Pub Date : 2025-08-28DOI: 10.1016/j.clim.2025.110590
Sha-Sha Tao , Hai-Fen Wei , Shu-Zhen Xu , Xiao-Xiao Li , Yan-Yu Zhu , Jian Tang , Wen-Jie Li , Yu-Wan Chang , Zhu Chen , Hai-Feng Pan
Maternally expressed gene 3 (MEG3) is implicated in autoimmunity, but its role in rheumatoid arthritis (RA) is unclear. This study aimed to investigate gene polymorphisms, expression patterns, and functional mechanisms of MEG3 in RA pathogenesis and its clinical associations. MEG3 single nucleotide polymorphisms (SNPs) were genotyped in 551 RA patients and 595 controls, finding no association with RA susceptibility. MEG3 expression was downregulated in peripheral blood mononuclear cells (PBMCs) from RA patients, particularly in ACPA-positive cases, but increased with NSAID use. In fibroblast-like synoviocytes (FLS), MEG3 was downregulated. Overexpression of MEG3 inhibited FLS proliferation and invasion, lowering IL-1β and IL-6 but not TNF-α. Whereas MEG3 knockdown enhanced FLS proliferation and invasion, elevating TNF-α and IL-1β without altering IL-6. Collectively, MEG3 polymorphisms are not associated with RA susceptibility. MEG3 dysregulation correlates with RA clinical indicators and regulates FLS pathogenicity, indicating its potential as a clinical biomarker and therapeutic target in RA.
{"title":"LncRNA MEG3 as a biomarker and therapeutic target in rheumatoid arthritis: Insights from gene polymorphisms, expression patterns, and functional mechanisms","authors":"Sha-Sha Tao , Hai-Fen Wei , Shu-Zhen Xu , Xiao-Xiao Li , Yan-Yu Zhu , Jian Tang , Wen-Jie Li , Yu-Wan Chang , Zhu Chen , Hai-Feng Pan","doi":"10.1016/j.clim.2025.110590","DOIUrl":"10.1016/j.clim.2025.110590","url":null,"abstract":"<div><div>Maternally expressed gene 3 (<em>MEG3</em>) is implicated in autoimmunity, but its role in rheumatoid arthritis (RA) is unclear. This study aimed to investigate gene polymorphisms, expression patterns, and functional mechanisms of <em>MEG3</em> in RA pathogenesis and its clinical associations. <em>MEG3</em> single nucleotide polymorphisms (SNPs) were genotyped in 551 RA patients and 595 controls, finding no association with RA susceptibility. <em>MEG3</em> expression was downregulated in peripheral blood mononuclear cells (PBMCs) from RA patients, particularly in ACPA-positive cases, but increased with NSAID use. In fibroblast-like synoviocytes (FLS), <em>MEG3</em> was downregulated. Overexpression of <em>MEG3</em> inhibited FLS proliferation and invasion, lowering IL-1β and IL-6 but not TNF-α. Whereas <em>MEG3</em> knockdown enhanced FLS proliferation and invasion, elevating TNF-α and IL-1β without altering IL-6. Collectively, <em>MEG3</em> polymorphisms are not associated with RA susceptibility. <em>MEG3</em> dysregulation correlates with RA clinical indicators and regulates FLS pathogenicity, indicating its potential as a clinical biomarker and therapeutic target in RA.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110590"},"PeriodicalIF":3.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144921484","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}
Although anti-cyclic citrullinated peptide is a biomarker, its contribution to rheumatoid arthritis pathogenesis is unknown, and it has not been a therapeutic target to date. As inflammatory pathology is present from an early stage, and increased immune complexes have been suggested to contribute to pathogenesis, we investigated the presence of disease-related antigens that form immune complexes that increase in abundance with disease progression. Using immune complexome analysis, we analyzed immune complex antigen to disease progression for very-early rheumatoid arthritis (n = 52) and early rheumatoid arthritis (n = 19), in comparison with healthy controls (n = 28). Very-early rheumatoid arthritis was defined as those positive for anti-cyclic citrullinated peptide antibody who did not fulfill the diagnostic criteria for rheumatoid arthritis. Seven antigens increased with disease progression and were detected at significantly higher abundance in early rheumatoid arthritis than in other major autoimmune diseases. Among these, three antigens have previously reported associations with rheumatoid arthritis pathogenesis.
{"title":"Identification of immune complex antigens that are detected prior to early rheumatoid arthritis symptoms and increase with disease progression: Comprehensive serum immune complexome analysis to identify candidate disease biomarkers in health checkup cohort study","authors":"Yuki Jimbayashi Kutsuna , Nozomi Aibara , Junya Hashizume , Sayaka Kawarabayashi , Mami Tamai , Jun Miyata , Hajime Yoshifuji , Hirotaka Miyamoto , Kayoko Sato , Yukinobu Kodama , Mikiro Nakashima , Atsushi Kawakami , Takahiro Maeda , Kaname Ohyama","doi":"10.1016/j.clim.2025.110591","DOIUrl":"10.1016/j.clim.2025.110591","url":null,"abstract":"<div><div>Although anti-cyclic citrullinated peptide is a biomarker, its contribution to rheumatoid arthritis pathogenesis is unknown, and it has not been a therapeutic target to date. As inflammatory pathology is present from an early stage, and increased immune complexes have been suggested to contribute to pathogenesis, we investigated the presence of disease-related antigens that form immune complexes that increase in abundance with disease progression. Using immune complexome analysis, we analyzed immune complex antigen to disease progression for very-early rheumatoid arthritis (<em>n</em> = 52) and early rheumatoid arthritis (<em>n</em> = 19), in comparison with healthy controls (<em>n</em> = 28). Very-early rheumatoid arthritis was defined as those positive for anti-cyclic citrullinated peptide antibody who did not fulfill the diagnostic criteria for rheumatoid arthritis. Seven antigens increased with disease progression and were detected at significantly higher abundance in early rheumatoid arthritis than in other major autoimmune diseases. Among these, three antigens have previously reported associations with rheumatoid arthritis pathogenesis.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110591"},"PeriodicalIF":3.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925322","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 : 2025-08-27DOI: 10.1016/j.clim.2025.110589
Dong-Yeon Kim , Green Kim , Taehwan Oh , YoungMin Woo , Bon-Sang Koo , Seung Ho Baek , Eun-Ha Hwang , Gukhui Min , You Jung An , Jinyoung Won , Youngjeon Lee , Kyung Seob Lim , Yujin Kim , Choong-Min Ryu , Victor Nizet , Jung Joo Hong
As the primary interface with the environment, the lungs require a robust local immune defense against pathogens. In a non-human primate model of SARS-CoV-2 Omicron infection, we used scRNA-seq, spatial transcriptomics, and immunoassays to investigate localized immune memory. Our results demonstrated established adaptive responses in lung tissue and medLNs, with significant activation of tissue-resident T cells and GC (germinal center) B cells. Inducible bronchus-associated lymphoid tissue (iBALT) formed a functional tertiary lymphoid structure, suggesting potential involvement in local immune responses. These findings highlight the pivotal role of local immunity in preventing re-infection and can facilitate targeted mucosal vaccine development.
{"title":"Structural and functional characteristics of local immune memory formation in SARS-CoV-2-infected cynomolgus macaques","authors":"Dong-Yeon Kim , Green Kim , Taehwan Oh , YoungMin Woo , Bon-Sang Koo , Seung Ho Baek , Eun-Ha Hwang , Gukhui Min , You Jung An , Jinyoung Won , Youngjeon Lee , Kyung Seob Lim , Yujin Kim , Choong-Min Ryu , Victor Nizet , Jung Joo Hong","doi":"10.1016/j.clim.2025.110589","DOIUrl":"10.1016/j.clim.2025.110589","url":null,"abstract":"<div><div>As the primary interface with the environment, the lungs require a robust local immune defense against pathogens. In a non-human primate model of SARS-CoV-2 Omicron infection, we used scRNA-seq, spatial transcriptomics, and immunoassays to investigate localized immune memory. Our results demonstrated established adaptive responses in lung tissue and medLNs, with significant activation of tissue-resident T cells and GC (germinal center) B cells. Inducible bronchus-associated lymphoid tissue (iBALT) formed a functional tertiary lymphoid structure, suggesting potential involvement in local immune responses. These findings highlight the pivotal role of local immunity in preventing re-infection and can facilitate targeted mucosal vaccine development.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110589"},"PeriodicalIF":3.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925321","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}
We report the case of a young boy with X-linked agammaglobulinemia (XLA) who developed progressive gait instability and postural difficulties. Initial cerebrospinal fluid (CSF) analyses and viral PCR testing were negative; however, a brain biopsy confirmed chronic enteroviral encephalitis. The patient was treated with two compassionate-use cycles of pocapavir, in combination with ongoing high-dose intravenous immunoglobulin (IVIG) therapy. Treatment was well tolerated and led to partial neurological improvement followed by clinical stabilization. This case highlights the diagnostic challenges of enteroviral encephalitis in immunocompromised patients and suggests that investigational antivirals such as pocapavir may offer therapeutic benefit in selected cases.
{"title":"Pocapavir treatment of enterovirus encephalitis in a patient with X-linked Agammaglobulinemia","authors":"Annarosa Soresina , Jessica Galli , Irene Bellicini , Silvia Gambara , Rosaria Scaduto , Sara Roversi , Alessandra Tozzo , Nardo Nardocci , Lorenzo Pinelli , Jeff Hincks , Elisa Fazzi , Raffaele Badolato","doi":"10.1016/j.clim.2025.110592","DOIUrl":"10.1016/j.clim.2025.110592","url":null,"abstract":"<div><div>We report the case of a young boy with X-linked agammaglobulinemia (XLA) who developed progressive gait instability and postural difficulties. Initial cerebrospinal fluid (CSF) analyses and viral PCR testing were negative; however, a brain biopsy confirmed chronic enteroviral encephalitis. The patient was treated with two compassionate-use cycles of pocapavir, in combination with ongoing high-dose intravenous immunoglobulin (IVIG) therapy. Treatment was well tolerated and led to partial neurological improvement followed by clinical stabilization. This case highlights the diagnostic challenges of enteroviral encephalitis in immunocompromised patients and suggests that investigational antivirals such as pocapavir may offer therapeutic benefit in selected cases.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110592"},"PeriodicalIF":3.8,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907450","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 : 2025-08-22DOI: 10.1016/j.clim.2025.110588
Yunping Cai , Jingjing Dou , Nihong Zhou , Han Shao , Xian Shen , Cui Lu , Xiaoli Fan , Song Guo Zheng
Background
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a potential contributor to RA pathogenesis.
Methods
A systematic literature review was conducted to explore the mechanisms of ferroptosis in RA, focusing on iron metabolism dysregulation, oxidative stress, and immune cell dysfunction. Databases including PubMed, Embase, and Web of Science were searched for relevant studies.
Results
RA patients exhibit paradoxical iron distribution, with systemic deficiency but synovial overload, promoting ferroptosis. Key findings include: (1) Iron accumulation and lipid peroxidation exacerbate synovial inflammation; (2) Ferroptosis differentially affects immune cells (M1/M2 macrophages, T cells) and fibroblast-like synoviocytes (FLS); (3) Antioxidant defenses (GPX4) are impaired in RA, while some disease-modifying drugs (leflunomide, sulfasalazine) may modulate ferroptosis.
Conclusion
Ferroptosis plays a critical role in RA progression by disrupting synovial homeostasis. Targeting ferroptosis pathways offers promising therapeutic potential, though further research is needed to clarify cell-specific effects and optimize interventions.
背景类风湿性关节炎（RA）是一种以滑膜炎症和关节破坏为特征的慢性自身免疫性疾病。铁下垂是一种由脂质过氧化驱动的铁依赖性细胞死亡形式，最近被认为是RA发病的潜在因素。方法系统回顾文献，从铁代谢失调、氧化应激、免疫细胞功能障碍等方面探讨RA中铁下垂的机制。检索PubMed、Embase和Web of Science等数据库查找相关研究。结果ra患者铁分布矛盾，全身缺铁但滑膜超载，促进铁下垂。主要发现包括：(1)铁积累和脂质过氧化加剧滑膜炎症；(2)铁下垂对免疫细胞（M1/M2巨噬细胞、T细胞）和成纤维细胞样滑膜细胞（FLS）的影响存在差异；(3)抗氧化防御（GPX4）在RA中受损，而一些疾病改善药物（来氟米特，磺胺吡啶）可能调节铁凋亡。结论上睑下垂通过破坏滑膜平衡在RA的进展中起关键作用。虽然需要进一步的研究来阐明细胞特异性效应和优化干预措施，但靶向铁下垂途径提供了有希望的治疗潜力。
{"title":"Ferroptosis in patients with rheumatoid arthritis","authors":"Yunping Cai , Jingjing Dou , Nihong Zhou , Han Shao , Xian Shen , Cui Lu , Xiaoli Fan , Song Guo Zheng","doi":"10.1016/j.clim.2025.110588","DOIUrl":"10.1016/j.clim.2025.110588","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a potential contributor to RA pathogenesis.</div></div><div><h3>Methods</h3><div>A systematic literature review was conducted to explore the mechanisms of ferroptosis in RA, focusing on iron metabolism dysregulation, oxidative stress, and immune cell dysfunction. Databases including PubMed, Embase, and Web of Science were searched for relevant studies.</div></div><div><h3>Results</h3><div>RA patients exhibit paradoxical iron distribution, with systemic deficiency but synovial overload, promoting ferroptosis. Key findings include: (1) Iron accumulation and lipid peroxidation exacerbate synovial inflammation; (2) Ferroptosis differentially affects immune cells (M1/M2 macrophages, T cells) and fibroblast-like synoviocytes (FLS); (3) Antioxidant defenses (GPX4) are impaired in RA, while some disease-modifying drugs (leflunomide, sulfasalazine) may modulate ferroptosis.</div></div><div><h3>Conclusion</h3><div>Ferroptosis plays a critical role in RA progression by disrupting synovial homeostasis. Targeting ferroptosis pathways offers promising therapeutic potential, though further research is needed to clarify cell-specific effects and optimize interventions.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110588"},"PeriodicalIF":3.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144921605","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 : 2025-08-21DOI: 10.1016/j.clim.2025.110587
Dingxian He , Lei Jin , Shuangshuang Wang , Huahua Zhong , Hongxi Chen , Hongyu Zhou , Zhangyu Zou , Chongbo Zhao , Xiao Huan , Jie Song , Jianying Xi , Chong Yan , Sushan Luo
Efgartigimod (EFG) is usually used to treat generalized myasthenia gravis (gMG) with long disease duration; the benefit in new-onset gMG remained unknown. This study included 87 new-onset gMG patients who received either oral steroid and immunosuppressive treatment (Conventional group, n = 30) or combined with EFG (EFG group, n = 57). The primary outcome was minimal symptom expression (MSE) responders, as denoted by a Myasthenia Gravis Activities of Daily Living (MG-ADL) of 0 or 1 for over 4 weeks. At 12 weeks, the proportion of MSE responders was significantly higher in the EFG group (45.61 %, 26/57 vs. 13.33 %, 4/30, p = 0.0026). With the EFG group, patients with late-onset gMG had greater reductions in MG-ADL than those associated with thymoma (7.06 ± 3.25 vs. 4.96 ± 3.40, p = 0.040). EFG may be a promising treatment for rapid disease control in new-onset gMG, but future studies are still required to assess the cost-effectiveness and long-term safety.
{"title":"Efgartigimod versus standard of care in new-Onset AChR subtype generalized myasthenia gravis: A prospective cohort study","authors":"Dingxian He , Lei Jin , Shuangshuang Wang , Huahua Zhong , Hongxi Chen , Hongyu Zhou , Zhangyu Zou , Chongbo Zhao , Xiao Huan , Jie Song , Jianying Xi , Chong Yan , Sushan Luo","doi":"10.1016/j.clim.2025.110587","DOIUrl":"10.1016/j.clim.2025.110587","url":null,"abstract":"<div><div>Efgartigimod (EFG) is usually used to treat generalized myasthenia gravis (gMG) with long disease duration; the benefit in new-onset gMG remained unknown. This study included 87 new-onset gMG patients who received either oral steroid and immunosuppressive treatment (Conventional group, <em>n</em> = 30) or combined with EFG (EFG group, <em>n</em> = 57). The primary outcome was minimal symptom expression (MSE) responders, as denoted by a Myasthenia Gravis Activities of Daily Living (MG-ADL) of 0 or 1 for over 4 weeks. At 12 weeks, the proportion of MSE responders was significantly higher in the EFG group (45.61 %, 26/57 vs. 13.33 %, 4/30, <em>p</em> = 0.0026). With the EFG group, patients with late-onset gMG had greater reductions in MG-ADL than those associated with thymoma (7.06 ± 3.25 vs. 4.96 ± 3.40, <em>p</em> = 0.040). EFG may be a promising treatment for rapid disease control in new-onset gMG, but future studies are still required to assess the cost-effectiveness and long-term safety.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110587"},"PeriodicalIF":3.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893349","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 : 2025-08-21DOI: 10.1016/j.clim.2025.110576
Yung-Ju Yeh , Hsin-Yi Peng , Ting-Yin Xue , Wei-Jing Li , Po-Hao Huang , Kai-Jieh Yeo , Chien-Chung Huang , Jiunn-Horng Chen , Chung-Ming Huang , Der-Yuan Chen , Joung-Liang Lan , Ming-Shiou Jan , Yu-Chao Chang , Han Chang , Chun-Hao Tsai , Hui-Chen Chen , Shin-Yi Liu , Gregory J. Tsay
Current serological markers for rheumatoid arthritis (RA) lack sensitivity in early or seronegative disease. We evaluated anti-BR1 antibodies, targeting a Porphyromonas gingivalis RgpA-derived peptide, as a novel biomarker. From 15 peptides screened in a training cohort, BR1 showed the highest diagnostic potential (AUC = 0.9553). In an independent validation cohort, anti-BR1 demonstrated an AUC of 0.7668, with 58.6 % sensitivity and 97.0 % specificity based on a ROC-derived cutoff. Anti-BR1 antibodies were detected in 82 of 140 (58.6 %) RA cases, including 35 of 58 (60.3 %) seronegative patients, and in 16 of 38 (42.1 %) early arthritis (EA) cases, outperforming RF and ACPA. Combining anti-BR1 with RF and ACPA increased the diagnostic yield from 58.6 % to 83.6 % in RA, and from 26.3 % to 55.3 % in EA.
{"title":"“Identification of an antibody against a novel peptide from Porphyromonas gingivalis as a biomarker for rheumatoid arthritis”","authors":"Yung-Ju Yeh , Hsin-Yi Peng , Ting-Yin Xue , Wei-Jing Li , Po-Hao Huang , Kai-Jieh Yeo , Chien-Chung Huang , Jiunn-Horng Chen , Chung-Ming Huang , Der-Yuan Chen , Joung-Liang Lan , Ming-Shiou Jan , Yu-Chao Chang , Han Chang , Chun-Hao Tsai , Hui-Chen Chen , Shin-Yi Liu , Gregory J. Tsay","doi":"10.1016/j.clim.2025.110576","DOIUrl":"10.1016/j.clim.2025.110576","url":null,"abstract":"<div><div>Current serological markers for rheumatoid arthritis (RA) lack sensitivity in early or seronegative disease. We evaluated anti-BR1 antibodies, targeting a <em>Porphyromonas gingivalis</em> RgpA-derived peptide, as a novel biomarker. From 15 peptides screened in a training cohort, BR1 showed the highest diagnostic potential (AUC = 0.9553). In an independent validation cohort, anti-BR1 demonstrated an AUC of 0.7668, with 58.6 % sensitivity and 97.0 % specificity based on a ROC-derived cutoff. Anti-BR1 antibodies were detected in 82 of 140 (58.6 %) RA cases, including 35 of 58 (60.3 %) seronegative patients, and in 16 of 38 (42.1 %) early arthritis (EA) cases, outperforming RF and ACPA. Combining anti-BR1 with RF and ACPA increased the diagnostic yield from 58.6 % to 83.6 % in RA, and from 26.3 % to 55.3 % in EA.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110576"},"PeriodicalIF":3.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903087","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 : 2025-08-18DOI: 10.1016/j.clim.2025.110586
Lian Gui , Zena Chen , Liudan Tu , Liuzhong Zhou , Qiujing Wei , Jieruo Gu
Abnormal monocytes are involved in the pathogenesis of ankylosing spondylitis (AS). We investigated the association between an imbalance of monocyte subpopulations and bone destruction in AS. Compared to controls, AS patients exhibited increased CD14+CD11c+HLA-II− monocytes and decreased CD14+CD11c+HLA-II+ monocytes in peripheral blood. LPS stimulation promoted a shift from CD14+CD11c+HLA-II− monocytes toward CD14+CD11c+HLA-II+ monocytes, enhancing the former's capacity to promote CD4+ T cell proliferation. Micro RNA-seq analysis indicated that AS CD14+CD11c+HLA-II− monocytes were involved in osteoclast differentiation and overproduced soluble osteoclastogenic cytokine CSF-1. In 40 AS patients, evaluated CD14+CD11c+HLA-II− monocytes correlated positively with Spondyloarthritis Research Consortium of Canada (SPARCC) MRI inflammation score (r = 0.336, P = 0.034) and bone erosion score (r = 0.423, P = 0.007), but inversely with ankylosis score (r = −0.346, P = 0.029). Conversely, CD14+CD11c+HLA-II+ monocytes showed the opposite correlation. Our findings demonstrate that expansion of CD14+CD11c+HLA-II− monocytes contribute to bone erosion in AS, potentially mediated through CSF-1-driven osteoclast differentiation.
异常单核细胞参与强直性脊柱炎（AS）的发病机制。我们研究了单核细胞亚群失衡与AS骨破坏之间的关系。与对照组相比，AS患者外周血中CD14+CD11c+HLA-II+单核细胞增加，CD14+CD11c+HLA-II+单核细胞减少。LPS刺激促进CD14+CD11c+HLA-II -单核细胞向CD14+CD11c+HLA-II+单核细胞的转变，增强了前者促进CD4+ T细胞增殖的能力。微RNA-seq分析表明，AS CD14+CD11c+HLA-II−单核细胞参与破骨细胞分化，并过量产生可溶性破骨细胞因子CSF-1。在40例AS患者中，CD14+CD11c+HLA-II -单核细胞与加拿大脊椎关节炎研究协会（SPARCC） MRI炎症评分（r = 0.336, P = 0.034）和骨侵蚀评分（r = 0.423, P = 0.007）呈正相关，与强直评分呈负相关（r = - 0.346, P = 0.029）。相反，CD14+CD11c+HLA-II+单核细胞表现出相反的相关性。我们的研究结果表明，CD14+CD11c+HLA-II -单核细胞的扩增有助于AS的骨侵蚀，可能通过csf -1驱动的破骨细胞分化介导。
{"title":"CD14+CD11c+HLA-II− monocytes are identified to be associated with osteoclastogenesis in ankylosing spondylitis","authors":"Lian Gui , Zena Chen , Liudan Tu , Liuzhong Zhou , Qiujing Wei , Jieruo Gu","doi":"10.1016/j.clim.2025.110586","DOIUrl":"10.1016/j.clim.2025.110586","url":null,"abstract":"<div><div>Abnormal monocytes are involved in the pathogenesis of ankylosing spondylitis (AS). We investigated the association between an imbalance of monocyte subpopulations and bone destruction in AS. Compared to controls, AS patients exhibited increased CD14<sup>+</sup>CD11c<sup>+</sup>HLA-II<sup>−</sup> monocytes and decreased CD14<sup>+</sup>CD11c<sup>+</sup>HLA-II<sup>+</sup> monocytes in peripheral blood. LPS stimulation promoted a shift from CD14<sup>+</sup>CD11c<sup>+</sup>HLA-II<sup>−</sup> monocytes toward CD14<sup>+</sup>CD11c<sup>+</sup>HLA-II<sup>+</sup> monocytes, enhancing the former's capacity to promote CD4<sup>+</sup> T cell proliferation. Micro RNA-seq analysis indicated that AS CD14<sup>+</sup>CD11c<sup>+</sup>HLA-II<sup>−</sup> monocytes were involved in osteoclast differentiation and overproduced soluble osteoclastogenic cytokine CSF-1. In 40 AS patients, evaluated CD14<sup>+</sup>CD11c<sup>+</sup>HLA-II<sup>−</sup> monocytes correlated positively with Spondyloarthritis Research Consortium of Canada (SPARCC) MRI inflammation score (<em>r</em> = 0.336, <em>P</em> = 0.034) and bone erosion score (<em>r</em> = 0.423, <em>P</em> = 0.007), but inversely with ankylosis score (<em>r</em> = −0.346, <em>P</em> = 0.029). Conversely, CD14<sup>+</sup>CD11c<sup>+</sup>HLA-II<sup>+</sup> monocytes showed the opposite correlation. Our findings demonstrate that expansion of CD14<sup>+</sup>CD11c<sup>+</sup>HLA-II<sup>−</sup> monocytes contribute to bone erosion in AS, potentially mediated through CSF-1-driven osteoclast differentiation.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110586"},"PeriodicalIF":3.8,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879551","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 : 2025-08-12DOI: 10.1016/j.clim.2025.110577
Shuang Pan , Mengshu Yu , Bowei Fan , Bin Wang , Xinrui Yang , Jiawen Zhang , Xiaoqi Liu , Xiaojian Hong , Wei Yang
Autoimmune myocarditis refers to the inflammation of myocardial tissue caused by innate and adaptive immune responses, characterized by elevated levels of tumour necrosis factor-α (TNF-α), a classic pro-inflammatory factor. Although hydrogen exhibits anti-inflammatory and antioxidant properties, its therapeutic effects in autoimmune myocarditis have not been evaluated. Therefore, the present study aimed to explore whether hydrogen can alleviate autoimmune myocarditis via TNF-α. An experimental autoimmune myocarditis (EAM) model was established in BALB/c mice via subcutaneous injection of pig-derived myocardial myoglobin emulsified with complete Freund's adjuvant. The treatment group received 2 % hydrogen inhalation twice a day (3 h each time) for 21 days. CD4+ T cell expression was higher in the EAM group than in the Control group, and this increase was attenuated following treatment with hydrogen. Additionally, the levels of TNF-α and related inflammatory factors were substantially higher in the EAM group than in the Control group, and these changes were reversed following hydrogen treatment. Echocardiography assessments demonstrated a significant improvement in heart function following treatment with hydrogen compared to that in the EAM group. Pathological results revealed significant inflammatory cell infiltration and fibrosis in the hearts of the untreated EAM group. Tissue immunofluorescence and protein immunoblotting indicated elevated necroptosis markers in the EAM group, which were downregulated after treatment with hydrogen. This study demonstrates that hydrogen effectively ameliorated autoimmune myocarditis by modulating necroptosis via the TNF/TNFR1 signalling pathway, making it a promising novel therapeutic strategy for myocarditis.
{"title":"Hydrogen protects against autoimmune myocarditis by inhibiting necroptosis via the TNF/TNFR1 signalling pathway","authors":"Shuang Pan , Mengshu Yu , Bowei Fan , Bin Wang , Xinrui Yang , Jiawen Zhang , Xiaoqi Liu , Xiaojian Hong , Wei Yang","doi":"10.1016/j.clim.2025.110577","DOIUrl":"10.1016/j.clim.2025.110577","url":null,"abstract":"<div><div>Autoimmune myocarditis refers to the inflammation of myocardial tissue caused by innate and adaptive immune responses, characterized by elevated levels of tumour necrosis factor-α (TNF-α), a classic pro-inflammatory factor. Although hydrogen exhibits anti-inflammatory and antioxidant properties, its therapeutic effects in autoimmune myocarditis have not been evaluated. Therefore, the present study aimed to explore whether hydrogen can alleviate autoimmune myocarditis via TNF-α. An experimental autoimmune myocarditis (EAM) model was established in BALB/c mice via subcutaneous injection of pig-derived myocardial myoglobin emulsified with complete Freund's adjuvant. The treatment group received 2 % hydrogen inhalation twice a day (3 h each time) for 21 days. CD4+ T cell expression was higher in the EAM group than in the Control group, and this increase was attenuated following treatment with hydrogen. Additionally, the levels of TNF-α and related inflammatory factors were substantially higher in the EAM group than in the Control group, and these changes were reversed following hydrogen treatment. Echocardiography assessments demonstrated a significant improvement in heart function following treatment with hydrogen compared to that in the EAM group. Pathological results revealed significant inflammatory cell infiltration and fibrosis in the hearts of the untreated EAM group. Tissue immunofluorescence and protein immunoblotting indicated elevated necroptosis markers in the EAM group, which were downregulated after treatment with hydrogen. This study demonstrates that hydrogen effectively ameliorated autoimmune myocarditis by modulating necroptosis via the TNF/TNFR1 signalling pathway, making it a promising novel therapeutic strategy for myocarditis.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110577"},"PeriodicalIF":3.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144830395","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 : 2025-08-12DOI: 10.1016/j.clim.2025.110578
Cheng Gong , Changming Zhang , Xu Han , Ying Jin , Yangyang Zhang , Chenlu Liu , Qintao Wang , Jiahui Zhang , Cheng Guo , Qing Zhou , Xiaomin Yu , Zhihong Liu
Genetic factors have been demonstrated to play essential roles in the pathogenesis of systemic lupus erythematosus (SLE). Identifying novel disease-causing genes of SLE helps to reveal its molecular mechanisms and new therapeutic targets. In this study, we identified biallelic loss-of-function variants of MAN2B2 gene in five unrelated SLE patients by whole exome sequencing. They were characterized by autoimmunity, glomerulonephritis, leukopenia, and immune dysregulation. All variants were absent or ultrarare in population databases and predicted to be damaging by multiple in silico tools. Functional study showed that all the identified variants resulted in complete or partial enzymatic activity loss. Analyses of MAN2B2 knockout HEK293T cells, patient-derived induced pluripotent stem cells (iPSCs) and serum samples revealed defects in glycan degradation and N-glycosylation. The patients exhibited enhanced inflammatory signatures, especially the type I interferon and NF-κB pathways. Mechanically, MAN2B2 deficiency leads to dysregulation of unfolded protein response (UPR) upon endoplasmic reticulum stress, resulting in enhanced expression of inflammatory cytokines. Our findings broaden the genetic etiology spectrum of SLE and identify MAN2B2 as a pivotal regulator in maintaining immune homeostasis, paving the way for innovative diagnostic approaches and molecular pathway-specific therapeutic interventions.
{"title":"Novel pathogenic MAN2B2 variants cause systemic lupus erythematosus and dysregulated glycosylation","authors":"Cheng Gong , Changming Zhang , Xu Han , Ying Jin , Yangyang Zhang , Chenlu Liu , Qintao Wang , Jiahui Zhang , Cheng Guo , Qing Zhou , Xiaomin Yu , Zhihong Liu","doi":"10.1016/j.clim.2025.110578","DOIUrl":"10.1016/j.clim.2025.110578","url":null,"abstract":"<div><div>Genetic factors have been demonstrated to play essential roles in the pathogenesis of systemic lupus erythematosus (SLE). Identifying novel disease-causing genes of SLE helps to reveal its molecular mechanisms and new therapeutic targets. In this study, we identified biallelic loss-of-function variants of <em>MAN2B2</em> gene in five unrelated SLE patients by whole exome sequencing. They were characterized by autoimmunity, glomerulonephritis, leukopenia, and immune dysregulation. All variants were absent or ultrarare in population databases and predicted to be damaging by multiple <em>in silico</em> tools. Functional study showed that all the identified variants resulted in complete or partial enzymatic activity loss. Analyses of MAN2B2 knockout HEK293T cells, patient-derived induced pluripotent stem cells (iPSCs) and serum samples revealed defects in glycan degradation and N-glycosylation. The patients exhibited enhanced inflammatory signatures, especially the type I interferon and NF-κB pathways. Mechanically, MAN2B2 deficiency leads to dysregulation of unfolded protein response (UPR) upon endoplasmic reticulum stress, resulting in enhanced expression of inflammatory cytokines. Our findings broaden the genetic etiology spectrum of SLE and identify MAN2B2 as a pivotal regulator in maintaining immune homeostasis, paving the way for innovative diagnostic approaches and molecular pathway-specific therapeutic interventions.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110578"},"PeriodicalIF":3.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854759","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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