Genetic homogeneity but IgG subclass–dependent clinical variability of alloimmune membranous nephropathy with anti-neutral endopeptidase antibodies

Background. The role of IgG subclass in idiopathic membranous nephropathy (IMN) was unclarified. Recent study found IgG subtype switches from IgG1 to IgG4 in the early pathological stage in IMN. The profile of IgG subclass in phospholipase A2 receptor- (PLA2R-) related and PLA2R-unrelated IMN was unrevealed. Our study is aimed at testifying whether IgG subclass switch existed in PLA2R-related and PLA2R-unrelated IMN, respectively. Methods. Our study retrospectively enrolled 157 Chinese patients with biopsy-confirmed IMN between September 2017 and November 2019. We measured glomerular PLA2R antigen and serum anti-PLA2R antibody to classify the patients into PLA2R-related ( n = 132 ) and PLA2R-unrelated ( n = 25 ) subgroup. We evaluated glomerular IgG subclass by immunofluorescence (IF) predominance. Our study defined IgG subclass deposition as predominant if the IF score was higher than the other three and ≥1 +, or as codominant if the IF intensity was equal to any other and ≥1 +. We explored the relationship between IF predominance of glomerular IgG subtype and electron microscopic (EM) stages of IMN. Results. We did not find statistical difference of predominant or codominant rate (pre/co-rate) among EM stages in any subclass ( P > 0.05 ). Pre/co-rate of IgG3 linearly associated with EM stage in total and PLA2R-related subgroup ( P = 0.044 , P = 0.013 ). PLA2R-related subgroup showed higher IgG4 intensity ( 2.1 ± 0.6 vs. 1.6 ± 0.7 , P = 0.001 ) and pre/co-rate of IgG4 in stage 1 (97% vs. 57%, P = 0.015 ) than PLA2R-unrelated group. We found no difference of IgG subclass pre/co-rate in different EM stages or linear association between pre/co-rate of IgG1, IgG2, IgG4, and EM stages ( P > 0.05 ). Conclusions. Pre/co-rate of IgG3 declined with EM stage in total and PLA2R-related subgroup. We did not find IgG subclass switches from IgG1 to IgG4 in either IMN patients or subgroups.

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Epitope Mapping of Human α3(IV)NC1-Induced Membranous Nephropathy in Mice

American Journal of Nephrology ◽

10.1159/000505443 ◽

2020 ◽

Vol 51 (2) ◽

pp. 99-107 ◽

Cited By ~ 1

Author(s):

Jia Wang ◽

Miao Wang ◽

Zhao Cui ◽

Ming-hui Zhao

Keyword(s):

Nephrotic Syndrome ◽

Electron Microscope ◽

Membranous Nephropathy ◽

Epitope Mapping ◽

Igg Subclass ◽

Common Cause ◽

Linear Peptide ◽

Dense Deposits ◽

Circulating Antibodies ◽

Gbm Thickening

Background and Aim: Primary membranous nephropathy (pMN) is the most common cause of nephrotic syndrome in adults. Recent studies suggested that immunization of DBA/1 mice with the main antigen of antiglomerular basement membrane disease (GBM) disease, α3(IV)NC1, could lead to MN lesions. This study aimed to explore the pathogenic epitopes for mouse MN. Methods: Twenty-four linear peptides were synthesized spanning human α3(IV)NC1. Male DBA/1 mice aged 6–8 weeks were immunized with the peptides 200 μg/mouse in Freund’s complete adjuvant subcutaneously and boosted 3 times with the peptides in Freund’s incomplete adjuvant in weeks 3, 5, and 7. The blood and 24-h urine samples were assessed every 2 weeks. The kidneys were examined when the mice were sacrificed at 18 weeks. Results: All the mice immunized with human α3(IV)NC1 and the 24 peptides produced circulating antibodies against the immunogens at 2 weeks and achieved the maximum titers at 8 weeks. About 5/6 (83%) mice immunized with α3(IV)NC1 and (3/6) 50% of the mice immunized with peptide 23 (α3141–154) showed proteinuria at 8–10 weeks and increased continuously. The kidneys showed granular depositions of IgG, C3, and C5b-9 along the glomerular capillary loops. The major IgG subclass was IgG1 (equivalent to human IgG4). GBM thickening with the formation of spikes and subepithelial electron-dense deposits were observed under electron microscope. Conclusion: The linear peptide of α3141–154 could induce clinical and histopathological features of MN in DBA/1 mice, which might give clues to the mechanism of MN in combination with anti-GBM disease.

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Anti-neutral endopeptidase, natriuretic peptides disarrangement, and proteinuria onset in membranous nephropathy

Molecular Biology Reports ◽

10.1007/s11033-012-2367-4 ◽

2012 ◽

Vol 40 (4) ◽

pp. 2963-2967 ◽

Cited By ~ 9

Author(s):

Peng Hu ◽

Qiang Xuan ◽

Bo Hu ◽

Ling Lu ◽

Yuan Han Qin

Keyword(s):

Natriuretic Peptides ◽

Membranous Nephropathy ◽

Neutral Endopeptidase

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Recent Progress in Deciphering the Etiopathogenesis of Primary Membranous Nephropathy

BioMed Research International ◽

10.1155/2017/1936372 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

Andreas Kronbichler ◽

Jun Oh ◽

Björn Meijers ◽

Gert Mayer ◽

Jae Il Shin

Keyword(s):

Membranous Nephropathy ◽

Treatment Resistance ◽

Spontaneous Remission ◽

Neutral Endopeptidase ◽

Rapid Decline ◽

Special Focus ◽

Risk Alleles ◽

Phospholipase A2 Receptor

Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50–100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up. Immunologic remission precedes reduction of proteinuria by months. Pretransplant evaluation of PLA2R antibodies is warranted to predict recurrence of disease following renal transplantation. Several risk alleles related to the PLA2R1 gene and within the HLA loci have been identified, whereas epitope spreading of PLA2R may predict treatment response. More recently, thrombospondin type 1 domain-containing 7A (THSD7A) antibodies have been discovered in primary MN. Several other rare antigens have been described, including antibodies against neutral endopeptidase as a cause of antenatal MN and circulating cationic bovine serum albumin as an antigen with implications in childhood MN. This review focuses on the progress with a special focus on diagnostic accuracy, predictive value, and treatment implications of the established and proposed antigens.

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Distribution of glomerular IgG subclass deposits in malignancy-associated membranous nephropathy

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfg616 ◽

2004 ◽

Vol 19 (3) ◽

pp. 574-579 ◽

Cited By ~ 126

Author(s):

H. Ohtani ◽

H. Wakui ◽

A. Komatsuda ◽

S. Okuyama ◽

R. Masai ◽

...

Keyword(s):

Membranous Nephropathy ◽

Igg Subclass

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Molecular Pathogenesis of Membranous Nephropathy

Annual Review of Pathology Mechanisms of Disease ◽

10.1146/annurev-pathol-020117-043811 ◽

2020 ◽

Vol 15 (1) ◽

pp. 287-313 ◽

Cited By ~ 7

Author(s):

Pierre Ronco ◽

Hanna Debiec

Keyword(s):

Membranous Nephropathy ◽

Human Leukocyte ◽

Neutral Endopeptidase ◽

Molecular Pathogenesis ◽

T Cell Epitopes ◽

Binding Domains ◽

Hla Dr ◽

Phospholipase A2 Receptor ◽

Kidney Glomerulus ◽

Hla Dq

Membranous nephropathy is a noninflammatory autoimmune disease of the kidney glomerulus, characterized by the formation of immune deposits, complement-mediated proteinuria, and risk of renal failure. Considerable advances in understanding the molecular pathogenesis have occurred with the identification of several antigens [neutral endopeptidase, phospholipase A2 receptor (PLA2R), thrombospondin domain-containing 7A (THSD7A)] in cases arising from the neonatal period to adulthood and the characterization of antibody-binding domains (that is, epitopes). Immunization against PLA2R occurs in 70% to 80% of adult cases. The development of highly specific and sensitive assays of circulating antibodies has induced a paradigm shift in diagnosis and treatment monitoring. In addition, several interacting loci in HLA-DQ, HLA-DR, and PLA2R1, as well as classical human leukocyte antigen (HLA)-D alleles have been identified as being risk factors, depending on a patient's ethnicity. Additionally, mechanisms of antibody pathogenicity and pathways of complement activation are now better understood. Further research is mandatory for designing new therapeutic strategies, including the identifying triggering events, the molecular bases of remission and progression, and the T cell epitopes involved.

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