Recent advances in NSCLC therapy remain limited by treatment resistance, much of which is influenced by epigenetic regulation of immune responses. In this study, we investigate the role of CTCF, a chromatin architectural protein that modulates enhancer–promoter interactions, in shaping T-helper (TH) cell differentiation and tumor immunity. Changes in CTCF expression coincided with altered chromatin-level enrichment patterns involving DNA repair–associated factors (ERCC1, XPF, CSA) and tumor-related proteins at the IFNG locus, as well as shifts in histone modification marks (H3K4me3 and H3K27me3) at TH1-associated genes, including TBX21 and IFNG. These chromatin-associated features were accompanied by increased nitric oxide production and enhanced cytotoxicity in functional assays. Collectively, these findings suggest that variation in CTCF levels is linked to coordinated epigenetic and immune-associated changes in NSCLC, supporting its potential relevance as an immuno-epigenetic factor in shaping anti-tumor immune responses.
{"title":"Involvement of CCCTC-binding factor (CTCF) in immunomodulation and epigenetic regulation of T helper cell differentiation during Non-Small Cell Lung Cancer (NSCLC)","authors":"Oishi Mukherjee , Sayani Bose , Sudeshna Rakshit , Geetha Shanmugam , Anuneha Baranwal , Srawsta Saha , Harsita Goswami , Melvin George , Koustav Sarkar","doi":"10.1016/j.clim.2025.110662","DOIUrl":"10.1016/j.clim.2025.110662","url":null,"abstract":"<div><div>Recent advances in NSCLC therapy remain limited by treatment resistance, much of which is influenced by epigenetic regulation of immune responses. In this study, we investigate the role of CTCF, a chromatin architectural protein that modulates enhancer–promoter interactions, in shaping T-helper (T<sub>H</sub>) cell differentiation and tumor immunity. Changes in CTCF expression coincided with altered chromatin-level enrichment patterns involving DNA repair–associated factors (ERCC1, XPF, CSA) and tumor-related proteins at the <em>IFNG</em> locus, as well as shifts in histone modification marks (H3K4me3 and H3K27me3) at T<sub>H</sub>1-associated genes, including <em>TBX21</em> and <em>IFNG</em>. These chromatin-associated features were accompanied by increased nitric oxide production and enhanced cytotoxicity in functional assays. Collectively, these findings suggest that variation in CTCF levels is linked to coordinated epigenetic and immune-associated changes in NSCLC, supporting its potential relevance as an immuno-epigenetic factor in shaping anti-tumor immune responses.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110662"},"PeriodicalIF":3.8,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-25DOI: 10.1016/j.clim.2025.110661
Wei Qiu , Ya Huang , Yan Gu , Yichi Sun , Ping Yue , KaiDe Xia , Shichao Zhang
Emerging data have revealed that m1A modification and its regulators are key participants in tumorigenesis and progression. The cell-free miRNAs have been demonstrated to circulate stably in the serum, making them biomarker candidates for cancer diagnosis. Here we included 16,902 serum samples to develop a diagnostic signature named m1A-miRNA signature based on serum circulating m1A-related miRNAs for cancer detection. The m1A-miRNA signature presented excellent accuracy, and the area under the curve (AUC) was 0.991 in the training cohort. The diagnostic capability of the m1A-miRNA signature was not affected by sexual distinction, age and non-cancer disease. As far as distinguishing cancer types is concerned, the signature exerted superior ability in identifying the types of glioblastoma multiforme, gastric cancer and lung cancer. We also found that the m1A-miRNA signature showed a satisfactory AUC in the early diagnosis of pan-cancer. Additionally, the accuracy of the m1A-miRNA signature was further verified by clinical samples.
{"title":"A novel diagnostic signature constructed based on serum-circulating m1A-related miRNAs for cancer detection","authors":"Wei Qiu , Ya Huang , Yan Gu , Yichi Sun , Ping Yue , KaiDe Xia , Shichao Zhang","doi":"10.1016/j.clim.2025.110661","DOIUrl":"10.1016/j.clim.2025.110661","url":null,"abstract":"<div><div>Emerging data have revealed that m<sup>1</sup>A modification and its regulators are key participants in tumorigenesis and progression. The cell-free miRNAs have been demonstrated to circulate stably in the serum, making them biomarker candidates for cancer diagnosis. Here we included 16,902 serum samples to develop a diagnostic signature named m1A-miRNA signature based on serum circulating m<sup>1</sup>A-related miRNAs for cancer detection. The m1A-miRNA signature presented excellent accuracy, and the area under the curve (AUC) was 0.991 in the training cohort. The diagnostic capability of the m1A-miRNA signature was not affected by sexual distinction, age and non-cancer disease. As far as distinguishing cancer types is concerned, the signature exerted superior ability in identifying the types of glioblastoma multiforme, gastric cancer and lung cancer. We also found that the m1A-miRNA signature showed a satisfactory AUC in the early diagnosis of pan-cancer. Additionally, the accuracy of the m1A-miRNA signature was further verified by clinical samples.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110661"},"PeriodicalIF":3.8,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.clim.2025.110660
Jun Han , Qifeng Yao , Qiuyue Huang , Zuoyou Ding , Guohao Wu
Cancer cachexia involves severe skeletal muscle and adipose tissue loss. The role of Apolipoprotein E (ApoE) in adipose remodeling remains unclear. This study investigated ApoE's function in cancer cachexia. We found cachectic patients had decreased plasma ApoE but elevated expression in subcutaneous adipose. In vitro, ApoE knockdown in adipocytes downregulated both lipogenesis and lipolysis genes. In vivo, ApoE−/− mice were protected against adipose wasting in a cachexia model. Single-cell RNA sequencing revealed ApoE deficiency altered immune cell dynamics, increasing total macrophages and enriching a specific Cbr2+ macrophage subpopulation with an M2-like phenotype. This was confirmed by immunofluorescence showing enhanced M2 macrophage infiltration in adipose tissue. We conclude that ApoE is a critical regulator of adipose homeostasis and immune modulation in cancer cachexia, representing a promising diagnostic and therapeutic target.
{"title":"Single-cell sequencing reveals APOE deletion alleviates adipose wasting in cancer cachexia via macrophage repolarization","authors":"Jun Han , Qifeng Yao , Qiuyue Huang , Zuoyou Ding , Guohao Wu","doi":"10.1016/j.clim.2025.110660","DOIUrl":"10.1016/j.clim.2025.110660","url":null,"abstract":"<div><div>Cancer cachexia involves severe skeletal muscle and adipose tissue loss. The role of Apolipoprotein E (ApoE) in adipose remodeling remains unclear. This study investigated ApoE's function in cancer cachexia. We found cachectic patients had decreased plasma ApoE but elevated expression in subcutaneous adipose. In vitro, ApoE knockdown in adipocytes downregulated both lipogenesis and lipolysis genes. In vivo, ApoE<sup>−/−</sup> mice were protected against adipose wasting in a cachexia model. Single-cell RNA sequencing revealed ApoE deficiency altered immune cell dynamics, increasing total macrophages and enriching a specific Cbr2+ macrophage subpopulation with an M2-like phenotype. This was confirmed by immunofluorescence showing enhanced M2 macrophage infiltration in adipose tissue. We conclude that ApoE is a critical regulator of adipose homeostasis and immune modulation in cancer cachexia, representing a promising diagnostic and therapeutic target.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110660"},"PeriodicalIF":3.8,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-21DOI: 10.1016/j.clim.2025.110659
Temesgen E. Andargie , Han Su , Moon Kyoo Jang , Xin Tian , Andrew H. Karaba , Sean Agbor-Enoh
The association between circulating cytokines and allograft injury due to allograft rejection (AR) remains poorly defined. We hypothesize that cytokines correlate with the degree of allograft injury during AR. This case-control study measured cytokines and cell-free DNA in 88 heart transplant plasma samples (54 AR, 34 non-rejecting (NR) controls) and 26 healthy controls. AR patients exhibited higher levels of total and percent donor-derived cfDNA (%dd-cfDNA) and proinflammatory cytokines, and lower levels of type II cytokines/chemokines and Th17/23 axis cytokines compared to NR or HCs. The cfDNA levels positively correlated with proinflammatory cytokines and negatively with MDC and cytokines of the Th17/IL-23 axis. A Lasso regression model combining cytokines and %dd-cfDNA (AUC = 0.93) showed better AR diagnostic performance than either cytokines or %dd-cfDNA alone. The study concluded that inflammatory and regulatory cytokine levels correlate with allograft injury, and combining cytokines with %dd-cfDNA may enhance AR detection.
{"title":"Systemic cytokine profiling enhances the performance of dd-cfDNA to detect cardiac rejection","authors":"Temesgen E. Andargie , Han Su , Moon Kyoo Jang , Xin Tian , Andrew H. Karaba , Sean Agbor-Enoh","doi":"10.1016/j.clim.2025.110659","DOIUrl":"10.1016/j.clim.2025.110659","url":null,"abstract":"<div><div>The association between circulating cytokines and allograft injury due to allograft rejection (AR) remains poorly defined. We hypothesize that cytokines correlate with the degree of allograft injury during AR. This case-control study measured cytokines and cell-free DNA in 88 heart transplant plasma samples (54 AR, 34 non-rejecting (NR) controls) and 26 healthy controls. AR patients exhibited higher levels of total and percent donor-derived cfDNA (%dd-cfDNA) and proinflammatory cytokines, and lower levels of type II cytokines/chemokines and Th17/23 axis cytokines compared to NR or HCs. The cfDNA levels positively correlated with proinflammatory cytokines and negatively with MDC and cytokines of the Th17/IL-23 axis. A Lasso regression model combining cytokines and %dd-cfDNA (AUC = 0.93) showed better AR diagnostic performance than either cytokines or %dd-cfDNA alone. The study concluded that inflammatory and regulatory cytokine levels correlate with allograft injury, and combining cytokines with %dd-cfDNA may enhance AR detection.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110659"},"PeriodicalIF":3.8,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145817674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.clim.2025.110658
Shanmuganathan Chandrakasan , Adrianna Westbrook , Linda M. Griffith , David Hagin , Sumathi Iyengar , Christina Mangurian , Chris Scalchunes , Kathleen E. Sullivan , Akiva Zablocki , Nitya Bakshi , Cynthia Sinha , Lauri M. Burroughs , Alice Y. Chan , Christopher C. Dvorak , Elie Haddad , Jennifer Heimall , Donald B. Kohn , Jennifer W. Leiding , Luigi D. Notarangelo , Sung-Yun Pai , Suhag Parikh
Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with microthrombocytopenia, eczema, immunodeficiency, autoimmunity and malignancies resulting from WAS pathogenic variants. Prevalence of disease in heterozygous female carriers has not been described previously.
An online Qualtrics survey was designed in collaboration with the Wiskott-Aldrich Foundation, the Immune Deficiency Foundation, the Primary Immune Deficiency Treatment Consortium and Emory University to describe the incidence of thrombocytopenia, eczema, infections, autoimmune disorders, malignancies, and psychosocial factors.
193 carriers with a median age of 39 years participated in this survey. Respondents were predominantly White and were mothers of WAS patients. We observed a high prevalence of thrombocytopenia (13 %), eczema (22 %), infections (33 %) and autoimmunity (24 %) in this self-reported survey. No hematological malignancies were reported. Guilt (91 %), anxiety (41 %) and depression (44 %) were very prevalent.
Comprehensive clinical and immunologic studies of WAS carriers should be prioritized to define appropriate health screening, preventive approaches, and counselling for carriers.
Summary
This self-reported survey describes the disease burden in 193 carriers of X-linked Wiskott-Aldrich syndrome. It highlights the increased incidence of thrombocytopenia, eczema, infections and autoimmunity in WAS carriers and the need for more comprehensive studies of WAS carriers.
{"title":"Clinical spectrum of Wiskott-Aldrich syndrome carriers: Self-reported survey of 193 carriers","authors":"Shanmuganathan Chandrakasan , Adrianna Westbrook , Linda M. Griffith , David Hagin , Sumathi Iyengar , Christina Mangurian , Chris Scalchunes , Kathleen E. Sullivan , Akiva Zablocki , Nitya Bakshi , Cynthia Sinha , Lauri M. Burroughs , Alice Y. Chan , Christopher C. Dvorak , Elie Haddad , Jennifer Heimall , Donald B. Kohn , Jennifer W. Leiding , Luigi D. Notarangelo , Sung-Yun Pai , Suhag Parikh","doi":"10.1016/j.clim.2025.110658","DOIUrl":"10.1016/j.clim.2025.110658","url":null,"abstract":"<div><div>Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with microthrombocytopenia, eczema, immunodeficiency, autoimmunity and malignancies resulting from WAS pathogenic variants. Prevalence of disease in heterozygous female carriers has not been described previously.</div><div>An online Qualtrics survey was designed in collaboration with the Wiskott-Aldrich Foundation, the Immune Deficiency Foundation, the Primary Immune Deficiency Treatment Consortium and Emory University to describe the incidence of thrombocytopenia, eczema, infections, autoimmune disorders, malignancies, and psychosocial factors.</div><div>193 carriers with a median age of 39 years participated in this survey. Respondents were predominantly White and were mothers of WAS patients. We observed a high prevalence of thrombocytopenia (13 %), eczema (22 %), infections (33 %) and autoimmunity (24 %) in this self-reported survey. No hematological malignancies were reported. Guilt (91 %), anxiety (41 %) and depression (44 %) were very prevalent.</div><div>Comprehensive clinical and immunologic studies of WAS carriers should be prioritized to define appropriate health screening, preventive approaches, and counselling for carriers.</div></div><div><h3>Summary</h3><div>This self-reported survey describes the disease burden in 193 carriers of X-linked Wiskott-Aldrich syndrome. It highlights the increased incidence of thrombocytopenia, eczema, infections and autoimmunity in WAS carriers and the need for more comprehensive studies of WAS carriers.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110658"},"PeriodicalIF":3.8,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1016/j.clim.2025.110657
Hui Wu , Xianglin Chu , Huahua Zhong , Ying Huang , Hongxia Yang , Guoyan Qi , Lei Jin , Ran Chen , Wenji Jia , Ji Xiong , Liewen Pang , Chongbo Zhao , Jie Song , Sushan Luo
The efficacy of eculizumab as a perioperative treatment in patients with thymoma-associated myasthenia gravis (TAMG) has not been evaluated. This prospective study included patients with TAMG who received standard-of-care therapy (Soc group, n = 20) or combined with eculizumab (Ecu group, n = 13). At 1 week, the Ecu group showed a marked improvement compared to the Soc group, as evidenced by a reduction in Quantitative Myasthenia Gravis (QMG) (7.39 ± 3.47 vs 0.25 ± 5.13, P= 0.0001), Manual Muscle Test (MMT) (6.39 ± 4.66 vs 0.15 ± 3.96, P = 0.0003), and MG Activities of Daily Living (MG-ADL) (4.85 ± 3.16 vs 0.30 ± 3.47, P = 0.0006). No significant differences were observed in operative time, or intraoperative blood loss. The rate of postoperative myasthenic crisis was 9.1 % (1/13) in the Ecu group, compared to 20 % (4/20) in the Soc group (P = 0.33). This study highlights the role of eculizumab in TAMG as a rapid symptom-control treatment before thymomectomy.
{"title":"Eculizumab as a new option for perioperative treatment in thymoma-associated myasthenia gravis","authors":"Hui Wu , Xianglin Chu , Huahua Zhong , Ying Huang , Hongxia Yang , Guoyan Qi , Lei Jin , Ran Chen , Wenji Jia , Ji Xiong , Liewen Pang , Chongbo Zhao , Jie Song , Sushan Luo","doi":"10.1016/j.clim.2025.110657","DOIUrl":"10.1016/j.clim.2025.110657","url":null,"abstract":"<div><div>The efficacy of eculizumab as a perioperative treatment in patients with thymoma-associated myasthenia gravis (TAMG) has not been evaluated. This prospective study included patients with TAMG who received standard-of-care therapy (Soc group, <em>n</em> = 20) or combined with eculizumab (Ecu group, <em>n</em> = 13). At 1 week, the Ecu group showed a marked improvement compared to the Soc group, as evidenced by a reduction in Quantitative Myasthenia Gravis (QMG) (7.39 ± 3.47 vs 0.25 ± 5.13, <em>P</em> <em>=</em> 0.0001), Manual Muscle Test (MMT) (6.39 ± 4.66 vs 0.15 ± 3.96, <em>P</em> = 0.0003), and MG Activities of Daily Living (MG-ADL) (4.85 ± 3.16 vs 0.30 ± 3.47, <em>P</em> = 0.0006). No significant differences were observed in operative time, or intraoperative blood loss. The rate of postoperative myasthenic crisis was 9.1 % (1/13) in the Ecu group, compared to 20 % (4/20) in the Soc group (<em>P</em> = 0.33). This study highlights the role of eculizumab in TAMG as a rapid symptom-control treatment before thymomectomy.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110657"},"PeriodicalIF":3.8,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.clim.2025.110656
Chrysanthi Sidiropoulou , Garyphallia Poulakou , Evdoxia Kyriazopoulou , Elisavet Tasouli , Efthymia Giannitsioti , Anna Strikou , Maria Tsilika , Eirini Christaki , Vassiliki Rapti , Vassiliki Evangelopoulou , Nikoletta Rovina , Nathalie Iannotti , Emanuele Nicastri , Eleonora Taddei , Helena Florou , Andrea Angheben , Matteo Bassetti , Lorenzo Dagna , Antonio Torres , Spyros Foutadakis , Evangelos J. Giamarellos-Bourboulis
Post-Acute COVID-19 syndrome (PACS) is heterogeneous in phenotype and functional state. This prospective, observational study studied adults six months after acute COVID-19. We defined clinical phenotypes and profiled plasma mediators grouped into functional pathways (IL-1, IL-17, IFNγ/IFNγ-related cytokines, pro−/anti-inflammatory clusters). A subset underwent RNA-seq and ChIP-seq experiments. Three cohorts were analyzed (Exploratory n = 46; Discovery n = 591; Validation Cohort n = 289). PACS compatible symptoms were identified in 69.6 %; 59.2 % and 54.7 % respectively. Five phenotypes emerged. IL-1 cytokines (OR: 3.17, 95 % CIs: 1.94–5.19, p: 4.5 × 10−6), IL-17 cytokines (OR: 2.45, 95 % CIs: 1.47–4.07 p: 5.88 × 10−4) and the anti-inflammatory biomarkers (OR: 2.15, 95 % CIs: 1.34–3.45, p: 1.5 × 10−3) were upregulated in PACS patients. Respiratory phenotype was correlated with IL-1 upregulation (OR 4.23; 95 % CIs, 1.69–10.8, p = 0.0025). Transcriptomic and epigenomic changes were observed. Distinct phenotypes of PACS are driven by different immunological mechanisms at the DNA, transcriptomic, and protein levels.
Pub Date : 2025-12-11DOI: 10.1016/j.clim.2025.110655
Qianwen Tian , Qi Xi , Qiaolin Zhang , Yun Chen , Yunxin Zhang , Fuxue Kuang , Lejie Sun , Song Peng , Huaxun Wu
Primary Sjögren disease (pSS) is an autoimmune disease characterized primarily by predominant lymphocytic infiltration of the exocrine glands. While the etiopathogenesis of pSS remains unclear, current therapeutic strategies lack efficacy. In human submandibular gland epithelial cells (HSGECs), endoplasmic reticulum stress (ERS) induces apoptosis, leading to the cellular redistribution of Ro52/SSA autoantigens, the activation of the immune system, and the production of a large number of autoantibodies. Cells initiate autophagy to resist cellular damage caused by ERS and restore the normal physiological status. The ERK1/2-mTOR-autophagy signaling pathway has been implicated in numerous pathological conditions. In this study, an experimental Sjögren disease (ESS) mouse model was established to evaluate reduced protein levels and altered intracellular distribution of Ro52/SSA autoantigens through modulation of ERS and the ERK1/2-mTOR-autophagy pathway, resulting in diminished autoantibody production and ameliorated ESS symptoms. These findings provide an experimental foundation for therapeutic strategies targeting Ro52/SSA production in pSS.
{"title":"Regulation of Ro52/SSA autoantigen by endoplasmic reticulum stress and ERK1/2-mTOR-autophagy signaling pathway in primary Sjögren disease","authors":"Qianwen Tian , Qi Xi , Qiaolin Zhang , Yun Chen , Yunxin Zhang , Fuxue Kuang , Lejie Sun , Song Peng , Huaxun Wu","doi":"10.1016/j.clim.2025.110655","DOIUrl":"10.1016/j.clim.2025.110655","url":null,"abstract":"<div><div>Primary Sjögren disease (pSS) is an autoimmune disease characterized primarily by predominant lymphocytic infiltration of the exocrine glands. While the etiopathogenesis of pSS remains unclear, current therapeutic strategies lack efficacy. In human submandibular gland epithelial cells (HSGECs), endoplasmic reticulum stress (ERS) induces apoptosis, leading to the cellular redistribution of Ro52/SSA autoantigens, the activation of the immune system, and the production of a large number of autoantibodies. Cells initiate autophagy to resist cellular damage caused by ERS and restore the normal physiological status. The ERK1/2-mTOR-autophagy signaling pathway has been implicated in numerous pathological conditions. In this study, an experimental Sjögren disease (ESS) mouse model was established to evaluate reduced protein levels and altered intracellular distribution of Ro52/SSA autoantigens through modulation of ERS and the ERK1/2-mTOR-autophagy pathway, resulting in diminished autoantibody production and ameliorated ESS symptoms. These findings provide an experimental foundation for therapeutic strategies targeting Ro52/SSA production in pSS.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110655"},"PeriodicalIF":3.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The type I IFN response plays an important role in the immune defence against invading pathogens and in certain autoinflammatory diseases. In this study, a flow cytometry-based assay to measure ISG15 production in response to stimulation with various TLR ligands and IFNα was developed. PBMCs of healthy controls or patients were stimulated with TLR7/8, TLR3 and TLR9 ligands and IFNα2 whereafter ISG15 expression was measured. The ability of the assay to analyse TLR-dependent type I IFN induction and type I IFN-dependent JAK/STAT activation was verified by inhibition of ISG15 induction by a TBK1/IKKε inhibitor and a JAK1 inhibitor, respectively. TLR7/8 ligand- and TLR9 ligand-induced ISG15 production but not IFNα2-induced ISG15 production was abolished in a patient with AR IRF7 deficiency. IFNα2-induced ISG15 expression was abolished by serum containing neutralizing anti-IFNα2 autoantibodies. The flow cytometry-based ISG15 induction assay can be applied to screen for defects in the type I IFN response.
{"title":"Development and validation of a flow cytometry-based ISG15 induction assay to monitor the type I interferon response","authors":"Birthe Michiels , Rudi Beyaert , Jens Staal , Doreen Dillaerts , Maaike Cockx , Glynis Frans , Birgit Timmermans , Natalie Lorent , Isabelle Meyts , Xavier Bossuyt","doi":"10.1016/j.clim.2025.110654","DOIUrl":"10.1016/j.clim.2025.110654","url":null,"abstract":"<div><div>The type I IFN response plays an important role in the immune defence against invading pathogens and in certain autoinflammatory diseases. In this study, a flow cytometry-based assay to measure ISG15 production in response to stimulation with various TLR ligands and IFNα was developed. PBMCs of healthy controls or patients were stimulated with TLR7/8, TLR3 and TLR9 ligands and IFNα2 whereafter ISG15 expression was measured. The ability of the assay to analyse TLR-dependent type I IFN induction and type I IFN-dependent JAK/STAT activation was verified by inhibition of ISG15 induction by a TBK1/IKKε inhibitor and a JAK1 inhibitor, respectively. TLR7/8 ligand- and TLR9 ligand-induced ISG15 production but not IFNα2-induced ISG15 production was abolished in a patient with AR IRF7 deficiency. IFNα2-induced ISG15 expression was abolished by serum containing neutralizing anti-IFNα2 autoantibodies. The flow cytometry-based ISG15 induction assay can be applied to screen for defects in the type I IFN response.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110654"},"PeriodicalIF":3.8,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-29DOI: 10.1016/j.clim.2025.110653
Fatima Hubaishi , Rami Karkout , Lydia Labrie , Raidan Mohammed Alyazidi , Magan Solomon , Haya Aldossary , Brian J. Ward , Elizabeth D. Fixman
Atopic dermatitis (AD) in infants is associated with increased risk of developing other allergic diseases, including asthma. This progression is known as atopic march (AM). We established a murine AM model by first inducing AD-like skin inflammation to house dust mite (HDM) allergen. Mice were subsequently challenged with HDM delivered to the lung. Our data show that epicutaneous sensitization with HDM increased serum IgE, ear thickness, and immune cell infiltration into the skin, accompanied by an increase in CD4+ tissue-resident memory T cells (Trm) in the lung. Following pulmonary HDM challenge, eosinophil influx and T2 inflammation were increased in the lung. Together, our data suggest communication between the skin and lung, where allergen sensitization on the skin increases lung Trm and amplifies the T2 allergic response to lung allergen challenge. This clinically relevant model could help identify novel targets for local interventions to reduce the progression of AD to asthma.
{"title":"Epicutaneous application of house dust mite induces allergic skin inflammation and atopic march to the lung upon airway allergen challenge","authors":"Fatima Hubaishi , Rami Karkout , Lydia Labrie , Raidan Mohammed Alyazidi , Magan Solomon , Haya Aldossary , Brian J. Ward , Elizabeth D. Fixman","doi":"10.1016/j.clim.2025.110653","DOIUrl":"10.1016/j.clim.2025.110653","url":null,"abstract":"<div><div>Atopic dermatitis (AD) in infants is associated with increased risk of developing other allergic diseases, including asthma. This progression is known as atopic march (AM). We established a murine AM model by first inducing AD-like skin inflammation to house dust mite (HDM) allergen. Mice were subsequently challenged with HDM delivered to the lung. Our data show that epicutaneous sensitization with HDM increased serum IgE, ear thickness, and immune cell infiltration into the skin, accompanied by an increase in CD4<sup>+</sup> tissue-resident memory T cells (Trm) in the lung. Following pulmonary HDM challenge, eosinophil influx and T2 inflammation were increased in the lung. Together, our data suggest communication between the skin and lung, where allergen sensitization on the skin increases lung Trm and amplifies the T2 allergic response to lung allergen challenge. This clinically relevant model could help identify novel targets for local interventions to reduce the progression of AD to asthma.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110653"},"PeriodicalIF":3.8,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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