Lessons from a rare disease: IgG subclass and disease severity in alloimmune antenatal membranous nephropathy

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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Serological Analysis Reveals an Imbalanced IgG Subclass Composition Associated with COVID-19 Disease Severity

Cell Reports Medicine ◽

10.1016/j.xcrm.2021.100329 ◽

2021 ◽

pp. 100329

Author(s):

Jennifer L. Yates ◽

Dylan J. Ehrbar ◽

Danielle T. Hunt ◽

Roxanne C. Girardin ◽

Alan P. Dupuis ◽

...

Keyword(s):

Disease Severity ◽

Igg Subclass ◽

Serological Analysis

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Increased soluble ST2 and IL‑4 serum levels are associated with disease severity in patients with membranous nephropathy

Molecular Medicine Reports ◽

10.3892/mmr.2017.8130 ◽

2017 ◽

Cited By ~ 1

Author(s):

Zhihui Zhang ◽

Xiaolei Liu ◽

Haifeng Wang ◽

Zhihui Qu ◽

Rebecca Crew ◽

...

Keyword(s):

Disease Severity ◽

Membranous Nephropathy ◽

Serum Levels ◽

Soluble St2

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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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Serological Analysis Reveals an Imbalanced IgG Subclass Composition Associated with COVID-19 Disease Severity

10.1101/2020.10.07.20208603 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jennifer L. Yates ◽

Dylan J. Ehrbar ◽

Danielle T. Hunt ◽

Roxanne C. Girardin ◽

Alan Dupuis ◽

...

Keyword(s):

Disease Severity ◽

Wide Spectrum ◽

Severe Disease ◽

Neutralizing Antibody ◽

Igg Subclass ◽

Serological Analysis ◽

Serum Samples ◽

Plasma Therapy ◽

Igg3 Subclass ◽

Antibody Levels

SummaryCOVID-19 is associated with a wide spectrum of disease severity, ranging from asymptomatic to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity, and the levels of circulating SARS-CoV-2-specific antibodies, including virus neutralizing titers. Through a serological analysis of serum samples from 536 convalescent healthcare workers, we found that SARS-CoV-2-specific and virus-neutralizing antibody levels were indeed elevated in individuals that experienced severe disease. The severity-associated increase in SARS-CoV-2-specific antibody was dominated by IgG, with an IgG subclass ratio skewed towards elevated receptor binding domain (RBD)- and S1-specific IgG3. However, RBD- and S1-specific IgG1, rather than IgG3 were best correlated with virus-neutralizing titers. We propose that Spike-specific IgG3 subclass utilization contributes to COVID-19 disease severity through potent Fc-mediated effector functions. These results have significant implications for SARS-CoV-2 vaccine design, and convalescent plasma therapy.

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