Clinical & Translational Immunology最新文献

{"title":"Robust immunity to influenza vaccination in haematopoietic stem cell transplant recipients following reconstitution of humoral and adaptive immunity","authors":"Wuji Zhang,&nbsp;Louise C Rowntree,&nbsp;Ramona Muttucumaru,&nbsp;Timon Damelang,&nbsp;Malet Aban,&nbsp;Aeron C Hurt,&nbsp;Maria Auladell,&nbsp;Robyn Esterbauer,&nbsp;Bruce Wines,&nbsp;Mark Hogarth,&nbsp;Stephen J Turner,&nbsp;Adam K Wheatley,&nbsp;Stephen J Kent,&nbsp;Sushrut Patil,&nbsp;Sharon Avery,&nbsp;Orla Morrissey,&nbsp;Amy W Chung,&nbsp;Marios Koutsakos,&nbsp;Thi HO Nguyen,&nbsp;Allen C Cheng,&nbsp;Tom C Kotsimbos,&nbsp;Katherine Kedzierska","doi":"10.1002/cti2.1456","DOIUrl":"https://doi.org/10.1002/cti2.1456","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Influenza causes significant morbidity and mortality, especially in high-risk populations. Although current vaccination regimens are the best method to combat annual influenza disease, vaccine efficacy can be low in high-risk groups, such as haematopoietic stem cell transplant (HSCT) recipients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We comprehensively assessed humoral immunity, antibody landscapes, systems serology and influenza-specific B-cell responses, together with their phenotypes and isotypes, to the inactivated influenza vaccine (IIV) in HSCT recipients in comparison to healthy controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Inactivated influenza vaccine significantly increased haemagglutination inhibition (HAI) titres in HSCT recipients, similar to healthy controls. Systems serology revealed increased IgG1 and IgG3 antibody levels towards the haemagglutinin (HA) head, but not to neuraminidase, nucleoprotein or HA stem. IIV also increased frequencies of total, IgG class-switched and CD21^loCD27⁺ influenza-specific B cells, determined by HA probes and flow cytometry. Strikingly, 40% of HSCT recipients had markedly higher antibody responses towards A/H3N2 vaccine strain than healthy controls and showed cross-reactivity to antigenically drifted A/H3N2 strains by antibody landscape analysis. These superior humoral responses were associated with a greater time interval after HSCT, while multivariant analyses revealed the importance of pre-existing immune memory. Conversely, in HSCT recipients who did not respond to the first dose, the second IIV dose did not greatly improve their humoral response, although 50% of second-dose patients reached a seroprotective HAI titre for at least one of vaccine strains.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study demonstrates efficient, although time-dependent, immune responses to IIV in HSCT recipients, and provides insights into influenza vaccination strategies targeted to immunocompromised high-risk groups.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1456","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5880939","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}

{"title":"Epstein–Barr virus and multiple sclerosis: the dawn of a new age","authors":"Tri Giang Phan","doi":"10.1002/cti2.1457","DOIUrl":"https://doi.org/10.1002/cti2.1457","url":null,"abstract":"<p>\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1457","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5741257","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}

{"title":"A novel dual NLRP1 and NLRP3 inflammasome inhibitor for the treatment of inflammatory diseases","authors":"Callum AH Docherty,&nbsp;Anuruddika J Fernando,&nbsp;Sarah Rosli,&nbsp;Maggie Lam,&nbsp;Roland E Dolle,&nbsp;Manuel A Navia,&nbsp;Ronald Farquhar,&nbsp;Danny La France,&nbsp;Michelle D Tate,&nbsp;Christopher K Murphy,&nbsp;Adriano G Rossi,&nbsp;Ashley Mansell","doi":"10.1002/cti2.1455","DOIUrl":"https://doi.org/10.1002/cti2.1455","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Inflammasomes induce maturation of the inflammatory cytokines IL-1β and IL-18, whose activity is associated with the pathophysiology of a wide range of infectious and inflammatory diseases. As validated therapeutic targets for the treatment of acute and chronic inflammatory diseases, there has been intense interest in developing small-molecule inhibitors to target inflammasome activity and reduce disease-associated inflammatory burden.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We examined the therapeutic potential of a novel small-molecule inhibitor, and associated derivatives, termed ADS032 to target and reduce inflammasome-mediated inflammation <i>in vivo</i>. <i>In vitro</i>, we characterised ADS032 function, target engagement and specificity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We describe ADS032 as the first dual NLRP1 and NLRP3 inhibitor. ADS032 is a rapid, reversible and stable inflammasome inhibitor that directly binds both NLRP1 and NLRP3, reducing secretion and maturation of IL-1β in human-derived macrophages and bronchial epithelial cells in response to the activation of NLPR1 and NLRP3. ADS032 also reduced NLRP3-induced ASC speck formation, indicative of targeting inflammasome formation. <i>In vivo</i>, ADS032 reduced IL-1β and TNF-α levels in the serum of mice challenged i.p. with LPS and reduced pulmonary inflammation in an acute model of lung silicosis. Critically, ADS032 protected mice from lethal influenza A virus challenge, displayed increased survival and reduced pulmonary inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>ADS032 is the first described dual inflammasome inhibitor and a potential therapeutic to treat both NLRP1- and NLRP3-associated inflammatory diseases and also constitutes a novel tool that allows examination of the role of NLRP1 in human disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1455","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5984407","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}

{"title":"The interaction between Epstein–Barr virus and multiple sclerosis genetic risk loci: insights into disease pathogenesis and therapeutic opportunities","authors":"Ali Afrasiabi,&nbsp;Chantelle Ahlenstiel,&nbsp;Sanjay Swaminathan,&nbsp;Grant P Parnell","doi":"10.1002/cti2.1454","DOIUrl":"https://doi.org/10.1002/cti2.1454","url":null,"abstract":"<p>Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease, characterised by the demyelination of neurons in the central nervous system. Whilst it is unclear what precisely leads to MS, it is believed that genetic predisposition combined with environmental factors plays a pivotal role. It is estimated that close to half the disease risk is determined by genetic factors. However, the risk of developing MS cannot be attributed to genetic factors alone, and environmental factors are likely to play a significant role by themselves or in concert with host genetics. Epstein–Barr virus (EBV) infection is the strongest known environmental risk factor for MS. There has been increasing evidence that leaves little doubt that EBV is necessary, but not sufficient, for developing MS. One plausible explanation is EBV may alter the host immune response in the presence of MS risk alleles and this contributes to the pathogenesis of MS. In this review, we discuss recent findings regarding how EBV infection may contribute to MS pathogenesis via interactions with genetic risk loci and discuss possible therapeutic interventions.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1454","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6185344","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}

{"title":"Released dsDNA-triggered inflammasomes serve as intestinal radioprotective targets","authors":"Long Chen,&nbsp;Ziwen Wang,&nbsp;Jie Wu,&nbsp;Quan Yao,&nbsp;Jingjing Peng,&nbsp;Chi Zhang,&nbsp;Hongdan Chen,&nbsp;Yingjie Li,&nbsp;Zhongyong Jiang,&nbsp;Yunsheng Liu,&nbsp;Chunmeng Shi","doi":"10.1002/cti2.1452","DOIUrl":"https://doi.org/10.1002/cti2.1452","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Intestinal mucositis is the major side effect during abdominal or pelvic radiotherapy, but the underlying immunogen remains to be further characterised and few radioprotective agents are available. This study investigated the role of dsDNA-triggered inflammasomes in intestinal mucositis during radiotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Pro-inflammatory cytokines were detected by ELISA. Radiation-induced intestinal injury in mice was analyzed by means of survival curves, body weight, HE staining of intestines, and intestinal barrier integrity. Western blot, immunofluorescence staining, co-immunoprecipitation assay and flow cytometry were used to investigate the regulatory role of dsDNA on inflammasomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we show that a high level of IL-1β and IL-18 is associated with diarrhoea in colorectal cancer (CRC) patients during radiotherapy, which accounts for intestinal radiotoxicity. Subsequently, we found that the dose-dependently released dsDNA from the intestinal epithelial cells (IECs) serves as the potential immunogenic molecule for radiation-induced intestinal mucositis. Our results further indicate that the released dsDNA transfers into the macrophages in an HMGB1/RAGE-dependent manner and then triggers absent in melanoma 2 (AIM2) inflammasome activation and the IL-1β and IL-18 secretion. Finally, we show that the FDA-approved disulfiram (DSF), a newly identified inflammasome inhibitor, could mitigate intestinal radiotoxicity by controlling inflammasome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings indicate that the extracellular self-dsDNA released from the irradiated IECs is a potential immunogen to stimulate immune cells and trigger the subsequent intestinal mucositis, while blunting the dsDNA-triggered inflammasome in macrophages may represent an exciting therapeutic strategy for side effects control during abdominal radiotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1452","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6185346","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}

{"title":"Circulating CXCR5+ natural killer cells are expanded in patients with myasthenia gravis","authors":"Meng-Ru Ge,&nbsp;Chun-Lin Yang,&nbsp;Tao Li,&nbsp;Tong Du,&nbsp;Peng Zhang,&nbsp;Xiao-Li Li,&nbsp;Ying-Chun Dou,&nbsp;Rui-Sheng Duan","doi":"10.1002/cti2.1450","DOIUrl":"https://doi.org/10.1002/cti2.1450","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Myasthenia gravis (MG) is a classic autoantibody-mediated disease in which pathogenic antibodies target postsynaptic membrane components, causing fluctuating skeletal muscle weakness and fatigue. Natural killer (NK) cells are heterogeneous lymphocytes that have gained increasing attention owing to their potential roles in autoimmune disorders. This study will investigate the relationship between the distinct NK cell subsets and MG pathogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 33 MG patients and 19 healthy controls were enrolled in the present study. Circulating NK cells, their subtypes and follicular helper T cells were analysed by flow cytometry. Serum acetylcholine receptor (AChR) antibody levels were determined by ELISA. The role of NK cells in the regulation of B cells was verified using a co-culture assay.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Myasthenia gravis patients with acute exacerbations had a reduced number of total NK cells, CD56^dim NK cells and IFN-γ-secreting NK cells in the peripheral blood, while CXCR5⁺ NK cells were significantly elevated. CXCR5⁺ NK cells expressed a higher level of ICOS and PD-1 and a lower level of IFN-γ than those in CXCR5⁻ NK cells and were positively correlated with Tfh cell and AChR antibody levels. <i>In vitro</i> experiments demonstrated that NK cells suppressed plasmablast differentiation while promoting CD80 and PD-L1 expression on B cells in an IFN-γ-dependent manner. Furthermore, CXCR5⁻ NK cells inhibited plasmablast differentiation, while CXCR5⁺ NK cells could more efficiently promote B cell proliferation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These results reveal that CXCR5⁺ NK cells exhibit distinct phenotypes and functions compared with CXCR5⁻ NK cells and might participate in the pathogenesis of MG.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1450","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5753590","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}

{"title":"Epstein–Barr virus and multiple sclerosis: moving from questions of association to questions of mechanism","authors":"Olivia G Thomas,&nbsp;Alan Rickinson,&nbsp;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}

{"title":"Hypoxia-inducible factor-1α regulates the interleukin-6 production by B cells in rheumatoid arthritis","authors":"Chaofan Fan,&nbsp;Jia Li,&nbsp;Yixuan Li,&nbsp;Yuyang Jin,&nbsp;Jiaqi Feng,&nbsp;Ruru Guo,&nbsp;Xinyu Meng,&nbsp;Dongcheng Gong,&nbsp;Qian Chen,&nbsp;Fang Du,&nbsp;Chunyan Zhang,&nbsp;Liangjing Lu,&nbsp;Jun Deng,&nbsp;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⁻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 <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}

{"title":"CD137 deficiency because of two novel biallelic TNFRSF9 mutations in a patient presenting with severe EBV-associated lymphoproliferative disease","authors":"Kefeng Shen,&nbsp;Jiachen Wang,&nbsp;Kuangguo Zhou,&nbsp;Wei Mu,&nbsp;Meilan Zhang,&nbsp;Xinyue Deng,&nbsp;Haodong Cai,&nbsp;Wei Zhang,&nbsp;Wei Huang,&nbsp;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⁺ LPD). <i>TNFRSF9</i> encodes a vital costimulatory molecule that enhances CD8⁺ 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−&gt;AT and c.452C&gt;A (p.T151K)] in a patient presenting with severe EBV⁺ 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⁺ 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.</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}

{"title":"The prometastatic relevance of tumor-infiltrating B lymphocytes in laryngeal squamous cell carcinoma","authors":"Francesco Missale,&nbsp;Mattia Bugatti,&nbsp;Filippo Marchi,&nbsp;Giulio E Mandelli,&nbsp;Maria Bruni,&nbsp;Giulia Palmerini,&nbsp;Matilde Monti,&nbsp;Anna M Bozzola,&nbsp;Giorgio Arena,&nbsp;Luca Guastini,&nbsp;Maurizio Boggio,&nbsp;Giampiero Parrinello,&nbsp;Giorgio Peretti,&nbsp;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⁺ 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.</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}