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":"2025-04-19","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 : 2025-04-15DOI: 10.1016/j.jtauto.2025.100287
Lillian Barra , Sheri Saunders , Mathias Mangion , Guillaume Paré , Halim Maaroufi , Alain Garnier , Ewa Cairns , Maria J. Fernandes
Objective
Rheumatoid arthritis is an autoimmune disease characterized by anti-citrullinated protein antibodies (ACPA). The pathogenic and protective roles of ACPA of distinct specificities are emerging and remains poorly understood. Thus, it is crucial to define the range of ACPA specificities and determine their contribution to disease and their potential clinical relevance. Since extracellular citrullination occurs in RA, we investigated whether autoantibodies in RA patients bind a citrullinated form of the cell-surface receptor CLEC12A that is expressed on neutrophils, the most abundant leukocyte in inflamed joints.
Methods
We generated a FLAG-tagged, recombinant form of the extracellular portion of human CLEC12A. After purification, the tag was removed prior to citrullination by PAD2 that was confirmed by mass spectrometry. We developed an ELISA for citrullinated CLEC12A to screen for seropositivity in sera of 68 RA patients and 36 healthy controls. Potential associations between these autoantibodies and clinical variables were determined.
Results
In our cohort, 40 % of RA patients were positive for anti-citrullinated CLEC12A autoantibodies. Those seropositive patients were younger than RA patients that tested negative for these autoantibodies (p = 0.0058). Most patients had antibodies to multiple citrullinated and homocitrullinated antigens; 17 % of patients negative for other ACPA were positive for anti-citrullinated CLEC12A autoantibodies.
Conclusion
This is the first report of seropositivity towards citrullinated CLEC12A in RA patients. A validation cohort will confirm our findings and identify additional correlations between these autoantibodies and clinical parameters. Citrullination may be a mechanism through which CLEC12A's inhibitory function is altered to exacerbate inflammation in RA. Identifying citrullinated neoantigens advances our understanding of the diverse molecular mechanisms that contribute to RA pathogenesis.
{"title":"Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients","authors":"Lillian Barra , Sheri Saunders , Mathias Mangion , Guillaume Paré , Halim Maaroufi , Alain Garnier , Ewa Cairns , Maria J. Fernandes","doi":"10.1016/j.jtauto.2025.100287","DOIUrl":"10.1016/j.jtauto.2025.100287","url":null,"abstract":"<div><h3>Objective</h3><div>Rheumatoid arthritis is an autoimmune disease characterized by anti-citrullinated protein antibodies (ACPA). The pathogenic and protective roles of ACPA of distinct specificities are emerging and remains poorly understood. Thus, it is crucial to define the range of ACPA specificities and determine their contribution to disease and their potential clinical relevance. Since extracellular citrullination occurs in RA, we investigated whether autoantibodies in RA patients bind a citrullinated form of the cell-surface receptor CLEC12A that is expressed on neutrophils, the most abundant leukocyte in inflamed joints.</div></div><div><h3>Methods</h3><div>We generated a FLAG-tagged, recombinant form of the extracellular portion of human CLEC12A. After purification, the tag was removed prior to citrullination by PAD2 that was confirmed by mass spectrometry. We developed an ELISA for citrullinated CLEC12A to screen for seropositivity in sera of 68 RA patients and 36 healthy controls. Potential associations between these autoantibodies and clinical variables were determined.</div></div><div><h3>Results</h3><div>In our cohort, 40 % of RA patients were positive for anti-citrullinated CLEC12A autoantibodies. Those seropositive patients were younger than RA patients that tested negative for these autoantibodies (p = 0.0058). Most patients had antibodies to multiple citrullinated and homocitrullinated antigens; 17 % of patients negative for other ACPA were positive for anti-citrullinated CLEC12A autoantibodies.</div></div><div><h3>Conclusion</h3><div>This is the first report of seropositivity towards citrullinated CLEC12A in RA patients. A validation cohort will confirm our findings and identify additional correlations between these autoantibodies and clinical parameters. Citrullination may be a mechanism through which CLEC12A's inhibitory function is altered to exacerbate inflammation in RA. Identifying citrullinated neoantigens advances our understanding of the diverse molecular mechanisms that contribute to RA pathogenesis.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100287"},"PeriodicalIF":4.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874692","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 : 2025-03-22DOI: 10.1016/j.jtauto.2025.100284
Xin Shen , Tingting Feng , Shangbin Li , Xingxin Wang , Wenhui Zhang , Shouyan Wang , Xiaohan Zhang , Jiguo Yang , Yuanxiang Liu
Background
Branched-chain amino acids (BCAAs), including isoleucine (Ile), leucine (Leu), and valine (Val), are substrates for synthesising nitrogenous compounds and signalling molecules involved in regulating immunity. To date, data on the role of BCAAs in autoimmune thyroiditis (AIT) are lacking; therefore, this study aimed to determine the causality using two-sample Mendelian randomisation (MR) and explored the role of BCAAs in the cGAS-STING-NLRP3 pathway in vitro.
Methods
The causal relationship between BCAAs and the pathogenesis of AIT were identified using a two-sample MR study. The anti-inflammatory effects of BCAAs and their role in the cGAS-STING-NLRP3 pathway were investigated in lipopolysaccharide (LPS)- induced thyroid follicular cells (TFCs).
Results
Our findings indicate that BCAAs are a pathogenic factor for AIT (IVW OR = 4.960; 95 % CI = (1.54,15.940); P = 0.007). Leu significantly exacerbated the inflammatory response of thyroid cells, as evidenced by the up-regulation of tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and down-regulation of TGF-β1; simultaneously aggravated cellular injury and oxidative stress; significantly increased the expression of Sestrin2/p-mTOR and cGAS/STING/NLRP3 in AIT cells. Furthermore, the expression of IL-18 and IL-1β was significantly increased. Conversely, Leu deprivation induced cell injury, decreased oxidative stress, and inhibited Sestrin2/p-mTOR and cGAS/STING/NLRP3 pathways.
Conclusion
Our findings suggest a potential causal effect of genetically predicted Leu on AIT; Leu significantly exacerbated the inflammatory response and cellular damage in AIT cells. The mechanism by which Leu induces inflammation involves activating the promoted Sestrin2/mTOR and cGAS-STING-NLRP3 signalling pathways. Our study proposes a novel mechanism for the contributions of Leu in AIT and potential therapeutic strategies involving Leu deprivation in treating AIT.
{"title":"Leucine enhances the cGAS-STING-NLRP3 pathway in autoimmune thyroiditis","authors":"Xin Shen , Tingting Feng , Shangbin Li , Xingxin Wang , Wenhui Zhang , Shouyan Wang , Xiaohan Zhang , Jiguo Yang , Yuanxiang Liu","doi":"10.1016/j.jtauto.2025.100284","DOIUrl":"10.1016/j.jtauto.2025.100284","url":null,"abstract":"<div><h3>Background</h3><div>Branched-chain amino acids (BCAAs), including isoleucine (Ile), leucine (Leu), and valine (Val), are substrates for synthesising nitrogenous compounds and signalling molecules involved in regulating immunity. To date, data on the role of BCAAs in autoimmune thyroiditis (AIT) are lacking; therefore, this study aimed to determine the causality using two-sample Mendelian randomisation (MR) and explored the role of BCAAs in the cGAS-STING-NLRP3 pathway <em>in vitro</em>.</div></div><div><h3>Methods</h3><div>The causal relationship between BCAAs and the pathogenesis of AIT were identified using a two-sample MR study. The anti-inflammatory effects of BCAAs and their role in the cGAS-STING-NLRP3 pathway were investigated in lipopolysaccharide (LPS)- induced thyroid follicular cells (TFCs).</div></div><div><h3>Results</h3><div>Our findings indicate that BCAAs are a pathogenic factor for AIT (IVW OR = 4.960; 95 % CI = (1.54,15.940); <em>P</em> = 0.007). Leu significantly exacerbated the inflammatory response of thyroid cells, as evidenced by the up-regulation of tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and down-regulation of TGF-β1; simultaneously aggravated cellular injury and oxidative stress; significantly increased the expression of Sestrin2/p-mTOR and cGAS/STING/NLRP3 in AIT cells. Furthermore, the expression of IL-18 and IL-1β was significantly increased. Conversely, Leu deprivation induced cell injury, decreased oxidative stress, and inhibited Sestrin2/p-mTOR and cGAS/STING/NLRP3 pathways.</div></div><div><h3>Conclusion</h3><div>Our findings suggest a potential causal effect of genetically predicted Leu on AIT; Leu significantly exacerbated the inflammatory response and cellular damage in AIT cells. The mechanism by which Leu induces inflammation involves activating the promoted Sestrin2/mTOR and cGAS-STING-NLRP3 signalling pathways. Our study proposes a novel mechanism for the contributions of Leu in AIT and potential therapeutic strategies involving Leu deprivation in treating AIT.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100284"},"PeriodicalIF":4.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706316","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}
While ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC), the autoimmune nature of PBC underscores the need for treatments targeting immunological pathways that may achieve a cure. E6011, a novel humanized anti-fractalkine monoclonal antibody, has emerged as a potential therapeutic option for PBC. We conducted a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of E6011 in patients with PBC with an incomplete response to UDCA.
Methods
The study was composed of 12-week Double-Blind Phase (placebo, E6011 10 mg/kg/month, 15 mg/kg/month, or 10 mg/kg/every other week [eow]) followed by a 52-week Open-Label Phase. The primary endpoint was the percent change in alkaline phosphatase (ALP) at Week 12.
Results
A total of 29 patients were enrolled. Histological evaluation at screening revealed that 83 % of the enrolled patients were classified as Stage 4 according to the Nakanuma Classification. The mean percent changes in ALP at Week 12 were +0.45 % in the placebo, +0.65 % in the 10 mg/kg/month, +1.23 % in the 15 mg/kg/month and +1.19 % in the 10 mg/kg/eow, with no observed trends toward ALP reduction in the E6011 treatment. Based on the interim analysis, the study was discontinued due to a lack of the efficacy. E6011 was generally safe and well tolerated.
Conclusion
This study of E6011 failed to meet the primary endpoint in patients with PBC with an incomplete response to UDCA. The advanced histological severity present in more than 80 % of patients at baseline may have contributed to these findings.
{"title":"A placebo-controlled Phase 2 trial of E6011, anti-human fractalkine monoclonal antibody, in primary biliary cholangitis","authors":"Atsushi Tanaka , Masanori Abe , Tadashi Namisaki , Shinji Shimoda , Mikio Zeniya , Akio Ido , Hitoshi Yoshiji , Hiromasa Ohira , Kenichi Harada , Yuko Kakuda , Atsushi Umeda , Yuki Kamiya , Yukari Higashine , Seiichiro Hojo , Toshio Imai , Tetsu Kawano , Yasuni Nakanuma , Hirohito Tsubouchi","doi":"10.1016/j.jtauto.2025.100283","DOIUrl":"10.1016/j.jtauto.2025.100283","url":null,"abstract":"<div><h3>Background</h3><div>While ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC), the autoimmune nature of PBC underscores the need for treatments targeting immunological pathways that may achieve a cure. E6011, a novel humanized anti-fractalkine monoclonal antibody, has emerged as a potential therapeutic option for PBC. We conducted a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of E6011 in patients with PBC with an incomplete response to UDCA.</div></div><div><h3>Methods</h3><div>The study was composed of 12-week Double-Blind Phase (placebo, E6011 10 mg/kg/month, 15 mg/kg/month, or 10 mg/kg/every other week [eow]) followed by a 52-week Open-Label Phase. The primary endpoint was the percent change in alkaline phosphatase (ALP) at Week 12.</div></div><div><h3>Results</h3><div>A total of 29 patients were enrolled. Histological evaluation at screening revealed that 83 % of the enrolled patients were classified as Stage 4 according to the Nakanuma Classification. The mean percent changes in ALP at Week 12 were +0.45 % in the placebo, +0.65 % in the 10 mg/kg/month, +1.23 % in the 15 mg/kg/month and +1.19 % in the 10 mg/kg/eow, with no observed trends toward ALP reduction in the E6011 treatment. Based on the interim analysis, the study was discontinued due to a lack of the efficacy. E6011 was generally safe and well tolerated.</div></div><div><h3>Conclusion</h3><div>This study of E6011 failed to meet the primary endpoint in patients with PBC with an incomplete response to UDCA. The advanced histological severity present in more than 80 % of patients at baseline may have contributed to these findings.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100283"},"PeriodicalIF":4.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697669","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 : 2025-03-20DOI: 10.1016/j.jtauto.2025.100286
Fei Yan , Jing Tao , Jie Liu , Yongliang Chen , Zongju Huang
Background
Psoriasis is a chronic, immune-mediated inflammatory skin disorder with a strong genetic component. Although numerous GWAS have identified risk loci, many associated variants lie in non-coding regions, complicating functional interpretation.
Objective
This study aimed to identify novel psoriasis susceptibility genes by integrating large-scale GWAS and eQTL data using a cross-tissue TWAS approach.
Methods
We integrated psoriasis GWAS summary statistics from the FinnGen database with GTEx V8 eQTL data. A cross-tissue TWAS was performed using UTMOST, followed by validation with single-tissue TWAS via FUSION. Conditional and joint analyses were conducted to delineate independent genetic signals, and gene-based analysis was performed using MAGMA. Causal relationships were evaluated using Mendelian randomization (MR) and Bayesian colocalization analyses. Key SNPs were functionally characterized using CADD, GERP++, and RegulomeDB for pathogenicity prediction and regulatory potential assessment. Finally, functional network analysis was conducted using GeneMANIA.
Results
The cross-tissue TWAS identified 259 genes significantly associated with psoriasis (p < 0.05), with 12 remaining significant after FDR correction. Single-tissue TWAS validation revealed 655 significant genes, with an overlap of three protein-coding candidates: POLI, NFKB1, and ZFYVE28. Cross-validation with MAGMA refined the candidate set to NFKB1 and ZFYVE28. MR and colocalization analyses supported a causal relationship for NFKB1 in Skeletal Muscle, Transverse Colon, and Cultured Fibroblasts, and for ZFYVE28 in Subcutaneous Adipose Tissue and Esophageal Mucosa tissues. Functional annotation identified key SNPs including rs4235405, rs3774960, and rs1598856 for NFKB1, and rs1203786 for ZFYVE28, with varying degrees of pathogenicity and regulatory potential. GeneMANIA network analysis further implicated NFKB1 in NF-κB signaling and ZFYVE28 in vesicle-mediated transport.
Conclusion
Our integrative multi-omics approach identifies NFKB1 and ZFYVE28 as novel psoriasis susceptibility genes, providing potential biomarkers and therapeutic targets for this complex disease.
{"title":"Cross-tissue transcriptome-wide association study reveals novel psoriasis susceptibility genes","authors":"Fei Yan , Jing Tao , Jie Liu , Yongliang Chen , Zongju Huang","doi":"10.1016/j.jtauto.2025.100286","DOIUrl":"10.1016/j.jtauto.2025.100286","url":null,"abstract":"<div><h3>Background</h3><div>Psoriasis is a chronic, immune-mediated inflammatory skin disorder with a strong genetic component. Although numerous GWAS have identified risk loci, many associated variants lie in non-coding regions, complicating functional interpretation.</div></div><div><h3>Objective</h3><div>This study aimed to identify novel psoriasis susceptibility genes by integrating large-scale GWAS and eQTL data using a cross-tissue TWAS approach.</div></div><div><h3>Methods</h3><div>We integrated psoriasis GWAS summary statistics from the FinnGen database with GTEx V8 eQTL data. A cross-tissue TWAS was performed using UTMOST, followed by validation with single-tissue TWAS via FUSION. Conditional and joint analyses were conducted to delineate independent genetic signals, and gene-based analysis was performed using MAGMA. Causal relationships were evaluated using Mendelian randomization (MR) and Bayesian colocalization analyses. Key SNPs were functionally characterized using CADD, GERP++, and RegulomeDB for pathogenicity prediction and regulatory potential assessment. Finally, functional network analysis was conducted using GeneMANIA.</div></div><div><h3>Results</h3><div>The cross-tissue TWAS identified 259 genes significantly associated with psoriasis (p < 0.05), with 12 remaining significant after FDR correction. Single-tissue TWAS validation revealed 655 significant genes, with an overlap of three protein-coding candidates: POLI, NFKB1, and ZFYVE28. Cross-validation with MAGMA refined the candidate set to NFKB1 and ZFYVE28. MR and colocalization analyses supported a causal relationship for NFKB1 in Skeletal Muscle, Transverse Colon, and Cultured Fibroblasts, and for ZFYVE28 in Subcutaneous Adipose Tissue and Esophageal Mucosa tissues. Functional annotation identified key SNPs including rs4235405, rs3774960, and rs1598856 for NFKB1, and rs1203786 for ZFYVE28, with varying degrees of pathogenicity and regulatory potential. GeneMANIA network analysis further implicated NFKB1 in NF-κB signaling and ZFYVE28 in vesicle-mediated transport.</div></div><div><h3>Conclusion</h3><div>Our integrative multi-omics approach identifies NFKB1 and ZFYVE28 as novel psoriasis susceptibility genes, providing potential biomarkers and therapeutic targets for this complex disease.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100286"},"PeriodicalIF":4.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143681246","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 : 2025-03-19DOI: 10.1016/j.jtauto.2025.100285
Yu Lai , Zishao Zhong , Runze Li , Tuliang Liang , Xizi He , Yuan Liu , Hao Yu , Chuanhai Zhang , Yao Xiao , Liang Liu , Hudan Pan
Background
Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease. While the chemokine signaling pathway plays a pivotal role in RA pathogenesis, the specific cellular interactions remain unclear.
Methods
A three-stage analytical framework was implemented. First, to uncover crucial signaling pathways in RA, we conducted an analysis of bulk RNA-seq data (GSE89408) sourced from the Gene Expression Omnibus (GEO) database. Second, utilizing single-cell transcriptome data from GEO (GSE200815 and GSE152805) and EMBL's European Bioinformatics Institute (E-MTAB-8322), we delved into key cell pairs and their ligand-receptor interactions within the chemokine signaling pathway. Third, spatial transcriptome data (SDY2213) from the IMMPORT database were employed to validate the colocalization of these pivotal cell pairs.
Results
Our enrichment analysis of bulk RNA-seq data underscored the chemokine signaling pathway's centrality in RA's pathogenesis. By integrating thirteen single-cell RNA sequencing datasets, we documented a notable elevation in the proportion of most lymphocyte types within RA synovium. The chemokine signaling pathway emerged as one of the primary pathways enriched in genes differentially expressed between RA and osteoarthritis in lymphocytes and CD8+ T cells. Cell-cell interaction analysis pinpointed the interaction between CD8+ T cells and endothelial cells (ECs) as a distinctive feature of the chemokine signaling pathway. Spatial transcriptome analysis further substantiated the co-localization of CD8+ T cells and ECs.
Conclusions
This study highlight CD8+ T cell- EC interactions via chemokine signaling as critical drivers of RA progression, potentially promoting leukocyte transendothelial migration and synovial immune infiltration.
{"title":"Unveiling the crucial role of CD8+ T cell and endothelial cell interaction in rheumatoid arthritis through the integrated analysis of spatial transcriptomics and bulk/single-cell RNA-seq","authors":"Yu Lai , Zishao Zhong , Runze Li , Tuliang Liang , Xizi He , Yuan Liu , Hao Yu , Chuanhai Zhang , Yao Xiao , Liang Liu , Hudan Pan","doi":"10.1016/j.jtauto.2025.100285","DOIUrl":"10.1016/j.jtauto.2025.100285","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease. While the chemokine signaling pathway plays a pivotal role in RA pathogenesis, the specific cellular interactions remain unclear.</div></div><div><h3>Methods</h3><div>A three-stage analytical framework was implemented. First, to uncover crucial signaling pathways in RA, we conducted an analysis of bulk RNA-seq data (GSE89408) sourced from the Gene Expression Omnibus (GEO) database. Second, utilizing single-cell transcriptome data from GEO (GSE200815 and GSE152805) and EMBL's European Bioinformatics Institute (E-MTAB-8322), we delved into key cell pairs and their ligand-receptor interactions within the chemokine signaling pathway. Third, spatial transcriptome data (SDY2213) from the IMMPORT database were employed to validate the colocalization of these pivotal cell pairs.</div></div><div><h3>Results</h3><div>Our enrichment analysis of bulk RNA-seq data underscored the chemokine signaling pathway's centrality in RA's pathogenesis. By integrating thirteen single-cell RNA sequencing datasets, we documented a notable elevation in the proportion of most lymphocyte types within RA synovium. The chemokine signaling pathway emerged as one of the primary pathways enriched in genes differentially expressed between RA and osteoarthritis in lymphocytes and CD8<sup>+</sup> T cells. Cell-cell interaction analysis pinpointed the interaction between CD8<sup>+</sup> T cells and endothelial cells (ECs) as a distinctive feature of the chemokine signaling pathway. Spatial transcriptome analysis further substantiated the co-localization of CD8<sup>+</sup> T cells and ECs.</div></div><div><h3>Conclusions</h3><div>This study highlight CD8<sup>+</sup> T cell- EC interactions via chemokine signaling as critical drivers of RA progression, potentially promoting leukocyte transendothelial migration and synovial immune infiltration.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100285"},"PeriodicalIF":4.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143681245","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 : 2025-03-07DOI: 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":"2025-03-07","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}
The COVID-19 pandemic has raised concerns about potential links between SARS-CoV-2 infection and autoimmune diseases. This study investigated changes in the incidence rate (IR) of autoimmune diseases among children following the pandemic's onset.
Methods
A retrospective cross-sectional study analyzed data from Clalit Health Services, Israel's largest healthcare provider, examining the IR of different autoimmune diseases in children aged 0–18. The study compared pre-pandemic (2019) with pandemic/post-pandemic periods (2020–2023), encompassing a cohort of over 1.5 million children.
Results
Significant IR increases were observed across multiple autoimmune diseases. Rheumatic diseases (Juvenile Idiopathic Arthritis, Systemic Lupus Erythematosus, Henoch Schoenlein Purpura (HSP)) showed consistent increases, with HSP demonstrating the most pronounced trend. Endocrine disorders exhibited diverse patterns, with autoimmune thyroid diseases and Type 1 diabetes showing overall increases, while diabetic ketoacidosis exhibited an initial spike followed by a decline. Gastrointestinal diseases displayed heterogeneous patterns; Celiac disease and Ulcerative colitis showed general increases, Crohn's disease showed a downward trend, and autoimmune hepatitis exhibited an initial significant decrease followed by a significant increase. Dermatological conditions, including Psoriasis and Vitiligo, demonstrated consistent elevations throughout 2020–2023. Immune Thrombocytopenia Purpura showed initial decreases followed by significant increases in 2022–2023.
Conclusions
This comprehensive analysis reveals significant changes in pediatric autoimmune disease incidence following the COVID-19 pandemic, suggesting potential associations between SARS-CoV-2 infection and autoimmune dysregulation. The diverse patterns observed across different conditions highlight the complex interplay between viral infection and autoimmunity, emphasizing the need for continued surveillance and investigation of long-term immunological consequences of COVID-19 in pediatric populations.
{"title":"Pediatric autoimmune diseases in the light of COVID-19 pandemic, A retrospective observational big data study","authors":"Rim Kasem Ali Sliman , Hilla Cohen , Shereen Shehadeh , Reut Batcir , Yigal Elenberg Alter , Keren Cohen , Ilana Koren , Inbal Halabi , Hussein Sliman , Mohamad Hamad Saied","doi":"10.1016/j.jtauto.2025.100281","DOIUrl":"10.1016/j.jtauto.2025.100281","url":null,"abstract":"<div><h3>Background</h3><div>The COVID-19 pandemic has raised concerns about potential links between SARS-CoV-2 infection and autoimmune diseases. This study investigated changes in the incidence rate (IR) of autoimmune diseases among children following the pandemic's onset.</div></div><div><h3>Methods</h3><div>A retrospective cross-sectional study analyzed data from Clalit Health Services, Israel's largest healthcare provider, examining the IR of different autoimmune diseases in children aged 0–18. The study compared pre-pandemic (2019) with pandemic/post-pandemic periods (2020–2023), encompassing a cohort of over 1.5 million children.</div></div><div><h3>Results</h3><div>Significant IR increases were observed across multiple autoimmune diseases. Rheumatic diseases (Juvenile Idiopathic Arthritis, Systemic Lupus Erythematosus, Henoch Schoenlein Purpura (HSP)) showed consistent increases, with HSP demonstrating the most pronounced trend. Endocrine disorders exhibited diverse patterns, with autoimmune thyroid diseases and Type 1 diabetes showing overall increases, while diabetic ketoacidosis exhibited an initial spike followed by a decline. Gastrointestinal diseases displayed heterogeneous patterns; Celiac disease and Ulcerative colitis showed general increases, Crohn's disease showed a downward trend, and autoimmune hepatitis exhibited an initial significant decrease followed by a significant increase. Dermatological conditions, including Psoriasis and Vitiligo, demonstrated consistent elevations throughout 2020–2023. Immune Thrombocytopenia Purpura showed initial decreases followed by significant increases in 2022–2023.</div></div><div><h3>Conclusions</h3><div>This comprehensive analysis reveals significant changes in pediatric autoimmune disease incidence following the COVID-19 pandemic, suggesting potential associations between SARS-CoV-2 infection and autoimmune dysregulation. The diverse patterns observed across different conditions highlight the complex interplay between viral infection and autoimmunity, emphasizing the need for continued surveillance and investigation of long-term immunological consequences of COVID-19 in pediatric populations.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100281"},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143611570","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}
NETosis, the process through which neutrophils release neutrophil extracellular traps (NETs), has emerged as a crucial mechanism in host defense and the pathogenesis of autoimmune responses. During the SARS-CoV-2 pandemic, this process received significant attention due to the central role of neutrophil recruitment and activation in infection control. However, elevated neutrophil levels and dysregulated NET formation have been linked to coagulopathy and endothelial damage, correlating with disease severity and poor prognosis in COVID-19. Moreover, it is known that SARS-CoV-2 can induce persistent low-grade systemic inflammation, known as long COVID, although the underlying causes remain unclear. It has been increasingly acknowledged that excessive NETosis and NET generation contribute to further pathophysiological abnormalities following SARS-CoV-2 infection. This review provides an updated overview of the role of NETosis in autoimmune diseases, but also the relationship between COVID-19 and long COVID with autoimmunity (e.g., latent and overt autoimmunity, molecular mimicry, epitope spreading) and NETosis (e.g., immune responses, NET markers). Finally, we discuss potential therapeutic strategies targeting dysregulated NETosis to mitigate the severe complications of COVID-19 and long COVID.
{"title":"NETosis: A key player in autoimmunity, COVID-19, and long COVID","authors":"Diana M. Monsalve , Yeny Acosta-Ampudia , Nicolás Guerrero Acosta , Mariana Celis-Andrade , Ali Şahin , Ahsen Morva Yilmaz , Yehuda Shoenfeld , Carolina Ramírez-Santana","doi":"10.1016/j.jtauto.2025.100280","DOIUrl":"10.1016/j.jtauto.2025.100280","url":null,"abstract":"<div><div>NETosis, the process through which neutrophils release neutrophil extracellular traps (NETs), has emerged as a crucial mechanism in host defense and the pathogenesis of autoimmune responses. During the SARS-CoV-2 pandemic, this process received significant attention due to the central role of neutrophil recruitment and activation in infection control. However, elevated neutrophil levels and dysregulated NET formation have been linked to coagulopathy and endothelial damage, correlating with disease severity and poor prognosis in COVID-19. Moreover, it is known that SARS-CoV-2 can induce persistent low-grade systemic inflammation, known as long COVID, although the underlying causes remain unclear. It has been increasingly acknowledged that excessive NETosis and NET generation contribute to further pathophysiological abnormalities following SARS-CoV-2 infection. This review provides an updated overview of the role of NETosis in autoimmune diseases, but also the relationship between COVID-19 and long COVID with autoimmunity (e.g., latent and overt autoimmunity, molecular mimicry, epitope spreading) and NETosis (e.g., immune responses, NET markers). Finally, we discuss potential therapeutic strategies targeting dysregulated NETosis to mitigate the severe complications of COVID-19 and long COVID.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100280"},"PeriodicalIF":4.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464117","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 : 2025-02-07DOI: 10.1016/j.jtauto.2025.100279
Aniek Plug , Liana Barenbrug , Bart G.J. Moerings , Elke M.G. de Jong , Renate G. van der Molen
Background
Pregnancy requires a careful immune balance between tolerance for the semi-allogenic fetus and protection against pathogens. Women with immune-mediated inflammatory diseases (IMIDs), where the interleukin (IL)-23/IL-17 axis plays an important role, often experience changes in disease severity during pregnancy. These changes and the association between disease flares and pregnancy complications, suggests a role for IL-17 and IL-23 in pregnancy.
Methods
We systemically searched PubMed, EMBASE, and Web of Science (March 2024), to assess the role of IL-17 and IL-23 in pregnancy-related in vitro assays, animal or human studies.
Results
Eighty articles (8 in vitro, 11 animal and 61 human studies) were included. Seventy-one studies reported on IL-17 and 16 studies on IL-23. In vitro trophoblast proliferation, migration and invasion was increased in the presence of IL-17, but impaired with IL-23. IL-17 levels were increased in animal models for pregnancy complications. In humans, IL-17 levels seemed to be increased in pregnant women versus non-pregnant women. Additionally, elevated IL-17 levels were associated with pregnancy complications. Although similar trends were found for IL-23, data were limited.
Conclusions
We identified a large, but heterogenic, body of evidence for a significant role of IL-17 in all stages of pregnancy: while an excessive increase seemed to be associated with complications. The limited number of studies prevents firm conclusions on the role of IL-23. Future research is needed to find biomarkers for patients with IMIDs to predict the effect of possible disease flares on pregnancy, and the effect of therapeutic inhibition of IL-17 or IL-23.
{"title":"Understanding the role of immune-mediated inflammatory disease related cytokines interleukin 17 and 23 in pregnancy: A systematic review","authors":"Aniek Plug , Liana Barenbrug , Bart G.J. Moerings , Elke M.G. de Jong , Renate G. van der Molen","doi":"10.1016/j.jtauto.2025.100279","DOIUrl":"10.1016/j.jtauto.2025.100279","url":null,"abstract":"<div><h3>Background</h3><div>Pregnancy requires a careful immune balance between tolerance for the semi-allogenic fetus and protection against pathogens. Women with immune-mediated inflammatory diseases (IMIDs), where the interleukin (IL)-23/IL-17 axis plays an important role, often experience changes in disease severity during pregnancy. These changes and the association between disease flares and pregnancy complications, suggests a role for IL-17 and IL-23 in pregnancy.</div></div><div><h3>Methods</h3><div>We systemically searched PubMed, EMBASE, and Web of Science (March 2024), to assess the role of IL-17 and IL-23 in pregnancy-related <em>in vitro</em> assays, animal or human studies.</div></div><div><h3>Results</h3><div>Eighty articles (8 <em>in vitro</em>, 11 animal and 61 human studies) were included. Seventy-one studies reported on IL-17 and 16 studies on IL-23. <em>In vitro</em> trophoblast proliferation, migration and invasion was increased in the presence of IL-17, but impaired with IL-23. IL-17 levels were increased in animal models for pregnancy complications. In humans, IL-17 levels seemed to be increased in pregnant women versus non-pregnant women. Additionally, elevated IL-17 levels were associated with pregnancy complications. Although similar trends were found for IL-23, data were limited.</div></div><div><h3>Conclusions</h3><div>We identified a large, but heterogenic, body of evidence for a significant role of IL-17 in all stages of pregnancy: while an excessive increase seemed to be associated with complications. The limited number of studies prevents firm conclusions on the role of IL-23. Future research is needed to find biomarkers for patients with IMIDs to predict the effect of possible disease flares on pregnancy, and the effect of therapeutic inhibition of IL-17 or IL-23.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100279"},"PeriodicalIF":4.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403512","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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