Autoimmunity最新文献

Neuropsychiatric systemic lupus erythematosus (NPSLE) represents a significant and growing challenge in both clinical practice and research, with its mechanistic investigation hindered by the lack of reliable animal models. Over the past two decades, we have established that immunogenic self-DNA can induce SLE disease model, which has been widely utilized in the academic community. To modify the doses of immunogenic self-DNA, validate the induction of SLE disease, and systematically characterize the resulting neuropsychiatric manifestations, aiming to provide an optimal model for NPSLE. Conventional genetic background BALB/c mice were immunized with 75 µg of immunogenic self-DNA. Based on the criteria and diagnostic recommendations from the ACR and EULAR, we conducted neurobehavioral experiments to assess the neuropsychiatric manifestations of clinical NPSLE patients. Whole-cell patch-clamp electrophysiological recordings were performed on mouse brain slices to assess electroencephalographic (EEG) abnormalities associated with NPSLE. Cerebrospinal fluid (CSF) abnormalities were evaluated by measuring inflammatory factors in the CSF. Additionally, histopathological analyses were conducted to evaluate MRI abnormalities in self-DNA immunized mice. Self-DNA immunized mice developed progressive cognitive impairments, exhibiting spatial and working memory deficits from week 8 post-immunization, which worsened by week 12, alongside the emergence of anxiety-like and depression-like behaviors. In parallel, electrophysiological analysis revealed synaptic transmission deficits and reduced neuronal excitability beginning at week 8, further deteriorating by week 12. Of note, blood-brain barrier (BBB) disruption was observed at 4-8 weeks post immunization, which was evidenced by IgG leakage and FITC-dextran extravasation. Such BBB disruption was accompanied by elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10), resembling neuropsychiatric lupus pathology. Finally, histologically, hippocampal neuronal loss and dendritic spine reduction in CA1, CA3, and DG subregions were observed, providing structural correlates for the observed memory deficits in self-DNA immunized mice. This model induced by immunogenic self-DNA recapitulated the neurological manifestations observed in clinical patients, rendering it a robust model for the research of NPSLE.

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.

Systemic lupus erythematosus (SLE), a chronic autoimmune disease, progresses to lupus nephritis (LN) in 50-60% of patients, driving end-stage renal disease (ESRD). Identifying LN-associated cellular senescence hub genes and drug targets is critical for elucidating pathogenesis and advancing targeted therapies. Integrated transcriptomic data from LN patients (GSE61635, GSE121239; n = 441) were analyzed to identify differentially expressed genes (DEGs) using the limma package (|log2FC| > 0.5 and FDR < 0.05). Cellular senescence-associated differentially expressed genes (CS-DEGs) were further filtered through hypergeometric testing using the CellAge database. Functional enrichment analysis performed with ClusterProfiler and DOSE packages revealed significantly enriched pathways based on GO, KEGG, and GSEA terms (FDR < 0.05). A protein-protein interaction (PPI) network was constructed using STRING data and visualized in Cytoscape to prioritize hub genes. The drug-target interactions of these hub genes were subsequently validated via molecular docking and dynamics simulations using CB-Dock2. A total of 1,098 DEGs (555 upregulated, 543 downregulated) were identified. Functional enrichment revealed 60 CS-DEGs significantly enriched in viral response, myeloid differentiation, and antiviral defense (FDR < 0.05). KEGG analysis highlighted their roles in lipid metabolism/atherosclerosis, NOD-like receptor signaling, and Influenza A. PPI-based topological and modular analyses prioritized CCL2, MYD88, STAT1, JUN, JAK2, and FOS as hub genes, further refined to CCL2, JUN, JAK2, and FOS via ceRNA network. Drug screening identified thalidomide as a potential candidate, with strong binding affinity to all targets, particularly CCL2 (ΔG = -92.7 kcal/mol, forming three stable hydrogen bonds). This study revealed the role of CS-DEGs in viral response, immune regulation, and lipid metabolism in LN. Network analysis prioritized CCL2, JUN, JAK2, and FOS as hub genes. Thalidomide exhibited strong binding to these targets, notably CCL2 (ΔG = -92.7 kcal/mol), suggesting therapeutic potential via CCL2-mediated mechanisms. These findings advance LN pathogenesis understanding and precision-targeted therapies.

Immune-mediated lipodystrophy syndromes are rare autoimmune disorders characterized by complete or partial destruction of adipocytes in the body. Recently, autoantibodies against perilipin-1 (PLIN1-autoAbs) have been linked to lipodystrophy. Since various perilipins are expressed in the adrenal cortex and ovaries, we asked whether PLIN1-autoAbs were present in patients with adrenal dysfunction and other autoimmune endocrinopathies. Using a sensitive radiobinding immune assay we analyzed anti-PLIN1-autoAbs in 521 patients with endocrinopathies including Sjögren's syndrome. We identified 22 (4.2%) PLIN1-autoAbs positive patients, of whom 15% had autoimmune polyendocrine syndrome type 1 (4/27), 4% autoimmune Addison's disease and/or autoimmune polyendocrine syndrome type 2 (11/274), 8% type 1 diabetes patients (4/53), and 2% Sjögren's syndrome patients (1/50). However, none of them had known lipodystrophy. In conclusion, PLIN1-autoAbs are found in subgroups of autoimmune endocrinopathies and indicate autoimmunity against adipose tissue, but their pathogenic role if any, remains to be defined. Investigating their role in disease progression and their potential as therapeutic targets could pave the way for novel interventions in autoimmune endocrine diseases.

Autoimmune diseases (ADs), such as Graves' disease (GD), Hashimoto's thyroiditis (HT), psoriasis, systemic lupus erythematosus (SLE), and type 1 diabetes (T1D), involve complex immune and inflammatory responses. This study employed Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data to examine the causal relationships among 91 circulating inflammatory proteins, 41 cytokines, 211 gut microbiota, and 731 immune cell traits in relation to ADs. Additionally, we integrated mediation and bioinformatics analyses, including protein-protein interaction (PPI) networks, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Subnetwork discovery and key protein identification were performed using the Molecular Complex Detection (MCODE) plugin, alongside colocalization analysis and drug target exploration to identify potential mechanisms. MR analysis identified significant causal relationships between various circulating inflammatory proteins, cytokines, gut microbiota species, immune cells, and ADs, with certain relationships retaining significance after false discovery rate (FDR) correction. Mediation analysis demonstrated that inflammatory proteins mediate pathogenic pathways linking immune cells to psoriasis and gut microbiota to Hashimoto's thyroiditis. PPI and bioinformatics analyses highlighted 22 key proteins involved in ADs, while subnetwork analysis identified 15 central proteins. Fms-related tyrosine kinase 3 ligand (FLT3LG) exhibited strong colocalization evidence. Molecular docking confirmed several proteins as viable drug targets. This comprehensive multi-omics study advances our understanding of ADs, identifies novel therapeutic targets, and offers valuable insights for developing new treatment strategies.

Myasthenia gravis (MG) is a common autoimmune disorder that causes skeletal muscle weakness. Most patients presented with skeletal muscle weakness and endurance decline. Mitophagy refers to removing and interpreting aging or damaged mitochondria in cells. This plays a vital role in maintaining cell homeostasis and normal function. This study explores the role of mitophagy-related genes (GM) in MG. Specifically, we collected the transcriptome data of MG and its control group from the GEO database (Gene Expression Omnibus database). The differentially expressed genes (DEGs) were identified by differential analysis and intersected with GM. Multiple machine learning algorithms were applied to screen and verify the diagnostic genes of intersection genes. In addition, we constructed diagnostic models and nomogram models based on diagnostic genes. The immune landscape of MG was explored by ssGSEA analysis. The correlation between the abundance of immune cell infiltration and diagnostic genes was explored by immune infiltration analysis. Finally, the diagnostic genes were further validated by qPCR experiments.

Rheumatoid arthritis (RA) has been associated with an elevated risk of developing disorders related to glucose metabolism, including decreased insulin secretion, impaired glucose tolerance, and type 2 diabetes mellitus. The previse mechanisms underlying this association remain incompletely elucidated. In this study, we utilized a cohort of fifty Wistar female rats, establishing a type II collagen-induced arthritis (CIA) model (n = 30). Out observations indicated abnormal glucose and inulin levels in the CIA rats, accompanied by diminished β cell function. Additionally, we detected elevated cytokines levels and increased apoptosis within the pancreatic tissue of the CIA rats. It is hypothesized that the heightened apoptosis may be induced by cytokines, potentially leading to reduced insulin synthesis and dysregulated glucose metabolism. Through transcriptomic and proteomic analyses, we identified differential expression of genes and proteins involved in pathways that directly or indirectly regulate glycolysis in the CIA rats. Notably, we discovered novel differentially expressed enzymes implicated in the glycolysis pathway, such as hexokinase and fructose-bisphosphate aldolase, within the CIA rat model, which may serve as new markers for the diagnosis of RA or provide new perspectives to treat RA or RA-related glucose metabolism disorder.

Objective: O-linked N-acetylglucosamine (O-GlcNAc) glycosylation represents a prevalent post-translational modification of proteins. Accumulating evidence indicates that dysregulated O-GlcNAcylation can induce glucose toxicity and plays critical roles in the pathogenesis of diabetic nephropathy (DN).

Methods: Human kidney proximal tubular epithelial HK-2 cells were exposed to high glucose (HG) conditions to establish DN cellular models. Co-immunoprecipitation (Co-IP) combined with western blot analysis was employed to assess the expression levels of O-GlcNAc, O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), ACSL4, and ferroptosis-associated proteins. Cell viability was evaluated using the CCK-8 assay, while cell death was analyzed through DAPI/propidium iodide (PI) double staining. Ferroptosis was assessed by measuring intracellular iron accumulation, glutathione (GSH) content, and reactive oxygen species (ROS) levels. Additionally, in vivo experiments were conducted using male C57BL/6J mice divided into four groups: control, DN, DN+shOGT, and DN+shNC. DN was induced by a high-fat diet (HFD) followed by streptozotocin (STZ) injection. OGT was specifically knocked down in the kidneys using AAV-shOGT. Kidney tissues were analyzed for pathological changes, O-GlcNAcylation levels, and ferroptosis markers.

Results: Our findings demonstrated that O-GlcNAc and OGT expressions were significantly upregulated in HG-treated HK-2 cells. OGT knockdown effectively attenuated HG-induced ferroptosis. Importantly, ACSL4 protein levels exhibited strong positive correlation with OGT expression. Subsequent investigation revealed direct interaction between ACSL4 and OGT. O-GlcNAcylation modification was found to enhance ACSL4 protein stability. Moreover, overexpression of ACSL4 counteracted the protective effects of OGT knockdown against ferroptosis. Additionally, OGT knockdown reversed the high iron concentration, ROS, and MDA levels, and restored GSH and SOD levels in DN mice. O-GlcNAc, OGT, and ACSL4 levels, which were markedly increased in the DN group, were downregulated by OGT knockdown treatment in vivo.

Conclusions: Collectively, these results demonstrate that high glucose promotes OGT-mediated O-GlcNAcylation of ACSL4, thereby stabilizing this enzyme and facilitating ferroptosis progression in DN.

Background: Cutaneous melanoma is a highly invasive tumor. It enhances metastasis and resistance to immunotherapy via immunosuppressive mechanisms. Understanding RNA-binding proteins (RBPs) in melanoma's immune alterations is limited. This study explores immune-regulatory RBPs in metastasis and clarifies RNASE6's role in immune regulation.

Methods: Utilizing the bulk RNA-seq datasets of melanoma, the immune status of the samples was assessed using CIBERSORT and ESTIMATE. WGCNA and five machine learning algorithms were employed to identify immune RBPs associated with metastasis. Further exploration of RNASE6 was mainly performed using COX, Kaplan-Meier survival analysis, and GSEA. Utilizing GWAS data, mendelian randomization was applied to demonstrate the causal relationship between RNASE6 and melanoma. Utilizing scRNA-seq dataset, the regulatory effect of RNASE6 on macrophages was validated through constructing a regulatory network. Finally, the key role of RNASE6 on macrophage polarization was validated through cell experiments.

Results: Using WGCNA and machine learning, we identified nine immune-related RBPs (CCDC86, CPEB3, EXO1, FASTKD2, MBNL1, RNASE6, RUVBL2, TLR8, URB2) associated with melanoma metastasis. Among these, RNASE6 emerged as a key regulator, with its expression highly positively correlated with M1 macrophage polarization and inhibition of metastasis. High RNASE6 expression was also correlated with improved prognosis and a better response to anti-PD-1 therapy. Mendelian randomization demonstrated that RNASE6 acts as a protective factor against melanoma. The regulatory network indicated that RNASE6 influences multiple macrophage polarization markers. Cell experiments confirmed the adverse effect of knocking down RNASE6 on M1 polarization of macrophages.

Conclusion: We identified RNASE6 as an immune-regulatory RBP in melanoma, capable of influencing metastasis progression and immunotherapy outcomes by promoting M1 macrophage polarization.

Real-world studies on vaccine effectiveness may suffer from several biases, typically distorting their results. A previous article on the population of an Italian province, correcting the "immortal time bias", showed worse results for the all-cause death of the vaccinated compared to the unvaccinated. This article highlights the "case counting window bias", that considers the vaccine recipients "unvaccinated" usually for 14 days, a time interval reputed necessary to express the vaccine immune response. We aim to document this bias in an Italian region, calculating the daily death incidence for each age class of vaccinated and unvaccinated and checking their all-cause mortality difference within the considered time window. Indeed, in this window the two groups showed huge differences in all-cause deaths, that cannot be attributed only to COVID-19 deaths (in the absence of reasons to expect significant vaccine effects on non-COVID-19 deaths). In conclusion, analyzing the data of an Italian Region, we found evidence of the 'case counting window bias', which artificially increases the 'unvaccinated' mortality and reduces the mortality in the vaccinated.