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}
Pub 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":"2025-12-08","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 : 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":"2025-12-06","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 : 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":"2025-12-03","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 : 2025-12-01DOI: 10.1016/j.jtauto.2025.100336
Wenjie Zhu , Fan Li , Yuchen Zhang , Yuting Chen , Ye Wu , Chengxin Zhang
Rheumatic heart disease (RHD), an autoimmune injury triggered by group A streptococcus (GAS) infection, exerts a significant pathological impact on the human heart. The pathogenesis of RHD is closely associated with abnormal epigenetic regulation, and primarily involves the four core epigenetic mechanisms: DNA methylation, histone modification, non-coding RNAs (ncRNAs), and chromatin remodeling. Currently, researches on RHD have shifted from focusing on late-stage diagnosis and treatment to investigating its multiple etiologies. Therefore, this article presents a systematic literature review aimed at reviewing the latest progress in the epigenetic research of RHD, providing in-depth elucidation of the interactions between RHD and these four core mechanisms, highlighting the value of potential biomarkers for the disease's early diagnosis and treatment, and outlining future research directions, including combined multi-omics analysis, minimally invasive interventional techniques, and gene chip-based approaches. This review aims to address the limitations of single-subject studies and small-sample cross-sectional surveys in epigenetic studies of RHD, thereby providing new strategies for disease prevention, control, and health management.
{"title":"Epigenetic advances in rheumatic heart disease","authors":"Wenjie Zhu , Fan Li , Yuchen Zhang , Yuting Chen , Ye Wu , Chengxin Zhang","doi":"10.1016/j.jtauto.2025.100336","DOIUrl":"10.1016/j.jtauto.2025.100336","url":null,"abstract":"<div><div>Rheumatic heart disease (RHD), an autoimmune injury triggered by group A streptococcus (GAS) infection, exerts a significant pathological impact on the human heart. The pathogenesis of RHD is closely associated with abnormal epigenetic regulation, and primarily involves the four core epigenetic mechanisms: DNA methylation, histone modification, non-coding RNAs (ncRNAs), and chromatin remodeling. Currently, researches on RHD have shifted from focusing on late-stage diagnosis and treatment to investigating its multiple etiologies. Therefore, this article presents a systematic literature review aimed at reviewing the latest progress in the epigenetic research of RHD, providing in-depth elucidation of the interactions between RHD and these four core mechanisms, highlighting the value of potential biomarkers for the disease's early diagnosis and treatment, and outlining future research directions, including combined multi-omics analysis, minimally invasive interventional techniques, and gene chip-based approaches. This review aims to address the limitations of single-subject studies and small-sample cross-sectional surveys in epigenetic studies of RHD, thereby providing new strategies for disease prevention, control, and health management.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100336"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681464","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}
Over the past decades immunoglobulin A (IgA) antibodies have gained increasing attention for their diagnostic and prognostic significance in rheumatoid arthritis (RA), complementing the well-established roles of IgM rheumatoid factor (RF) and IgG anti-citrullinated protein antibodies (ACPA). IgA-RF and IgA-ACPA are found in a subset of RA patients and have been associated with more severe disease phenotypes, including increased joint erosion and extra-articular manifestations, especially cardiovascular disease and lung involvement. Moreover, concerning prediction of therapeutic responses IgA isotypes seem to have potential, as their presence has been shown to be associated with a blunted response to treatment with TNF inhibitors suggesting their usefulness for disease monitoring during follow-up once a diagnosis has been established. Although the diagnostic value of IgA autoantibodies in identifying seronegative RA cases is limited, their presence confirms a diagnosis of RA and may be helpful in the preclinical detection of individuals at risk for developing RA.
Increasing evidence suggests that IgA-RF and IgA-ACPA may contribute to disease pathogenesis. They can activate myeloid cells through engagement with the Fc alpha receptor I, leading to enhanced pro-inflammatory cytokine release, phagocytosis, and the formation of neutrophil extracellular traps that exacerbate tissue damage. Taken together, measuring IgA isotypes may be considered a valuable addition to the serological armamentarium for RA, with potential to improve early diagnosis, risk stratification, and personalized therapeutic approaches.
This review summarizes the current knowledge regarding the value of IgA-RF and IgA-ACPA as diagnostic and prognostic markers for RA. In addition, we discuss how the presence of IgA autoantibodies fits into the mucosal origin theory and describe their potential pathologic effects.
{"title":"Rheumatoid factor and anti-citrullinated protein IgA antibodies in the diagnosis, prognosis and monitoring of patients with rheumatoid arthritis","authors":"Ulrike Steffen , Daniela Sieghart , Günter Steiner","doi":"10.1016/j.jtauto.2025.100332","DOIUrl":"10.1016/j.jtauto.2025.100332","url":null,"abstract":"<div><div>Over the past decades immunoglobulin A (IgA) antibodies have gained increasing attention for their diagnostic and prognostic significance in rheumatoid arthritis (RA), complementing the well-established roles of IgM rheumatoid factor (RF) and IgG anti-citrullinated protein antibodies (ACPA). IgA-RF and IgA-ACPA are found in a subset of RA patients and have been associated with more severe disease phenotypes, including increased joint erosion and extra-articular manifestations, especially cardiovascular disease and lung involvement. Moreover, concerning prediction of therapeutic responses IgA isotypes seem to have potential, as their presence has been shown to be associated with a blunted response to treatment with TNF inhibitors suggesting their usefulness for disease monitoring during follow-up once a diagnosis has been established. Although the diagnostic value of IgA autoantibodies in identifying seronegative RA cases is limited, their presence confirms a diagnosis of RA and may be helpful in the preclinical detection of individuals at risk for developing RA.</div><div>Increasing evidence suggests that IgA-RF and IgA-ACPA may contribute to disease pathogenesis. They can activate myeloid cells through engagement with the Fc alpha receptor I, leading to enhanced pro-inflammatory cytokine release, phagocytosis, and the formation of neutrophil extracellular traps that exacerbate tissue damage. Taken together, measuring IgA isotypes may be considered a valuable addition to the serological armamentarium for RA, with potential to improve early diagnosis, risk stratification, and personalized therapeutic approaches.</div><div>This review summarizes the current knowledge regarding the value of IgA-RF and IgA-ACPA as diagnostic and prognostic markers for RA. In addition, we discuss how the presence of IgA autoantibodies fits into the mucosal origin theory and describe their potential pathologic effects.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100332"},"PeriodicalIF":3.6,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568201","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号