USP25 attenuates anti-GBM nephritis in mice by negative feedback regulation of Th17 cell differentiation

This study aimed to elucidate the role of USP25 in a mouse model of anti-glomerular basement membrane glomerulonephritis (anti-GBM GN). USP25-deficient anti-GBM GN mice were generated, and their nephritis progression was monitored. Naïve CD4+ T cells were isolated from spleen lymphocytes and stimulated to differentiate into Th1, Th2, and Th17 cells. This approach was used to investigate the impact of USP25 on CD4+ T lymphocyte differentiation in vitro. Furthermore, changes in USP25 expression were monitored during Th17 differentiation, both in vivo and in vitro. USP25−/− mice with anti-GBM GN exhibited accelerated renal function deterioration, increased infiltration of Th1 and Th17 cells, and elevated RORγt transcription. In vitro experiments demonstrated that USP25−/− CD4+ T lymphocytes had a higher proportion for Th17 cell differentiation and exhibited higher RORγt levels upon stimulation. Wild-type mice with anti-GBM GN showed higher USP25 levels compared to healthy mice, and a positive correlation was observed between USP25 levels and Th17 cell counts. Similar trends were observed in vitro. USP25 plays a crucial role in mitigating renal histopathological and functional damage during anti-GBM GN in mice. This protective effect is primarily attributed to USP25’s ability to inhibit the differentiation of naïve CD4+ T cells into Th17 cells. The underlying mechanism may involve the downregulation of RORγt. Additionally, during increased inflammatory responses or Th17 cell differentiation, USP25 expression is activated, forming a negative feedback regulatory loop that attenuates immune activation.</p

Proportion of all 14 quality assessment of diagnostic accuracy studies tool criteria that were fulfilled for the studies included in the meta-analysis.

<p>Proportion of all 14 quality assessment of diagnostic accuracy studies tool criteria that were fulfilled for the studies included in the meta-analysis.</p

Sensitivity analyses for the accuracy of PLA2R-AB test on iMN detection.

<p>Sensitivity analyses for the accuracy of PLA2R-AB test on iMN detection.</p

The Diagnosis Accuracy of PLA2R-AB in the Diagnosis of Idiopathic Membranous Nephropathy: A Meta-Analysis

<div><p>Background</p><p>The presence of antibodies against the M-type phospholipase A2 receptor (PLA2R-AB) is considered to be a promising serological diagnostic biomarker of idiopathic membranous nephropathy (iMN). However, controversy remains about the diagnostic accuracy of serum PLA2R-AB testing. Here, we performed a comprehensive meta-analysis to assess the overall diagnostic value of serum PLA2R-AB testing in iMN detection.</p><p>Methods</p><p>PubMed, Embase, and CNKI (Chinese National Knowledge Infrastructure) were searched for relevant original articles through January 31, 2014. The summary sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio (DOR) were estimated using the bivariate model. The heterogeneity among studies was explored by subgroup and meta-regression analysis.</p><p>Results</p><p>9 articles, including 15 studies, were eventually identified with a total of 2212 patients. The summary sensitivity of all studies is 78% (95% CI: 66% to 87%) and the specificity is 99% (95% CI: 96% to 100%). The summary positive and negative likelihood ratios are 96.1 (95% CI, 19.5 to 472.1) and 0.22 (95% CI: 0.14 to 0.35), respectively. The DOR is 437 (95%CI, 74 to 2592). The subgroup analysis and meta-regression suggest the test interval is the main source of heterogeneity.</p><p>Conclusions</p><p>Serum PLA2R-AB testing is a useful tool to detect iMN. In addition, considering the high heterogeneity and potential publication bias, further high quality studies are needed in the future.</p></div

Flowchart for identification of studies.

<p>Flowchart for identification of studies.</p

Subgroup analysis for accuracy of PLA2R-AB for MN detection.

<p>Subgroup analysis for accuracy of PLA2R-AB for MN detection.</p

Forrest plots of the sensitivity and specificity of each individual study, summary sensitivity and specificity and I² statistic for heterogeneity.

<p>Forrest plots of the sensitivity and specificity of each individual study, summary sensitivity and specificity and I² statistic for heterogeneity.</p

Summary receiver operating characteristic (SROC) graph with 95% confidence region and 95% prediction region for the diagnosis value of iMN by PLA2R-AB.

<p>Black square represents the summary estimate of sensitivity and specificity with the 95% confidence ellipse from the bivariate model. Numbers represent the reference numbers.</p