Primary immunodeficiency diseases (PIDs) are a heterogeneous group of inherited disorders characterized by impaired immune function, leading to increased susceptibility to infections, autoimmunity, and malignancies. While traditionally defined by immune cell defects, emerging evidence highlights the critical role of inflammation in PID pathogenesis. This review explores the intricate relationship between mitochondrial dysfunction and inflammation in PIDs. We examine how genetic defects in PIDs disrupt immune homeostasis, promoting pro-inflammatory states through cytokine dysregulation. Additionally, we discuss the vicious cycle involving oxidative stress, mitochondrial dysfunction, and inflammation, emphasizing the contribution of mitochondrial ROS production, mtDNA damage, and inflammasome activation in sustaining chronic inflammation. Furthermore, we propose that impaired mitochondrial function —potentially through mechanisms involving calcium signalling, ATP synthase regulation, and mitochondrial permeability transition pore formation — may serve as a central link between immune deficiency and hyperinflammation in PIDs. Understanding these complex interactions may provide new insights into the pathogenesis of PIDs and open avenues for targeted therapeutic strategies to improve patient outcomes.
{"title":"Primary immunodeficiency diseases, inflammation and mitochondrial dysfunction","authors":"Salvatore Nesci , Francesca Oppedisano , Giovanni Romeo , Silvia Granata","doi":"10.1016/j.clim.2025.110595","DOIUrl":"10.1016/j.clim.2025.110595","url":null,"abstract":"<div><div>Primary immunodeficiency diseases (PIDs) are a heterogeneous group of inherited disorders characterized by impaired immune function, leading to increased susceptibility to infections, autoimmunity, and malignancies. While traditionally defined by immune cell defects, emerging evidence highlights the critical role of inflammation in PID pathogenesis. This review explores the intricate relationship between mitochondrial dysfunction and inflammation in PIDs. We examine how genetic defects in PIDs disrupt immune homeostasis, promoting pro-inflammatory states through cytokine dysregulation. Additionally, we discuss the vicious cycle involving oxidative stress, mitochondrial dysfunction, and inflammation, emphasizing the contribution of mitochondrial ROS production, mtDNA damage, and inflammasome activation in sustaining chronic inflammation. Furthermore, we propose that impaired mitochondrial function —potentially through mechanisms involving calcium signalling, ATP synthase regulation, and mitochondrial permeability transition pore formation — may serve as a central link between immune deficiency and hyperinflammation in PIDs. Understanding these complex interactions may provide new insights into the pathogenesis of PIDs and open avenues for targeted therapeutic strategies to improve patient outcomes.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110595"},"PeriodicalIF":3.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999887","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 : 2025-08-31DOI: 10.1016/j.clim.2025.110594
Yu-Jie Zhan , Wei Liu , Bu-Yi Wang , Bo-Yang Ma , Jia-Ye Wang , Yi-Lin Zhao , Xin-Xin Wang , Yue Jiang , Dan Wang , Li Wang , Hong Ling , Min Zhuang
Incomplete immune reconstitution poses a significant challenge for anti-retroviral therapy (ART) in HIV-infected individuals. The role of B cell receptors (BCRs) in immune reconstitution, a critical aspect of the immune system, has not been well elucidated in ART-experienced people. We analyzed the BCR heavy chain repertoire in immune non-responders (INRs) and immune responders (IRs) by next-generation sequencing. The BCR repertoire of INRs was characterized by a higher proportion of longer HCDR3 and reduced frequencies of IGHV1–69, IGHJ2, and IGHV1–69/IGHJ4 and IGHV5–51/IGHJ4 pairings. INRs, rather than IRs, carried HCDR3 genes which were highly homologous to anti-HIV broadly neutralizing antibodies targeting the six-helix bundle (6HB) in envelope gp41. The plasmas of INRs also exhibited an increased reactivity to FPPR-N36, a peptide within 6HB. These findings indicated a potential association between BCR, antibodies to partial gp41, and incomplete immune reconstitution and provided new perspectives for understanding the BCR repertoire and immune reconstitution.
{"title":"B cell receptor repertoires identified by next-generation sequencing showed signatures associated with incomplete immune reconstitution in people living with HIV","authors":"Yu-Jie Zhan , Wei Liu , Bu-Yi Wang , Bo-Yang Ma , Jia-Ye Wang , Yi-Lin Zhao , Xin-Xin Wang , Yue Jiang , Dan Wang , Li Wang , Hong Ling , Min Zhuang","doi":"10.1016/j.clim.2025.110594","DOIUrl":"10.1016/j.clim.2025.110594","url":null,"abstract":"<div><div>Incomplete immune reconstitution poses a significant challenge for anti-retroviral therapy (ART) in HIV-infected individuals. The role of B cell receptors (BCRs) in immune reconstitution, a critical aspect of the immune system, has not been well elucidated in ART-experienced people. We analyzed the BCR heavy chain repertoire in immune non-responders (INRs) and immune responders (IRs) by next-generation sequencing. The BCR repertoire of INRs was characterized by a higher proportion of longer HCDR3 and reduced frequencies of IGHV1–69, IGHJ2, and IGHV1–69/IGHJ4 and IGHV5–51/IGHJ4 pairings. INRs, rather than IRs, carried HCDR3 genes which were highly homologous to anti-HIV broadly neutralizing antibodies targeting the six-helix bundle (6HB) in envelope gp41. The plasmas of INRs also exhibited an increased reactivity to FPPR-N36, a peptide within 6HB. These findings indicated a potential association between BCR, antibodies to partial gp41, and incomplete immune reconstitution and provided new perspectives for understanding the BCR repertoire and immune reconstitution.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110594"},"PeriodicalIF":3.8,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944973","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 : 2025-08-29DOI: 10.1016/j.clim.2025.110593
Alanna M. Kelly , Emilio G. Vozza , Brenda Morris , Seán C. Cahill , Charlotte M. Leane , Sinéad C. Corr , Rachel M. McLoughlin
Staphylococcus aureus nasal colonisation is commonplace among healthy individuals, yet the immune mechanisms enabling bacterial persistence remain unclear. S. aureus drives local immunosuppression during nasal colonisation to facilitate persistence. This study reveals that S. aureus subverts microRNA-21 activity to promote IL-10 production within nasal tissue, while simultaneously impeding local pro-inflammatory responses. MiR-21 activity helps establish a S. aureus-induced immunosuppressive microenvironment, which supports S. aureus persistence. Macrophages, which are key IL-10 producers, rapidly upregulate miR-21 upon S. aureus exposure. MiR-21 expression also coincides with an increase in intracellular survival of S. aureus within macrophages. Furthermore, S. aureus represses macrophage glycolysis to promote intracellular survival, which is dependent upon miR-21. Upon S. aureus colonisation, miR-21−/− mice demonstrate an overall improved bacterial clearance compared to their wild-type counterparts. These findings highlight the targeting of miR-21, which controls glycolytic activity in macrophages, as a potential avenue to reducing bacterial persistence during S. aureus colonisation.
{"title":"Staphylococcus aureus induces miR-21 expression to promote bacterial persistence during nasal colonisation","authors":"Alanna M. Kelly , Emilio G. Vozza , Brenda Morris , Seán C. Cahill , Charlotte M. Leane , Sinéad C. Corr , Rachel M. McLoughlin","doi":"10.1016/j.clim.2025.110593","DOIUrl":"10.1016/j.clim.2025.110593","url":null,"abstract":"<div><div><em>Staphylococcus aureus</em> nasal colonisation is commonplace among healthy individuals, yet the immune mechanisms enabling bacterial persistence remain unclear. <em>S. aureus</em> drives local immunosuppression during nasal colonisation to facilitate persistence. This study reveals that <em>S. aureus</em> subverts microRNA-21 activity to promote IL-10 production within nasal tissue, while simultaneously impeding local pro-inflammatory responses. MiR-21 activity helps establish a <em>S. aureus</em>-induced immunosuppressive microenvironment, which supports <em>S. aureus</em> persistence. Macrophages, which are key IL-10 producers, rapidly upregulate miR-21 upon <em>S. aureus</em> exposure. MiR-21 expression also coincides with an increase in intracellular survival of <em>S. aureus</em> within macrophages. Furthermore, <em>S. aureus</em> represses macrophage glycolysis to promote intracellular survival, which is dependent upon miR-21. Upon <em>S. aureus</em> colonisation, miR-21<sup>−/−</sup> mice demonstrate an overall improved bacterial clearance compared to their wild-type counterparts. These findings highlight the targeting of miR-21, which controls glycolytic activity in macrophages, as a potential avenue to reducing bacterial persistence during <em>S. aureus</em> colonisation.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110593"},"PeriodicalIF":3.8,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945094","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 : 2025-08-28DOI: 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.
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