Olivia G Thomas, Alan Rickinson, Umaimainthan Palendira
The link between Epstein–Barr virus (EBV) and multiple sclerosis (MS) has puzzled researchers since it was first discovered over 40 years ago. Until that point, EBV was primarily viewed as a cancer-causing agent, but the culmination of evidence now shows that EBV has a pivotal role in development of MS. Early MS disease is characterised by episodic neuroinflammation and focal lesions in the central nervous system (CNS) that over time develop into progressive neurodegeneration and disability. Risk of MS is vanishingly low in EBV seronegative individuals, history of infectious mononucleosis (acute symptomatic primary infection with EBV) significantly increases risk and elevated antibody titres directed against EBV antigens are well-characterised in patients. However, the underlying mechanism – or mechanisms – responsible for this interplay remains to be fully elucidated; how does EBV-induced immune dysregulation either trigger or drive MS in susceptible individuals? Furthermore, deep understanding of virological and immunological events during primary infection and long-term persistence in B cells will help to answer the many questions that remain regarding MS pathogenesis. This review discusses the current evidence and mechanisms surrounding EBV and MS, which have important implications for the future of MS therapies and prevention.
{"title":"Epstein–Barr virus and multiple sclerosis: moving from questions of association to questions of mechanism","authors":"Olivia G Thomas, Alan Rickinson, Umaimainthan Palendira","doi":"10.1002/cti2.1451","DOIUrl":"https://doi.org/10.1002/cti2.1451","url":null,"abstract":"<p>The link between Epstein–Barr virus (EBV) and multiple sclerosis (MS) has puzzled researchers since it was first discovered over 40 years ago. Until that point, EBV was primarily viewed as a cancer-causing agent, but the culmination of evidence now shows that EBV has a pivotal role in development of MS. Early MS disease is characterised by episodic neuroinflammation and focal lesions in the central nervous system (CNS) that over time develop into progressive neurodegeneration and disability. Risk of MS is vanishingly low in EBV seronegative individuals, history of infectious mononucleosis (acute symptomatic primary infection with EBV) significantly increases risk and elevated antibody titres directed against EBV antigens are well-characterised in patients. However, the underlying mechanism – or mechanisms – responsible for this interplay remains to be fully elucidated; how does EBV-induced immune dysregulation either trigger or drive MS in susceptible individuals? Furthermore, deep understanding of virological and immunological events during primary infection and long-term persistence in B cells will help to answer the many questions that remain regarding MS pathogenesis. This review discusses the current evidence and mechanisms surrounding EBV and MS, which have important implications for the future of MS therapies and prevention.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1451","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5905809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chaofan Fan, Jia Li, Yixuan Li, Yuyang Jin, Jiaqi Feng, Ruru Guo, Xinyu Meng, Dongcheng Gong, Qian Chen, Fang Du, Chunyan Zhang, Liangjing Lu, Jun Deng, Xiao-Xiang Chen
Objectives
Rheumatoid arthritis (RA) is a disease characterised by bone destruction and systemic inflammation, and interleukin-6 (IL-6) is a therapeutic target for treating it. The study aimed at investigating the sources of IL-6 and the influence of hypoxia-inducible factor-1α (HIF-1α) on IL-6 production by B cells in RA patients.
Methods
The phenotype of IL-6-producing cells in the peripheral blood of RA patients was analysed using flow cytometry. Bioinformatics, real-time polymerase chain reaction, Western blot and immunofluorescence staining were used to determine the IL-6 production and HIF-1α levels in B cells. A dual-luciferase reporter assay and chromatin immunoprecipitation were used to investigate the regulatory role of HIF-1α on IL-6 production in human and mouse B cells.
Results
Our findings revealed that B cells are major sources of IL-6 in the peripheral blood of RA patients, with the proportion of IL-6-producing B cells significantly correlated with RA disease activity. The CD27−IgD+ naïve B cell subset was identified as the typical IL-6-producing subset in RA patients. Both HIF-1α and IL-6 were co-expressed by B cells in the peripheral blood and synovium of RA patients, and HIF-1α was found to directly bind to the IL6 promoter and enhance its transcription.
Conclusion
This study highlights the role of B cells in producing IL-6 and the regulation of this production by HIF-1α in patients with RA. Targeting HIF-1α might provide a new therapeutic strategy for treating RA.
{"title":"Hypoxia-inducible factor-1α regulates the interleukin-6 production by B cells in rheumatoid arthritis","authors":"Chaofan Fan, Jia Li, Yixuan Li, Yuyang Jin, Jiaqi Feng, Ruru Guo, Xinyu Meng, Dongcheng Gong, Qian Chen, Fang Du, Chunyan Zhang, Liangjing Lu, Jun Deng, Xiao-Xiang Chen","doi":"10.1002/cti2.1447","DOIUrl":"https://doi.org/10.1002/cti2.1447","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Rheumatoid arthritis (RA) is a disease characterised by bone destruction and systemic inflammation, and interleukin-6 (IL-6) is a therapeutic target for treating it. The study aimed at investigating the sources of IL-6 and the influence of hypoxia-inducible factor-1α (HIF-1α) on IL-6 production by B cells in RA patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The phenotype of IL-6-producing cells in the peripheral blood of RA patients was analysed using flow cytometry. Bioinformatics, real-time polymerase chain reaction, Western blot and immunofluorescence staining were used to determine the IL-6 production and HIF-1α levels in B cells. A dual-luciferase reporter assay and chromatin immunoprecipitation were used to investigate the regulatory role of HIF-1α on IL-6 production in human and mouse B cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our findings revealed that B cells are major sources of IL-6 in the peripheral blood of RA patients, with the proportion of IL-6-producing B cells significantly correlated with RA disease activity. The CD27<sup>−</sup>IgD<sup>+</sup> naïve B cell subset was identified as the typical IL-6-producing subset in RA patients. Both HIF-1α and IL-6 were co-expressed by B cells in the peripheral blood and synovium of RA patients, and HIF-1α was found to directly bind to the <i>IL6</i> promoter and enhance its transcription.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study highlights the role of B cells in producing IL-6 and the regulation of this production by HIF-1α in patients with RA. Targeting HIF-1α might provide a new therapeutic strategy for treating RA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1447","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5779416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Increasing evidence indicates that some germline genetic mutations that impair pathways required for robust host immune surveillance against EBV infection may result in an extremely high susceptibility to EBV-associated lymphoproliferative disease (EBV+ LPD). TNFRSF9 encodes a vital costimulatory molecule that enhances CD8+ T-cell proliferation, survival and cytolytic activity. To date, no relevant case resulting from TNFRSF9 heterozygous mutations has been identified.
Methods
Here, we report the first case of CD137 deficiency caused by two novel biallelic heterozygous TNFRSF9 mutations [NM_001561.5: c.208 + 1−>AT and c.452C>A (p.T151K)] in a patient presenting with severe EBV+ LPD. Immunophenotyping and in vitro assays of lymphocyte function and NK cell activity were performed.
Results
Biallelic TNFRSF9 mutations resulted in markedly reduced or abrogated expression of CD137 on activated T, B and NK cells. CD8+ T cells from the patient had impaired activation, reduced expression/release of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), perforin and granzyme B, and diminished cytotoxic activity. Functional experiments identified both variations were hypomorphic mutations and played a contributing role in CD137 deficiency and the development of EBV+ LPD.
Conclusion
Our study expands the genetic spectrum and clinical phenotype of patients with CD137 deficiency and provides additional evidence that the TNFRSF9 gene plays a critical role in host immune responses to EBV infection.
{"title":"CD137 deficiency because of two novel biallelic TNFRSF9 mutations in a patient presenting with severe EBV-associated lymphoproliferative disease","authors":"Kefeng Shen, Jiachen Wang, Kuangguo Zhou, Wei Mu, Meilan Zhang, Xinyue Deng, Haodong Cai, Wei Zhang, Wei Huang, Min Xiao","doi":"10.1002/cti2.1448","DOIUrl":"https://doi.org/10.1002/cti2.1448","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Increasing evidence indicates that some germline genetic mutations that impair pathways required for robust host immune surveillance against EBV infection may result in an extremely high susceptibility to EBV-associated lymphoproliferative disease (EBV<sup>+</sup> LPD). <i>TNFRSF9</i> encodes a vital costimulatory molecule that enhances CD8<sup>+</sup> T-cell proliferation, survival and cytolytic activity. To date, no relevant case resulting from <i>TNFRSF9</i> heterozygous mutations has been identified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we report the first case of CD137 deficiency caused by two novel biallelic heterozygous <i>TNFRSF9</i> mutations [NM_001561.5: c.208 + 1−>AT and c.452C>A (p.T151K)] in a patient presenting with severe EBV<sup>+</sup> LPD. Immunophenotyping and <i>in vitro</i> assays of lymphocyte function and NK cell activity were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Biallelic <i>TNFRSF9</i> mutations resulted in markedly reduced or abrogated expression of CD137 on activated T, B and NK cells. CD8<sup>+</sup> T cells from the patient had impaired activation, reduced expression/release of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), perforin and granzyme B, and diminished cytotoxic activity. Functional experiments identified both variations were hypomorphic mutations and played a contributing role in CD137 deficiency and the development of EBV<sup>+</sup> LPD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study expands the genetic spectrum and clinical phenotype of patients with CD137 deficiency and provides additional evidence that the <i>TNFRSF9</i> gene plays a critical role in host immune responses to EBV infection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1448","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6047180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francesco Missale, Mattia Bugatti, Filippo Marchi, Giulio E Mandelli, Maria Bruni, Giulia Palmerini, Matilde Monti, Anna M Bozzola, Giorgio Arena, Luca Guastini, Maurizio Boggio, Giampiero Parrinello, Giorgio Peretti, William Vermi
Objectives
Laryngeal squamous cell carcinomas (LSCCs) typically have an excellent prognosis for stage I tumors but a significant risk of locoregional and distant recurrence for intermediate to advanced disease. This study will investigate the clinical relevance of the tumor microenvironment in a large cohort of treatment-naïve patients affected by stage II–IV LSCC.
Methods
Whole slide-based digital pathology analysis was applied to measure six immune cell populations identified by immunohistochemistry (IHC) staining for CD3, CD8, CD20, CD66b, CD163 and CD38. Survival analysis was performed by Cox proportional hazards models and unsupervised hierarchical clustering using the k-means method. Double IHC staining and in-situ hybridisation by RNAscope allowed further analysis of a protumoral B cell population.
Results
A cohort of 98 patients was enrolled and analysed. The cluster of immune-infiltrated LSCCs demonstrated a significantly worse disease-specific survival rate. We also discovered a new association between high CD20+ B cells and a greater risk of distant recurrence. The phenotypic analysis of infiltrating CD20+ B cells showed a naïve (BCL6−CD27−Mum1−) regulatory phenotype, producing TGFβ but not IL10, according to an active TGFβ pathway, as proved by positive pSMAD2 staining.
Conclusion
The identification of regulatory B cells in the context of LSCC, along with the activation of the TGFβ pathway, could provide the basis for new trials investigating the efficacy of already available molecules targeting the TGFβ pathway in the treatment of LSCC.
{"title":"The prometastatic relevance of tumor-infiltrating B lymphocytes in laryngeal squamous cell carcinoma","authors":"Francesco Missale, Mattia Bugatti, Filippo Marchi, Giulio E Mandelli, Maria Bruni, Giulia Palmerini, Matilde Monti, Anna M Bozzola, Giorgio Arena, Luca Guastini, Maurizio Boggio, Giampiero Parrinello, Giorgio Peretti, William Vermi","doi":"10.1002/cti2.1445","DOIUrl":"https://doi.org/10.1002/cti2.1445","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Laryngeal squamous cell carcinomas (LSCCs) typically have an excellent prognosis for stage I tumors but a significant risk of locoregional and distant recurrence for intermediate to advanced disease. This study will investigate the clinical relevance of the tumor microenvironment in a large cohort of treatment-naïve patients affected by stage II–IV LSCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Whole slide-based digital pathology analysis was applied to measure six immune cell populations identified by immunohistochemistry (IHC) staining for CD3, CD8, CD20, CD66b, CD163 and CD38. Survival analysis was performed by Cox proportional hazards models and unsupervised hierarchical clustering using the k-means method. Double IHC staining and <i>in-situ</i> hybridisation by RNAscope allowed further analysis of a protumoral B cell population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A cohort of 98 patients was enrolled and analysed. The cluster of immune-infiltrated LSCCs demonstrated a significantly worse disease-specific survival rate. We also discovered a new association between high CD20<sup>+</sup> B cells and a greater risk of distant recurrence. The phenotypic analysis of infiltrating CD20<sup>+</sup> B cells showed a naïve (BCL6<sup>−</sup>CD27<sup>−</sup>Mum1<sup>−</sup>) regulatory phenotype, producing TGFβ but not IL10, according to an active TGFβ pathway, as proved by positive pSMAD2 staining.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The identification of regulatory B cells in the context of LSCC, along with the activation of the TGFβ pathway, could provide the basis for new trials investigating the efficacy of already available molecules targeting the TGFβ pathway in the treatment of LSCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1445","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5829956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dragana Dragoljevic, Man Kit Sam Lee, Gerard Pernes, Pooranee K Morgan, Cynthia Louis, Waled Shihata, Kevin Huynh, Arina A Kochetkova, Patrick W Bell, Natalie A Mellett, Peter J Meikle, Graeme I Lancaster, Michael J Kraakman, Prabhakara R Nagareddy, Beatriz Y Hanaoka, Ian P Wicks, Andrew J Murphy
Objectives
The leading cause of mortality in patients with rheumatoid arthritis is atherosclerotic cardiovascular disease (CVD). We have shown that murine arthritis impairs atherosclerotic lesion regression, because of cellular cholesterol efflux defects in haematopoietic stem and progenitor cells (HSPCs), causing monocytosis and impaired atherosclerotic regression. Therefore, we hypothesised that improving cholesterol efflux using a Liver X Receptor (LXR) agonist would improve cholesterol efflux and improve atherosclerotic lesion regression in arthritis.
Methods
Ldlr−/− mice were fed a western-type diet for 14 weeks to initiate atherogenesis, then switched to a chow diet to induce lesion regression and divided into three groups; (1) control, (2) K/BxN serum transfer inflammatory arthritis (K/BxN) or (3) K/BxN arthritis and LXR agonist T0901317 daily for 2 weeks.
Results
LXR activation during murine inflammatory arthritis completely restored atherosclerotic lesion regression in arthritic mice, evidenced by reduced lesion size, macrophage abundance and lipid content. Mechanistically, serum from arthritic mice promoted foam cell formation, demonstrated by increased cellular lipid accumulation in macrophages and paralleled by a reduction in mRNA of the cholesterol efflux transporters Abca1, Abcg1 and Apoe. T0901317 reduced lipid loading and increased Abca1 and Abcg1 expression in macrophages exposed to arthritic serum and increased ABCA1 levels in atherosclerotic lesions of arthritic mice. Moreover, arthritic clinical score was also attenuated with T0901317.
Conclusion
Taken together, we show that the LXR agonist T0901317 rescues impaired atherosclerotic lesion regression in murine arthritis because of enhanced cholesterol efflux transporter expression and reduced foam cell development in atherosclerotic lesions.
{"title":"Administration of an LXR agonist promotes atherosclerotic lesion remodelling in murine inflammatory arthritis","authors":"Dragana Dragoljevic, Man Kit Sam Lee, Gerard Pernes, Pooranee K Morgan, Cynthia Louis, Waled Shihata, Kevin Huynh, Arina A Kochetkova, Patrick W Bell, Natalie A Mellett, Peter J Meikle, Graeme I Lancaster, Michael J Kraakman, Prabhakara R Nagareddy, Beatriz Y Hanaoka, Ian P Wicks, Andrew J Murphy","doi":"10.1002/cti2.1446","DOIUrl":"https://doi.org/10.1002/cti2.1446","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The leading cause of mortality in patients with rheumatoid arthritis is atherosclerotic cardiovascular disease (CVD). We have shown that murine arthritis impairs atherosclerotic lesion regression, because of cellular cholesterol efflux defects in haematopoietic stem and progenitor cells (HSPCs), causing monocytosis and impaired atherosclerotic regression. Therefore, we hypothesised that improving cholesterol efflux using a Liver X Receptor (LXR) agonist would improve cholesterol efflux and improve atherosclerotic lesion regression in arthritis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p><i>Ldlr</i><sup><i>−/−</i></sup> mice were fed a western-type diet for 14 weeks to initiate atherogenesis, then switched to a chow diet to induce lesion regression and divided into three groups; (1) control, (2) K/BxN serum transfer inflammatory arthritis (K/BxN) or (3) K/BxN arthritis and LXR agonist T0901317 daily for 2 weeks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>LXR activation during murine inflammatory arthritis completely restored atherosclerotic lesion regression in arthritic mice, evidenced by reduced lesion size, macrophage abundance and lipid content. Mechanistically, serum from arthritic mice promoted foam cell formation, demonstrated by increased cellular lipid accumulation in macrophages and paralleled by a reduction in mRNA of the cholesterol efflux transporters <i>Abca1</i>, <i>Abcg1</i> and <i>Apoe</i>. T0901317 reduced lipid loading and increased <i>Abca1</i> and <i>Abcg1</i> expression in macrophages exposed to arthritic serum and increased ABCA1 levels in atherosclerotic lesions of arthritic mice. Moreover, arthritic clinical score was also attenuated with T0901317.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Taken together, we show that the LXR agonist T0901317 rescues impaired atherosclerotic lesion regression in murine arthritis because of enhanced cholesterol efflux transporter expression and reduced foam cell development in atherosclerotic lesions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1446","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5710054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yun Shan Goh, Siew-Wai Fong, Angeline Rouers, Zi Wei Chang, Matthew Zirui Tay, Jean-Marc Chavatte, Nicole Ziyi Zhuo, Pei Xiang Hor, Chiew Yee Loh, Yuling Huang, Joel Xu En Wong, Yong Jie Tan, Daniel Rui Xiang Lim, Bei Wang, Eve Zi Xian Ngoh, Siti Nazihah Mohd Salleh, Raphael Tze Chuen Lee, Surinder Pada, Louisa Jin Sun, Desmond Luan Seng Ong, Jyoti Somani, Eng Sing Lee, NCID Study Group, COVID-19 Study Group, Sebastian Maurer-Stroh, Cheng-I Wang, Yee-Sin Leo, Raymond TP Lin, Ee Chee Ren, David C Lye, Barnaby Edward Young, Poh Lian Lim, Lisa FP Ng & Laurent Renia
Correction to: Clin Trans Immunol 2022; 11: e1043. https://doi.org/10.1002/cti2.1403. Published online 23 August 2022
The authors inadvertently excluded a funding body in the Acknowledgments section. The corrected version appears below:
Yun山高、Siew-Wai方,安吉莉Rouers,子张,马修·Zirui泰jean - marc Chavatte,妮可章子怡卓,裴湘何珥卫生绮Loh,玉玲黄,乔尔徐黄,永杰,丹尼尔•瑞翔Lim贝王夜子西安Ngoh,西蒂Nazihah穆罕默德Salleh,拉斐尔老子村李萨伦德篇,路易莎金太阳,德斯蒙德的菜肴Seng Ong Jyoti Somani, Eng唱Lee NCID研究小组,COVID-19研究小组,Sebastian Maurer-Stroh Cheng-I Wang Yee-Sin Leo,雷蒙德•林TP Ee Chee任,David C . Lye, Barnaby Edward Young，林宝莲，Lisa FP Ng &;Laurent reniical &《转化免疫学》2023;12: e1449。修正:clinin Trans Immunol 2022;11: e1043。https://doi.org/10.1002/cti2.1403。作者无意中在致谢部分排除了一个资助机构。更正后的版本如下:
{"title":"Heterologous booster vaccination with CoronaVac following prime vaccination with mRNA vaccine","authors":"","doi":"10.1002/cti2.1449","DOIUrl":"https://doi.org/10.1002/cti2.1449","url":null,"abstract":"<p>Yun Shan Goh, Siew-Wai Fong, Angeline Rouers, Zi Wei Chang, Matthew Zirui Tay, Jean-Marc Chavatte, Nicole Ziyi Zhuo, Pei Xiang Hor, Chiew Yee Loh, Yuling Huang, Joel Xu En Wong, Yong Jie Tan, Daniel Rui Xiang Lim, Bei Wang, Eve Zi Xian Ngoh, Siti Nazihah Mohd Salleh, Raphael Tze Chuen Lee, Surinder Pada, Louisa Jin Sun, Desmond Luan Seng Ong, Jyoti Somani, Eng Sing Lee, NCID Study Group, COVID-19 Study Group, Sebastian Maurer-Stroh, Cheng-I Wang, Yee-Sin Leo, Raymond TP Lin, Ee Chee Ren, David C Lye, Barnaby Edward Young, Poh Lian Lim, Lisa FP Ng & Laurent Renia</p><p><i>Clinical & Translational Immunology</i> 2023; <b>12:</b> e1449.</p><p><b>Correction to:</b> Clin Trans Immunol 2022; 11: e1043. https://doi.org/10.1002/cti2.1403. Published online 23 August 2022</p><p>The authors inadvertently excluded a funding body in the Acknowledgments section. The corrected version appears below:</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1449","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5708513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Martina Severa, Fabiana Rizzo, Alessandro Sinigaglia, Daniela Ricci, Marilena Paola Etna, Gaia Cola, Doriana Landi, Maria Chiara Buscarinu, Catia Valdarchi, Giovanni Ristori, Silvia Riccetti, Chiara Piubelli, Pierangela Palmerini, Antonio Rosato, Federico Gobbi, Stefano Balducci, Girolama Alessandra Marfia, Marco Salvetti, Luisa Barzon, Eliana Marina Coccia
Objectives
The very rapidly approved mRNA-based vaccines against SARS-CoV-2 spike glycoprotein, including Pfizer-BioNTech BNT162b2, are effective in protecting from severe coronavirus disease 2019 (COVID-19) in immunocompetent population. However, establishing the duration and identifying correlates of vaccine-induced protection will be crucial to optimise future immunisation strategies. Here, we studied in healthy vaccine recipients and people with multiple sclerosis (pwMS), undergoing different therapies, the regulation of innate immune response by mRNA vaccination in order to correlate it with the magnitude of vaccine-induced protective humoral responses.
Methods
Healthy subjects (n = 20) and matched pwMS (n = 22) were longitudinally sampled before and after mRNA vaccination. Peripheral blood mononuclear cell (PBMC)-associated type I and II interferon (IFN)-inducible gene expression, serum innate cytokine/chemokine profile as well as binding and neutralising anti-SARS-COV-2 antibodies (Abs) were measured.
Results
We identified an early immune module composed of the IFN-inducible genes Mx1, OAS1 and IRF1, the serum cytokines IL-15, IL-6, TNF-α and IFN-γ and the chemokines IP-10, MCP-1 and MIG, induced 1 day post second and third BNT162b2 vaccine doses, strongly correlating with magnitude of humoral response to vaccination in healthy and MS vaccinees. Moreover, induction of the early immune module was dramatically affected in pwMS treated with fingolimod and ocrelizumab, both groups unable to induce a protective humoral response to COVID-19 vaccine.
Conclusion
Overall, this study suggests that the vaccine-induced early regulation of innate immunity is mediated by IFN signalling, impacts on the magnitude of adaptive responses and it might be indicative of vaccine-induced humoral protection.
{"title":"A specific anti-COVID-19 BNT162b2 vaccine-induced early innate immune signature positively correlates with the humoral protective response in healthy and multiple sclerosis vaccine recipients","authors":"Martina Severa, Fabiana Rizzo, Alessandro Sinigaglia, Daniela Ricci, Marilena Paola Etna, Gaia Cola, Doriana Landi, Maria Chiara Buscarinu, Catia Valdarchi, Giovanni Ristori, Silvia Riccetti, Chiara Piubelli, Pierangela Palmerini, Antonio Rosato, Federico Gobbi, Stefano Balducci, Girolama Alessandra Marfia, Marco Salvetti, Luisa Barzon, Eliana Marina Coccia","doi":"10.1002/cti2.1434","DOIUrl":"https://doi.org/10.1002/cti2.1434","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The very rapidly approved mRNA-based vaccines against SARS-CoV-2 spike glycoprotein, including Pfizer-BioNTech BNT162b2, are effective in protecting from severe coronavirus disease 2019 (COVID-19) in immunocompetent population. However, establishing the duration and identifying correlates of vaccine-induced protection will be crucial to optimise future immunisation strategies. Here, we studied in healthy vaccine recipients and people with multiple sclerosis (pwMS), undergoing different therapies, the regulation of innate immune response by mRNA vaccination in order to correlate it with the magnitude of vaccine-induced protective humoral responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Healthy subjects (<i>n</i> = 20) and matched pwMS (<i>n</i> = 22) were longitudinally sampled before and after mRNA vaccination. Peripheral blood mononuclear cell (PBMC)-associated type I and II interferon (IFN)-inducible gene expression, serum innate cytokine/chemokine profile as well as binding and neutralising anti-SARS-COV-2 antibodies (Abs) were measured.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified an early immune module composed of the IFN-inducible genes Mx1, OAS1 and IRF1, the serum cytokines IL-15, IL-6, TNF-α and IFN-γ and the chemokines IP-10, MCP-1 and MIG, induced 1 day post second and third BNT162b2 vaccine doses, strongly correlating with magnitude of humoral response to vaccination in healthy and MS vaccinees. Moreover, induction of the early immune module was dramatically affected in pwMS treated with fingolimod and ocrelizumab, both groups unable to induce a protective humoral response to COVID-19 vaccine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Overall, this study suggests that the vaccine-induced early regulation of innate immunity is mediated by IFN signalling, impacts on the magnitude of adaptive responses and it might be indicative of vaccine-induced humoral protection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1434","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5778072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christopher M Harpur, Alison C West, Mélanie A Le Page, Maggie Lam, Christopher Hodges, Osezua Oseghale, Andrew J Gearing, Michelle D Tate
Objectives
Novel host-targeted therapeutics could treat severe influenza A virus (IAV) infections, with reduced risk of drug resistance. LAT8881 is a synthetic form of the naturally occurring C-terminal fragment of human growth hormone. Acting independently of the growth hormone receptor, it can reduce inflammation-induced damage and promote tissue repair in an animal model of osteoarthritis. LAT8881 has been assessed in clinical trials for the treatment of obesity and neuropathy and has an excellent safety profile. We investigated the potential for LAT8881, its metabolite LAT9991F and LAT7771 derived from prolactin, a growth hormone structural homologue, to treat severe IAV infection.
Methods
LAT8881, LAT9991F and LAT7771 were evaluated for their effects on cell viability and IAV replication in vitro, as well as their potential to limit disease in a preclinical mouse model of severe IAV infection.
Results
In vitro LAT8881 treatment enhanced cell viability, particularly in the presence of cytotoxic stress, which was countered by siRNA inhibition of host lanthionine synthetase C-like proteins. Daily intranasal treatment of mice with LAT8881 or LAT9991F, but not LAT7771, from day 1 postinfection significantly improved influenza disease resistance, which was associated with reduced infectious viral loads, reduced pro-inflammatory cytokines and increased abundance of protective alveolar macrophages. LAT8881 treatment in combination with the antiviral oseltamivir phosphate led to more pronounced reduction in markers of disease severity than treatment with either compound alone.
Conclusion
These studies provide the first evidence identifying LAT8881 and LAT9991F as novel host-protective therapies that improve survival, limit viral replication, reduce local inflammation and curtail tissue damage during severe IAV infection. Evaluation of LAT8881 and LAT9991F in other infectious and inflammatory conditions of the airways is warranted.
{"title":"Naturally derived cytokine peptides limit virus replication and severe disease during influenza A virus infection","authors":"Christopher M Harpur, Alison C West, Mélanie A Le Page, Maggie Lam, Christopher Hodges, Osezua Oseghale, Andrew J Gearing, Michelle D Tate","doi":"10.1002/cti2.1443","DOIUrl":"https://doi.org/10.1002/cti2.1443","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Novel host-targeted therapeutics could treat severe influenza A virus (IAV) infections, with reduced risk of drug resistance. LAT8881 is a synthetic form of the naturally occurring C-terminal fragment of human growth hormone. Acting independently of the growth hormone receptor, it can reduce inflammation-induced damage and promote tissue repair in an animal model of osteoarthritis. LAT8881 has been assessed in clinical trials for the treatment of obesity and neuropathy and has an excellent safety profile. We investigated the potential for LAT8881, its metabolite LAT9991F and LAT7771 derived from prolactin, a growth hormone structural homologue, to treat severe IAV infection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>LAT8881, LAT9991F and LAT7771 were evaluated for their effects on cell viability and IAV replication <i>in vitro</i>, as well as their potential to limit disease in a preclinical mouse model of severe IAV infection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>In vitro</i> LAT8881 treatment enhanced cell viability, particularly in the presence of cytotoxic stress, which was countered by siRNA inhibition of host lanthionine synthetase C-like proteins. Daily intranasal treatment of mice with LAT8881 or LAT9991F, but not LAT7771, from day 1 postinfection significantly improved influenza disease resistance, which was associated with reduced infectious viral loads, reduced pro-inflammatory cytokines and increased abundance of protective alveolar macrophages. LAT8881 treatment in combination with the antiviral oseltamivir phosphate led to more pronounced reduction in markers of disease severity than treatment with either compound alone.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These studies provide the first evidence identifying LAT8881 and LAT9991F as novel host-protective therapies that improve survival, limit viral replication, reduce local inflammation and curtail tissue damage during severe IAV infection. Evaluation of LAT8881 and LAT9991F in other infectious and inflammatory conditions of the airways is warranted.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1443","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5687221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emergence of a definitive link between Epstein–Barr virus (EBV) and multiple sclerosis has provided an impetus to develop immune-based therapies to target EBV-infected B cells. Initial studies with autologous EBV-specific T-cell therapy demonstrated that this therapy is safe with minimal side effects and more importantly multiple patients showed both symptomatic and objective neurological improvements including improved quality of life, reduction of fatigue and reduced intrathecal IgG production. These observations have been successfully extended to an ‘off-the-shelf’ allogeneic EBV-specific T-cell therapy manufactured using peripheral blood lymphocytes of healthy seropositive individuals. This adoptive immunotherapy has also been shown to be safe with encouraging clinical responses. Allogeneic EBV T-cell therapy overcomes some of the limitations of autologous therapy and can be rapidly delivered to patients with improved therapeutic potential.
{"title":"Adoptive T-cell therapy targeting Epstein–Barr virus as a treatment for multiple sclerosis","authors":"Corey Smith, Rajiv Khanna","doi":"10.1002/cti2.1444","DOIUrl":"https://doi.org/10.1002/cti2.1444","url":null,"abstract":"<p>Emergence of a definitive link between Epstein–Barr virus (EBV) and multiple sclerosis has provided an impetus to develop immune-based therapies to target EBV-infected B cells. Initial studies with autologous EBV-specific T-cell therapy demonstrated that this therapy is safe with minimal side effects and more importantly multiple patients showed both symptomatic and objective neurological improvements including improved quality of life, reduction of fatigue and reduced intrathecal IgG production. These observations have been successfully extended to an ‘off-the-shelf’ allogeneic EBV-specific T-cell therapy manufactured using peripheral blood lymphocytes of healthy seropositive individuals. This adoptive immunotherapy has also been shown to be safe with encouraging clinical responses. Allogeneic EBV T-cell therapy overcomes some of the limitations of autologous therapy and can be rapidly delivered to patients with improved therapeutic potential.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5760476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guillaume Dorcet, Marie Benaiteau, Jérémie Pariente, Fabienne Ory-Magne, Emmanuel Cheuret, Marie Rafiq, Wesley Brooks, Bénédicte Puissant-Lubrano, Fran?oise Fortenfant, Yves Renaudineau, Chloé Bost
Objective
Because of its heterogeneity in clinical presentation and course, predicting autoimmune encephalitis (AIE) evolution remains challenging. Hence, our aim was to explore the correlation of several biomarkers with the clinical course of disease.
Methods
Thirty-seven cases of AIE were selected retrospectively and divided into active (N = 9), improved (N = 12) and remission (N = 16) AIE according to their disease evolution. Nine proteins were tested in both serum and cerebrospinal fluid (CSF) at diagnosis (T0) and during the follow-up (T1), in particular activated MMP-9 (MMP-9A) and YKL-40 (or chitinase 3-like 1).
Results
From diagnosis to revaluation, AIE remission was associated with decreased YKL-40 and MMP-9A levels in the CSF, and with decreased NfL and NfH levels in the serum. The changes in YKL-40 concentrations in the CSF were associated with (1) still active AIE when increasing >10% (P-value = 0.0093); (2) partial improvement or remission when the changes were between +9% and −20% (P-value = 0.0173); and remission with a reduction > −20% (P-value = 0.0072; overall difference between the three groups: P-value = 0.0088). At T1, the CSF YKL-40 levels were significantly decreased between active and improved as well as improved and remission AIE groups but with no calculable threshold because of patient heterogeneity.
Conclusion
The concentration of YKL-40, a cytokine-like proinflammatory protein produced by glial cells, is correlated in the CSF with the clinical course of AIE. Its introduction as a biomarker may assist in following disease activity and in evaluating therapeutic response.
{"title":"Cerebrospinal fluid YKL-40 level evolution is associated with autoimmune encephalitis remission","authors":"Guillaume Dorcet, Marie Benaiteau, Jérémie Pariente, Fabienne Ory-Magne, Emmanuel Cheuret, Marie Rafiq, Wesley Brooks, Bénédicte Puissant-Lubrano, Fran?oise Fortenfant, Yves Renaudineau, Chloé Bost","doi":"10.1002/cti2.1439","DOIUrl":"https://doi.org/10.1002/cti2.1439","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Because of its heterogeneity in clinical presentation and course, predicting autoimmune encephalitis (AIE) evolution remains challenging. Hence, our aim was to explore the correlation of several biomarkers with the clinical course of disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Thirty-seven cases of AIE were selected retrospectively and divided into active (<i>N</i> = 9), improved (<i>N</i> = 12) and remission (<i>N</i> = 16) AIE according to their disease evolution. Nine proteins were tested in both serum and cerebrospinal fluid (CSF) at diagnosis (T0) and during the follow-up (T1), in particular activated MMP-9 (MMP-9A) and YKL-40 (or chitinase 3-like 1).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>From diagnosis to revaluation, AIE remission was associated with decreased YKL-40 and MMP-9A levels in the CSF, and with decreased NfL and NfH levels in the serum. The changes in YKL-40 concentrations in the CSF were associated with (1) still active AIE when increasing >10% (<i>P-</i>value = 0.0093); (2) partial improvement or remission when the changes were between +9% and −20% (<i>P-</i>value = 0.0173); and remission with a reduction > −20% <i>(P-</i>value = 0.0072; overall difference between the three groups: <i>P-</i>value = 0.0088). At T1, the CSF YKL-40 levels were significantly decreased between active and improved as well as improved and remission AIE groups but with no calculable threshold because of patient heterogeneity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The concentration of YKL-40, a cytokine-like proinflammatory protein produced by glial cells, is correlated in the CSF with the clinical course of AIE. Its introduction as a biomarker may assist in following disease activity and in evaluating therapeutic response.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1439","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6152821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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