Pub Date : 2025-12-01Epub Date: 2025-06-11DOI: 10.1016/j.jtauto.2025.100296
Julius Lindblom , Guillermo Barturen , Lorenzo Beretta , Daniel Toro-Domínguez , Elena Carnero-Montoro , Maria Orietta Borghi , Jessica Castillo , Ellen Iacobaeus , Yvonne Enman
Objectives
To gain insights into the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) and identify potential drug targets through investigation of whole-blood human transcriptome.
Methods
We analysed differentially expressed genes in peripheral blood from active central nervous system (CNS) lupus (n = 26) and active non-neuropsychiatric SLE (n = 38) patients versus healthy controls (n = 497) from the European PRECISESADS project (NTC02890121). We further explored dysregulated gene modules in active CNS lupus and their correlation with serological markers. Lastly, we performed regulatory network and druggability analysis.
Results
Unsupervised weighted gene co-expression network analysis (WGCNA) revealed 23 dysregulated gene modules and two subgroups of active CNS lupus. The interferon gene module was prominently upregulated in subgroup 1, while the B cell, T cell, and cytotoxic/natural killer (NK) cell modules were downregulated. Subgroup 2 showed less marked dysregulation patterns. Subgroup 1 had lower estimated proportions of lymphoid cell subsets and proportionally more patients positive for anti-dsDNA antibodies compared to subgroup 2, pointing to molecularly distinct subgroups or misclassification of subgroup 2. In silico prediction algorithms demonstrated a greater anticipated response to anifrolumab, C3 inhibitors, and calcineurin inhibitors for patients in CNS lupus subgroup 1 compared with subgroup 2.
Conclusions
Gene dysregulation patterns related to innate and adaptive lymphoid immunity separated active CNS lupus patients into two distinct subgroups with differential anticipated response to type I interferon, C3, and calcineurin inhibition. Our study provides a conceptual framework for precision medicine in NPSLE and implications for overcoming the major clinical challenge of attributing neuropsychiatric features to SLE versus other causes.
{"title":"Dysregulation of innate and adaptive lymphoid immunity may have implications for symptom attribution and predict responses to targeted therapies in neuropsychiatric systemic lupus erythematosus","authors":"Julius Lindblom , Guillermo Barturen , Lorenzo Beretta , Daniel Toro-Domínguez , Elena Carnero-Montoro , Maria Orietta Borghi , Jessica Castillo , Ellen Iacobaeus , Yvonne Enman","doi":"10.1016/j.jtauto.2025.100296","DOIUrl":"10.1016/j.jtauto.2025.100296","url":null,"abstract":"<div><h3>Objectives</h3><div>To gain insights into the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) and identify potential drug targets through investigation of whole-blood human transcriptome.</div></div><div><h3>Methods</h3><div>We analysed differentially expressed genes in peripheral blood from active central nervous system (CNS) lupus (n = 26) and active non-neuropsychiatric SLE (n = 38) patients versus healthy controls (n = 497) from the European PRECISESADS project (NTC02890121). We further explored dysregulated gene modules in active CNS lupus and their correlation with serological markers. Lastly, we performed regulatory network and druggability analysis.</div></div><div><h3>Results</h3><div>Unsupervised weighted gene co-expression network analysis (WGCNA) revealed 23 dysregulated gene modules and two subgroups of active CNS lupus. The interferon gene module was prominently upregulated in subgroup 1, while the B cell, T cell, and cytotoxic/natural killer (NK) cell modules were downregulated. Subgroup 2 showed less marked dysregulation patterns. Subgroup 1 had lower estimated proportions of lymphoid cell subsets and proportionally more patients positive for anti-dsDNA antibodies compared to subgroup 2, pointing to molecularly distinct subgroups or misclassification of subgroup 2. <em>In silico</em> prediction algorithms demonstrated a greater anticipated response to anifrolumab, C3 inhibitors, and calcineurin inhibitors for patients in CNS lupus subgroup 1 compared with subgroup 2.</div></div><div><h3>Conclusions</h3><div>Gene dysregulation patterns related to innate and adaptive lymphoid immunity separated active CNS lupus patients into two distinct subgroups with differential anticipated response to type I interferon, C3, and calcineurin inhibition. Our study provides a conceptual framework for precision medicine in NPSLE and implications for overcoming the major clinical challenge of attributing neuropsychiatric features to SLE versus other causes.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100296"},"PeriodicalIF":4.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144502082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-11-12DOI: 10.1016/j.jtauto.2025.100333
Xin Zhuang , Tianen Pan
Background
Observational studies have suggested a potential association between autoimmune diseases and anemia, but the direction of causality remains unclear. To investigate the potential causal relationship between autoimmune diseases and anemia using Mendelian randomization (MR).
Methods
We conducted a bidirectional two-sample MR study using summary-level genetic data from the EBI and FinnGen databases. We examined 21 autoimmune diseases as exposures and anemia as the outcome, and vice versa. Multivariable MR, meta-analysis, and two-step mediation analysis involving 43 candidate mediators were also performed. Proteomic MR and colocalization analyses were used to validate causal relationships involving proteins. Functional annotations including KEGG pathway, GO enrichment, protein–protein interaction networks, and drug enrichment analyses were performed to identify potential therapeutic targets.
Results
Genetically determined type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), and primary biliary cholangitis (PBC) were associated with an increased risk of anemia (P < 0.05 in meta-analysis). Reverse MR analyses suggested potential bidirectional causality between anemia and mixed connective tissue disease, hypothyroidism, and asthma. Mediation analysis indicated that hypothyroidism may contribute to anemia by elevating IgG levels. Proteomic and colocalization analyses identified several proteins associated with anemia (e.g., MCCD1, TMEM106B), T1DM (e.g., CTRB1, CTRB2, IL7RA), RA (e.g., TGFBI, IL1RN), and PBC (e.g., ALDH2, CXCL16).
Conclusion
This MR study supports a causal effect of certain autoimmune diseases on anemia risk and highlights potential protein targets for intervention, offering new insights for anemia prevention and treatment.
{"title":"Mendelian randomization study of the causal relationship between autoimmune diseases and anemia using proteomic and genetic data","authors":"Xin Zhuang , Tianen Pan","doi":"10.1016/j.jtauto.2025.100333","DOIUrl":"10.1016/j.jtauto.2025.100333","url":null,"abstract":"<div><h3>Background</h3><div>Observational studies have suggested a potential association between autoimmune diseases and anemia, but the direction of causality remains unclear. To investigate the potential causal relationship between autoimmune diseases and anemia using Mendelian randomization (MR).</div></div><div><h3>Methods</h3><div>We conducted a bidirectional two-sample MR study using summary-level genetic data from the EBI and FinnGen databases. We examined 21 autoimmune diseases as exposures and anemia as the outcome, and vice versa. Multivariable MR, meta-analysis, and two-step mediation analysis involving 43 candidate mediators were also performed. Proteomic MR and colocalization analyses were used to validate causal relationships involving proteins. Functional annotations including KEGG pathway, GO enrichment, protein–protein interaction networks, and drug enrichment analyses were performed to identify potential therapeutic targets.</div></div><div><h3>Results</h3><div>Genetically determined type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), and primary biliary cholangitis (PBC) were associated with an increased risk of anemia (<em>P</em> < 0.05 in meta-analysis). Reverse MR analyses suggested potential bidirectional causality between anemia and mixed connective tissue disease, hypothyroidism, and asthma. Mediation analysis indicated that hypothyroidism may contribute to anemia by elevating IgG levels. Proteomic and colocalization analyses identified several proteins associated with anemia (e.g., MCCD1, TMEM106B), T1DM (e.g., CTRB1, CTRB2, IL7RA), RA (e.g., TGFBI, IL1RN), and PBC (e.g., ALDH2, CXCL16).</div></div><div><h3>Conclusion</h3><div>This MR study supports a causal effect of certain autoimmune diseases on anemia risk and highlights potential protein targets for intervention, offering new insights for anemia prevention and treatment.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100333"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-08-29DOI: 10.1016/j.jtauto.2025.100313
Shan Xu , Christina James Thomas , Sunilgowda Sunnagatta Nagaraja , Rakesh Kumar , Kamlesh Sawant , Duminduni Hewa Angappulige , Andy Fang Song , Krish Suman , Benjamin Borja , Paul de Figueiredo , Jianxun Song
Multiple sclerosis (MS) is a chronic autoimmune disorder marked by immune-driven demyelination and neurodegeneration in the central nervous system. This Review explores the immunological, molecular, and epigenetic underpinnings of MS, emphasizing T and B cell involvement, dysregulated signaling pathways (e.g., TGF-β, Akt, Wnt), and the role of cell death in disease progression. Epigenetic mechanisms—such as DNA methylation and histone modifications, further modulate immune responses. While current therapies broadly suppress immunity, emerging approaches, including engineered bacteria, microbiome-based interventions, and cell therapies, offer targeted immune modulation and neuroprotection. Together, these strategies illuminate a path toward next-generation MS treatments with improved precision and efficacy.
{"title":"Redefining multiple sclerosis therapy through microbial immunomodulation and epigenetic control","authors":"Shan Xu , Christina James Thomas , Sunilgowda Sunnagatta Nagaraja , Rakesh Kumar , Kamlesh Sawant , Duminduni Hewa Angappulige , Andy Fang Song , Krish Suman , Benjamin Borja , Paul de Figueiredo , Jianxun Song","doi":"10.1016/j.jtauto.2025.100313","DOIUrl":"10.1016/j.jtauto.2025.100313","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is a chronic autoimmune disorder marked by immune-driven demyelination and neurodegeneration in the central nervous system. This Review explores the immunological, molecular, and epigenetic underpinnings of MS, emphasizing T and B cell involvement, dysregulated signaling pathways (e.g., TGF-β, Akt, Wnt), and the role of cell death in disease progression. Epigenetic mechanisms—such as DNA methylation and histone modifications, further modulate immune responses. While current therapies broadly suppress immunity, emerging approaches, including engineered bacteria, microbiome-based interventions, and cell therapies, offer targeted immune modulation and neuroprotection. Together, these strategies illuminate a path toward next-generation MS treatments with improved precision and efficacy.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100313"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-06-07DOI: 10.1016/j.jtauto.2025.100295
Pedro Carrera-Bastos , Abel Plaza-Florido , Alejandro Santos-Lozano , Vânia Borba , Gabriel Rodríguez-Romo , Celia García-Chico , Simone Lista , Gonzalo Saco-Ledo , Enzo Emanuele , Yehuda Shoenfeld , Alejandro Lucia
Objective
To identify signature proteins potentially linked to resistance to autoimmunity in the blood of centenarians.
Methods
We conducted in silico data mining of previously published proteomic results using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and PHENOPEDIA databases.
Results
Sixteen autoimmune disease-related proteins were identified within the proteomic signatures of centenarians. Albumin was the most connected hub protein, notably elevated in centenarians compared to younger controls, suggesting a protective role. Eight of the identified autoimmunity-related proteins—ADIPOQ, C1S, C5, C7, C9, CFD, MASP1, and SERPING1—were associated with the complement system.
Conclusion
Elevated albumin levels and a prominent complement system presence in centenarians' blood proteome may contribute to resistance to autoimmunity, highlighting potential protective mechanisms against autoimmune diseases in extreme longevity.
目的鉴定百岁老人血液中可能与自身免疫抵抗相关的特征蛋白。方法利用Search Tool for Retrieval of Interacting Genes/Proteins （STRING）和PHENOPEDIA数据库对已发表的蛋白质组学结果进行计算机数据挖掘。结果在百岁老人的蛋白质组学特征中鉴定出16种自身免疫性疾病相关蛋白。白蛋白是最相关的中心蛋白，与年轻的对照组相比，百岁老人的白蛋白明显升高，这表明白蛋白具有保护作用。鉴定出的8种自身免疫相关蛋白（adipoq、C1S、C5、C7、C9、CFD、MASP1和serping1）与补体系统相关。结论百岁老人血液蛋白质组中白蛋白水平的升高和补体系统的显著存在可能有助于自身免疫的抵抗，揭示了超长寿命对自身免疫性疾病的潜在保护机制。
{"title":"The ‘autoimmunome’ of centenarians","authors":"Pedro Carrera-Bastos , Abel Plaza-Florido , Alejandro Santos-Lozano , Vânia Borba , Gabriel Rodríguez-Romo , Celia García-Chico , Simone Lista , Gonzalo Saco-Ledo , Enzo Emanuele , Yehuda Shoenfeld , Alejandro Lucia","doi":"10.1016/j.jtauto.2025.100295","DOIUrl":"10.1016/j.jtauto.2025.100295","url":null,"abstract":"<div><h3>Objective</h3><div>To identify signature proteins potentially linked to resistance to autoimmunity in the blood of centenarians.</div></div><div><h3>Methods</h3><div>We conducted <em>in silico</em> data mining of previously published proteomic results using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and PHENOPEDIA databases.</div></div><div><h3>Results</h3><div>Sixteen autoimmune disease-related proteins were identified within the proteomic signatures of centenarians. Albumin was the most connected hub protein, notably elevated in centenarians compared to younger controls, suggesting a protective role. Eight of the identified autoimmunity-related proteins—ADIPOQ, C1S, C5, C7, C9, CFD, MASP1, and SERPING1—were associated with the complement system.</div></div><div><h3>Conclusion</h3><div>Elevated albumin levels and a prominent complement system presence in centenarians' blood proteome may contribute to resistance to autoimmunity, highlighting potential protective mechanisms against autoimmune diseases in extreme longevity.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100295"},"PeriodicalIF":4.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144255113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-10-15DOI: 10.1016/j.jtauto.2025.100326
Qing Luo , Zhiwei Wu , Qiuyun Xiao , Mengfan Lan , Shiqian Wang , Peng Fu , Biqi Fu , Zikun Huang , Junming Li
Objective
CD4+T cells are significant compositions of immune cells in rheumatoid arthritis (RA) and the aberrant function of CD4+T cells have been demonstrated to promote RA's progression. N6-methyladenosine (m6A) is a highly enriched modification found in CircRNAs. However, the role of m6A-methylated circRNA in regulation of CD4+T cells function in RA and its association with RA disease activity are presently unclear.
Methods
We used m6A-circRNA epitranscriptomic microarray analysis and m6A RNA immunocoprecipitation-quantitative polymerase chain reaction (MeRIP-qPCR) to screen and verify the differentially expressed m6A-methylated circRNAs in CD4+T cells from RA and HC.
Results
Many m6A-methylated circRNAs were differentially expressed in patients with new-onset RA. M6A-methylated circFOXK2 in the CD4+T cells of patients with new-onset RA was significantly decreased, the expression level of circFOXK2 in the CD4+T cells of patients with new-onset RA was significantly increased and correlated with treatment, Th17 %, autophagy. CircFOXK2 could function as competing endogenous RNAs to regulate miR-486-3p expression. In many m6A regulators, only a-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) was significantly increased in the CD4+T cells of patients with new-onset RA, and its level positively correlated with rheumatoid factor, the expression of circFOXK2. Moreover, the change of ALKBH5 could affect the level of m6A and circFOXK2 in Jurkat cell line.
Conclusion
We indicated a notable decrease in the m6A-methylated level of circFOXK2 in CD4+T cells from human RA, indicating a potential role of hypomethylated circFOXK2 in CD4+T cells function and RA pathogenesis. This may show valuable insight into the ALKBH5/m6A-circFOXK2/miRNA interaction network and the mechanism of RA.
{"title":"The significance of m6A-circFOXK2 in CD4+T cells from patients with rheumatoid arthritis and circFOXK2 correlates with Th17 % and autophagy","authors":"Qing Luo , Zhiwei Wu , Qiuyun Xiao , Mengfan Lan , Shiqian Wang , Peng Fu , Biqi Fu , Zikun Huang , Junming Li","doi":"10.1016/j.jtauto.2025.100326","DOIUrl":"10.1016/j.jtauto.2025.100326","url":null,"abstract":"<div><h3>Objective</h3><div>CD4<sup>+</sup>T cells are significant compositions of immune cells in rheumatoid arthritis (RA) and the aberrant function of CD4<sup>+</sup>T cells have been demonstrated to promote RA's progression. N6-methyladenosine (m6A) is a highly enriched modification found in CircRNAs. However, the role of m6A-methylated circRNA in regulation of CD4<sup>+</sup>T cells function in RA and its association with RA disease activity are presently unclear.</div></div><div><h3>Methods</h3><div>We used m6A-circRNA epitranscriptomic microarray analysis and m6A RNA immunocoprecipitation-quantitative polymerase chain reaction (MeRIP-qPCR) to screen and verify the differentially expressed m6A-methylated circRNAs in CD4<sup>+</sup>T cells from RA and HC.</div></div><div><h3>Results</h3><div>Many m6A-methylated circRNAs were differentially expressed in patients with new-onset RA. M6A-methylated circFOXK2 in the CD4<sup>+</sup>T cells of patients with new-onset RA was significantly decreased, the expression level of circFOXK2 in the CD4<sup>+</sup>T cells of patients with new-onset RA was significantly increased and correlated with treatment, Th17 %, autophagy. CircFOXK2 could function as competing endogenous RNAs to regulate miR-486-3p expression. In many m6A regulators, only a-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) was significantly increased in the CD4<sup>+</sup>T cells of patients with new-onset RA, and its level positively correlated with rheumatoid factor, the expression of circFOXK2. Moreover, the change of ALKBH5 could affect the level of m6A and circFOXK2 in Jurkat cell line.</div></div><div><h3>Conclusion</h3><div>We indicated a notable decrease in the m6A-methylated level of circFOXK2 in CD4<sup>+</sup>T cells from human RA, indicating a potential role of hypomethylated circFOXK2 in CD4<sup>+</sup>T cells function and RA pathogenesis. This may show valuable insight into the ALKBH5/m6A-circFOXK2/miRNA interaction network and the mechanism of RA.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100326"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145319466","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 : 2025-06-01Epub Date: 2025-03-07DOI: 10.1016/j.jtauto.2025.100282
Arno Belpaire , Annelies Demeyer , Elise Van Caelenberg , Nanja van Geel , Reinhart Speeckaert
Despite significant progress in the treatment of alopecia areata (AA), many aspects of its immune-based pathogenesis remain unexplored. IFN-γ, primarily produced by CD8+ T cells and NK cells, is considered central to AA pathogenesis. However, the complex immune signaling network contributes to therapeutic resistance and frequent disease flares after treatment discontinuation. The aryl hydrocarbon receptor (AhR) pathway, upregulated by IFN-γ, modulates Th17 responses, but its inhibitory effects on IFN-γ remain unclear. Although IL-17 levels are elevated in AA, clinical trials indicate that IL-17A inhibitors are ineffective. AhR expression is known to induce immune checkpoints (ICPs) such as PD-1, suggesting a potential role as a negative feedback mechanism. This study investigated AhR expression in lymphocytes from AA patients and its association with clinical and laboratory markers of disease activity. AhR expression was significantly reduced in CD4, CD8, Th1, and Th17 lymphocytes in AA patients compared to healthy controls (p < 0.005), and it correlated inversely with SALTII scores (p < 0.05). ROC analysis showed that AhR levels in CD8 cells could differentiate mild AA from healthy controls with a sensitivity of 82.35 % and specificity of 86.84 %, suggesting potential diagnostic utility. Lower AhR levels were associated with increased IFN-γ+ lymphocytes and decreased IL-17+ immune cells. Interestingly, immune profiles differed between atopic and non-atopic patients: in severe AA, higher AhR expression was linked to increased sPD-1 concentrations, whereas in limited AA, AhR failed to upregulate any investigated ICP. These findings highlight the significant downregulation of the AhR pathway in AA and suggest its potential as a therapeutic target. Future research should explore the development of AhR agonists or antagonists to modulate immune responses in AA.
{"title":"The AhR pathway is dysregulated in alopecia areata","authors":"Arno Belpaire , Annelies Demeyer , Elise Van Caelenberg , Nanja van Geel , Reinhart Speeckaert","doi":"10.1016/j.jtauto.2025.100282","DOIUrl":"10.1016/j.jtauto.2025.100282","url":null,"abstract":"<div><div>Despite significant progress in the treatment of alopecia areata (AA), many aspects of its immune-based pathogenesis remain unexplored. IFN-γ, primarily produced by CD8<sup>+</sup> T cells and NK cells, is considered central to AA pathogenesis. However, the complex immune signaling network contributes to therapeutic resistance and frequent disease flares after treatment discontinuation. The aryl hydrocarbon receptor (AhR) pathway, upregulated by IFN-γ, modulates Th17 responses, but its inhibitory effects on IFN-γ remain unclear. Although IL-17 levels are elevated in AA, clinical trials indicate that IL-17A inhibitors are ineffective. AhR expression is known to induce immune checkpoints (ICPs) such as PD-1, suggesting a potential role as a negative feedback mechanism. This study investigated AhR expression in lymphocytes from AA patients and its association with clinical and laboratory markers of disease activity. AhR expression was significantly reduced in CD4, CD8, Th1, and Th17 lymphocytes in AA patients compared to healthy controls (<em>p</em> < 0.005), and it correlated inversely with SALTII scores (<em>p</em> < 0.05). ROC analysis showed that AhR levels in CD8 cells could differentiate mild AA from healthy controls with a sensitivity of 82.35 % and specificity of 86.84 %, suggesting potential diagnostic utility. Lower AhR levels were associated with increased IFN-γ+ lymphocytes and decreased IL-17+ immune cells. Interestingly, immune profiles differed between atopic and non-atopic patients: in severe AA, higher AhR expression was linked to increased sPD-1 concentrations, whereas in limited AA, AhR failed to upregulate any investigated ICP. These findings highlight the significant downregulation of the AhR pathway in AA and suggest its potential as a therapeutic target. Future research should explore the development of AhR agonists or antagonists to modulate immune responses in AA.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100282"},"PeriodicalIF":4.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143601375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2024-12-16DOI: 10.1016/j.jtauto.2024.100264
Pedro Franco-Fuquen , Juana Figueroa-Aguirre , David A. Martínez , Eider F. Moreno-Cortes , Juan E. Garcia-Robledo , Fabio Vargas-Cely , Daniela A. Castro-Martínez , Mustafa Almaini , Januario E. Castro
A substantial proportion of patients diagnosed with rheumatologic and musculoskeletal diseases (RMDs) exhibit resistance to conventional therapies or experience recurrent symptoms. These diseases, which include autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, are marked by the presence of autoreactive B cells that play a critical role in their pathogenesis. The persistence of these autoreactive B cells within lymphatic organs and inflamed tissues impairs the effectiveness of B-cell-depleting monoclonal antibodies like rituximab.
A promising therapeutic approach involves using T cells genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens. This strategy has demonstrated efficacy in treating B-cell malignancies by achieving long-term depletion of malignant and normal B cells. Preliminary data from patients with RMDs, particularly those with lupus erythematosus and dermatomyositis, suggest that CAR T-cells targeting CD19 can induce rapid and sustained depletion of circulating B cells, leading to complete clinical and serological responses in cases that were previously unresponsive to conventional therapies.
This review will provide an overview of the current state of preclinical and clinical studies on the use of CAR T-cells and other cellular therapies for RMDs. Additionally, it will explore potential future applications of these innovative treatment modalities for managing patients with refractory and recurrent manifestations of these diseases.
{"title":"Cellular therapies in rheumatic and musculoskeletal diseases","authors":"Pedro Franco-Fuquen , Juana Figueroa-Aguirre , David A. Martínez , Eider F. Moreno-Cortes , Juan E. Garcia-Robledo , Fabio Vargas-Cely , Daniela A. Castro-Martínez , Mustafa Almaini , Januario E. Castro","doi":"10.1016/j.jtauto.2024.100264","DOIUrl":"10.1016/j.jtauto.2024.100264","url":null,"abstract":"<div><div>A substantial proportion of patients diagnosed with rheumatologic and musculoskeletal diseases (RMDs) exhibit resistance to conventional therapies or experience recurrent symptoms. These diseases, which include autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, are marked by the presence of autoreactive B cells that play a critical role in their pathogenesis. The persistence of these autoreactive B cells within lymphatic organs and inflamed tissues impairs the effectiveness of B-cell-depleting monoclonal antibodies like rituximab.</div><div>A promising therapeutic approach involves using T cells genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens. This strategy has demonstrated efficacy in treating B-cell malignancies by achieving long-term depletion of malignant and normal B cells. Preliminary data from patients with RMDs, particularly those with lupus erythematosus and dermatomyositis, suggest that CAR T-cells targeting CD19 can induce rapid and sustained depletion of circulating B cells, leading to complete clinical and serological responses in cases that were previously unresponsive to conventional therapies.</div><div>This review will provide an overview of the current state of preclinical and clinical studies on the use of CAR T-cells and other cellular therapies for RMDs. Additionally, it will explore potential future applications of these innovative treatment modalities for managing patients with refractory and recurrent manifestations of these diseases.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100264"},"PeriodicalIF":4.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143174020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CD40−CD40L is essential for immune system modulation because it coordinates both adaptive and inflammatory responses.
Systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, thrombocytopenic purpura, and rheumatoid arthritis are among the autoimmune illnesses in which it is especially prominent. Thus, the CD40−CD40L axis is a significant therapeutic target, despite the fact that its inhibition was first constrained by thromboembolic adverse effects.
New therapeutic approaches, such as nanotechnological methods and new-generation monoclonal antibodies, have been developed as a result of recent research with the goal of enhancing therapy efficacy and safety. This study opens up new avenues for the treatment of autoimmune illnesses by examining the pathophysiological consequences of CD40−CD40L and reviewing new treatments that target this pathway.
{"title":"The role of soluble CD40L in autoimmune diseases","authors":"Meryem Mabrouk , Hicham Wahnou , Yahye Merhi , Haissam Abou-Saleh , Fadila Guessous , Younes Zaid","doi":"10.1016/j.jtauto.2025.100288","DOIUrl":"10.1016/j.jtauto.2025.100288","url":null,"abstract":"<div><div>CD40<sup>−</sup>CD40L is essential for immune system modulation because it coordinates both adaptive and inflammatory responses.</div><div>Systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, thrombocytopenic purpura, and rheumatoid arthritis are among the autoimmune illnesses in which it is especially prominent. Thus, the CD40<sup>−</sup>CD40L axis is a significant therapeutic target, despite the fact that its inhibition was first constrained by thromboembolic adverse effects.</div><div>New therapeutic approaches, such as nanotechnological methods and new-generation monoclonal antibodies, have been developed as a result of recent research with the goal of enhancing therapy efficacy and safety. This study opens up new avenues for the treatment of autoimmune illnesses by examining the pathophysiological consequences of CD40<sup>−</sup>CD40L and reviewing new treatments that target this pathway.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100288"},"PeriodicalIF":4.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851985","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 : 2025-06-01Epub Date: 2024-11-05DOI: 10.1016/j.jtauto.2024.100260
Zheng Zhang , Jiayi Zhang , Xinyang Yan , Jiachen Wang , Haoxiang Huang , Menghao Teng , Qingguang Liu , Shaoshan Han
Background
Autoimmune liver diseases (AILDs) encompass autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The onset of these diseases is fundamentally influenced by genetic susceptibility. Although various extrahepatic factors are potentially linked to AILDs, the genetic underpinnings and mechanisms of these associations remain unclear.
Methods
Utilizing large-scale genome-wide association study (GWAS) data, this study systematically investigated the relationships between extrahepatic autoimmune diseases (EHAIDs), immune cells, and various triggering factors with AILDs. Mendelian randomization (MR) was employed to assess the causal effects of these extrahepatic factors on AILDs, complemented by linkage disequilibrium score (LDSC) regression to uncover shared genetic architecture and causal effects underlying the associations between autoimmune diseases. We employed colocalization, enrichment analysis, and protein-protein interaction (PPI) network to identify the functions of shared loci. Additionally, we proposed that activated immune cells in the circulation may contribute to liver and biliary tract inflammation via migration, mediating the impact of extrahepatic factors on AILDs. This hypothesis was tested using two mediation analysis methods: two-step MR (TSMR) and multivariable MR (MVMR).
Results
Causal associations between multiple extrahepatic factors and AILDs were identified. Notably, CD27+ B cells were found to be a risk factor for PBC, while PSC progression was associated with CD28+ CD8+ T cells exhaustion and increased levels of CD28− CD8+ T cells. Mediation analyses revealed 64 pathways via TSMR and 15 pathways via MVMR, indicating that the effects of extrahepatic factors on AILDs may be mediated by circulating immune cells. The shared genetic architecture also contributed to these associations. Analysis of shared loci and gene functions identified ATXN2 as being shared between PBC and 9 EHAIDs, while SH2B3 and PSMG1 were shared with 6 and 5 EHAIDs, respectively, in PSC.
Conclusions
Our research compared three distinct AILDs, enhancing the understanding of their etiology and providing new evidence on risk factors, diagnostic markers, and potential therapeutic targets.
{"title":"Dissecting the genetic basis and mechanisms underlying the associations between multiple extrahepatic factors and autoimmune liver diseases","authors":"Zheng Zhang , Jiayi Zhang , Xinyang Yan , Jiachen Wang , Haoxiang Huang , Menghao Teng , Qingguang Liu , Shaoshan Han","doi":"10.1016/j.jtauto.2024.100260","DOIUrl":"10.1016/j.jtauto.2024.100260","url":null,"abstract":"<div><h3>Background</h3><div>Autoimmune liver diseases (AILDs) encompass autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The onset of these diseases is fundamentally influenced by genetic susceptibility. Although various extrahepatic factors are potentially linked to AILDs, the genetic underpinnings and mechanisms of these associations remain unclear.</div></div><div><h3>Methods</h3><div>Utilizing large-scale genome-wide association study (GWAS) data, this study systematically investigated the relationships between extrahepatic autoimmune diseases (EHAIDs), immune cells, and various triggering factors with AILDs. Mendelian randomization (MR) was employed to assess the causal effects of these extrahepatic factors on AILDs, complemented by linkage disequilibrium score (LDSC) regression to uncover shared genetic architecture and causal effects underlying the associations between autoimmune diseases. We employed colocalization, enrichment analysis, and protein-protein interaction (PPI) network to identify the functions of shared loci. Additionally, we proposed that activated immune cells in the circulation may contribute to liver and biliary tract inflammation via migration, mediating the impact of extrahepatic factors on AILDs. This hypothesis was tested using two mediation analysis methods: two-step MR (TSMR) and multivariable MR (MVMR).</div></div><div><h3>Results</h3><div>Causal associations between multiple extrahepatic factors and AILDs were identified. Notably, CD27<sup>+</sup> B cells were found to be a risk factor for PBC, while PSC progression was associated with CD28<sup>+</sup> CD8<sup>+</sup> T cells exhaustion and increased levels of CD28<sup>−</sup> CD8<sup>+</sup> T cells. Mediation analyses revealed 64 pathways via TSMR and 15 pathways via MVMR, indicating that the effects of extrahepatic factors on AILDs may be mediated by circulating immune cells. The shared genetic architecture also contributed to these associations. Analysis of shared loci and gene functions identified ATXN2 as being shared between PBC and 9 EHAIDs, while SH2B3 and PSMG1 were shared with 6 and 5 EHAIDs, respectively, in PSC.</div></div><div><h3>Conclusions</h3><div>Our research compared three distinct AILDs, enhancing the understanding of their etiology and providing new evidence on risk factors, diagnostic markers, and potential therapeutic targets.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100260"},"PeriodicalIF":4.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2025-01-07DOI: 10.1016/j.jtauto.2025.100268
Yves Renaudineau , Amandine Charras , Valentina Natoli , Nicolas Congy-Jolivet , Sam Haldenby , Xuan Liu , Yongxiang Fang , Eve MD. Smith , Michael W. Beresford , Christian M. Hedrich
Objective
Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease with a strong genetic component. Genetic burden is higher in children when compared to patients with adult-onset SLE, contributing to earlier disease expression and more severe phenotypes. The human leukocyte antigen (HLA) cluster on chromosome 6p21.3 is among the most variable genomic regions, representing a major risk-factor for SLE in adults. Its impact on juvenile-onset (j)SLE remains largely unstudied.
Methods
High-resolution sequencing of HLA class I (A, B, C), class II (DRB1, DQA1, DQB1) and class III (complement C2) was undertaken in the multi-ancestral UK JSLE Cohort including participants of Caucasian (n = 151, 48.8 %), Asian (n = 108, 35.0 %) and African/Caribbean (n = 50, 16.2 %) descent. Considering ancestral variation, clinical associations were tested at the level of alleles (2-field resolution), associated HLA protein sequences (antigen binding domains, 4-field resolution), and extended haplotypes (DRh).
Results
Although important ancestral recombination was reported for HLA-DR2 and -DR3 haplotypes, risk associated with jSLE was conserved at related alleles (DR2h: DRB1∗15:01, DQA∗01:02, DQB1∗06:02; DR3h: C∗07:02 [Asian], B∗08:01, C2 rs9332730 [Asian], DRB1∗03:01). HLA-DR7 haplotypes (DRB1∗07:01, OR = 0.44, 95 % CI:0.27–0.72, p = 0.0004; DQA1∗02:01, OR = 0.34, 95 % CI:0.21–0.56, p = 1.8 × 10−6) protect Asians from jSLE development. Among 23 clinical variables recorded, the main association was found between low levels of complement C4 in Caucasian carriers of HLA-DR3h. This was not the case in Asians due to recombination with HLA-C∗07:02 and integration of the C2 rs9332730 minor allele. Low C4 serum levels associated with HLA-DQA1∗01:02 (DR2h) in Caucasians after excluding HLA-DR3h carriers from the analysis. An association between low white blood cell counts and HLA-A∗03:01P was observed across ancestries.
Conclusion
Genetic variation in the HLA cluster associates with organ domain involvement (hematological) and complement levels in jSLE. Lupus-associated HLA haplotypes vary between ancestral groups, underscoring the importance of multi-ancestral approaches to genetic studies in SLE and other autoimmune/inflammatory diseases.
{"title":"Across ancestries, HLA-B∗08:01∼DRB1∗03:01 (DR3) and HLA-DQA∗01:02 (DR2) increase the risk to develop juvenile-onset systemic lupus erythematosus through low complement C4 levels","authors":"Yves Renaudineau , Amandine Charras , Valentina Natoli , Nicolas Congy-Jolivet , Sam Haldenby , Xuan Liu , Yongxiang Fang , Eve MD. Smith , Michael W. Beresford , Christian M. Hedrich","doi":"10.1016/j.jtauto.2025.100268","DOIUrl":"10.1016/j.jtauto.2025.100268","url":null,"abstract":"<div><h3>Objective</h3><div>Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease with a strong genetic component. Genetic burden is higher in children when compared to patients with adult-onset SLE, contributing to earlier disease expression and more severe phenotypes. The human leukocyte antigen (HLA) cluster on chromosome 6p21.3 is among the most variable genomic regions, representing a major risk-factor for SLE in adults. Its impact on juvenile-onset (j)SLE remains largely unstudied.</div></div><div><h3>Methods</h3><div>High-resolution sequencing of HLA class I (A, B, C), class II (DRB1, DQA1, DQB1) and class III (complement <em>C2</em>) was undertaken in the multi-ancestral UK JSLE Cohort including participants of Caucasian (n = 151, 48.8 %), Asian (n = 108, 35.0 %) and African/Caribbean (n = 50, 16.2 %) descent. Considering ancestral variation, clinical associations were tested at the level of alleles (2-field resolution), associated HLA protein sequences (antigen binding domains, 4-field resolution), and extended haplotypes (DRh).</div></div><div><h3>Results</h3><div>Although important ancestral recombination was reported for HLA-DR2 and -DR3 haplotypes, risk associated with jSLE was conserved at related alleles (DR2h: DRB1∗15:01, DQA∗01:02, DQB1∗06:02; DR3h: C∗07:02 [Asian], B∗08:01, <em>C2</em> rs9332730 [Asian], DRB1∗03:01). HLA-DR7 haplotypes (DRB1∗07:01, OR = 0.44, 95 % CI:0.27–0.72, p = 0.0004; DQA1∗02:01, OR = 0.34, 95 % CI:0.21–0.56, p = 1.8 × 10<sup>−6</sup>) protect Asians from jSLE development. Among 23 clinical variables recorded, the main association was found between low levels of complement C4 in Caucasian carriers of HLA-DR3h. This was not the case in Asians due to recombination with HLA-C∗07:02 and integration of the <em>C2</em> rs9332730 minor allele. Low C4 serum levels associated with HLA-DQA1∗01:02 (DR2h) in Caucasians after excluding HLA-DR3h carriers from the analysis. An association between low white blood cell counts and HLA-A∗03:01P was observed across ancestries.</div></div><div><h3>Conclusion</h3><div>Genetic variation in the <em>HLA</em> cluster associates with organ domain involvement (hematological) and complement levels in jSLE. Lupus-associated <em>HLA</em> haplotypes vary between ancestral groups, underscoring the importance of multi-ancestral approaches to genetic studies in SLE and other autoimmune/inflammatory diseases.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100268"},"PeriodicalIF":4.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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