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}
Pub Date : 2025-11-25DOI: 10.1016/j.clim.2025.110646
Pengbo Yang , Huhe Bao , Guanwen Sun , Yaxing Zhang
Background
Type 1 diabetes (T1DM) is characterized by autoimmune destruction of pancreatic β-cells and systemic immune dysregulation, yet the cellular networks driving disease progression and their potential link to diabetic complications remain unclear.
Methods
We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from 46 stage 3 T1DM patients and 31 matched controls, integrating transcriptomic, cellular interaction, and functional enrichment analyses.
Results
Unsupervised clustering of 87,542 cells revealed profound immune dysregulation in T1DM, including cytotoxic CD8+ T cell expansion (70 % increase) and Treg depletion (>50 % reduction). CD8+ T cells exhibited hyperactivation of cytotoxic effectors (GNLY, GZMB) and inflammatory mediators (IL32, S100A4), alongside suppressed regulatory genes (FOXP3, IL2RA). Cell-cell communication analysis identified amplified GALECTIN-CD44 signaling between monocytes/DCs and CD8+ T/NK cells, driving proinflammatory crosstalk. Strikingly, a novel exhausted CD4+ subset (PDCD1+, LAG3+) emerged exclusively in T1DM.
Conclusion
Our findings establish CD8+ T cells as central orchestrators of T1DM pathogenesis through synergistic cytotoxic hyperactivity and regulatory collapse. The identified GALECTIN-CD44 axis and JAK-STAT/TGF-β imbalances may extend beyond pancreatic autoimmunity, providing mechanistic insights into systemic complications (e.g., impaired wound healing and chronic inflammation) observed in diabetic patients. These dysregulated networks offer novel therapeutic targets for restoring immune homeostasis in T1DM and its associated comorbidities.
{"title":"Single-cell dissection of CD8+ T cell-driven immune dysregulation in type 1 diabetes mellitus: Mechanistic links to diabetic foot pathogenesis","authors":"Pengbo Yang , Huhe Bao , Guanwen Sun , Yaxing Zhang","doi":"10.1016/j.clim.2025.110646","DOIUrl":"10.1016/j.clim.2025.110646","url":null,"abstract":"<div><h3>Background</h3><div>Type 1 diabetes (T1DM) is characterized by autoimmune destruction of pancreatic β-cells and systemic immune dysregulation, yet the cellular networks driving disease progression and their potential link to diabetic complications remain unclear.</div></div><div><h3>Methods</h3><div>We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from 46 stage 3 T1DM patients and 31 matched controls, integrating transcriptomic, cellular interaction, and functional enrichment analyses.</div></div><div><h3>Results</h3><div>Unsupervised clustering of 87,542 cells revealed profound immune dysregulation in T1DM, including cytotoxic CD8+ T cell expansion (70 % increase) and Treg depletion (>50 % reduction). CD8+ T cells exhibited hyperactivation of cytotoxic effectors (GNLY, GZMB) and inflammatory mediators (IL32, S100A4), alongside suppressed regulatory genes (FOXP3, IL2RA). Cell-cell communication analysis identified amplified GALECTIN-CD44 signaling between monocytes/DCs and CD8+ T/NK cells, driving proinflammatory crosstalk. Strikingly, a novel exhausted CD4+ subset (PDCD1+, LAG3+) emerged exclusively in T1DM.</div></div><div><h3>Conclusion</h3><div>Our findings establish CD8+ T cells as central orchestrators of T1DM pathogenesis through synergistic cytotoxic hyperactivity and regulatory collapse. The identified GALECTIN-CD44 axis and JAK-STAT/TGF-β imbalances may extend beyond pancreatic autoimmunity, providing mechanistic insights into systemic complications (e.g., impaired wound healing and chronic inflammation) observed in diabetic patients. These dysregulated networks offer novel therapeutic targets for restoring immune homeostasis in T1DM and its associated comorbidities.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110646"},"PeriodicalIF":3.8,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623447","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}
{"title":"Remaining molecular scarring in the skin of patients with psoriasis: What are the reversal factors?","authors":"Parvaneh Hatami , Hamed Nicknam Asl , Zeinab Aryanian , Azadeh Khayyat , Mona Homayouni , Arash Mostaghimi","doi":"10.1016/j.clim.2025.110645","DOIUrl":"10.1016/j.clim.2025.110645","url":null,"abstract":"","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110645"},"PeriodicalIF":3.8,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623444","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}
Human endogenous retrovirus W (HERV-W) has been linked to multiple sclerosis (MS), yet its pathogenic role remains unclear. Epstein–Barr virus (EBV), a key MS risk factor, can transactivate HERVs, suggesting a potential interplay. We analyzed immune responses to a HERV-W₁₀₃–₁₁₀ peptide homologous to EBV EBNA1₃₈₆–₄₀₅ in sera from Japanese MS patients (n = 44), neurological controls (n = 28), and healthy controls (n = 48), including an unrelated control antigen (BCG) to assess general humoral activation. MS patients exhibited elevated antibodies to both peptides, indicating cross-reactive immunity. In C57BL/6 J mice, pre-immunization with either peptide modestly modulated experimental autoimmune encephalomyelitis (EAE), whereas combined pre-immunization exacerbated disease, expanding CD4+ and CD8+ T cells and promoting systemic activation. These results support a model in which EBV-driven HERV-W activation elicits cross-reactive humoral and cellular responses that amplify neuroinflammation in MS.
{"title":"Cross-reactive HERV-W and EBV peptides elicit antibody responses in MS patients and synergistically exacerbate neuroinflammation in EAE","authors":"Davide Cossu , Yuji Tomizawa , Tamami Sakanishi , Stefano Ruberto , Taku Hatano , Nobutaka Hattori","doi":"10.1016/j.clim.2025.110644","DOIUrl":"10.1016/j.clim.2025.110644","url":null,"abstract":"<div><div><em>Human endogenous retrovirus W</em> (HERV-W) has been linked to multiple sclerosis (MS), yet its pathogenic role remains unclear. <em>Epstein–Barr virus</em> (EBV), a key MS risk factor, can transactivate HERVs, suggesting a potential interplay. We analyzed immune responses to a HERV-W₁₀₃–₁₁₀ peptide homologous to EBV EBNA1₃₈₆–₄₀₅ in sera from Japanese MS patients (<em>n</em> = 44), neurological controls (<em>n</em> = 28), and healthy controls (<em>n</em> = 48), including an unrelated control antigen (BCG) to assess general humoral activation. MS patients exhibited elevated antibodies to both peptides, indicating cross-reactive immunity. In C57BL/6 J mice, pre-immunization with either peptide modestly modulated experimental autoimmune encephalomyelitis (EAE), whereas combined pre-immunization exacerbated disease, expanding CD4<sup>+</sup> and CD8<sup>+</sup> T cells and promoting systemic activation. These results support a model in which EBV-driven HERV-W activation elicits cross-reactive humoral and cellular responses that amplify neuroinflammation in MS.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110644"},"PeriodicalIF":3.8,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594800","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 : 2025-11-22DOI: 10.1016/j.clim.2025.110643
Ahmed Salem Al-Dhahi , Hayder M. Al-kuraishy , Nawar R. Hussain , Mohamed N. Fawzy , Mubarak Alruwaili , Huda J. Waheed , Ali I. Al-Gareeb , Ali K. Albuhadily , Gaber El-Saber Batiha
Multiple sclerosis (MS) is a chronic neuroinflammatory and demyelinating disease of the central nervous system (CNS). The cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) axis plays a complex, dual role in its pathogenesis. Although its upregulation typically induces neuroinflammation, oligodendrocyte apoptosis, and demyelination, certain PGE2 receptors (EP2/EP4) can also mediate protective effects. In experimental models, inhibiting COX-2 (using celecoxib or meloxicam) or blocking pro-inflammatory receptors (EP1/EP3) alleviates disease pathology by reducing immune cell infiltration and cytokine production and protecting oligodendrocytes via both COX-2-dependent and independent mechanisms. This review discusses the potential of selectively targeting the detrimental effects of the COX-2/PGE2 axis (such as EP1/EP3 signaling) while preserving protective pathways as a sophisticated therapeutic strategy for MS. However, cardiovascular risks limit the clinical translation of COX-2 inhibitors, necessitating the development of safer, more precise modulation of this pathway.
{"title":"The dual role of the COX-2/PGE2 Axis in multiple sclerosis: From pathogenesis to pharmacological inhibition","authors":"Ahmed Salem Al-Dhahi , Hayder M. Al-kuraishy , Nawar R. Hussain , Mohamed N. Fawzy , Mubarak Alruwaili , Huda J. Waheed , Ali I. Al-Gareeb , Ali K. Albuhadily , Gaber El-Saber Batiha","doi":"10.1016/j.clim.2025.110643","DOIUrl":"10.1016/j.clim.2025.110643","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is a chronic neuroinflammatory and demyelinating disease of the central nervous system (CNS). The cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) axis plays a complex, dual role in its pathogenesis. Although its upregulation typically induces neuroinflammation, oligodendrocyte apoptosis, and demyelination, certain PGE2 receptors (EP2/EP4) can also mediate protective effects. In experimental models, inhibiting COX-2 (using celecoxib or meloxicam) or blocking pro-inflammatory receptors (EP1/EP3) alleviates disease pathology by reducing immune cell infiltration and cytokine production and protecting oligodendrocytes via both COX-2-dependent and independent mechanisms. This review discusses the potential of selectively targeting the detrimental effects of the COX-2/PGE2 axis (such as EP1/EP3 signaling) while preserving protective pathways as a sophisticated therapeutic strategy for MS. However, cardiovascular risks limit the clinical translation of COX-2 inhibitors, necessitating the development of safer, more precise modulation of this pathway.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"283 ","pages":"Article 110643"},"PeriodicalIF":3.8,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594799","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 : 2025-11-19DOI: 10.1016/j.clim.2025.110642
Josephine Diony Nanda , Tzong-Shiann Ho , Rahmat Dani Satria , Yung-Ting Wang , Chun-Hao Lai , Ya-Lan Lin , Chiou-Feng Lin
Serum cytokines and chemokines play a pivotal role in dengue immunopathogenesis and may serve as biomarkers of disease severity. This study aimed to identify applicable blood biomarkers during the acute stage of infection to support early severity evaluation using Principal Component Analysis (PCA)–based feature integration. Ninety-two dengue patients were consecutively enrolled from hospital admissions with laboratory-confirmed dengue during the 2015–2017 epidemic. Only those with NS1-positive or PCR-positive cases were included in this study, spanning asymptomatic, symptomatic, and severe cases, which were assessed for hematological, viral, and cytokine/chemokine parameters. Key variables—platelet count, GPT, creatinine, NS1, NST, IL-18, RANTES, IL-6, IFN-α2, and IL-7—were incorporated into a Prediction Panel. Validation showed that several biomarker combinations achieved up to 90 % accuracy in distinguishing severity groups, while others reached ∼70 %. Principal component analysis further refined the panel, showing accuracy above 90 % when NS1 or NST were included (A–B: 92.1 %, A–C: up to 91.8 %). These findings highlight the potential of an integrated biomarker-based Prediction Panel for early and reliable assessment of dengue severity within the first week of illness.
{"title":"An integrated biomarker panel for early computational prediction of dengue severity during the acute phase","authors":"Josephine Diony Nanda , Tzong-Shiann Ho , Rahmat Dani Satria , Yung-Ting Wang , Chun-Hao Lai , Ya-Lan Lin , Chiou-Feng Lin","doi":"10.1016/j.clim.2025.110642","DOIUrl":"10.1016/j.clim.2025.110642","url":null,"abstract":"<div><div>Serum cytokines and chemokines play a pivotal role in dengue immunopathogenesis and may serve as biomarkers of disease severity. This study aimed to identify applicable blood biomarkers during the acute stage of infection to support early severity evaluation using Principal Component Analysis (PCA)–based feature integration. Ninety-two dengue patients were consecutively enrolled from hospital admissions with laboratory-confirmed dengue during the 2015–2017 epidemic. Only those with NS1-positive or PCR-positive cases were included in this study, spanning asymptomatic, symptomatic, and severe cases, which were assessed for hematological, viral, and cytokine/chemokine parameters. Key variables—platelet count, GPT, creatinine, NS1, NST, IL-18, RANTES, IL-6, IFN-α2, and IL-7—were incorporated into a Prediction Panel. Validation showed that several biomarker combinations achieved up to 90 % accuracy in distinguishing severity groups, while others reached ∼70 %. Principal component analysis further refined the panel, showing accuracy above 90 % when NS1 or NST were included (A–B: 92.1 %, A–C: up to 91.8 %). These findings highlight the potential of an integrated biomarker-based Prediction Panel for early and reliable assessment of dengue severity within the first week of illness.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"282 ","pages":"Article 110642"},"PeriodicalIF":3.8,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562981","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 : 2025-11-17DOI: 10.1016/j.clim.2025.110641
Qian Huang , Xue-Qian Cai , Zhi-Qiang Li , Yan Liu , Hai-Feng Pan
Objective
Mitochondrial dysfunction is closely related to the pathogenesis of various autoimmune diseases, and mitochondrial DNA (mtDNA) gene variations are associated with the susceptibility to autoimmune diseases. This study aimed to investigate association between mtDNA genetic variants, methylation levels and rheumatoid arthritis (RA).
Method
We performed mtDNA whole genome sequencing in 32 RA patients and 32 controls, and then validated 8 mtDNA variants using the SNaPshot™ multiplex technique in 452 RA patients and 457 controls. The methylation levels of 4 mtDNA genes were measured in 108 RA patients and 107 controls by MethylTarget technique.
Results
We found that ND5 gene m.12705 T genotype, tRNA-Pro gene m.16304C genotype, tRNA-Pro gene m.16319 A genotype were significantly associated with RA susceptibility in entire population and female population. Moreover, the increased frequency of m.12705 T and the decreased frequency of m.16304C were significantly related to anti-CCP positive in RA patients. While tRNA-Pro gene m.16092 T > C, m.16189 T > C, RNR2 gene m.2706 T > G, ND2 gene m.4833 A > G, m.5108 T > C showed no association with the risk of RA. When compared to controls, the methylation levels of ND5, RNR2, ND2 genes were significantly decreased in RA patients. In addition, ND5, RNR2 methylation levels were linked to erythrocyte sedimentation rate, and m.12705C > T variant significantly influenced ND5 methylation level among RA patients.
Conclusion
Multiple mtDNA variants in ND5, tRNA-Pro genes and methylation levels of ND5, RNR2, ND2 genes were significantly associated with genetic susceptibility to RA in Chinese population.
目的：线粒体功能障碍与多种自身免疫性疾病的发病密切相关，线粒体DNA （mtDNA）基因变异与自身免疫性疾病的易感性相关。本研究旨在探讨mtDNA遗传变异、甲基化水平与类风湿关节炎（RA）之间的关系。方法：我们对32名RA患者和32名对照者进行mtDNA全基因组测序，然后在452名RA患者和457名对照者中使用SNaPshot™多重技术验证8个mtDNA变异。采用MethylTarget技术检测了108例RA患者和107例对照者4个mtDNA基因的甲基化水平。结果：发现ND5基因m.12705 T基因型、tRNA-Pro基因m.16304C基因型、tRNA-Pro基因m.16319一个基因型与整个人群和女性人群RA易感性显著相关。此外，RA患者抗ccp阳性与m.12705 T频率升高和m.16304C频率降低有显著关系。虽然tRNA-Pro基因m.16092 T > C, m.16189 T > C, RNR2基因m.2706 T > G,阐述基因m.4833 一 > G, m.5108 T > C没有显示出与患风湿性关节炎的风险。与对照组相比，RA患者ND5、RNR2、ND2基因的甲基化水平显著降低。此外，ND5、RNR2甲基化水平与红细胞沉降率相关，m.12705C > T变异显著影响RA患者ND5甲基化水平。结论：ND5、tRNA-Pro基因mtDNA多变异及ND5、RNR2、ND2基因甲基化水平与中国人群RA遗传易感性显著相关。
{"title":"Association of peripheral blood mitochondrial DNA gene variation and methylation levels with rheumatoid arthritis","authors":"Qian Huang , Xue-Qian Cai , Zhi-Qiang Li , Yan Liu , Hai-Feng Pan","doi":"10.1016/j.clim.2025.110641","DOIUrl":"10.1016/j.clim.2025.110641","url":null,"abstract":"<div><h3>Objective</h3><div>Mitochondrial dysfunction is closely related to the pathogenesis of various autoimmune diseases, and mitochondrial DNA (mtDNA) gene variations are associated with the susceptibility to autoimmune diseases. This study aimed to investigate association between mtDNA genetic variants, methylation levels and rheumatoid arthritis (RA).</div></div><div><h3>Method</h3><div>We performed mtDNA whole genome sequencing in 32 RA patients and 32 controls, and then validated 8 mtDNA variants using the SNaPshot™ multiplex technique in 452 RA patients and 457 controls. The methylation levels of 4 mtDNA genes were measured in 108 RA patients and 107 controls by MethylTarget technique.</div></div><div><h3>Results</h3><div>We found that <em>ND5</em> gene m.12705 T genotype, <em>tRNA-Pro</em> gene m.16304C genotype, <em>tRNA-Pro</em> gene m.16319 A genotype were significantly associated with RA susceptibility in entire population and female population. Moreover, the increased frequency of m.12705 T and the decreased frequency of m.16304C were significantly related to anti-CCP positive in RA patients. While <em>tRNA-Pro</em> gene m.16092 T > C, m.16189 T > C, <em>RNR2</em> gene m.2706 T > G, <em>ND2</em> gene m.4833 A > G, m.5108 T > C showed no association with the risk of RA. When compared to controls, the methylation levels of <em>ND5, RNR2, ND2</em> genes were significantly decreased in RA patients. In addition, <em>ND5, RNR2</em> methylation levels were linked to erythrocyte sedimentation rate, and m.12705C > T variant significantly influenced <em>ND5</em> methylation level among RA patients.</div></div><div><h3>Conclusion</h3><div>Multiple mtDNA variants in <em>ND5</em>, <em>tRNA-Pro</em> genes and methylation levels of <em>ND5, RNR2, ND2</em> genes were significantly associated with genetic susceptibility to RA in Chinese population.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"282 ","pages":"Article 110641"},"PeriodicalIF":3.8,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556372","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 : 2025-11-14DOI: 10.1016/j.clim.2025.110639
Aidé Tamara Staines-Boone , Edna Venegas-Montoya , Jorge Alberto García Campos , Jennifer Alejandra Obregón García , Julieta C. Marmolejo Bjirsdorp , Yuridia Salazar Gálvez , Mario Ernesto Cruz-Muñoz , Lizbeth Blancas Galicia , Edgar Alejandro Medina-Torres , Sara Elva Espinosa-Padilla , Diana Olguín Calderón , Laura Berrón-Ruiz , Saul O. Lugo Reyes
The Bacille Calmette-Guérin (BCG) vaccine is widely used to prevent tuberculosis (TB), especially in newborns and children in high TB prevalence areas. Though generally safe, it can cause adverse reactions like BCG-itis, a localized inflammatory response, and BCG-osis, a systemic infection. This case report details the clinical journey of a male toddler from a non-consanguineous family who presented with regional BCG-itis and later developed a disseminated mycobacterial infection. The patient had a history of recurrent suppurative otitis media and chronic granulomatous inflammation, with mycobacteria identified through biopsy. Despite initial treatments, he exhibited persistent and severe symptoms, including central nervous system abscesses, onychomycosis, and elevated serum Immunoglobulin E levels (13,160 IU/ml). Whole-exome sequencing identified a pathogenic heterozygous missense variant in STAT3 exon 13 (c.1144C > T, p.Arg382Trp), confirming autosomal dominant Hyper-IgE Syndrome. The patient showed improvement with antibiotics and intravenous immunoglobulin, yet struggled with relapses upon dose reduction of antitubercular drugs. The literature review revealed two similar cases, underscoring the importance of genetic and immunological insights in managing adverse vaccine reactions in Hyper-IgE Syndrome. CD4+ Th17 cells and interleukins 17, 21, 22, and 23 are crucial in fighting mycobacteria by activating autophagy in infected monocytes and MAIT cells. Type 2 interferon immunity and superoxide production are key in combating mycobacterial diseases like Mendelian Susceptibility to Mycobacterial Disease and Chronic Granulomatous Disease. Studies show that Asian and Latin American patients are overrepresented in non-tuberculous mycobacterial infections due to mandatory BCG vaccination at birth. It is recommended to contraindicate BCG vaccination in patients with known or suspected immune deficiencies and delay live vaccines until 6 months of age.
{"title":"Job's not done: BCG-itis as the first manifestation of hyper-IgE syndrome. A case report and review of the literature","authors":"Aidé Tamara Staines-Boone , Edna Venegas-Montoya , Jorge Alberto García Campos , Jennifer Alejandra Obregón García , Julieta C. Marmolejo Bjirsdorp , Yuridia Salazar Gálvez , Mario Ernesto Cruz-Muñoz , Lizbeth Blancas Galicia , Edgar Alejandro Medina-Torres , Sara Elva Espinosa-Padilla , Diana Olguín Calderón , Laura Berrón-Ruiz , Saul O. Lugo Reyes","doi":"10.1016/j.clim.2025.110639","DOIUrl":"10.1016/j.clim.2025.110639","url":null,"abstract":"<div><div>The <em>Bacille Calmette-Guérin</em> (BCG) vaccine is widely used to prevent tuberculosis (TB), especially in newborns and children in high TB prevalence areas. Though generally safe, it can cause adverse reactions like BCG-itis, a localized inflammatory response, and BCG-osis, a systemic infection. This case report details the clinical journey of a male toddler from a non-consanguineous family who presented with regional BCG-itis and later developed a disseminated mycobacterial infection. The patient had a history of recurrent suppurative otitis media and chronic granulomatous inflammation, with mycobacteria identified through biopsy. Despite initial treatments, he exhibited persistent and severe symptoms, including central nervous system abscesses, onychomycosis, and elevated serum Immunoglobulin E levels (13,160 IU/ml). Whole-exome sequencing identified a pathogenic heterozygous missense variant in <em>STAT3</em> exon 13 (c.1144C > T, p.Arg382Trp), confirming autosomal dominant Hyper-IgE Syndrome. The patient showed improvement with antibiotics and intravenous immunoglobulin, yet struggled with relapses upon dose reduction of antitubercular drugs. The literature review revealed two similar cases, underscoring the importance of genetic and immunological insights in managing adverse vaccine reactions in Hyper-IgE Syndrome. CD4+ Th17 cells and interleukins 17, 21, 22, and 23 are crucial in fighting mycobacteria by activating autophagy in infected monocytes and MAIT cells. Type 2 interferon immunity and superoxide production are key in combating mycobacterial diseases like Mendelian Susceptibility to Mycobacterial Disease and Chronic Granulomatous Disease. Studies show that Asian and Latin American patients are overrepresented in non-tuberculous mycobacterial infections due to mandatory BCG vaccination at birth. It is recommended to contraindicate BCG vaccination in patients with known or suspected immune deficiencies and delay live vaccines until 6 months of age.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"282 ","pages":"Article 110639"},"PeriodicalIF":3.8,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534394","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 : 2025-11-13DOI: 10.1016/j.clim.2025.110640
Ahmad Meshkin , Fateme Zare , Mohammad Erfan Abbasi , Maryam sadat Montazeri , Fatemeh Badiee , Mohammad Masoud Khodaei
Leukemia inhibitory factor (LIF) is a multifunctional cytokine of the IL-6 family, originally identified in murine leukemia cells. Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), primarily affecting the intestine, liver, and skin. Preclinical studies suggest that LIF may protect against GvHD by preserving intestinal stem cells, reducing radiation- and cytokine-induced tissue injury, decreasing donor T-cell infiltration, and suppressing inflammatory cytokine production; importantly, it appears to preserve graft-versus-leukemia (GVL) activity. This review summarizes current knowledge on the immunopathogenesis of acute GvHD (aGvHD) and examines the emerging but limited evidence on the immunomodulatory role of LIF. We propose a hypothesis-driven framework for its potential therapeutic application. We highlight the immunomodulatory properties of LIF, including its roles in suppressing proinflammatory responses and promoting regulatory mechanisms. LIF's ability to reduce GvHD severity without compromising GVL highlights its potential as a therapeutic agent. Given the limited but promising data, further research is warranted to evaluate LIF's clinical applicability and safety in transplant recipients.
{"title":"Leukemia inhibitory factor (LIF) in acute graft-versus-host disease: A hypothesis-generating review","authors":"Ahmad Meshkin , Fateme Zare , Mohammad Erfan Abbasi , Maryam sadat Montazeri , Fatemeh Badiee , Mohammad Masoud Khodaei","doi":"10.1016/j.clim.2025.110640","DOIUrl":"10.1016/j.clim.2025.110640","url":null,"abstract":"<div><div>Leukemia inhibitory factor (LIF) is a multifunctional cytokine of the IL-6 family, originally identified in murine leukemia cells. Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), primarily affecting the intestine, liver, and skin. Preclinical studies suggest that LIF may protect against GvHD by preserving intestinal stem cells, reducing radiation- and cytokine-induced tissue injury, decreasing donor T-cell infiltration, and suppressing inflammatory cytokine production; importantly, it appears to preserve graft-versus-leukemia (GVL) activity. This review summarizes current knowledge on the immunopathogenesis of acute GvHD (aGvHD) and examines the emerging but limited evidence on the immunomodulatory role of LIF. We propose a hypothesis-driven framework for its potential therapeutic application. We highlight the immunomodulatory properties of LIF, including its roles in suppressing proinflammatory responses and promoting regulatory mechanisms. LIF's ability to reduce GvHD severity without compromising GVL highlights its potential as a therapeutic agent. Given the limited but promising data, further research is warranted to evaluate LIF's clinical applicability and safety in transplant recipients.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"282 ","pages":"Article 110640"},"PeriodicalIF":3.8,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530317","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 : 2025-11-08DOI: 10.1016/j.clim.2025.110634
Yingjie Ren , Tao Wu , Zhaojun Liu , Lifang Li , Ying Li , Guanghao Xin , Shanshan Peng , Jingyan Niu , Biying Chen , Hanlu Cai , Qinghua Tian , Lihua Wang , Huixue Zhang
<div><h3>Background</h3><div>Myasthenia gravis (MG) is a T cell-mediated autoimmune disease characterized by abnormal immune responses, particularly the hyperactivation of CD4+ T cells, which may disrupt signal transmission at the neuromuscular junction. Inosine-5′-monophosphate dehydrogenase-2 (IMPDH2) has been reported to participate in immune activation and is likely associated with T cells, but its role in the pathogenesis of MG remains unclear. Therefore, the present study aimed to elucidate the mechanism through which IMPDH2 regulates CD4+ T cells in MG.</div></div><div><h3>Methods</h3><div>In this study, IMPDH2 expression was measured by qRT-PCR in peripheral blood mononuclear cells (PBMCs) collected from 60 MG patients and 60 healthy controls. Western blotting was additionally performed to detect IMPDH2 protein expression in six MG patients (three ocular and three generalized), compared with six healthy controls matched by age, gender, and sample collection time. CD4+ T cells were then isolated from PBMCs of MG patients and healthy controls by immunomagnetic bead sorting, and IMPDH2 expression was further analyzed by qRT-PCR. Subsequently, correlations between IMPDH2 expression levels and clinical indices (neutrophil and lymphocyte counts) as well as disease severity (Myasthenia Gravis Activities of Daily Living scores and Quantitative Myasthenia Gravis scores) were assessed. Additionally, flow cytometry, EdU assays, and CCK-8 assays were employed to evaluate the effects of IMPDH2 knockdown or overexpression on CD4+ T cell apoptosis and proliferation. The expression of apoptosis-related proteins was detected by western blotting. Mass spectrometry (MS), co-immunoprecipitation (Co-IP), and kinase inhibitor-based Co-IP validation assays were used to screen and verify proteins potentially interacting with IMPDH2 in CD4+ T cells. The colocalization of IMPDH2 and its binding proteins in CD4+ T cells was confirmed by confocal fluorescence microscopy and quantitative analysis. Furthermore, western blotting was performed to assess regulatory interactions between IMPDH2 and its binding proteins upon knockdown of either molecule. Western blotting was also used to detect protein levels within MG-related signaling pathways following IMPDH2 knockdown or overexpression.</div></div><div><h3>Results</h3><div>IMPDH2 expression was significantly elevated in PBMCs and CD4+ T cells from MG patients compared with healthy controls. Clinical data analysis demonstrated a positive correlation between IMPDH2 expression and both lymphocyte and neutrophil counts in MG patients. Additionally, IMPDH2 expression positively correlated with MG disease severity. Functionally, upregulation or downregulation of IMPDH2 correspondingly promoted or suppressed CD4+ T cell proliferation and apoptosis. Mechanistically, direct interactions between IMPDH2 and SRPK1 were confirmed in vitro, and IMPDH2 was found to regulate SRPK1 expression, subsequently affecting CD4+ T cell prolifer
{"title":"IMPDH2 facilitates CD4+ T cell activation through AKT/mTOR pathway by upregulating SRPK1 in myasthenia gravis","authors":"Yingjie Ren , Tao Wu , Zhaojun Liu , Lifang Li , Ying Li , Guanghao Xin , Shanshan Peng , Jingyan Niu , Biying Chen , Hanlu Cai , Qinghua Tian , Lihua Wang , Huixue Zhang","doi":"10.1016/j.clim.2025.110634","DOIUrl":"10.1016/j.clim.2025.110634","url":null,"abstract":"<div><h3>Background</h3><div>Myasthenia gravis (MG) is a T cell-mediated autoimmune disease characterized by abnormal immune responses, particularly the hyperactivation of CD4+ T cells, which may disrupt signal transmission at the neuromuscular junction. Inosine-5′-monophosphate dehydrogenase-2 (IMPDH2) has been reported to participate in immune activation and is likely associated with T cells, but its role in the pathogenesis of MG remains unclear. Therefore, the present study aimed to elucidate the mechanism through which IMPDH2 regulates CD4+ T cells in MG.</div></div><div><h3>Methods</h3><div>In this study, IMPDH2 expression was measured by qRT-PCR in peripheral blood mononuclear cells (PBMCs) collected from 60 MG patients and 60 healthy controls. Western blotting was additionally performed to detect IMPDH2 protein expression in six MG patients (three ocular and three generalized), compared with six healthy controls matched by age, gender, and sample collection time. CD4+ T cells were then isolated from PBMCs of MG patients and healthy controls by immunomagnetic bead sorting, and IMPDH2 expression was further analyzed by qRT-PCR. Subsequently, correlations between IMPDH2 expression levels and clinical indices (neutrophil and lymphocyte counts) as well as disease severity (Myasthenia Gravis Activities of Daily Living scores and Quantitative Myasthenia Gravis scores) were assessed. Additionally, flow cytometry, EdU assays, and CCK-8 assays were employed to evaluate the effects of IMPDH2 knockdown or overexpression on CD4+ T cell apoptosis and proliferation. The expression of apoptosis-related proteins was detected by western blotting. Mass spectrometry (MS), co-immunoprecipitation (Co-IP), and kinase inhibitor-based Co-IP validation assays were used to screen and verify proteins potentially interacting with IMPDH2 in CD4+ T cells. The colocalization of IMPDH2 and its binding proteins in CD4+ T cells was confirmed by confocal fluorescence microscopy and quantitative analysis. Furthermore, western blotting was performed to assess regulatory interactions between IMPDH2 and its binding proteins upon knockdown of either molecule. Western blotting was also used to detect protein levels within MG-related signaling pathways following IMPDH2 knockdown or overexpression.</div></div><div><h3>Results</h3><div>IMPDH2 expression was significantly elevated in PBMCs and CD4+ T cells from MG patients compared with healthy controls. Clinical data analysis demonstrated a positive correlation between IMPDH2 expression and both lymphocyte and neutrophil counts in MG patients. Additionally, IMPDH2 expression positively correlated with MG disease severity. Functionally, upregulation or downregulation of IMPDH2 correspondingly promoted or suppressed CD4+ T cell proliferation and apoptosis. Mechanistically, direct interactions between IMPDH2 and SRPK1 were confirmed in vitro, and IMPDH2 was found to regulate SRPK1 expression, subsequently affecting CD4+ T cell prolifer","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"282 ","pages":"Article 110634"},"PeriodicalIF":3.8,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145488124","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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