ABSTRACT Primary membranous nephropathy (pMN) is an autoimmune glomerular disease characterized by subepithelial immune complex deposition, involving IgG4 dominant autoantibodies targeting podocyte antigens. Although glomerular IgG3 deposition has been identified in some cases of pMN, its clinical significance remains unclear. This was a retrospective cohort study. One hundred and eighty-nine patients with biopsy-proven pMN from Tianjin Medical University General Hospital between July 2021 and December 2022 were retrospectively enrolled. Clinical, laboratory, pathological features, and treatment outcomes were compared between patients with and without glomerular IgG3 deposition. The primary endpoint of this study was the remission of proteinuria, including complete remission (CR) and partial remission (PR). The deposition of IgG3 was detected by direct immunofluorescence. Among the 189 patients with pMN, glomerular IgG subclasses were observed as follows: IgG1 in 167 patients (88.4%), IgG2 in 25 (13.2%), IgG3 in 44 (23.3%) patients, and IgG4 in 185 (97.9%) patients. Compared to those without glomerular IgG3 deposition, patients with IgG3 deposition were significantly younger, exhibited a lower level of anti-phospholipase A2 receptor (PLA2R) antibodies and a lower level of urinary protein. Pathologically, they showed less glomerular segmental sclerosis, less IgG1 deposition and a lower positivity rate of PLA2R expression. During a median follow-up of 20 months, Kaplan–Meier analysis showed that patients with IgG3 deposition achieved higher rates of both renal remission (log-rank, P = 0.005) and complete remission (log-rank, P = 0.011), particularly among those with stronger IgG3 staining. Multivariate Cox analysis identified IgG3 deposition was associated with cumulative remission (HR = 1.998, P = 0.020) and complete remission (HR = 1.065, P = 0.002), with high anti-PLA2R antibody level, and urinary protein identified as independent risk factors. Compared with patients without renal IgG3 deposition, patients with renal IgG3 deposition had higher levels of total IgG3 and IgG3 subclass anti-PLA2R antibodies in blood, but lower levels of total IgG1 and IgG1 subclass anti-PLA2R antibodies. The ability of blood anti-PLA2R antibodies to activate complement was slightly higher but without statistical significance. Within the cohort of the current study, patients with pMN with renal IgG3 deposition did not show more severe clinical manifestations, which might be related to the lower total autoantibody levels in the blood.

ABSTRACT Cell stress, including endoplasmic reticulum (ER) stress, heat shock, and hypoxia, plays a pivotal role in cellular homeostasis and immune regulation, particularly in the intestine. ER stress, a key aspect of cell stress, triggers the unfolded protein response (UPR) to restore balance by managing misfolded proteins or inducing apoptosis if unresolved. The activation of these stress responses has emerged as a critical contributor to intestinal inflammation in conditions like inflammatory bowel disease (IBD). Regulatory T cells (Tregs), vital for maintaining mucosal immune tolerance, are strongly influenced by cellular stress, with the UPR shaping their stability, metabolic programming, and function. Microbial dysbiosis and reduced short-chain fatty acids (SCFAs) disrupt these adaptive pathways, further impairing Treg function. In this review, we explore how UPR signaling shapes Treg metabolism and intestinal inflammation. Identifying gaps in UPR-mediated adaptation and stress thresholds, we thus propose microbiome- and ER-stress-based therapeutic strategies as putative strategies for restoring immune balance in IBD.

Cryptorchidism, a common male reproductive disorder characterized by undescended testes, is associated with infertility and increased cancer risk. While its etiology remains incompletely understood, accumulating evidence suggests that immune-inflammatory responses contribute to disease progression. This study investigated the role of carboxypeptidase N subunit 2 (CPN2) in modulating immune activation and testicular pathology via the NF-κB signaling pathway. Key regulatory genes were identified through transcriptomic analysis, weighted gene co-expression network analysis (WGCNA), and machine learning approaches. A di-n-butyl phthalate (DBP)-induced rat model of cryptorchidism and CRISPR/Cas9-mediated CPN2 knockout rats were employed, alongside histological, immunohistochemical, Western blotting, and co-culture assays to explore immune activation and spermatogonial cell fate. CPN2 was identified as a pivotal factor that suppresses NF-κB activation and plasma cell infiltration. Its overexpression alleviated inflammatory cytokine production, preserved spermatogonial stem cell proliferation, and reduced apoptosis in both in vivo and in vitro models. These effects were reversed upon NF-κB activation, confirming the regulatory role of the CPN2/NF-κB axis. Our findings reveal that CPN2 mitigates cryptorchidism progression by modulating immune-inflammatory responses, highlighting it as a promising molecular target for non-surgical intervention in this condition.

Autoimmune diseases are diverse, necessitating a mechanistic understanding of the protracted disease process to improve diagnostic accuracy and therapeutic efficacy. From human and animal model studies, it has become clear that T cells are critical for autoimmune pathogenesis but the involvement of B cells is unmistakable, as evidenced by the efficacy of B cell depletion therapy in alleviating systemic and organ-specific autoimmune conditions. This paper reviews the roles that kinds of murine models have played and continue to play in developing mechanistic understanding of autoimmune diseases, with particular though not exclusive attention to B cells emphasizing their unique contributions to autoimmunity via adaptive and innate mechanisms.

Background Juvenile idiopathic arthritis (JIA), superseding juvenile rheumatoid arthritis (JRA), is a chronic autoimmune disease affecting children and characterized by various types of childhood arthritis. JIA manifests clinically with joint inflammation, swelling, pain, and limited mobility, potentially leading to long-term joint damage if untreated. This study aimed to identify genes associated with the progression and prognosis of JIA polyarticular to enhance clinical diagnosis and treatment. Methods We analyzed the gene expression omnibus (GEO) dataset GSE1402 to screen for differentially expressed genes (DEGs) in peripheral blood single nucleated cells (PBMCs) of JIA polyarticular patients. Weighted gene co-expression network analysis (WGCNA) was applied to identify key gene modules, and protein–protein interaction networks (PPIs) were constructed to select hub genes. The random forest model was employed for biomarker gene screening. Functional enrichment analysis was conducted using David’s online database, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to annotate and identify potential JIA pathways. Hub genes were validated using the receiver operating characteristic (ROC) curve. Results PHLDA1, EGR3, CXCL2, and PF4V1 were identified as significantly associated with the progression and prognosis of JIA polyarticular phenotype, demonstrating high diagnostic and prognostic assessment value. Conclusion These genes can be utilized as potential molecular biomarkers, offering valuable insights for the early diagnosis and personalized treatment of JIA polyarticular patients.

Graves’ ophthalmopathy (GO) obvious manifestation is the imbalance of Th17/Treg. N6-methyladenosine (m6A) methylation is an important regulator of Th17/Treg balance. However, few reports narrate how m6A regulators mediate the role of genes in GO progression. We explored the m6A modification of THBS1 mediated by WTAP, and the mechanism by which THBS1 regulated glycolysis and Th17/Treg balance. A total of 12 peripheral blood (4 GO samples, 4 GH samples, and 4 health samples) were collected to measure the percentage of Th17/Treg in monocytes by flow cytometry. RNA sequencing (RNA-seq) combined with MeRIP sequencing (MeRIP-seq) was used to screen differentially expressed and methylated genes. MeRIP-qPCR was performed to evaluate the m6A abundance of THBS1 after WTAP silencing. Glycolysis of CD4+ T cells was reflected by the lactate content and glucose uptake. The number of Th17 cells was increased in GO peripheral blood, whereas the Treg cells decreased. RNA-seq acquired 679 differentially expressed genes (308 up-regulated, and 371 down-regulated) in the CD4+ T cells of GO compared to healthy control. MeRIP-seq identified 3277 m6A peaks between the GO group and the healthy control group, corresponding with 2744 genes (1143 hypermethylated and 1601 hypomethylated). Combined analysis of RNA-seq and MeRIP-seq showed 81 hypermethylated and up-regulated genes. Among the six candidate genes in the PI3K-signaling pathway, THBS1 was the most significantly differentially expressed and hypermethylated. THBS1 silencing resulted in decreased lactate content and glucose uptake in CD4+ T cells. WTAP was significantly upregulated in CD4+ T cells of GO, and WTAP silencing significantly reduced m6A abundance and expression of THBS1. Upregulated and hypermethylated THBS1 mediated by WTAP promoted glycolysis of CD4+ T cells, affected Th17/Treg balance, and facilitated GO progression. We provided a novel potential target for GO treatment and revealed the molecular mechanism of WTAP and THBS1 in GO under the m6A perspective.

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease, and understanding its genetic and molecular basis is crucial for early diagnosis, treatment, and prevention. Objective This study aims to explore the association between IL-4 polymorphisms (rs2227284, rs2243267, rs2243270, and rs2243283) and RA risk. Methods The four IL-4 polymorphisms were genotyped in 493 RA patients and 493 healthy controls using Agena MassARRAY. Logistic regression analysis calculated odds ratio (OR) and 95% confidence interval (CI) to estimate the relationship between IL-4 polymorphisms and RA risk. Results Overall analysis revealed that rs2243267 (GG vs. CC: OR = 0.26, FDR-p = .032; Recessive: OR = 0.27, FDR-p = .048) and rs2243270 (AA vs. GG: OR = 0.26, FDR-p = .024; Recessive: OR = 0.27, FDR-p = .024) were associated with a decreased risk of RA. Stratified analysis indicated that rs2243267 and rs2243270 were correlated with reduced RA risk in female, smoking, BMI <24, and drinking population; rs2227284 was associated with a decreased RA risk in BMI <24 and drinking population. Moreover, rs2243267 and rs2243270 were significantly associated with reduced ACPA positivity. Conclusions Our findings suggest that IL-4 polymorphisms (rs2227284, rs2243267, and rs2243270) act as protective factors for RA in the Chinese Han population.

Lupus nephritis (LN) is the most severe end-organ pathology in Systemic Lupus Erythematosus (SLE). Research has enhanced our understanding of immune effectors and inflammatory pathways in LN. However, even with the best available therapy, the rate of complete remission for proliferative LN remains below 50%. A deeper understanding of the resistance or susceptibility of renal cells to injury during the progression of SLE is critical for identifying new targets and developing effective long-term therapies. The complex and heterogeneous nature of LN, combined with the limitations of clinical research, make it challenging to investigate the aetiology of this disease directly in patients. Hence, multiple murine models resembling SLE-driven nephritis are utilised to dissect LN's cellular and genetic mechanisms, identify therapeutic targets, and screen novel compounds. This review discusses commonly used spontaneous and inducible mouse models that have provided insights into pathogenic mechanisms and long-term maintenance therapies in LN.

Patients with systemic lupus erythematosus (SLE), a heterogeneous and chronic autoimmune disease, exhibit unique changes in the complex composition and transcriptional signatures of peripheral blood mononuclear cells (PBMCs). While the mechanism of pathogenesis for both childhood-onset SLE (cSLE) and adult-onset SLE (aSLE) remains unclear, cSLE patients are considered more unpredictable and dangerous than aSLE patients. In this study, we analysed single-cell RNA sequencing data (scRNA-seq) to profile the PBMC clusters of cSLE/aSLE patients and matched healthy donors and compared the PBMC composition and transcriptional variations between the two groups. Our analysis revealed that the PBMC composition and transcriptional variations in cSLE patients were similar to those in aSLE patients. Comparative single-cell transcriptome analysis between healthy donors and SLE patients revealed IFITM3, ISG15, IFI16 and LY6E as potential therapeutic targets for both aSLE and cSLE patients. Additionally, we observed that the percentage of pre-B cells (CD34-) was increased in cSLE patients, while the percentage of neutrophil cells was upregulated in aSLE patients. Notably, we found decreased expression of TPM2 in cSLE patients, and similarly, TMEM150B, IQSEC2, CHN2, LRP8 and USP46 were significantly downregulated in neutrophil cells from aSLE patients. Overall, our study highlights the differences in complex PBMC composition and transcriptional profiles between cSLE and aSLE patients, providing potential biomarkers that could aid in diagnosing SLE.

Our previous study found that Cullin 4B (CUL4B) inhibited rheumatoid arthritis (RA) pathology through glycogen synthase kinase-3beta (GSK3β)/canonical Wnt signalling pathway. In this work, pre-experiment and bioinformatics analysis suggested that circ_0011058 may lead to the up-regulation of CUL4B expression by inhibiting miR-335-5p. Therefore, we studied whether circ_0011058 can promote the expression of CUL4B through sponging the miR-335-5p and further promote the pathological development of RA. Bioinformatics prediction, real-time quantitative PCR (RT-qPCR), western blot (WB), double luciferase reporter gene and other relevant methods were used to study the inhibition of circ_0011058 on RA pathology and its molecular mechanism. Results showed that the expression of circ_0011058 was significantly increased in adjuvant arthritis (AA) rats and RA fibroblast-like synoviocytes (FLS). The knockout of circ_0011058 inhibited the proliferation of AA FLS and RA FLS, decreased the levels of interleukin-1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), and inhibited the expression of matrix metalloproteinase 3 (MMP3), fibronectin, which showed that circ_0011058 had a strong role in promoting RA pathology. Furthermore, miR-335-5p expression was reduced in AA rats and RA FLS. The highly expressed circ_0011058 directly sponged the miR-335-5p, which led to the increase of CUL4B expression and promoted the activation of the GSK3β/canonical signalling pathway. Finally, we confirmed that miR-335-5p mediated the roles of circ_0011058 in promoting RA pathological development, which showed that the circ_0011058/miR-335-5p/CUL4B signal axis was involved in RA pathology. This work was of great significance for clarifying the roles of circ_0011058 in RA pathology, and further work was needed to establish whether circ_0011058 was a potential therapeutic target or diagnostic marker for RA.