomerular diseases and show which inhibitors are used in trials for these renal disorders (http://clinicaltrials.gov).

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“…Additionally, in cases of anti-neutral endopeptidase-associated MN, a relationship between the neutral endopeptidase system and the activation of complement within immune deposits and the generation of C5b-9 has been described [23,43]. Recently, Seikrit et al [44] reported an interesting case of DOI: 10.1159/000506948 a patient with anti-PLA2R1-associated MN and antibodies against complement factor H, an important regulator of the alternative complement pathway. However, a subsequent study did not support the hypothesis that such antibodies contribute to hyperactivation of the complement system in the setting of MN [45].…”

Section: The Complement Systemmentioning

confidence: 99%

New Ways of Understanding Membranous Nephropathy

Trujillo

Alonso

Praga

2020

Nephron

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Background: In the last decade, great advances have been made in the field of membranous nephropathy (MN). The autoimmune nature of the disease has been confirmed with the description of diverse antigens, and few but very important prospective trials regarding treatment alternatives have been published, changing profoundly the way we understand this entity. Nowadays, an individualized therapeutic scheme based on clinical and serologic data appears to be the most appropriate method to manage patients with MN. Although there is still a long way to go, it is expected that future scientific progress will enable a patient-centered medicine based on concept-driven therapies. Summary: MN is the most common cause of nephrotic syndrome (NS) in white adults. Approximately one-third of patients achieve spontaneous remission, one-third remain stable, and onethird have an aggressive course with persistent NS and deterioration of renal function. About 80% of patients have circulating autoantibodies to phospholipase A2 receptor 1. Numerous therapies have been described including alkylating agents, rituximab, and calcineurin inhibitors, but new drugs are currently being explored. Here, we review the most important aspects regarding MN with an emphasis on results of the most recent clinical trials and pathophysiologic advances. Key Messages: 1. Evolving pathophysiologic concepts and recently published clinical trials have deeply changed our view of MN. 2. Most patients with MN present autoantibodies against diverse glomerular antigens. 3. Currently, an individual patient-centered management based on clinical and serologic markers is the most adequate approach to treat patients with MN.

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Factor H Autoantibodies and Membranous Nephropathy

Cited by 36 publications

References 4 publications

Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation

Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation

Complement Inhibitors in Clinical Trials for Glomerular Diseases

New Ways of Understanding Membranous Nephropathy

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