Pub Date : 2026-01-21DOI: 10.1016/j.jtauto.2026.100352
Bitte Sjöström , Anders Bredberg , Peter Olsson , Susann Ullén , Johannes H. van der Stoep , Gunnel Henriksson
In primary Sjögren's disease (pSjD), there is a well-documented increased risk of hematological malignancies, particularly lymphomas, whereas studies examining the incidence of solid tumors have often yielded conflicting results. Data concerning the incidence of breast and gynecological cancers are similarly inconsistent. The aim of this study was to further investigate the incidence of these so-called female cancers by assessing not only their occurrence following the diagnosis of pSjD but also prior to it. By linking the Malmö Sjögren's disease register with the Swedish National Cancer Register, 25 cases of female cancers were identified among patients with pSjD (mean follow-up time: 45.8 years), compared to 50.70 expected cases (SIR, 0.49; 95 % CI, 0.30–0.69; P < 0.001). The incidence of female cancers was significantly reduced both prior to (P < 0.001) and following (P < 0.001) the diagnosis of pSjD. The decrease was most evident for breast cancer (SIR, 0.46; 95 % CI, 0.24–0.69; P < 0.001). A reduction was also noted for ovarian cancer (SIR, 0.21; 95 % CI, 0.00–0.62; P < 0.001); however, the reliability of this estimate is limited by the small number of observed cases. Our findings suggest a reduced risk of female cancers, primarily driven by a decrease in breast cancer incidence, not only following but also preceding the diagnosis of pSjD. These results, combined with the observation that autoantibodies characteristic of pSjD often emerge several years before clinical onset, raise the question of whether an autoimmune component may confer a protective effect against breast cancer in pSjD.
在原发性Sjögren病（pSjD）中，有充分证据表明血液系统恶性肿瘤，特别是淋巴瘤的风险增加，而检查实体瘤发病率的研究往往产生相互矛盾的结果。关于乳腺癌和妇科癌症发病率的数据也同样不一致。这项研究的目的是进一步调查这些所谓的女性癌症的发病率，不仅评估她们在pSjD诊断后的发病率，还评估她们在诊断前的发病率。通过将Malmö Sjögren的疾病登记与瑞典国家癌症登记联系起来，在pSjD患者中发现了25例女性癌症（平均随访时间：45.8年），而预期病例为50.70例（SIR, 0.49; 95% CI, 0.30-0.69; P < 0.001）。女性癌症的发病率在诊断pSjD之前（P < 0.001）和之后（P < 0.001）都显著降低。乳腺癌的下降最为明显（SIR, 0.46; 95% CI, 0.24-0.69; P < 0.001）。卵巢癌的发病率也有所下降（SIR, 0.21; 95% CI, 0.00-0.62; P < 0.001）；然而，由于观察到的病例数量较少，这一估计的可靠性受到限制。我们的研究结果表明，女性患癌症的风险降低，主要是由于乳腺癌发病率的降低，不仅在pSjD诊断之后，而且在诊断之前。这些结果，结合观察到pSjD的自身抗体特征通常在临床发病前几年出现，提出了一个问题，即自身免疫成分是否可能赋予pSjD对乳腺癌的保护作用。
{"title":"Female cancer incidence before and after diagnosis of primary Sjögren's disease: A retrospective cohort study","authors":"Bitte Sjöström , Anders Bredberg , Peter Olsson , Susann Ullén , Johannes H. van der Stoep , Gunnel Henriksson","doi":"10.1016/j.jtauto.2026.100352","DOIUrl":"10.1016/j.jtauto.2026.100352","url":null,"abstract":"<div><div>In primary Sjögren's disease (pSjD), there is a well-documented increased risk of hematological malignancies, particularly lymphomas, whereas studies examining the incidence of solid tumors have often yielded conflicting results. Data concerning the incidence of breast and gynecological cancers are similarly inconsistent. The aim of this study was to further investigate the incidence of these so-called female cancers by assessing not only their occurrence following the diagnosis of pSjD but also prior to it. By linking the Malmö Sjögren's disease register with the Swedish National Cancer Register, 25 cases of female cancers were identified among patients with pSjD (mean follow-up time: 45.8 years), compared to 50.70 expected cases (SIR, 0.49; 95 % CI, 0.30–0.69; <em>P</em> < 0.001). The incidence of female cancers was significantly reduced both prior to (<em>P</em> < 0.001) and following (<em>P</em> < 0.001) the diagnosis of pSjD. The decrease was most evident for breast cancer (SIR, 0.46; 95 % CI, 0.24–0.69; <em>P</em> < 0.001). A reduction was also noted for ovarian cancer (SIR, 0.21; 95 % CI, 0.00–0.62; <em>P</em> < 0.001); however, the reliability of this estimate is limited by the small number of observed cases. Our findings suggest a reduced risk of female cancers, primarily driven by a decrease in breast cancer incidence, not only following but also preceding the diagnosis of pSjD. These results, combined with the observation that autoantibodies characteristic of pSjD often emerge several years before clinical onset, raise the question of whether an autoimmune component may confer a protective effect against breast cancer in pSjD.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100352"},"PeriodicalIF":3.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146077625","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 : 2026-01-12DOI: 10.1016/j.jtauto.2026.100349
Li Jiang , Liting He , Duo Li , Xin Luo , Ming Yang , Haijing Wu , Hai Long
Objectives
This study aimed to explore the prophylactic and therapeutic role of liraglutide for lupus-associated diffuse alveolar hemorrhage (DAH).
Methods
A lupus-associated DAH model was established in 6-8-week-old female C57BL/6 mice via intraperitoneal injection of 0.5 mL pristane. Mice were randomized to receive daily intraperitoneal injections of either saline or liraglutide (2 mg/kg/day), starting either 14 days before or on the day of pristane injection, and continuing until 14 days post-injection. Body weight and blood glucose were monitored. Serum levels of anti-dsDNA, ANA, total IgM and IgG were quantified using ELISA. Lung tissues were collected for histopathological analysis with H&E and Prussian blue staining, respectively, characterization of different types of immune cells infiltration with flow cytometry (t-SNE for subset dimensionality reduction) and immunofluorescence, and quantification of protein levels with Western blot.
Results
Liraglutide significantly alleviated pulmonary hemorrhage, as evidenced by reduced lung wet weight, incidence of lung hemorrhage, pulmonary hemosiderin-laden macrophages, and total serum IgG, without affecting body weight or glucose. Mechanistically, liraglutide treatment reduced pulmonary infiltration of multiple T and B lymphocyte subsets (e.g., CD4+, CD8+, B220+), while concurrently increasing alveolar macrophages and promoting M2 macrophage polarization. The phenotypic shift was demonstrated by increased M2 cell numbers, elevated CD206 expression, and downregulation of M1 marker CD86 and upregulation of M2 marker CD163 as confirmed at the protein level.
Conclusion
Liraglutide treatment effectively ameliorates lupus-associated DAH, potentially through modulation of T cells, B cells, and macrophages polarization, offering a novel prophylactic and therapeutic strategy for this fatal complication of lupus.
{"title":"Liraglutide prevents lupus-associated diffuse alveolar hemorrhage via inhibiting lymphocyte infiltration and promoting macrophage M2 polarization","authors":"Li Jiang , Liting He , Duo Li , Xin Luo , Ming Yang , Haijing Wu , Hai Long","doi":"10.1016/j.jtauto.2026.100349","DOIUrl":"10.1016/j.jtauto.2026.100349","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to explore the prophylactic and therapeutic role of liraglutide for lupus-associated diffuse alveolar hemorrhage (DAH).</div></div><div><h3>Methods</h3><div>A lupus-associated DAH model was established in 6-8-week-old female C57BL/6 mice via intraperitoneal injection of 0.5 mL pristane. Mice were randomized to receive daily intraperitoneal injections of either saline or liraglutide (2 mg/kg/day), starting either 14 days before or on the day of pristane injection, and continuing until 14 days post-injection. Body weight and blood glucose were monitored. Serum levels of anti-dsDNA, ANA, total IgM and IgG were quantified using ELISA. Lung tissues were collected for histopathological analysis with H&E and Prussian blue staining, respectively, characterization of different types of immune cells infiltration with flow cytometry (t-SNE for subset dimensionality reduction) and immunofluorescence, and quantification of protein levels with Western blot.</div></div><div><h3>Results</h3><div>Liraglutide significantly alleviated pulmonary hemorrhage, as evidenced by reduced lung wet weight, incidence of lung hemorrhage, pulmonary hemosiderin-laden macrophages, and total serum IgG, without affecting body weight or glucose. Mechanistically, liraglutide treatment reduced pulmonary infiltration of multiple T and B lymphocyte subsets (e.g., CD4<sup>+</sup>, CD8<sup>+</sup>, B220<sup>+</sup>), while concurrently increasing alveolar macrophages and promoting M2 macrophage polarization. The phenotypic shift was demonstrated by increased M2 cell numbers, elevated CD206 expression, and downregulation of M1 marker CD86 and upregulation of M2 marker CD163 as confirmed at the protein level.</div></div><div><h3>Conclusion</h3><div>Liraglutide treatment effectively ameliorates lupus-associated DAH, potentially through modulation of T cells, B cells, and macrophages polarization, offering a novel prophylactic and therapeutic strategy for this fatal complication of lupus.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100349"},"PeriodicalIF":3.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022431","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 : 2026-01-11DOI: 10.1016/j.jtauto.2026.100350
Min Zhou , Yu Liu , Jinxia He , Chengyin Li , Bin Wu
<div><h3>Background</h3><div>Sjögren's syndrome (SS) is a common autoimmune disease characterized clinically by dry mouth and dry eyes resulting from impaired exocrine gland function. However, its precise pathogenesis remains incompletely understood. Mitochondria, as cellular energy hubs, maintain homeostasis via fatty acid β-oxidation (FAO), the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. ECHS1 and HADH are key enzymes in the mitochondria that catalyze the FAO process, playing crucial regulatory roles in cellular energy metabolic balance. This study aims to systematically investigate alterations in mitochondrial structure and function in the salivary glands of SS patients and mice and to elucidate the potential mechanisms of ECHS1 and HADH in SS-related mitochondrial dysfunction.</div></div><div><h3>Methods</h3><div>To systematically evaluate the association between mitochondrial abnormalities and salivary gland secretory function in SS, human salivary gland samples from SS patients and non-SS controls, alongside non-obese diabetic (NOD) mice and ICR-control mice, were analyzed. Mitochondrial ultrastructure was examined via transmission electron microscopy (TEM), and functional indicators were measured. Transcriptome sequencing identified differentially expressed genes (DEGs), which were cross-referenced with MitoCarta3.0 to pinpoint mitochondrial-related DEGs (MR-DEGs). KEGG pathway enrichment analysis and GO functional annotation were performed. A protein-protein interaction (PPI) network was then constructed using the TCMNP database to identify key hub genes. Finally, Key hub genes ECHS1 and HADH were validated at both the transcriptional and protein levels using the GEO dataset (GSE40611), qPCR, and immunofluorescence.</div></div><div><h3>Results</h3><div>The results revealed significant mitochondrial structural and functional abnormalities in both SS patients with salivary gland dysfunction and NOD mice. Compared to controls, salivary gland mitochondria in NOD mice exhibited marked ultrastructural damage, including swelling and cristae fragmentation, accompanied by increased ROS levels and decreased mitochondrial membrane potential. Transcriptomic analysis identified 81 MR-DEGs. KEGG enrichment analysis indicated these genes were significantly enriched in energy metabolism-related pathways such as Fatty acid biosynthesis, Fatty acid metabolism, and TCA cycle. GO analysis showed that MR-DEGs were primarily involved in biological processes like the fatty acid metabolic process, localized to the mitochondrial matrix, and possessed molecular functions such as ligase activity. PPI network analysis further screened seven hub genes (ECHS1, HADH, PCX, ACADM, ACACA, FASN, ACLY), among which ECHS1 and HADH exhibited the highest interaction score. Consistent results from GEO database analysis and qPCR validation demonstrated significantly downregulated mRNA expression levels of ECHS1 and HADH in the salivary glands of both SS patien
{"title":"Downregulated ECHS1 and HADH-mediated fatty acid β-oxidation contributes to mitochondrial dysfunction in salivary glands of Sjögren's syndrome","authors":"Min Zhou , Yu Liu , Jinxia He , Chengyin Li , Bin Wu","doi":"10.1016/j.jtauto.2026.100350","DOIUrl":"10.1016/j.jtauto.2026.100350","url":null,"abstract":"<div><h3>Background</h3><div>Sjögren's syndrome (SS) is a common autoimmune disease characterized clinically by dry mouth and dry eyes resulting from impaired exocrine gland function. However, its precise pathogenesis remains incompletely understood. Mitochondria, as cellular energy hubs, maintain homeostasis via fatty acid β-oxidation (FAO), the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. ECHS1 and HADH are key enzymes in the mitochondria that catalyze the FAO process, playing crucial regulatory roles in cellular energy metabolic balance. This study aims to systematically investigate alterations in mitochondrial structure and function in the salivary glands of SS patients and mice and to elucidate the potential mechanisms of ECHS1 and HADH in SS-related mitochondrial dysfunction.</div></div><div><h3>Methods</h3><div>To systematically evaluate the association between mitochondrial abnormalities and salivary gland secretory function in SS, human salivary gland samples from SS patients and non-SS controls, alongside non-obese diabetic (NOD) mice and ICR-control mice, were analyzed. Mitochondrial ultrastructure was examined via transmission electron microscopy (TEM), and functional indicators were measured. Transcriptome sequencing identified differentially expressed genes (DEGs), which were cross-referenced with MitoCarta3.0 to pinpoint mitochondrial-related DEGs (MR-DEGs). KEGG pathway enrichment analysis and GO functional annotation were performed. A protein-protein interaction (PPI) network was then constructed using the TCMNP database to identify key hub genes. Finally, Key hub genes ECHS1 and HADH were validated at both the transcriptional and protein levels using the GEO dataset (GSE40611), qPCR, and immunofluorescence.</div></div><div><h3>Results</h3><div>The results revealed significant mitochondrial structural and functional abnormalities in both SS patients with salivary gland dysfunction and NOD mice. Compared to controls, salivary gland mitochondria in NOD mice exhibited marked ultrastructural damage, including swelling and cristae fragmentation, accompanied by increased ROS levels and decreased mitochondrial membrane potential. Transcriptomic analysis identified 81 MR-DEGs. KEGG enrichment analysis indicated these genes were significantly enriched in energy metabolism-related pathways such as Fatty acid biosynthesis, Fatty acid metabolism, and TCA cycle. GO analysis showed that MR-DEGs were primarily involved in biological processes like the fatty acid metabolic process, localized to the mitochondrial matrix, and possessed molecular functions such as ligase activity. PPI network analysis further screened seven hub genes (ECHS1, HADH, PCX, ACADM, ACACA, FASN, ACLY), among which ECHS1 and HADH exhibited the highest interaction score. Consistent results from GEO database analysis and qPCR validation demonstrated significantly downregulated mRNA expression levels of ECHS1 and HADH in the salivary glands of both SS patien","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100350"},"PeriodicalIF":3.6,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022432","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 : 2026-01-07DOI: 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":"2026-01-07","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 : 2025-12-24DOI: 10.1016/j.jtauto.2025.100347
Marc Scherlinger , Eloi Schmauch , Raphaël Carapito , Angélique Pichot , Ghada Alsaleh , Nicodème Paul , Anne Molitor , François Lefebvre , Catherine Schmidt-Mutter , Seiamak Bahram , Jean Sibilia , Philippe Georgel
Objective
Pregnancy induces profound immunological adaptations that usually promote tolerance and reduce autoimmune activity. However, women with systemic lupus erythematosus (SLE) remain at increased risk of disease flares and pregnancy complications, whereas rheumatoid arthritis (RA) often improves during gestation. To better understand this divergence, we longitudinally characterized transcriptomic and microRNA (miRNA) changes in circulating monocytes from healthy, RA, and SLE pregnancies.
Methods
Pregnant women with SLE (n = 5), RA (n = 4), and healthy controls (n = 5) were followed from preconception to three months postpartum. CD14+ monocytes were isolated at each visit and profiled using RNA sequencing and miRNA sequencing. Differential expression analyses were performed using DESeq2, modelling patient ID as a covariate. Pathway enrichment and upstream regulator analyses were conducted using Ingenuity Pathway Analysis and Reactome. Correlation-based miRNA–mRNA regulatory networks were inferred using miRTarBase-validated interactions.
Results
Healthy and RA pregnancies exhibited a shift toward an alternatively activated (anti-inflammatory) monocyte phenotype, characterized by downregulation of TNF, IFN-γ, and IL-1 signalling pathways. In contrast, SLE pregnancies maintained a persistent M1-like (pro-inflammatory) program throughout gestation and postpartum, independent of clinical flare status. miRNA profiling revealed selective downregulation of miR-106a-5p and miR-148b-5p in SLE monocytes, accompanied by enrichment of cytokine-related pathways among their predicted targets. These dysregulated miRNAs were linked to activation of immune pathways including IL-12 signalling, interferon responses, apoptosis, and complement activation.
Conclusion
SLE pregnancies are characterized by a failure to achieve monocyte immunotolerance, driven in part by aberrant miRNA regulation. These findings highlight molecular mechanisms underlying persistent inflammation in SLE pregnancy and identify candidate transcriptomic and miRNA biomarkers that may support future risk stratification or therapeutic modulation.
{"title":"Systemic lupus pregnancies are characterized by an intrinsic pro-inflammatory monocyte transcriptome, driven by an aberrant miRNA signature","authors":"Marc Scherlinger , Eloi Schmauch , Raphaël Carapito , Angélique Pichot , Ghada Alsaleh , Nicodème Paul , Anne Molitor , François Lefebvre , Catherine Schmidt-Mutter , Seiamak Bahram , Jean Sibilia , Philippe Georgel","doi":"10.1016/j.jtauto.2025.100347","DOIUrl":"10.1016/j.jtauto.2025.100347","url":null,"abstract":"<div><h3>Objective</h3><div>Pregnancy induces profound immunological adaptations that usually promote tolerance and reduce autoimmune activity. However, women with systemic lupus erythematosus (SLE) remain at increased risk of disease flares and pregnancy complications, whereas rheumatoid arthritis (RA) often improves during gestation. To better understand this divergence, we longitudinally characterized transcriptomic and microRNA (miRNA) changes in circulating monocytes from healthy, RA, and SLE pregnancies.</div></div><div><h3>Methods</h3><div>Pregnant women with SLE (n = 5), RA (n = 4), and healthy controls (n = 5) were followed from preconception to three months postpartum. CD14<sup>+</sup> monocytes were isolated at each visit and profiled using RNA sequencing and miRNA sequencing. Differential expression analyses were performed using DESeq2, modelling patient ID as a covariate. Pathway enrichment and upstream regulator analyses were conducted using Ingenuity Pathway Analysis and Reactome. Correlation-based miRNA–mRNA regulatory networks were inferred using miRTarBase-validated interactions.</div></div><div><h3>Results</h3><div>Healthy and RA pregnancies exhibited a shift toward an alternatively activated (anti-inflammatory) monocyte phenotype, characterized by downregulation of TNF, IFN-γ, and IL-1 signalling pathways. In contrast, SLE pregnancies maintained a persistent M1-like (pro-inflammatory) program throughout gestation and postpartum, independent of clinical flare status. miRNA profiling revealed selective downregulation of miR-106a-5p and miR-148b-5p in SLE monocytes, accompanied by enrichment of cytokine-related pathways among their predicted targets. These dysregulated miRNAs were linked to activation of immune pathways including IL-12 signalling, interferon responses, apoptosis, and complement activation.</div></div><div><h3>Conclusion</h3><div>SLE pregnancies are characterized by a failure to achieve monocyte immunotolerance, driven in part by aberrant miRNA regulation. These findings highlight molecular mechanisms underlying persistent inflammation in SLE pregnancy and identify candidate transcriptomic and miRNA biomarkers that may support future risk stratification or therapeutic modulation.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100347"},"PeriodicalIF":3.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926253","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 : 2025-12-23DOI: 10.1016/j.jtauto.2025.100337
Sree Ishan Kolukula
Crohn’s Disease (CD) is a chronic autoinflammatory disease of the gastrointestinal tract. Anatomical labels like Ileal Crohn’s Disease (ICD) and Colonic Crohn’s Disease (CCD) do not capture the molecular heterogeneity which contributes to trial and error therapy. This trial and error pattern costs patients who switch biologics higher annual expenses. We analyzed bulk RNA-seq from 2353 biopsies across two independent data sets (GSE193677 and GSE57945) using a standardized pipeline. Principal component analysis confirmed clear molecular separation between ICD and CCD samples. Differential expression modeling (DESeq2, FDR 0.05) identified the top 300 differentially expressed genes (DEGs) across subtype specific signatures. Pathway analysis confirmed known subtype biology, with ICD driven by autophagy-related processes and CCD by immune activation pathways. Subtype-specific PPI networks diverged sharply, with CKB driving barrier-related processes in ICD and SPP1 coordinating immune activation in CCD. Known CD susceptibility genes (e.g., NOD2, ATG16L1, IL23R) were recovered within leading-edge sets, supporting construct validity. Proteomic validation using ProteomeXchange PXD012284 confirmed concordant enrichment of ICD-associated autophagy and lysosomal modules and CCD-associated innate immune pathways at the protein level. Single-cell transcriptomic validation further localized leading-edge genes to epithelial lineages in ICD and to myeloid and glial populations in CCD, supporting cellular specificity of subtype programs. Together, these results indicate that ICD and CCD are biologically distinct at the transcriptome, proteome, and network levels. The prioritized hubs and pathways nominate tractable, subtype-specific hypotheses for prospective validation and provide a framework for precision therapeutics in CD.
{"title":"Identifying subtype-specific molecular pathways in Crohn’s disease through RNA-seq and protein–protein interaction network analysis","authors":"Sree Ishan Kolukula","doi":"10.1016/j.jtauto.2025.100337","DOIUrl":"10.1016/j.jtauto.2025.100337","url":null,"abstract":"<div><div>Crohn’s Disease (CD) is a chronic autoinflammatory disease of the gastrointestinal tract. Anatomical labels like Ileal Crohn’s Disease (ICD) and Colonic Crohn’s Disease (CCD) do not capture the molecular heterogeneity which contributes to trial and error therapy. This trial and error pattern costs patients who switch biologics higher annual expenses. We analyzed bulk RNA-seq from 2353 biopsies across two independent data sets (GSE193677 and GSE57945) using a standardized pipeline. Principal component analysis confirmed clear molecular separation between ICD and CCD samples. Differential expression modeling (DESeq2, FDR <span><math><mo>≤</mo></math></span> 0.05) identified the top 300 differentially expressed genes (DEGs) across subtype specific signatures. Pathway analysis confirmed known subtype biology, with ICD driven by autophagy-related processes and CCD by immune activation pathways. Subtype-specific PPI networks diverged sharply, with CKB driving barrier-related processes in ICD and SPP1 coordinating immune activation in CCD. Known CD susceptibility genes (e.g., NOD2, ATG16L1, IL23R) were recovered within leading-edge sets, supporting construct validity. Proteomic validation using ProteomeXchange PXD012284 confirmed concordant enrichment of ICD-associated autophagy and lysosomal modules and CCD-associated innate immune pathways at the protein level. Single-cell transcriptomic validation further localized leading-edge genes to epithelial lineages in ICD and to myeloid and glial populations in CCD, supporting cellular specificity of subtype programs. Together, these results indicate that ICD and CCD are biologically distinct at the transcriptome, proteome, and network levels. The prioritized hubs and pathways nominate tractable, subtype-specific hypotheses for prospective validation and provide a framework for precision therapeutics in CD.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100337"},"PeriodicalIF":3.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926251","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 : 2025-12-20DOI: 10.1016/j.jtauto.2025.100346
Jan Damoiseaux , Yves Renaudineau
Originally developed for the diagnosis of autoimmune diseases, the application of autoantibodies and related biomarkers has been extended in certain cases to monitor therapeutic efficacy and to predict disease recurrence and/or severity. Several critical considerations must be addressed prior to employing autoantibodies for monitoring purposes: (i) whether the autoantibody is pathogenic, as exemplified by anti-glomerular basement membrane and anti-acetylcholine receptor autoantibodies; (ii) whether the autoantibody level is essential for tracking disease activity, which may necessitate establishing prognostic thresholds and/or adapting detection methodologies; (iii) whether there is added value in combining autoantibodies, as demonstrated with anti-dsDNA and anti-chromatin antibodies in systemic lupus erythematosus; (iv) which immunoglobulin isotype is optimal for monitoring; and (v) whether alternative biomarkers exist that provide greater accuracy for patient follow-up. Additional issues remain unresolved, including appropriate intervals between measurements, intra- and inter-laboratory reproducibility, inter-assay variations, and ethnic variability, among others. To address these challenges, the European Autoimmunity Standardization Initiative (EASI) has proposed adapted strategies for utilizing autoantibodies in the longitudinal assessment of selected autoimmune diseases, as presented in this special issue.
{"title":"Autoantibody and biomarker detection in the follow-up of autoimmune diseases: state of the art and future perspectives","authors":"Jan Damoiseaux , Yves Renaudineau","doi":"10.1016/j.jtauto.2025.100346","DOIUrl":"10.1016/j.jtauto.2025.100346","url":null,"abstract":"<div><div>Originally developed for the diagnosis of autoimmune diseases, the application of autoantibodies and related biomarkers has been extended in certain cases to monitor therapeutic efficacy and to predict disease recurrence and/or severity. Several critical considerations must be addressed prior to employing autoantibodies for monitoring purposes: (i) whether the autoantibody is pathogenic, as exemplified by anti-glomerular basement membrane and anti-acetylcholine receptor autoantibodies; (ii) whether the autoantibody level is essential for tracking disease activity, which may necessitate establishing prognostic thresholds and/or adapting detection methodologies; (iii) whether there is added value in combining autoantibodies, as demonstrated with anti-dsDNA and anti-chromatin antibodies in systemic lupus erythematosus; (iv) which immunoglobulin isotype is optimal for monitoring; and (v) whether alternative biomarkers exist that provide greater accuracy for patient follow-up. Additional issues remain unresolved, including appropriate intervals between measurements, intra- and inter-laboratory reproducibility, inter-assay variations, and ethnic variability, among others. To address these challenges, the European Autoimmunity Standardization Initiative (EASI) has proposed adapted strategies for utilizing autoantibodies in the longitudinal assessment of selected autoimmune diseases, as presented in this special issue.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100346"},"PeriodicalIF":3.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926254","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}
Rheumatoid arthritis (RA) is characterized by autoimmune responses against citrullinated and homocitrullinated proteins/peptides (CitP and HomoCitP respectively), resulting in joint pain, inflammation, and damage. Although the collagen induced arthritis (CIA) model shares pathological features with RA, it remains unclear whether this model is suitable for studying RA-specific immune responses. Therefore, we investigated whether immune responses to CitP and HomoCitP influence arthritis severity in CIA.
Male DBA/1J mice were immunized with bovine type II collagen (CII) (N = 58) or PBS (N = 14) in adjuvant. Arthritis was assessed by clinical arthritis score, caliper measurements of joint swelling, von Frey pain testing, micro-CT, histopathology, and immunofluorescence. Splenocyte proliferation was measured using flow cytometry and serum antibodies via ELISAs.
Although anti-bovine and anti-mouse CII IgG developed in all bovine CII-immunized mice, only 31 % developed clinical arthritis. Arthritis closely resembled RA pathology, including joint pain, reduced bone mineral density, and histopathological damage. Immunofluorescence showed higher CitP and HomoCitP in joints from arthritic vs. PBS-injected mice. At day 49 post primary immunization, HomoCitP, but not CitP, stimulation induced higher proliferation in splenic T cells from arthritic mice compared to controls and strongly correlated with joint swelling, pain, and histopathology, as well as with serum anti-CII IgG. Anti-HomoCitP IgG were rare, and anti-CitP IgG were undetected, in arthritic mice.
This study identifies RA-specific antigens and immune responses to HomoCitP as potentially relevant in CIA. These results support the use of CIA to study RA-specific immunopathogenic mechanisms and highlight HomoCitP-specific T cells as potential contributors to disease.
{"title":"T cell proliferative response to a homocitrullinated peptide correlates with joint pathology in collagen induced arthritis","authors":"Jaspreet Kaur , Sofya Ulanova , Ewa Cairns , Lillian Barra","doi":"10.1016/j.jtauto.2025.100345","DOIUrl":"10.1016/j.jtauto.2025.100345","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is characterized by autoimmune responses against citrullinated and homocitrullinated proteins/peptides (CitP and HomoCitP respectively), resulting in joint pain, inflammation, and damage. Although the collagen induced arthritis (CIA) model shares pathological features with RA, it remains unclear whether this model is suitable for studying RA-specific immune responses. Therefore, we investigated whether immune responses to CitP and HomoCitP influence arthritis severity in CIA.</div><div>Male DBA/1J mice were immunized with bovine type II collagen (CII) (N = 58) or PBS (N = 14) in adjuvant. Arthritis was assessed by clinical arthritis score, caliper measurements of joint swelling, von Frey pain testing, micro-CT, histopathology, and immunofluorescence. Splenocyte proliferation was measured using flow cytometry and serum antibodies via ELISAs.</div><div>Although anti-bovine and anti-mouse CII IgG developed in all bovine CII-immunized mice, only 31 % developed clinical arthritis. Arthritis closely resembled RA pathology, including joint pain, reduced bone mineral density, and histopathological damage. Immunofluorescence showed higher CitP and HomoCitP in joints from arthritic vs. PBS-injected mice. At day 49 post primary immunization, HomoCitP, but not CitP, stimulation induced higher proliferation in splenic T cells from arthritic mice compared to controls and strongly correlated with joint swelling, pain, and histopathology, as well as with serum anti-CII IgG. Anti-HomoCitP IgG were rare, and anti-CitP IgG were undetected, in arthritic mice.</div><div>This study identifies RA-specific antigens and immune responses to HomoCitP as potentially relevant in CIA. These results support the use of CIA to study RA-specific immunopathogenic mechanisms and highlight HomoCitP-specific T cells as potential contributors to disease.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100345"},"PeriodicalIF":3.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926250","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 : 2025-12-09DOI: 10.1016/j.jtauto.2025.100342
Vojtech Petr , Shrey Purohit , Felix Poppelaars , Brandon Renner , Jennifer Laskowski , Russell Whelan , Liudmila Kulik , Jessica Kendrick , Ashley Frazer-Abel , Diana Jalal , Barbara Marcolin , Isabelle Schmelzer , Hanna Debiec , Pierre Ronco , Moin A. Saleem , Simon C. Satchell , Joshua M. Thurman
Rationale & objective
Membranous nephropathy (MN) is a glomerular disease caused by autoantibodies reactive with podocyte antigens. The most common antigen is the M-type phospholipase A2 receptor (PLA2R), but autoantibodies to other podocyte antigens have also been identified. Investigators have reported elevated levels of complement fragments in plasma. However, most complement fragments generated on podocytes are likely to pass into the urine and not enter the bloodstream. Further, anti-PLA2R antibodies are usually IgG4 subclass and do not activate the classical pathway of complement. To look for additional autoantibodies capable of generating endovascular complement fragments, we examined whether MN patients have antibodies reactive with endothelial cell antigens.
Study design
Retrospective cohort study.
Setting & participants
We analyzed plasma samples from 64 patients with MN, and results were compared to healthy controls and patients with chronic kidney disease.
Exposure
Plasma and urine complement activation fragments, glomerular endothelial cell and podocyte antibody binding assays, anti-cardiolipin antibody enzyme linked immunosorbent assay.
Groups were compared with Wilcoxon, Kruskal-Wallis or chi-square tests. Correlations were performed using Pearson's correlation.
Results
Plasma C3a, C4a, C5a, and sC5b-9 levels were elevated in MN patients. Some patients had IgG reacted with glomerular endothelial cells or with podocytes. These antibodies were seen in distinct subsets of patients and did not correlate with the presence of anti-PLA2R antibodies. Higher titers of anti-glomerular endothelial cell antibodies correlated with systemic complement activation, seen by sC5b-9, and disease severity, determined by proteinuria. Anti-cardiolipin IgG levels associated with proteinuria.
Limitations
Assays used immortalized cell lines, and target antigens have not yet been identified.
Conclusions
MN is a disease of autoimmunity directed against podocyte antigens, but some patients may also produce autoantibodies that target antigens on glomerular endothelial cells. The level of these antibodies correlates with adverse clinical findings.
{"title":"Autoantibodies reactive with glomerular endothelial cells and podocytes in patients with membranous nephropathy","authors":"Vojtech Petr , Shrey Purohit , Felix Poppelaars , Brandon Renner , Jennifer Laskowski , Russell Whelan , Liudmila Kulik , Jessica Kendrick , Ashley Frazer-Abel , Diana Jalal , Barbara Marcolin , Isabelle Schmelzer , Hanna Debiec , Pierre Ronco , Moin A. Saleem , Simon C. Satchell , Joshua M. Thurman","doi":"10.1016/j.jtauto.2025.100342","DOIUrl":"10.1016/j.jtauto.2025.100342","url":null,"abstract":"<div><h3>Rationale & objective</h3><div>Membranous nephropathy (MN) is a glomerular disease caused by autoantibodies reactive with podocyte antigens. The most common antigen is the M-type phospholipase A2 receptor (PLA2R), but autoantibodies to other podocyte antigens have also been identified. Investigators have reported elevated levels of complement fragments in plasma. However, most complement fragments generated on podocytes are likely to pass into the urine and not enter the bloodstream. Further, anti-PLA2R antibodies are usually IgG4 subclass and do not activate the classical pathway of complement. To look for additional autoantibodies capable of generating endovascular complement fragments, we examined whether MN patients have antibodies reactive with endothelial cell antigens.</div></div><div><h3>Study design</h3><div>Retrospective cohort study.</div></div><div><h3>Setting & participants</h3><div>We analyzed plasma samples from 64 patients with MN, and results were compared to healthy controls and patients with chronic kidney disease.</div></div><div><h3>Exposure</h3><div>Plasma and urine complement activation fragments, glomerular endothelial cell and podocyte antibody binding assays, anti-cardiolipin antibody enzyme linked immunosorbent assay.</div></div><div><h3>Outcome</h3><div>Proteinuria, estimated glomerular filtration rate.</div></div><div><h3>Analytical approach</h3><div>Groups were compared with Wilcoxon, Kruskal-Wallis or chi-square tests. Correlations were performed using Pearson's correlation.</div></div><div><h3>Results</h3><div>Plasma C3a, C4a, C5a, and sC5b-9 levels were elevated in MN patients. Some patients had IgG reacted with glomerular endothelial cells or with podocytes. These antibodies were seen in distinct subsets of patients and did not correlate with the presence of anti-PLA2R antibodies. Higher titers of anti-glomerular endothelial cell antibodies correlated with systemic complement activation, seen by sC5b-9, and disease severity, determined by proteinuria. Anti-cardiolipin IgG levels associated with proteinuria.</div></div><div><h3>Limitations</h3><div>Assays used immortalized cell lines, and target antigens have not yet been identified.</div></div><div><h3>Conclusions</h3><div>MN is a disease of autoimmunity directed against podocyte antigens, but some patients may also produce autoantibodies that target antigens on glomerular endothelial cells. The level of these antibodies correlates with adverse clinical findings.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"12 ","pages":"Article 100342"},"PeriodicalIF":3.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791081","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 : 2025-12-08DOI: 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":"2025-12-08","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}
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