Pub Date : 2025-10-10DOI: 10.1016/j.clim.2025.110607
Julia Snyder , Marni Slavik , Patrick Harvey , Roxana Del Rio-Guerra , Bernardo A. Mainou , Alessandro Sette , Beth D. Kirkpatrick , Alba Grifoni , Jessica W. Crothers
Summary
Little is known about the immunologic mechanisms responsible for observed differences in mucosal immunity following vaccination with oral live attenuated polio vaccines (OPVs) compared to inactivated polio vaccines (IPVs). Here, we used a flow cytometric activation-induced marker (AIM)-based approach to investigate vaccine-related differences in T cell response using peripheral blood samples from healthy adults enrolled in two polio vaccine trials. Our findings indicate that vaccination with OPVs (1) enhances CD4+ T cell responses, and (2) expands CD4+ and CD8+ antigen recognition of non-structural proteins. Fecal shedding of OPVs was associated with enhanced T cell responses, and primary CD8+ T cell responses appear to correlate with early control of fecal viral shedding. Our results indicate that OPVs induce broad cellular immunity to polioviruses, which may help explain their enhanced ability to stimulate effective pathogen-specific mucosal immunity.
{"title":"Oral live attenuated polio vaccines induce enhanced T-cell responses with broad antigen recognition compared to inactivated polio vaccines","authors":"Julia Snyder , Marni Slavik , Patrick Harvey , Roxana Del Rio-Guerra , Bernardo A. Mainou , Alessandro Sette , Beth D. Kirkpatrick , Alba Grifoni , Jessica W. Crothers","doi":"10.1016/j.clim.2025.110607","DOIUrl":"10.1016/j.clim.2025.110607","url":null,"abstract":"<div><h3>Summary</h3><div>Little is known about the immunologic mechanisms responsible for observed differences in mucosal immunity following vaccination with oral live attenuated polio vaccines (OPVs) compared to inactivated polio vaccines (IPVs). Here, we used a flow cytometric activation-induced marker (AIM)-based approach to investigate vaccine-related differences in T cell response using peripheral blood samples from healthy adults enrolled in two polio vaccine trials. Our findings indicate that vaccination with OPVs (1) enhances CD4+ T cell responses, and (2) expands CD4+ and CD8+ antigen recognition of non-structural proteins. Fecal shedding of OPVs was associated with enhanced T cell responses, and primary CD8+ T cell responses appear to correlate with early control of fecal viral shedding. Our results indicate that OPVs induce broad cellular immunity to polioviruses, which may help explain their enhanced ability to stimulate effective pathogen-specific mucosal immunity.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"282 ","pages":"Article 110607"},"PeriodicalIF":3.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279098","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}
B cells contribute to systemic lupus erythematosus (SLE) pathogenesis through autoantibody production. DNA hypomethylation in B cells is a hallmark of SLE and may be associated with altered expression of key epigenetic regulators. This study investigated the mRNA expression of DNMT1 and UHRF1, which maintain DNA methylation, and TET2 and TET3, which mediate demethylation, in B cells from SLE patients.
Methods
Participants included individuals with active SLE, inactive SLE, and healthy controls. Purified B cells were stimulated in vitro with anti-human IgM. Gene expression of DNMT1, UHRF1, TET2, and TET3 was quantified by qRT-PCR
Results
At baseline, UHRF1 mRNA expression was significantly decreased, and TET3 expression significantly increased in B cells from active SLE patients compared to controls. Upon anti-IgM activation, further reductions in UHRF1 and increases in TET3 expression were observed in active SLE B cells. DNMT1 and TET2 expression did not differ significantly across groups or conditions.
Conclusion
The altered expression of UHRF1 and TET3 mRNA in B cells from active SLE patients may reflect underlying epigenetic dysregulation associated with disease activity. These findings provide preliminary support for further investigation into their potential involvement in the pathobiology of SLE.
{"title":"Altered methylation-related genes expression in B cells of systemic lupus erythematosus patients","authors":"Amin Azizan , Elham Farhadi , Seyedeh Tahereh Faezi , Majid Alikhani , Mahdi Mahmoudi , Ahmadreza Jamshidi , Mohammad Vodjgani","doi":"10.1016/j.clim.2025.110606","DOIUrl":"10.1016/j.clim.2025.110606","url":null,"abstract":"<div><h3>Background and objective</h3><div>B cells contribute to systemic lupus erythematosus (SLE) pathogenesis through autoantibody production. DNA hypomethylation in B cells is a hallmark of SLE and may be associated with altered expression of key epigenetic regulators. This study investigated the mRNA expression of DNMT1 and UHRF1, which maintain DNA methylation, and TET2 and TET3, which mediate demethylation, in B cells from SLE patients.</div></div><div><h3>Methods</h3><div>Participants included individuals with active SLE, inactive SLE, and healthy controls. Purified B cells were stimulated in vitro with anti-human IgM. Gene expression of DNMT1, UHRF1, TET2, and TET3 was quantified by qRT-PCR</div></div><div><h3>Results</h3><div>At baseline, UHRF1 mRNA expression was significantly decreased, and TET3 expression significantly increased in B cells from active SLE patients compared to controls. Upon anti-IgM activation, further reductions in UHRF1 and increases in TET3 expression were observed in active SLE B cells. DNMT1 and TET2 expression did not differ significantly across groups or conditions.</div></div><div><h3>Conclusion</h3><div>The altered expression of UHRF1 and TET3 mRNA in B cells from active SLE patients may reflect underlying epigenetic dysregulation associated with disease activity. These findings provide preliminary support for further investigation into their potential involvement in the pathobiology of SLE.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110606"},"PeriodicalIF":3.8,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274121","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 : 2025-10-02DOI: 10.1016/j.clim.2025.110605
Jagoda Siemaszko , Piotr Łacina , Donata Szymczak , Agnieszka Szeremet , Maciej Majcherek , Anna Czyż , Małgorzata Sobczyk-Kruszelnicka , Wojciech Fidyk , Iwona Solarska , Barbara Nasiłowska-Adamska , Patrycja Skowrońska , Maria Bieniaszewska , Agnieszka Tomaszewska , Grzegorz W. Basak , Sebastian Giebel , Tomasz Wróbel , Katarzyna Bogunia-Kubik
Background
NK cell activity after allogeneic haematopoietic stem cell transplantation (HSCT) is still not fully understood. Their cytotoxic activity is modulated by a range of inhibitory and activating surface receptors. Among these, the inhibitory receptors ILT-2 and ILT-4 have yet to be explored in relation to HSCT and its outcomes.
Methods
Genotyping for ILT-2 and ILT-4 was performed using TaqMan assays. ILT-2 and ILT-4 surface expression on NK cells was assessed by flow cytometry. Levels of sHLA-F and sHLA-G were determined using ELISA. mRNA expression of ILT-2, ILT-4 and IFN-γ was measured with quantitative real-time PCR with TaqMan Gene Expression probes.
Results
Presence of donor ILT-2 rs1061681 T allele was associated with increased risk of chronic graft-versus-host disease (cGVHD) (p = 0.0239). Donor ILT-4 rs1128646 T allele was related with decreased risk of overall survival after HSCT (p = 0.0506) and with higher risk of acute GvHD (aGvHD) (p = 0.0834). Serum levels of sHLA-F and sHLA-G were significantly higher at day +30 than day +90 after HSCT (p = 0.0002 and p < 0.0001, respectively). Expression of ILT2 at mRNA level was significantly decreased among recipients with aGvHD (p = 0.0266). ILT-4 expression correlated negatively with expression of interferon gamma (p = 0.0280, R = -0.532). The percentages of LILRB1/ILT-2+ and LILRB2/ILT4+ NK cells were the highest at day +21 after HSCT (p = 0.0014 and p < 0.0001 for ILT-2 and ILT-4, respectively).
Conclusions
Both ILT-2 and ILT-4 inhibitory receptors were found to be associated with allogeneic HSCT outcome. This suggests that ILT receptor expression on NK cells may potentially play a role in post-transplant complications.
{"title":"ILT-2 and ILT-4 expression and donor genotype as factors associated with HSCT outcome","authors":"Jagoda Siemaszko , Piotr Łacina , Donata Szymczak , Agnieszka Szeremet , Maciej Majcherek , Anna Czyż , Małgorzata Sobczyk-Kruszelnicka , Wojciech Fidyk , Iwona Solarska , Barbara Nasiłowska-Adamska , Patrycja Skowrońska , Maria Bieniaszewska , Agnieszka Tomaszewska , Grzegorz W. Basak , Sebastian Giebel , Tomasz Wróbel , Katarzyna Bogunia-Kubik","doi":"10.1016/j.clim.2025.110605","DOIUrl":"10.1016/j.clim.2025.110605","url":null,"abstract":"<div><h3>Background</h3><div>NK cell activity after allogeneic haematopoietic stem cell transplantation (HSCT) is still not fully understood. Their cytotoxic activity is modulated by a range of inhibitory and activating surface receptors. Among these, the inhibitory receptors ILT-2 and ILT-4 have yet to be explored in relation to HSCT and its outcomes.</div></div><div><h3>Methods</h3><div>Genotyping for ILT-2 and ILT-4 was performed using TaqMan assays. ILT-2 and ILT-4 surface expression on NK cells was assessed by flow cytometry. Levels of sHLA-F and sHLA-G were determined using ELISA. mRNA expression of <em>ILT-2</em>, <em>ILT-4</em> and <em>IFN-γ</em> was measured with quantitative real-time PCR with TaqMan Gene Expression probes.</div></div><div><h3>Results</h3><div>Presence of donor ILT-2 rs1061681 <em>T</em> allele was associated with increased risk of chronic graft-versus-host disease (cGVHD) (<em>p</em> = 0.0239). Donor ILT-4 rs1128646 <em>T</em> allele was related with decreased risk of overall survival after HSCT (<em>p</em> = 0.0506) and with higher risk of acute GvHD (aGvHD) (<em>p</em> = 0.0834). Serum levels of sHLA-F and sHLA-G were significantly higher at day +30 than day +90 after HSCT (<em>p</em> = 0.0002 and <em>p</em> < 0.0001, respectively). Expression of ILT2 at mRNA level was significantly decreased among recipients with aGvHD (<em>p</em> = 0.0266). ILT-4 expression correlated negatively with expression of interferon gamma (<em>p</em> = 0.0280, R = -0.532). The percentages of <em>LILRB1</em>/ILT-2+ and <em>LILRB2</em>/ILT4+ NK cells were the highest at day +21 after HSCT (<em>p</em> = 0.0014 and <em>p</em> < 0.0001 for ILT-2 and ILT-4, respectively).</div></div><div><h3>Conclusions</h3><div>Both ILT-2 and ILT-4 inhibitory receptors were found to be associated with allogeneic HSCT outcome. This suggests that ILT receptor expression on NK cells may potentially play a role in post-transplant complications.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110605"},"PeriodicalIF":3.8,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228466","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 : 2025-09-11DOI: 10.1016/j.clim.2025.110603
Hai-Feng Li , Shi-Min Hu , Wei Han , Yan-Su Guo
{"title":"Regarding the “Efgartigimod versus standard of care in new-onset AChR subtype generalized myasthenia gravis: A prospective cohort study”","authors":"Hai-Feng Li , Shi-Min Hu , Wei Han , Yan-Su Guo","doi":"10.1016/j.clim.2025.110603","DOIUrl":"10.1016/j.clim.2025.110603","url":null,"abstract":"","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110603"},"PeriodicalIF":3.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058430","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 : 2025-09-05DOI: 10.1016/j.clim.2025.110596
Youmna El-Orfali , Hagop Mardirossian , Habib Al-Kalamouni , Zeinab El-Zein , Samar Dalle , Dima Khreis , Amani Haddara , Rima Hanna-Wakim , Ghassan Dbaibo , Michel J. Massaad
Chronic Granulomatous Disease (CGD) is caused by mutations in the NADPH oxidase complex that impair the ability of phagocytes to eliminate injested pathogens. As a result, patients with CGD suffer from recurrent infections and chronic inflammation. We report the clinical, biochemical, and genetic basis of the disease in 17 CGD patients from Lebanon. Whole exome sequencing (WES) identified 2 distinct mutations in NCF2 resulting in the deletion of exons 3 and 5, accounting for 82 % of the cases that underwent WES. This high prevalence provided the rationale for a diagnostic strategy involving assessment of NADPH oxidase function, identification of the affected protein, and targeted gene sequencing. Using this approach, 3 additional CGD patients with simmilar deletions were identified, supporting the presence of a founder effect in the Lebanese population. This biochemical and tageted sequencing approach is rapid, reliable, and cost-effective, making it a particularly valuable diagnostic option for families who cannot afford WES.
{"title":"Clinical, biochemical, and genetic characterization of Lebanese patients with chronic granulomatous disease due to NCF2 pathogenic variants","authors":"Youmna El-Orfali , Hagop Mardirossian , Habib Al-Kalamouni , Zeinab El-Zein , Samar Dalle , Dima Khreis , Amani Haddara , Rima Hanna-Wakim , Ghassan Dbaibo , Michel J. Massaad","doi":"10.1016/j.clim.2025.110596","DOIUrl":"10.1016/j.clim.2025.110596","url":null,"abstract":"<div><div>Chronic Granulomatous Disease (CGD) is caused by mutations in the NADPH oxidase complex that impair the ability of phagocytes to eliminate injested pathogens. As a result, patients with CGD suffer from recurrent infections and chronic inflammation. We report the clinical, biochemical, and genetic basis of the disease in 17 CGD patients from Lebanon. Whole exome sequencing (WES) identified 2 distinct mutations in <em>NCF2</em> resulting in the deletion of exons 3 and 5, accounting for 82 % of the cases that underwent WES. This high prevalence provided the rationale for a diagnostic strategy involving assessment of NADPH oxidase function, identification of the affected protein, and targeted gene sequencing. Using this approach, 3 additional CGD patients with simmilar deletions were identified, supporting the presence of a founder effect in the Lebanese population. This biochemical and tageted sequencing approach is rapid, reliable, and cost-effective, making it a particularly valuable diagnostic option for families who cannot afford WES.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"281 ","pages":"Article 110596"},"PeriodicalIF":3.8,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007608","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}
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}
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