Novel ELISA for thrombospondin type 1 domain-containing 7A autoantibodies in membranous nephropathy

Zaghrini, Christelle; Seitz-Polski, Barbara; Justino, Joana; Dolla, Guillaume; Payré, Christine; Jourde-Chiche, Noémie; Logt, Anne-Els van de; Booth, Caroline; Rigby, Emma; Lönnbro-Widgren, Jennie; Nyström, Jenny; Mariat, Christophe; Cui, Zhao; Wetzels, Jack F.M.; Ghiggeri, Gian Marco; Beck, Laurence H.; Ronco, Pierre; Dębiec, Hanna; Lambeau, Gérard

doi:10.1016/j.kint.2018.10.024

Cited by 71 publications

(65 citation statements)

References 79 publications

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“…Although anti-PLA 2 R Ab was considered a reliable biomarker for primary MGN [5], its appearance in secondary MGN was not surprising since the biomarker was reported to be associated with hepatitis B virus infection [14,15]. A biomarker, anti-THSD7A Ab can be used to make a diagnosis of primary MGN variants not detected by anti-PLA 2 R Ab [16]. In this study, serum anti-THSD7A Ab was positive in four biopsy-proven primary MGN subjects and two secondary MGN subjects (one of which was associated with malignancy and the other was due to lupus nephritis type V).…”

Section: Role Of Biomarkers (Pla 2 R and Thsd7a) In The Diagnosis Of Mgnmentioning

confidence: 99%

RETRACTED: Role of Serum and Urine Biomarkers (PLA2R and THSD7A) in Diagnosis, Monitoring and Prognostication of Primary Membranous Glomerulonephritis

et al. 2020

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Differentiating primary and secondary membranous glomerulonephritis (MGN) using biomarkers for MGN is essential in patients’ diagnosis, treatment and follow-up. Although biopsy has been the primary tool in making the diagnosis, not all patients can withstand it due to its invasive nature, and it cannot be used to monitor treatment. Hence, there is the need for less invasive or even non-invasive biomarkers for effective diagnosis, treatment monitoring and prognostication. This study aimed at providing an alternative way of differentiating primary and secondary MGN using enzyme-linked immunosorbent assay (ELISA) technique for serum and urine biomarkers (M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A)) for prompt diagnosis, treatment and prognosis. A total of 125 subjects, including 81 primary and 44 secondary MGN subjects, were diagnosed from January 2012 to October 2019 at Hospital Serdang and Hospital Kuala Lumpur from which 69 subjects consisting of 47 primary and 22 secondary MGN subjects participated in the study. Of these, 13 primary MGN subjects were positive for both serum and urine anti-PLA2R antibodies (Ab) whereas only one secondary MGN subject associated with hepatitis B virus was positive for both serum and urine anti-PLA2R Ab. At the same time, anti-THSD7A Ab was found positive in four primary MGN subjects and two secondary MGN subjects with malignancy.

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Section: Role Of Biomarkers (Pla 2 R and Thsd7a) In The Diagnosis Of Mgnmentioning

confidence: 99%

RETRACTED: Role of Serum and Urine Biomarkers (PLA2R and THSD7A) in Diagnosis, Monitoring and Prognostication of Primary Membranous Glomerulonephritis

et al. 2020

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“…23 Thus, with regard to PLA2R, a retrospective study showed 89.6% prevalence of PLA2Rassociated MN at the Tenon Hospital, 24 while there was a prevalence of only 48.1% among 592 biopsies of nonlupus MN at the Mayo Clinic (S. Sethi, 2019, unpublished data). Similarly, a recent study on THSD7A-associated MN reported a prevalence of 2.8% among the 1012 patients from 6 European cohorts, 25 while only 1 of 181 patients enrolled in Membranous Nephropathy Trial of Rituximab (MENTOR) study, 26 and 2 of 422 (<0.5%) patients screened at Mayo Clinic locations-Rochester, MN; Jacksonville, FL; and Phoenix, AZ-were found to be THSD7A positive (S. Sethi, 2019, unpublished data).…”

Section: Discussionmentioning

confidence: 80%

Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy

Sethi

Dębiec

Madden

et al. 2020

Kidney International

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“…It is defined by the presence of subepithelial immune complex deposits with alteration of the glomerular membrane and podocyte injury [2]. Most MN cases are associated with autoantibodies directed against podocyte antigens such as the M-type phospholipase A2 receptor (PLA2R1) [3] and thrombospondin type 1 domain-containing 7A (THSD7A) [4,5] in 70% and 3% of adult patients, respectively. Disease evolution is highly variable from spontaneous remission to persistent proteinuria or end-stage renal disease [6].…”

Section: Introductionmentioning

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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Novel ELISA for thrombospondin type 1 domain-containing 7A autoantibodies in membranous nephropathy

Cited by 71 publications

References 79 publications

RETRACTED: Role of Serum and Urine Biomarkers (PLA2R and THSD7A) in Diagnosis, Monitoring and Prognostication of Primary Membranous Glomerulonephritis

RETRACTED: Role of Serum and Urine Biomarkers (PLA2R and THSD7A) in Diagnosis, Monitoring and Prognostication of Primary Membranous Glomerulonephritis

Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy

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

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