Alternative Pathway Is Essential for Glomerular Complement Activation and Proteinuria in a Mouse Model of Membranous Nephropathy

Luo, Weijia; Olaru, Florina; Miner, Jeffrey H.; Beck, Laurence H.; Vlag, Johan van der; Thurman, Joshua M.; Borza, Dorin-Bogdan

doi:10.3389/fimmu.2018.01433

Cited by 49 publications

(49 citation statements)

References 62 publications

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“…Vivarelli et al demonstrated a predominant role of the classical pathway for neutral endopeptidase protein-associated MN [41]. In a mouse model of MN, Luo et al showed a role of the alternative pathway in the pathogenicity induced by glomerular subepithelial immune complexes [42]. However, no C3 deposition has been found in the renal tissue of mice following immunization with rabbit anti-THSD7A antibodies or purified human anti-THSD7A while these antibodies induced proteinuria and IgG deposits.…”

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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“…Furthermore, the model can be developed rapidly and reliably. luo et al (58) found that factor B-null mice lacked glomerular deposition of c3 and c5b-9 and did not develop albuminuria. albuminuria was reduced but not completely abolished in the C5-deficient mice.…”

Section: Mouse Models Of Imn T H R O M B O S P O N D I N T Y P E -1 Dmentioning

confidence: 99%

“…Furthermore, the complement pathways of most models are unclear (Table ii). an aP is essential to complement activation in the anti-α3nc1 mouse model via factor B knockout (58). The human anti-THSd7a-related mouse model provides an opportunity to use genetic intervention in complement activation.…”

Section: Pathogenesis Of Imn: From Model To Humanmentioning

confidence: 99%

Advances of the experimental models of idiopathic membranous nephropathy (Review)

et al. 2020

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idiopathic membranous nephropathy (iMn) is one of the main types of chronic kidney disease in adults and one of the most common causes of end-stage renal disease. in recent years, the morbidity of iMn among primary glomerular diseases has markedly increased, while the pathogenesis of the disease remains unclear. To address this, a number of experimental models, including Heymann nephritis, anti-thrombospondin type-1 domain-containing 7a antibody-induced iMn, cationic bovine serum albumin, anti-human podocyte antibodies and zymosan-activated serum-induced c5b-9, have been established. This review comprehensively summarized the available animal and cell models for iMn. The limitations and advantages of the current models were discussed and two improved models were introduced to facilitate the selection of an appropriate model for further studies on iMn. Contents 1. introduction 2. rat models of iMn 3. Mouse models of iMn 4. limitations and advantages of the animal models 5. cell models of iMn 6. limitations and advantages of the cell models 7.

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“…Mice immunized with α3(IV) collagen NC1 domain develop subepithelial immune complexes and proteinuria, recapitulating clinical and morphologic hallmarks of MN ( 54 , 55 ). In factor B −/− mice, without a functional AP, glomerular C3c and C5b–9 deposition and proteinuria were prevented, while circulating and kidney-bound IgG were unchanged ( 56 ). These findings imply that the AP is required for complement activation and proteinuria in experimental MN.…”

Section: Complement Activation In Mnmentioning

confidence: 99%

Alternative Pathway Dysregulation and the Conundrum of Complement Activation by IgG4 Immune Complexes in Membranous Nephropathy

Borza

2016

Front. Immunol.

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Membranous nephropathy (MN), a major cause of nephrotic syndrome, is a non-inflammatory immune kidney disease mediated by IgG antibodies that form glomerular subepithelial immune complexes. In primary MN, autoantibodies target proteins expressed on the podocyte surface, often phospholipase A2 receptor (PLA2R1). Pathology is driven by complement activation, leading to podocyte injury and proteinuria. This article overviews the mechanisms of complement activation and regulation in MN, addressing the paradox that anti-PLA2R1 and other antibodies causing primary MN are predominantly (but not exclusively) IgG4, an IgG subclass that does not fix complement. Besides immune complexes, alterations of the glomerular basement membrane (GBM) in MN may lead to impaired regulation of the alternative pathway (AP). The AP amplifies complement activation on surfaces insufficiently protected by complement regulatory proteins. Whereas podocytes are protected by cell-bound regulators, the GBM must recruit plasma factor H, which inhibits the AP on host surfaces carrying certain polyanions, such as heparan sulfate (HS) chains. Because HS chains present in the normal GBM are lost in MN, we posit that the local complement regulation by factor H may be impaired as a result. Thus, the loss of GBM HS in MN creates a micro-environment that promotes local amplification of complement activation, which in turn may be initiated via the classical or lectin pathways by subsets of IgG in immune complexes. A detailed understanding of the mechanisms of complement activation and dysregulation in MN is important for designing more effective therapies.

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Alternative Pathway Is Essential for Glomerular Complement Activation and Proteinuria in a Mouse Model of Membranous Nephropathy

Cited by 49 publications

References 62 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

Advances of the experimental models of idiopathic membranous nephropathy (Review)

Alternative Pathway Dysregulation and the Conundrum of Complement Activation by IgG4 Immune Complexes in Membranous Nephropathy

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