Pub Date : 2026-06-01Epub Date: 2025-12-03DOI: 10.1016/j.jtauto.2025.100338
Jianbin Li , Suiran Li , Wei Liu
Background
Primary Sjögren’s Syndrome (pSS) exhibits significant clinical heterogeneity, and traditional organ-based classification systems fail to capture the underlying disease mechanisms. This study aims to identify distinct clinical immune phenotypes of pSS through a data-driven approach and explore their predictive biomarkers.
Method
This cross-sectional study included 1087 patients who met the 2016 ACR/EULAR classification criteria for primary Sjögren’s syndrome between 2014 and 2024. Unsupervised K-means clustering analysis was applied to 10 organ involvement variables to identify natural patient subgroups. Network analysis was used to explore the associations between organ involvement and laboratory biomarkers. Multivariable logistic regression was employed to identify independent predictors of subgroup assignment, and restricted cubic spline analysis was conducted to assess the nonlinear relationships between key biomarkers and subtype risk.
Results
Clustering analysis identified two distinct phenotypes: Phenotype 1 (multi-system inflammatory subtype, n = 594) was characterized by widespread musculoskeletal involvement (100 %) and significantly elevated inflammatory markers (RF: 246.41 ± 1177.49 vs 32.75 ± 126.74 IU/mL, P < 0.001); Phenotype 2 (glandular-limited high immunoglobulin subtype, n = 493) was primarily characterized by glandular involvement (40.7 %), higher IgG levels, and less systemic involvement. Network analysis revealed a strong correlation between RF and musculoskeletal involvement (r = 0.32, P < 0.001). Independent predictors of Phenotype 1 included male gender (OR 2.559, 95 % CI 1.109–6.090), elevated potassium (OR 1.607, 95 % CI 1.061–2.433), and elevated RF levels (OR 1.004, 95 % CI 1.002–1.005). A composite clinical prediction score incorporating these biomarkers achieved an AUC of 0.717 (95 % CI: 0.684–0.751) for phenotype discrimination. Nonlinear analysis showed complex U-shaped and inverted U-shaped relationships between key biomarkers and phenotype risk.
Conclusion
pSS consists of distinct clinical phenotypes with varying pathophysiological characteristics. The data-driven classification system complements traditional severity grading and provides new insights into precision medicine approaches. RF is a key biomarker linking musculoskeletal manifestations with the severity of systemic inflammation and may serve as an important indicator for precise subtyping and targeted therapy.
原发性Sjögren综合征（pSS）表现出明显的临床异质性，传统的基于器官的分类系统无法捕捉潜在的疾病机制。本研究旨在通过数据驱动的方法识别pSS不同的临床免疫表型，并探索其预测性生物标志物。方法本横断面研究纳入了2014年至2024年间1087例符合2016年ACR/EULAR原发性Sjögren综合征分类标准的患者。对10个器官受累变量进行无监督k均值聚类分析，以确定自然患者亚组。网络分析用于探索器官受累与实验室生物标志物之间的关系。采用多变量logistic回归确定亚组分配的独立预测因子，并采用限制性三次样条分析评估关键生物标志物与亚型风险之间的非线性关系。结果聚类分析确定了两种不同的表型：表型1（多系统炎症亚型，n = 594）以广泛的肌肉骨骼受累（100%）和显著升高的炎症标志物为特征（RF: 246.41±1177.49 vs 32.75±126.74 IU/mL, P < 0.001）；表型2（腺限制性高免疫球蛋白亚型，n = 493）的主要特征是腺体受累（40.7%），IgG水平较高，全身受累较少。网络分析显示射频与肌肉骨骼受累之间有很强的相关性（r = 0.32, P < 0.001）。表型1的独立预测因子包括男性（OR 2.559, 95% CI 1.109-6.090）、钾离子升高（OR 1.607, 95% CI 1.061-2.433）和射频水平升高（OR 1.004, 95% CI 1.002-1.005）。结合这些生物标志物的综合临床预测评分在表型区分方面的AUC为0.717 （95% CI: 0.684-0.751）。非线性分析显示，关键生物标志物与表型风险之间存在复杂的u型和倒u型关系。结论pss具有不同的临床表型和不同的病理生理特征。数据驱动的分类系统补充了传统的严重程度分级，并为精准医学方法提供了新的见解。RF是连接肌肉骨骼表现与全身炎症严重程度的关键生物标志物，可作为精确分型和靶向治疗的重要指标。
{"title":"Data-driven classification of primary Sjögren’s syndrome: From cluster analysis to clinical immune phenotypes and predictive biomarkers","authors":"Jianbin Li , Suiran Li , Wei Liu","doi":"10.1016/j.jtauto.2025.100338","DOIUrl":"10.1016/j.jtauto.2025.100338","url":null,"abstract":"<div><h3>Background</h3><div>Primary Sjögren’s Syndrome (pSS) exhibits significant clinical heterogeneity, and traditional organ-based classification systems fail to capture the underlying disease mechanisms. This study aims to identify distinct clinical immune phenotypes of pSS through a data-driven approach and explore their predictive biomarkers.</div></div><div><h3>Method</h3><div>This cross-sectional study included 1087 patients who met the 2016 ACR/EULAR classification criteria for primary Sjögren’s syndrome between 2014 and 2024. Unsupervised K-means clustering analysis was applied to 10 organ involvement variables to identify natural patient subgroups. Network analysis was used to explore the associations between organ involvement and laboratory biomarkers. Multivariable logistic regression was employed to identify independent predictors of subgroup assignment, and restricted cubic spline analysis was conducted to assess the nonlinear relationships between key biomarkers and subtype risk.</div></div><div><h3>Results</h3><div>Clustering analysis identified two distinct phenotypes: Phenotype 1 (multi-system inflammatory subtype, n = 594) was characterized by widespread musculoskeletal involvement (100 %) and significantly elevated inflammatory markers (RF: 246.41 ± 1177.49 vs 32.75 ± 126.74 IU/mL, P < 0.001); Phenotype 2 (glandular-limited high immunoglobulin subtype, n = 493) was primarily characterized by glandular involvement (40.7 %), higher IgG levels, and less systemic involvement. Network analysis revealed a strong correlation between RF and musculoskeletal involvement (r = 0.32, P < 0.001). Independent predictors of Phenotype 1 included male gender (OR 2.559, 95 % CI 1.109–6.090), elevated potassium (OR 1.607, 95 % CI 1.061–2.433), and elevated RF levels (OR 1.004, 95 % CI 1.002–1.005). A composite clinical prediction score incorporating these biomarkers achieved an AUC of 0.717 (95 % CI: 0.684–0.751) for phenotype discrimination. Nonlinear analysis showed complex U-shaped and inverted U-shaped relationships between key biomarkers and phenotype risk.</div></div><div><h3>Conclusion</h3><div>pSS consists of distinct clinical phenotypes with varying pathophysiological characteristics. The data-driven classification system complements traditional severity grading and provides new insights into precision medicine approaches. RF is a key biomarker linking musculoskeletal manifestations with the severity of systemic inflammation and may serve as an important indicator for precise subtyping and targeted therapy.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100338"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2025-12-08DOI: 10.1016/j.jtauto.2025.100334
Xiang Zhu , Yujie Yang , Yi Zhu
<div><h3>Background</h3><div>Ulcerative colitis (UC) is an immune-mediated chronic inflammatory bowel disease, and with the rising global incidence and the risk of malignant transformation, the treatment of UC is challenged by heterogeneous progression and limited targeted therapies, and its underlying pathogenesis remains unclear. This study aims to identify novel therapeutic targets for UC, elucidate the genetic factors associated with UC development, and advance precision medicine strategies for UC.</div></div><div><h3>Methods</h3><div>Differential expression analysis was performed on three independent UC datasets from the Gene Expression Omnibus (GEO) database, identifying differentially expressed genes (DEGs) associated with UC. An eQTL-MR analysis was conducted to identify UC-related gene expression loci, and the results were intersected with the GEO differential analysis using a Venn diagram. Subsequently, a protein-protein interaction network was constructed based on the 20 intersecting genes identified through both eQTL-MR and differential expression analysis, using STRING. Key hub genes were then identified based on centrality scores calculated in Cytoscape. Additionally, Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to explore the functional roles and pathways of these genes. Finally, the results obtained for the target genes were validated.</div></div><div><h3>Results</h3><div>Twenty intersecting genes were identified, specifically PITPNC1, OLFM1, PARP9, BATF2, PDGFRB, LEF1, CST7, HCLS1, SLC16A6, CCR7, KMO, ITGA4, SLC22A5, ASB13, SLC22A4, DNMBP, PGAP3, FAAH, SLC7A9, and BTNL8. These genes are involved in fundamental biological processes and pathways, including immune response modulation and epithelial barrier regulation. Additionally, CIBERSORT analysis revealed a unique immune cell distribution in UC and highlighted the association between immune cells and the intersecting genes. Gene Set Enrichment Analysis (GSEA) showed that high expression levels of HCLS1, ITGA4, and PDGFRB may collectively contribute to the recruitment and activation of inflammatory cells, as well as the amplification of immune signaling. Conversely, lower expression levels of these genes suggest that the tissue may be in a state of reduced inflammation or repair. The MR analysis was consistent with the results of variance analysis in the validation cohort, further reinforcing the reliability of our MR findings.</div></div><div><h3>Conclusions</h3><div>HCLS1, ITGA4, and PDGFRB may represent core modules involved in T/B cell homing and activation, pro-inflammatory macrophage recruitment, and extracellular matrix responses. These genes interact with upregulated genes to promote the amplification of inflammation, counteracting with downregulated metabolic-related genes. Together, they contribute to the molecular foundation of the inflammatory and metabolic protective phenotype
{"title":"Decoding ulcerative colitis pathogenesis through transcriptomics: from dysregulated gene networks to targeted intervention strategies","authors":"Xiang Zhu , Yujie Yang , Yi Zhu","doi":"10.1016/j.jtauto.2025.100334","DOIUrl":"10.1016/j.jtauto.2025.100334","url":null,"abstract":"<div><h3>Background</h3><div>Ulcerative colitis (UC) is an immune-mediated chronic inflammatory bowel disease, and with the rising global incidence and the risk of malignant transformation, the treatment of UC is challenged by heterogeneous progression and limited targeted therapies, and its underlying pathogenesis remains unclear. This study aims to identify novel therapeutic targets for UC, elucidate the genetic factors associated with UC development, and advance precision medicine strategies for UC.</div></div><div><h3>Methods</h3><div>Differential expression analysis was performed on three independent UC datasets from the Gene Expression Omnibus (GEO) database, identifying differentially expressed genes (DEGs) associated with UC. An eQTL-MR analysis was conducted to identify UC-related gene expression loci, and the results were intersected with the GEO differential analysis using a Venn diagram. Subsequently, a protein-protein interaction network was constructed based on the 20 intersecting genes identified through both eQTL-MR and differential expression analysis, using STRING. Key hub genes were then identified based on centrality scores calculated in Cytoscape. Additionally, Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to explore the functional roles and pathways of these genes. Finally, the results obtained for the target genes were validated.</div></div><div><h3>Results</h3><div>Twenty intersecting genes were identified, specifically PITPNC1, OLFM1, PARP9, BATF2, PDGFRB, LEF1, CST7, HCLS1, SLC16A6, CCR7, KMO, ITGA4, SLC22A5, ASB13, SLC22A4, DNMBP, PGAP3, FAAH, SLC7A9, and BTNL8. These genes are involved in fundamental biological processes and pathways, including immune response modulation and epithelial barrier regulation. Additionally, CIBERSORT analysis revealed a unique immune cell distribution in UC and highlighted the association between immune cells and the intersecting genes. Gene Set Enrichment Analysis (GSEA) showed that high expression levels of HCLS1, ITGA4, and PDGFRB may collectively contribute to the recruitment and activation of inflammatory cells, as well as the amplification of immune signaling. Conversely, lower expression levels of these genes suggest that the tissue may be in a state of reduced inflammation or repair. The MR analysis was consistent with the results of variance analysis in the validation cohort, further reinforcing the reliability of our MR findings.</div></div><div><h3>Conclusions</h3><div>HCLS1, ITGA4, and PDGFRB may represent core modules involved in T/B cell homing and activation, pro-inflammatory macrophage recruitment, and extracellular matrix responses. These genes interact with upregulated genes to promote the amplification of inflammation, counteracting with downregulated metabolic-related genes. Together, they contribute to the molecular foundation of the inflammatory and metabolic protective phenotype ","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100334"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2026-01-12DOI: 10.1016/j.jtauto.2026.100351
Jerrold S. Levine , Céleste Pilon , Rebecca Subang , David Salem , Elena Lonina , Salman T. Qureshi , Gregory J. Fonseca , Philippe Gros , Joyce Rauch
Systemic lupus erythematosus (SLE) is characterized by the development of autoantibodies against diverse self-antigens and damage to multiple organs. Immunization with the SLE autoantigen β2-glycoprotein I and lipopolysaccharide (LPS) induces a murine model of SLE with the sequential emergence of multiple hallmark SLE autoantibodies. LPS is a TLR4 trigger of innate immunity and inflammation that signals through adaptor proteins MyD88 and TRIF, resulting in the production of both inflammatory cytokines and type I interferons (IFN-I). We hypothesized that both IFN-I-dependent and -independent mechanisms are important in the initiation of SLE. Using our induced murine model of SLE, we found that TRIF deficiency completely abrogated autoantibody production. Downstream of TRIF, both IRF3 and IFNaR (IFN-I receptor) deficiency significantly diminished autoantibody production. Using transcriptomics, we identified 27 upregulated and 4 downregulated TRIF- and IRF3-dependent genes differentially expressed by both dendritic cells (DCs) and macrophages upon induction of the SLE model. While most genes were dependent on IFN-I signalling, some showed little or no IFN-I dependence. Notably, the 27 upregulated genes correlated with published datasets for human SLE. Our findings map the transcriptional response of macrophages and DCs early during pathogenesis of SLE, including pathways associated with both IFN-I-dependent and -independent genes in SLE. Investigation of candidate genes within both gene subsets may provide insight into the events leading up to SLE as well as potential therapeutic targets.
{"title":"Type I interferon-dependent and -independent signaling underlie autoantibody production in a murine lupus model","authors":"Jerrold S. Levine , Céleste Pilon , Rebecca Subang , David Salem , Elena Lonina , Salman T. Qureshi , Gregory J. Fonseca , Philippe Gros , Joyce Rauch","doi":"10.1016/j.jtauto.2026.100351","DOIUrl":"10.1016/j.jtauto.2026.100351","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is characterized by the development of autoantibodies against diverse self-antigens and damage to multiple organs. Immunization with the SLE autoantigen β2-glycoprotein I and lipopolysaccharide (LPS) induces a murine model of SLE with the sequential emergence of multiple hallmark SLE autoantibodies. LPS is a TLR4 trigger of innate immunity and inflammation that signals through adaptor proteins MyD88 and TRIF, resulting in the production of both inflammatory cytokines and type I interferons (IFN-I). We hypothesized that both IFN-I-dependent and -independent mechanisms are important in the initiation of SLE. Using our induced murine model of SLE, we found that TRIF deficiency completely abrogated autoantibody production. Downstream of TRIF, both IRF3 and IFNaR (IFN-I receptor) deficiency significantly diminished autoantibody production. Using transcriptomics, we identified 27 upregulated and 4 downregulated TRIF- and IRF3-dependent genes differentially expressed by both dendritic cells (DCs) and macrophages upon induction of the SLE model. While most genes were dependent on IFN-I signalling, some showed little or no IFN-I dependence. Notably, the 27 upregulated genes correlated with published datasets for human SLE. Our findings map the transcriptional response of macrophages and DCs early during pathogenesis of SLE, including pathways associated with both IFN-I-dependent and -independent genes in SLE. Investigation of candidate genes within both gene subsets may provide insight into the events leading up to SLE as well as potential therapeutic targets.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100351"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146173458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2026-01-07DOI: 10.1016/j.jtauto.2026.100348
Amirhesan Yahyapour , Ali Najafi , Ali Ahmadi , Navvabeh Salarizadeh
Psoriasis impacts nearly 100 million people globally and is associated with neuropsychiatric comorbidities such as depression and anxiety. With gut microbiome dysbiosis serving as a primary pathophysiological factor, the gut-brain-skin axis provides a crucial framework for understanding this relationship. This review evaluates the mechanisms of the gut-brain-skin axis in psoriasis pathophysiology and assesses the therapeutic potential of microbiome-based treatments, combining preclinical, clinical, and multi-omics data. Patients with psoriasis show specific gut dysbiosis patterns, including reduced microbial diversity, lower SCFA-producing bacteria (especially Faecalibacterium and Akkermansia), and increased pro-inflammatory bacteria. This microbial imbalance damages intestinal barrier integrity, triggers systemic inflammation, activates cutaneous Th17 pathways, and induces neuroinflammation through blood-brain barrier disruption. Axis communication occurs through immune-inflammatory mechanisms mediated by SCFAs and neuroendocrine pathways involving microbially-derived neurotransmitters (GABA, serotonin, dopamine). Metagenomic research indicates functional deficiencies in neurotransmitter and SCFA synthesis pathways are more significant than taxonomic alterations. Machine learning models can utilize these functional features to identify patients at risk for neuropsychiatric comorbidities and predict treatment response. Recent randomized controlled trials demonstrate that targeted interventions (probiotics, prebiotics, postbiotics, fecal microbiota transplantation) significantly improve Psoriasis Area and Severity Index scores, inflammatory markers, and microbiota composition. The evidence supports a shift toward integrated microbiome strategies, emphasizing functional approaches including mitochondrial therapies, psychobiotics, precision nutrition, and multi-omics-guided therapies.
{"title":"Immunoprotective and neuroprotective properties of gut microbiome in psoriasis","authors":"Amirhesan Yahyapour , Ali Najafi , Ali Ahmadi , Navvabeh Salarizadeh","doi":"10.1016/j.jtauto.2026.100348","DOIUrl":"10.1016/j.jtauto.2026.100348","url":null,"abstract":"<div><div>Psoriasis impacts nearly 100 million people globally and is associated with neuropsychiatric comorbidities such as depression and anxiety. With gut microbiome dysbiosis serving as a primary pathophysiological factor, the gut-brain-skin axis provides a crucial framework for understanding this relationship. This review evaluates the mechanisms of the gut-brain-skin axis in psoriasis pathophysiology and assesses the therapeutic potential of microbiome-based treatments, combining preclinical, clinical, and multi-omics data. Patients with psoriasis show specific gut dysbiosis patterns, including reduced microbial diversity, lower SCFA-producing bacteria (especially Faecalibacterium and Akkermansia), and increased pro-inflammatory bacteria. This microbial imbalance damages intestinal barrier integrity, triggers systemic inflammation, activates cutaneous Th17 pathways, and induces neuroinflammation through blood-brain barrier disruption. Axis communication occurs through immune-inflammatory mechanisms mediated by SCFAs and neuroendocrine pathways involving microbially-derived neurotransmitters (GABA, serotonin, dopamine). Metagenomic research indicates functional deficiencies in neurotransmitter and SCFA synthesis pathways are more significant than taxonomic alterations. Machine learning models can utilize these functional features to identify patients at risk for neuropsychiatric comorbidities and predict treatment response. Recent randomized controlled trials demonstrate that targeted interventions (probiotics, prebiotics, postbiotics, fecal microbiota transplantation) significantly improve Psoriasis Area and Severity Index scores, inflammatory markers, and microbiota composition. The evidence supports a shift toward integrated microbiome strategies, emphasizing functional approaches including mitochondrial therapies, psychobiotics, precision nutrition, and multi-omics-guided therapies.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100348"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2025-12-06DOI: 10.1016/j.jtauto.2025.100339
Shivam Singh, Ashish Kumar Sharma
A newly identified autoinflammatory condition called CANDLE syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and increased temperature) is characterized by early onset, recurring fever, skin lesions, and multisystemic inflammatory symptoms. It has been demonstrated that the majority of patients had PSMB8 gene mutations. It leads to dysfunction in the proteasome/immunoproteasome system and subsequent overproduction of type 1 interferons. Patients usually exhibit lipodystrophy, fever, rashes on the skin, and malnutrition in the early stages of infancy. The results of skin biopsies, laboratory tests, and clinical symptoms all support the diagnosis of CANDLE syndrome. Although there isn't a specific treatment for CANDLE syndrome, JAK inhibitors like baricitinib have demonstrated some effectiveness in treating its symptoms. For CANDLE syndrome patients to receive the right therapeutic interventions, early diagnosis and molecular testing are essential. A positive interferon signature has also been found to be a diagnostic indicator for the condition. Although there are no particular treatments for CANDLE syndrome, research is still being done to determine how well immunosuppressive medications, biological agents, and glucocorticoids work in treating the condition. Current research generally aims to improve the quality of life for individuals with CANDLE syndrome through the development of targeted medications, the elucidation of genetic determinants, and the advancement of diagnostic methods.
{"title":"“CANDLE syndrome: A closer look at a rare autoinflammatory disorder”","authors":"Shivam Singh, Ashish Kumar Sharma","doi":"10.1016/j.jtauto.2025.100339","DOIUrl":"10.1016/j.jtauto.2025.100339","url":null,"abstract":"<div><div>A newly identified autoinflammatory condition called CANDLE syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and increased temperature) is characterized by early onset, recurring fever, skin lesions, and multisystemic inflammatory symptoms. It has been demonstrated that the majority of patients had PSMB8 gene mutations. It leads to dysfunction in the proteasome/immunoproteasome system and subsequent overproduction of type 1 interferons. Patients usually exhibit lipodystrophy, fever, rashes on the skin, and malnutrition in the early stages of infancy. The results of skin biopsies, laboratory tests, and clinical symptoms all support the diagnosis of CANDLE syndrome. Although there isn't a specific treatment for CANDLE syndrome, JAK inhibitors like baricitinib have demonstrated some effectiveness in treating its symptoms. For CANDLE syndrome patients to receive the right therapeutic interventions, early diagnosis and molecular testing are essential. A positive interferon signature has also been found to be a diagnostic indicator for the condition. Although there are no particular treatments for CANDLE syndrome, research is still being done to determine how well immunosuppressive medications, biological agents, and glucocorticoids work in treating the condition. Current research generally aims to improve the quality of life for individuals with CANDLE syndrome through the development of targeted medications, the elucidation of genetic determinants, and the advancement of diagnostic methods.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100339"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2025-12-08DOI: 10.1016/j.jtauto.2025.100341
Yeny Acosta-Ampudia , Diana M. Monsalve , Daniel Galeano-Sánchez , Manuel Rojas , Carolina Ramírez-Santana
Background
Autoimmune diseases are multifactorial, with environmental contaminants increasingly recognized as risk factors. This pilot study investigated the in vitro effects of particulate matter (PM), silica, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on peripheral blood mononuclear cells (PBMCs) from healthy donors (HD) and patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).
Methods
PBMCs were obtained from HD (n = 6), RA patients (n = 5), and SLE patients (n = 5) and stimulated for 24 h with PM (100 μg/mL), silica (30 μg/mL), or TCDD (250 pg/mL). Immunophenotyping by flow cytometry was performed in HD, characterizing T cell subsets, B cells, NK/NKT cells, monocytes, and dendritic cells, including activation markers. Production of 18 cytokines and chemokines was quantified in all groups using Cytometric Bead Array. Activation of intracellular signaling pathways (AKT, NFκB, p38 MAPK, STAT1, STAT3) was assessed by Western blot.
Results
All contaminants induced strong immune activation. In HD, flow cytometry revealed strong activation of monocytes and dendritic cells, with increased co-stimulatory markers (CD40, CD80, CD83) and skewing of T cells toward effector phenotypes. Cytokine analysis showed substantial overlap in inflammatory profiles across HD, RA, and SLE, despite the significant upregulation of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), growth factors (GM-CSF, G-CSF), and regulatory cytokines (IL-10). Western blot confirmed modulation of signaling pathways, with PM notably enhancing p38 MAPK phosphorylation in HD and RA.
Conclusion
Environmental contaminants elicit robust immunomodulatory effects in PBMCs. The overlap in cytokine profiles and signaling responses across HD, RA, and SLE indicates a highly conserved cellular response to environmental stressors, independent of autoimmune disease status.
{"title":"Exploring the immunomodulatory effects of environmental contaminants on autoimmune patients: An in vitro approach","authors":"Yeny Acosta-Ampudia , Diana M. Monsalve , Daniel Galeano-Sánchez , Manuel Rojas , Carolina Ramírez-Santana","doi":"10.1016/j.jtauto.2025.100341","DOIUrl":"10.1016/j.jtauto.2025.100341","url":null,"abstract":"<div><h3>Background</h3><div>Autoimmune diseases are multifactorial, with environmental contaminants increasingly recognized as risk factors. This pilot study investigated the <em>in vitro</em> effects of particulate matter (PM), silica, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on peripheral blood mononuclear cells (PBMCs) from healthy donors (HD) and patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).</div></div><div><h3>Methods</h3><div>PBMCs were obtained from HD (n = 6), RA patients (n = 5), and SLE patients (n = 5) and stimulated for 24 h with PM (100 μg/mL), silica (30 μg/mL), or TCDD (250 pg/mL). Immunophenotyping by flow cytometry was performed in HD, characterizing T cell subsets, B cells, NK/NKT cells, monocytes, and dendritic cells, including activation markers. Production of 18 cytokines and chemokines was quantified in all groups using Cytometric Bead Array. Activation of intracellular signaling pathways (AKT, NFκB, p38 MAPK, STAT1, STAT3) was assessed by Western blot.</div></div><div><h3>Results</h3><div>All contaminants induced strong immune activation. In HD, flow cytometry revealed strong activation of monocytes and dendritic cells, with increased co-stimulatory markers (CD40, CD80, CD83) and skewing of T cells toward effector phenotypes. Cytokine analysis showed substantial overlap in inflammatory profiles across HD, RA, and SLE, despite the significant upregulation of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), growth factors (GM-CSF, G-CSF), and regulatory cytokines (IL-10). Western blot confirmed modulation of signaling pathways, with PM notably enhancing p38 MAPK phosphorylation in HD and RA.</div></div><div><h3>Conclusion</h3><div>Environmental contaminants elicit robust immunomodulatory effects in PBMCs. The overlap in cytokine profiles and signaling responses across HD, RA, and SLE indicates a highly conserved cellular response to environmental stressors, independent of autoimmune disease status.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100341"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2026-02-06DOI: 10.1016/j.jtauto.2026.100355
Cristina Vicenzetto , Andrea Silvio Giordani , Anna Baritussio , Federico Scognamiglio , Maria Grazia Peloso-Cattini , Elena Pontara , Elisa Bison , Gloria Brigiari , Giuseppe Tarantini , Massimo Napodano , Giuseppe Toscano , Dario Gregori , Elisa Carturan , Monica De Gaspari , Stefania Rizzo , Cristina Basso , Renzo Marcolongo , Alida Linda Patrizia Caforio
Background
Myocarditis is an inflammatory disease of the myocardium with infectious or immune-mediated/autoimmune etiology; etiology diagnosis relays on endomyocardial biopsy (EMB). High titre serum anti-heart autoantibodies (AHA) define severe autoimmune forms. In autoimmune myocarditis immunosuppression (IS) may be required to prevent progression to dilated cardiomyopathy, heart transplant or death, but it is not always effective. This study aimed to identify non-invasive cellular biomarkers of etiology and response to IS in biopsy-proven myocarditis peripheral blood.
Methods
Fifty-eight EMB-proven myocarditis patients out of IS were enrolled and compared with 9 healthy controls and 20 EMB-proven myocarditis on IS. Cells distribution was evaluated by flow cytometry; results were related to clinical, EMB and AHA findings.
Results
Compared to healthy controls, plasmacytoid dendritic cells percentage was reduced in autoimmune (p = 0.017), in lymphocytic (p = 0.012) myocarditis patients, in those without extra-cardiac autoimmune diseases (AD, p = 0.01), and in myocarditis not on IS (p = 0.003). Viral myocarditis had higher CD62L+/CD56+ NK cells percentage (p = 0.001) and CCR2 over-expression in intermediate monocytes when compared with autoimmune myocarditis (p = 0.013). Autoimmune myocarditis was characterized by higher Th1/Th2 (p = 0.004) and Th17/Treg ratio (p = 0.008), Th1 (p = 0.028) and Th17 lymphocytes (p = 0.017) percentage vs. healthy controls. A reduction of Treg cells percentage was specific for autoimmune lymphocytic (p = 0.047 vs healthy controls), for AHA-positive myocarditis (p = 0.03 vs healthy controls) and for myocarditis unresponsive to IS (p = 0.036).
Conclusions
Biopsy-proven myocarditis patients showed distinct peripheral immunophenotypes of either innate or adaptive immune cells according to different histology, etiology and response to IS, unveiling potential novel non-invasive etiological biomarkers for myocarditis.
{"title":"Biopsy-proven myocarditis: peripheral immunophenotypes correlate with histology, etiology, immunosuppressive therapy","authors":"Cristina Vicenzetto , Andrea Silvio Giordani , Anna Baritussio , Federico Scognamiglio , Maria Grazia Peloso-Cattini , Elena Pontara , Elisa Bison , Gloria Brigiari , Giuseppe Tarantini , Massimo Napodano , Giuseppe Toscano , Dario Gregori , Elisa Carturan , Monica De Gaspari , Stefania Rizzo , Cristina Basso , Renzo Marcolongo , Alida Linda Patrizia Caforio","doi":"10.1016/j.jtauto.2026.100355","DOIUrl":"10.1016/j.jtauto.2026.100355","url":null,"abstract":"<div><h3>Background</h3><div>Myocarditis is an inflammatory disease of the myocardium with infectious or immune-mediated/autoimmune etiology; etiology diagnosis relays on endomyocardial biopsy (EMB). High titre serum anti-heart autoantibodies (AHA) define severe autoimmune forms. In autoimmune myocarditis immunosuppression (IS) may be required to prevent progression to dilated cardiomyopathy, heart transplant or death, but it is not always effective. This study aimed to identify non-invasive cellular biomarkers of etiology and response to IS in biopsy-proven myocarditis peripheral blood.</div></div><div><h3>Methods</h3><div>Fifty-eight EMB-proven myocarditis patients out of IS were enrolled and compared with 9 healthy controls and 20 EMB-proven myocarditis on IS. Cells distribution was evaluated by flow cytometry; results were related to clinical, EMB and AHA findings.</div></div><div><h3>Results</h3><div>Compared to healthy controls, plasmacytoid dendritic cells percentage was reduced in autoimmune (p = 0.017), in lymphocytic (p = 0.012) myocarditis patients, in those without extra-cardiac autoimmune diseases (AD, p = 0.01), and in myocarditis not on IS (p = 0.003). Viral myocarditis had higher CD62L+/CD56+ NK cells percentage (p = 0.001) and CCR2 over-expression in intermediate monocytes when compared with autoimmune myocarditis (p = 0.013). Autoimmune myocarditis was characterized by higher Th1/Th2 (p = 0.004) and Th17/Treg ratio (p = 0.008), Th1 (p = 0.028) and Th17 lymphocytes (p = 0.017) percentage vs. healthy controls. A reduction of Treg cells percentage was specific for autoimmune lymphocytic (p = 0.047 vs healthy controls), for AHA-positive myocarditis (p = 0.03 vs healthy controls) and for myocarditis unresponsive to IS (p = 0.036).</div></div><div><h3>Conclusions</h3><div>Biopsy-proven myocarditis patients showed distinct peripheral immunophenotypes of either innate or adaptive immune cells according to different histology, etiology and response to IS, unveiling potential novel non-invasive etiological biomarkers for myocarditis.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100355"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146173486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-07-24DOI: 10.1016/j.jtauto.2025.100301
Daan A.R. Castelijn , Nicolette J. Wierdsma , Kim de Buck , Maaike A. van Bree , Tracy-Jane T.H.D. Eisden , Jolien C. Hollander , Gerd Bouma , Hetty J. Bontkes
Objectives
Discrepancy between serology and small bowel histology, such as seronegative CD, poses a diagnostic challenge in celiac disease (CD) diagnosis. Recently described methods to detect gliadin-specific T-cells are too laborious even in a specialized diagnostic setting. We developed a method, which can be implemented in specialized diagnostic laboratories.
Methods
Gliadin-specific T-cells were analyzed by α1-and α2-gliadin peptide loaded Dextramers (Dm) in healthy controls (HC, n = 18), patients with non-celiac gluten sensitivity (NCGS, n = 9), active CD (aCD, n = 7) and CD on a gluten free diet (GFD, n = 14). Control peptide (CLIP)-loaded Dm were used as background controls. The α-gliadin-Dm:CLIP-Dm ratio was calculated. In CD patients ≥5 years on GFD (n = 8), a randomized two-dose gluten challenge was performed to increase gliadin-specific T-cell frequencies.
Results
Gliadin-specific CD4+ T-cell frequencies were significantly higher in aCD and GFD than in HC and NCGS (p ≤ 0.0001). In CD patients on a GFD ≥5 years, gliadin-specific T-cells were detectable in 6/8 patients after a week gluten challenge, and all tested positive within 4 weeks. Gliadin-specific T-cells significantly upregulated CD38 after 1 week of gluten ingestion (p < 0.008). Real world data from sixteen patients demonstrated the applicability of this test in diagnostic challenging cases.
Conclusions
Gliadin-specific T-cells can be detected in peripheral blood of CD patients using commercially available dextramers. These cells persist in CD patients on a GFD but may decline over time. A short term low-dose gluten challenge increased sensitivity. This simplified detection method of gliadin-specific T-cells is suitable for diagnostic challenging CD cases.
目的血清学与小肠组织学的差异，如血清乳糜泻阴性，对乳糜泻的诊断提出了挑战。最近描述的检测麦胶蛋白特异性t细胞的方法即使在专门的诊断设置中也过于费力。我们开发了一种方法，可以在专门的诊断实验室实施。方法采用α1和α2麦胶蛋白肽负载葡聚糖（Dm）对健康对照组（HC, n = 18）、非乳糜泻谷蛋白敏感患者（NCGS, n = 9）、活性乳糜泻患者（aCD, n = 7）和无麸质饮食的乳糜泻患者（GFD, n = 14）的麦胶蛋白特异性t细胞进行分析。对照肽（CLIP）加载Dm作为背景对照。计算α-麦胶蛋白- dm:CLIP-Dm比值。在接受GFD治疗≥5年的CD患者中（n = 8），进行随机双剂量谷蛋白刺激以增加麦胶蛋白特异性t细胞频率。结果aCD和GFD的gliadin特异性CD4+ t细胞频率显著高于HC和NCGS （p≤0.0001）。在GFD≥5年的CD患者中，6/8的患者在一周的麸质攻击后检测到麦胶蛋白特异性t细胞，并且在4周内全部检测出阳性。麦胶蛋白特异性t细胞在摄入谷蛋白1周后显著上调CD38 (p <；0.008)。来自16名患者的真实世界数据证明了该测试在诊断挑战性病例中的适用性。结论市售右旋聚物可在CD患者外周血中检测到麦胶蛋白特异性t细胞。这些细胞在患有GFD的乳糜泻患者体内持续存在，但可能随着时间的推移而减少。短期低剂量谷蛋白刺激会增加敏感性。这种简化的麦胶蛋白特异性t细胞检测方法适用于诊断挑战性CD病例。
{"title":"A laboratory test to detect gliadin-specific CD4+ T-cells for difficult to diagnose celiac disease","authors":"Daan A.R. Castelijn , Nicolette J. Wierdsma , Kim de Buck , Maaike A. van Bree , Tracy-Jane T.H.D. Eisden , Jolien C. Hollander , Gerd Bouma , Hetty J. Bontkes","doi":"10.1016/j.jtauto.2025.100301","DOIUrl":"10.1016/j.jtauto.2025.100301","url":null,"abstract":"<div><h3>Objectives</h3><div>Discrepancy between serology and small bowel histology, such as seronegative CD, poses a diagnostic challenge in celiac disease (CD) diagnosis. Recently described methods to detect gliadin-specific T-cells are too laborious even in a specialized diagnostic setting. We developed a method, which can be implemented in specialized diagnostic laboratories.</div></div><div><h3>Methods</h3><div>Gliadin-specific T-cells were analyzed by α1-and α2-gliadin peptide loaded Dextramers (Dm) in healthy controls (HC, n = 18), patients with non-celiac gluten sensitivity (NCGS, n = 9), active CD (aCD, n = 7) and CD on a gluten free diet (GFD, n = 14). Control peptide (CLIP)-loaded Dm were used as background controls. The α-gliadin-Dm:CLIP-Dm ratio was calculated. In CD patients ≥5 years on GFD (n = 8), a randomized two-dose gluten challenge was performed to increase gliadin-specific T-cell frequencies.</div></div><div><h3>Results</h3><div>Gliadin-specific CD4<sup>+</sup> T-cell frequencies were significantly higher in aCD and GFD than in HC and NCGS (p ≤ 0.0001). In CD patients on a GFD ≥5 years, gliadin-specific T-cells were detectable in 6/8 patients after a week gluten challenge, and all tested positive within 4 weeks. Gliadin-specific T-cells significantly upregulated CD38 after 1 week of gluten ingestion (p < 0.008). Real world data from sixteen patients demonstrated the applicability of this test in diagnostic challenging cases.</div></div><div><h3>Conclusions</h3><div>Gliadin-specific T-cells can be detected in peripheral blood of CD patients using commercially available dextramers. These cells persist in CD patients on a GFD but may decline over time. A short term low-dose gluten challenge increased sensitivity. This simplified detection method of gliadin-specific T-cells is suitable for diagnostic challenging CD cases.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100301"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144721792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-07-07DOI: 10.1016/j.jtauto.2025.100300
Daopo Lin , Jiayue Xu , Mengqian Ye , Luyan Fang , Tianhao Xia , Wenyu Tong , Gokuljayanth Jayaseelan Ranichandra , Yifan Bao , Bo Zheng , Yi Jiang , Lianpin Wu , Dingyuan Hu
The primary objective of treating Crohn's disease (CD) is to achieve and sustain endoscopic remission. However, repeated endoscopic examination leads to decreased patient compliance and procedural risks. Non-invasive biomarkers for endoscopic activity of CD are thus promising in clinical use. This study compared proteomic profiles between inflammatory and non-inflammatory intestinal tissues on 10 active CD patients through liquid chromatography–tandem mass spectrometry, and identified 384 differentially expressed proteins. Four candidate secretory proteins (MXRA5, AZU/HBP, CRYAB, DEFA3) were validated via ELISA in serum from 74 CD patients (43 active CD and 31 in remission). Serum MXRA5 levels were notably increased in CD patients in remission compared to active cases (P < 0.001) and showed an inverse correlation with SES-CD scores (r = −0.33, P < 0.05). ROC analysis demonstrated MXRA5's utility in distinguishing endoscopic activity of patients with CD (AUC = 0.80), which was improved when combined with CRP (AUC = 0.89). Besides, higher baseline serum MXRA5 levels predicted better endoscopic response to infliximab (IFX). In conclusion, our study indicates that MXRA5 might serve as a new potential serum biomarker for CD activity and IFX response prediction. Further prospective and muli-center studies are needed to validate its predictive performance.
{"title":"Matrix remodeling-associated protein 5 as a novel biomarker for predicting disease activity and endoscopic response to infliximab in Crohn's disease","authors":"Daopo Lin , Jiayue Xu , Mengqian Ye , Luyan Fang , Tianhao Xia , Wenyu Tong , Gokuljayanth Jayaseelan Ranichandra , Yifan Bao , Bo Zheng , Yi Jiang , Lianpin Wu , Dingyuan Hu","doi":"10.1016/j.jtauto.2025.100300","DOIUrl":"10.1016/j.jtauto.2025.100300","url":null,"abstract":"<div><div>The primary objective of treating Crohn's disease (CD) is to achieve and sustain endoscopic remission. However, repeated endoscopic examination leads to decreased patient compliance and procedural risks. Non-invasive biomarkers for endoscopic activity of CD are thus promising in clinical use. This study compared proteomic profiles between inflammatory and non-inflammatory intestinal tissues on 10 active CD patients through liquid chromatography–tandem mass spectrometry, and identified 384 differentially expressed proteins. Four candidate secretory proteins (MXRA5, AZU/HBP, CRYAB, DEFA3) were validated via ELISA in serum from 74 CD patients (43 active CD and 31 in remission). Serum MXRA5 levels were notably increased in CD patients in remission compared to active cases (<em>P</em> < 0.001) and showed an inverse correlation with SES-CD scores (r = −0.33, <em>P</em> < 0.05). ROC analysis demonstrated MXRA5's utility in distinguishing endoscopic activity of patients with CD (AUC = 0.80), which was improved when combined with CRP (AUC = 0.89). Besides, higher baseline serum MXRA5 levels predicted better endoscopic response to infliximab (IFX). In conclusion, our study indicates that MXRA5 might serve as a new potential serum biomarker for CD activity and IFX response prediction. Further prospective and muli-center studies are needed to validate its predictive performance.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100300"},"PeriodicalIF":4.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-10-19DOI: 10.1016/j.jtauto.2025.100327
Shasha Wang, Hongmin Hu, Jingru Chen, Chengyin Li
Objective
Oxidative phosphorylation (OXPHOS) dysfunction is increasingly recognized as a key factor in systemic lupus erythematosus (SLE) pathogenesis. This study aimed to identify OXPHOS-related core genes as potential SLE biomarkers and therapeutic targets.
Methods
mRNA sequencing and GSEA were performed on MRL/lpr mouse kidneys. Cross-species differentially expressed genes (DEGs) were identified by integrating mouse data with human SLE kidney datasets from the Gene Expression Omnibus (GEO). Overlapping DEGs with OXPHOS-related genes from GeneCards, a protein–protein interaction (PPI) network was constructed to screen core genes, followed by GO and KEGG enrichment analyses. Gene expression was validated in SLE whole blood, skin lesions, and immune cell subsets using independent GEO datasets. Diagnostic value was assessed by receiver operating characteristic (ROC) analysis; correlation with disease activity was evaluated using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Drug-target interactions were analyzed via DrugBank and STRING. Key genes were validated by qPCR in MRL/lpr kidneys.
Results
The OXPHOS pathway was significantly downregulated in MRL/lpr kidneys. Ten consistently upregulated core genes—CCNA2, KIF11, CDC20, TOP2A, TPX2, AURKB, DLGAP5, FOXM1, MKI67, and CEP55—were identified and enriched in cell cycle regulation and cellular senescence. All ten were upregulated in SLE blood; seven in skin lesions. They were broadly overexpressed in immune cells, especially plasmablasts and CD4+ T cells. CDC20, DLGAP5, and CEP55 showed high diagnostic accuracy (AUC >0.8). CCNA2 (r = 0.50) and CDC20 (r = 0.56) correlated significantly with SLEDAI. Six genes interacted with known SLE drug targets. Integrating expression and interaction profiles, CCNA2, AURKB, FOXM1, and MKI67 were prioritized as top therapeutic candidates. Quantitative real-time polymerase chain reaction (qPCR) confirmed CCNA2 and FOXM1 upregulation in MRL/lpr kidneys.
Conclusion
This study identifies a systemic OXPHOS-related gene signature in SLE, highlighting promising candidates for diagnosis and targeted therapy.
{"title":"Identification of key oxidative phosphorylation-related genes in systemic lupus erythematosus based on transcriptomics and bioinformatics analysis","authors":"Shasha Wang, Hongmin Hu, Jingru Chen, Chengyin Li","doi":"10.1016/j.jtauto.2025.100327","DOIUrl":"10.1016/j.jtauto.2025.100327","url":null,"abstract":"<div><h3>Objective</h3><div>Oxidative phosphorylation (OXPHOS) dysfunction is increasingly recognized as a key factor in systemic lupus erythematosus (SLE) pathogenesis. This study aimed to identify OXPHOS-related core genes as potential SLE biomarkers and therapeutic targets.</div></div><div><h3>Methods</h3><div>mRNA sequencing and GSEA were performed on MRL/lpr mouse kidneys. Cross-species differentially expressed genes (DEGs) were identified by integrating mouse data with human SLE kidney datasets from the Gene Expression Omnibus (GEO). Overlapping DEGs with OXPHOS-related genes from GeneCards, a protein–protein interaction (PPI) network was constructed to screen core genes, followed by GO and KEGG enrichment analyses. Gene expression was validated in SLE whole blood, skin lesions, and immune cell subsets using independent GEO datasets. Diagnostic value was assessed by receiver operating characteristic (ROC) analysis; correlation with disease activity was evaluated using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Drug-target interactions were analyzed via DrugBank and STRING. Key genes were validated by qPCR in MRL/lpr kidneys.</div></div><div><h3>Results</h3><div>The OXPHOS pathway was significantly downregulated in MRL/lpr kidneys. Ten consistently upregulated core genes—CCNA2, KIF11, CDC20, TOP2A, TPX2, AURKB, DLGAP5, FOXM1, MKI67, and CEP55—were identified and enriched in cell cycle regulation and cellular senescence. All ten were upregulated in SLE blood; seven in skin lesions. They were broadly overexpressed in immune cells, especially plasmablasts and CD4<sup>+</sup> T cells. CDC20, DLGAP5, and CEP55 showed high diagnostic accuracy (AUC >0.8). CCNA2 (r = 0.50) and CDC20 (r = 0.56) correlated significantly with SLEDAI. Six genes interacted with known SLE drug targets. Integrating expression and interaction profiles, CCNA2, AURKB, FOXM1, and MKI67 were prioritized as top therapeutic candidates. Quantitative real-time polymerase chain reaction (qPCR) confirmed CCNA2 and FOXM1 upregulation in MRL/lpr kidneys.</div></div><div><h3>Conclusion</h3><div>This study identifies a systemic OXPHOS-related gene signature in SLE, highlighting promising candidates for diagnosis and targeted therapy.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100327"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145361002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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