Clinical & Translational Immunology最新文献

{"title":"Design, optimisation and standardisation of a high-dimensional spectral flow cytometry workflow assessing T-cell immunophenotype in patients with melanoma","authors":"Jack M Edwards,&nbsp;Miles C Andrews,&nbsp;Hayley Burridge,&nbsp;Robin Smith,&nbsp;Carole Owens,&nbsp;Mark Edinger,&nbsp;Katherine Pilkington,&nbsp;Juliette Desfrancois,&nbsp;Mark Shackleton,&nbsp;Sashendra Senthi,&nbsp;Menno C van Zelm","doi":"10.1002/cti2.1466","DOIUrl":"https://doi.org/10.1002/cti2.1466","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Despite the success of immune checkpoint blockade, most metastatic melanoma patients fail to respond to therapy or experience severe toxicity. Assessment of biomarkers and immunophenotypes before or early into treatment will help to understand favourable responses and improve therapeutic outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We present a high-dimensional approach for blood T-cell profiling using three multi-parameter cytometry panels: (1) a TruCount panel for absolute cell counts, (2) a 27-colour spectral panel assessing T-cell markers and (3) a 20-colour spectral panel evaluating intracellular cytokine expression. Pre-treatment blood mononuclear cells from patients and healthy controls were cryopreserved before staining across 11 batches. Batch effects were tracked using a single-donor control and the suitability of normalisation was assessed. The data were analysed using manual gating and high-dimensional strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Batch-to-batch variation was minimal, as demonstrated by the dimensionality reduction of batch-control samples, and normalisation did not improve manual or high-dimensional analysis. Application of the workflow demonstrated the capacity of the panels and showed that patients had fewer lymphocytes than controls (<i>P</i> = 0.0027), due to lower naive CD4⁺ (<i>P</i> = 0.015) and CD8⁺ (<i>P</i> = 0.011) T cells and follicular helper T cells (<i>P</i> = 0.00076). Patients showed trends for higher proportions of Ki67 and IL-2-expressing cells within CD4⁺ and CD8⁺ memory subsets, and increased CD57 and EOMES expression within TCRγδ⁺ T cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our optimised high-parameter spectral cytometry approach provided in-depth profiling of blood T cells and found differences in patient immunophenotype at baseline. The robustness of our workflow, as demonstrated by minimal batch effects, makes this approach highly suitable for the longitudinal evaluation of immunotherapy effects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 9","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6303019","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":"Assessment of antibodies in the upper and lower human respiratory tract at steady state and after respiratory viral infection","authors":"Marios Koutsakos,&nbsp;Jackson S Turner,&nbsp;M Cristina Vazquez Guillamet,&nbsp;Daniel Reynolds,&nbsp;Tingting Lei,&nbsp;Derek E Byers,&nbsp;Ali H Ellebedy,&nbsp;Philip A Mudd","doi":"10.1002/cti2.1460","DOIUrl":"https://doi.org/10.1002/cti2.1460","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>There is an increasing appreciation for the need to study mucosal antibody responses in humans. Our aim was to determine the utility of different types of samples from the human respiratory tract, specifically nasopharyngeal (NP) swabs obtained for diagnostic purposes and bronchoalveolar lavage (BAL) obtained in outpatient and inpatient settings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed antibody levels in plasma and NP swabs from 67 individuals with acute influenza as well as plasma and BAL from individuals undergoing bronchoscopy, including five control subjects as well as seven moderately and seven severely ill subjects with a respiratory viral infection. Levels of α2-macroglobulin were determined in BAL and plasma to assess plasma exudation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>IgG and IgA were readily detectable in BAL and NP swabs, albeit at different ratios, while IgM levels were low. The total amount of antibody recovered from NP swabs varied greatly between study participants. Accordingly, the levels of influenza HA-specific antibodies varied, and individuals with lower amounts of total Ig in NP swabs had undetectable levels of HA-specific Ig. Similarly, the total amount of antibody recovered from BAL varied between study participants. However, severely ill patients showed evidence of increased plasma exudation, which may confound analysis of their BAL samples for mucosal antibodies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Nasopharyngeal swabs collected for diagnostic purposes may have utility in assessing antibodies from the human nasal mucosa, but variability in sampling should be accounted for. BAL samples can be utilised to study antibodies from the lower respiratory tract, but the possibility of plasma exudation should be excluded.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 8","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1460","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6183924","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":"Inverse relationship between Fusobacterium nucleatum amount and tumor CD274 (PD-L1) expression in colorectal carcinoma","authors":"Tomotaka Ugai,&nbsp;Takashi Shimizu,&nbsp;Hidetaka Kawamura,&nbsp;Satoko Ugai,&nbsp;Yasutoshi Takashima,&nbsp;Genki Usui,&nbsp;Juha P V?yrynen,&nbsp;Kazuo Okadome,&nbsp;Koichiro Haruki,&nbsp;Naohiko Akimoto,&nbsp;Yohei Masugi,&nbsp;Annacarolina da Silva,&nbsp;Kosuke Mima,&nbsp;Xuehong Zhang,&nbsp;Andrew T Chan,&nbsp;Molin Wang,&nbsp;Wendy S Garrett,&nbsp;Gordon J Freeman,&nbsp;Jeffrey A Meyerhardt,&nbsp;Jonathan A Nowak,&nbsp;Mingyang Song,&nbsp;Marios Giannakis,&nbsp;Shuji Ogino","doi":"10.1002/cti2.1453","DOIUrl":"https://doi.org/10.1002/cti2.1453","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) immune checkpoint axis is known to regulate the antitumor immune response. Evidence also supports an immunosuppressive effect of <i>Fusobacterium nucleatum</i>. We hypothesised that tumor CD274 overexpression might be inversely associated with abundance of <i>F. nucleatum</i> in colorectal carcinoma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We assessed tumor CD274 expression by immunohistochemistry and <i>F. nucleatum</i> DNA within tumor tissue by quantitative PCR in 812 cases among 4465 incident rectal and colon cancer cases that had occurred in two prospective cohort studies. Multivariable logistic regression analyses with inverse probability weighting were used to adjust for selection bias because of tissue data availability and potential confounders including microsatellite instability status, CpG island methylator phenotype, LINE-1 methylation level and <i>KRAS</i>, <i>BRAF</i> and <i>PIK3CA</i> mutations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>Fusobacterium nucleatum</i> DNA was detected in tumor tissue in 109 (13%) cases. Tumor CD274 expression level was inversely associated with the amount of <i>F. nucleatum</i> in colorectal cancer tissue (<i>P</i> = 0.0077). For one category-unit increase in three ordinal <i>F. nucleatum</i> categories (negative vs. low vs. high), multivariable-adjusted odds ratios (with 95% confidence interval) of the low, intermediate and high CD274 categories (vs. negative) were 0.78 (0.41–1.51), 0.64 (0.32–1.28) and 0.50 (0.25–0.99), respectively (<i>P</i>_trend = 0.032).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Tumor CD274 expression level was inversely associated with the amount of <i>F. nucleatum</i> in colorectal cancer tissue, suggesting that different immunosuppressive mechanisms (i.e. PDCD1 immune checkpoint activation and tumor <i>F. nucleatum</i> enrichment) tend to be used by different tumor subgroups.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 8","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1453","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6083231","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 case of T-cell-Epstein–Barr virus-haemophagocytic lymphohistiocytosis and sustained remission following ruxolitinib therapy","authors":"Syed Ali,&nbsp;Sharon Choo,&nbsp;Laine Hosking,&nbsp;Anthony Smith,&nbsp;Tiffany Hughes","doi":"10.1002/cti2.1459","DOIUrl":"https://doi.org/10.1002/cti2.1459","url":null,"abstract":"Epstein–Barr virus (EBV) is a common cause of secondary haemophagocytic lymphohistiocytosis (HLH). While B cells are reservoirs for EBV, infection within T cells and NK cells in this disease can be difficult to treat.","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 7","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1459","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5803734","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":"Allogeneic haematopoietic cell transplants as dynamical systems: influence of early-term immune milieu on long-term T-cell recovery","authors":"Viktoriya Zelikson,&nbsp;Roy Sabo,&nbsp;Myrna Serrano,&nbsp;Younus Aqeel,&nbsp;Savannah Ward,&nbsp;Taha Al Juhaishi,&nbsp;May Aziz,&nbsp;Elizabeth Krieger,&nbsp;Gary Simmons,&nbsp;Catherine Roberts,&nbsp;Jason Reed,&nbsp;Gregory Buck,&nbsp;Amir Toor","doi":"10.1002/cti2.1458","DOIUrl":"https://doi.org/10.1002/cti2.1458","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Immune recovery following haematopoietic cell transplantation (HCT) functions as a dynamical system. Reducing the duration of intense immune suppression and augmenting antigen presentation has the potential to optimise T-cell reconstitution, potentially influencing long-term outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Based on donor-derived T-cell recovery, 26 patients were adaptively randomised between mycophenolate mofetil (MMF) administered for 30-day post-transplant with filgrastim for cytokine support (MMF30 arm, <i>N</i> = 11), or MMF given for 15 days with sargramostim (MMF15 arm, <i>N</i> = 15). All patients underwent <i>in vivo</i> T-cell depletion with 5.1 mg kg⁻¹ antithymocyte globulin (administered over 3 days, Day −9 through to Day −7) and received reduced intensity 450 cGy total body irradiation (3 fractions on Day −1 and Day 0). Patients underwent HLA-matched related and unrelated donor haematopoietic cell transplantation (HCT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Clinical outcomes were equivalent between the two groups. The MMF15 arm demonstrated superior T-cell, as well as T-cell subset recovery and a trend towards superior T-cell receptor (TCR) diversity in the first month with this difference persisting through the first year. T-cell repertoire recovery was more rapid and sustained, as well as more diverse in the MMF15 arm.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The long-term superior immune recovery in the MMF15 arm, administered GMCSF, is consistent with a disproportionate impact of early interventions in HCT. Modifying the ‘immune-milieu’ following allogeneic HCT is feasible and may influence long-term T-cell recovery.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 7","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1458","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5839002","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":"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}