Clinical & Translational Immunology最新文献

{"title":"Safety and immunogenicity of an adjuvanted human onchocerciasis vaccine candidate, OvMANE1: preclinical evaluation in a mice model","authors":"Derrick Neba Nebangwa,&nbsp;Mary Teke Efeti,&nbsp;Sonia M. E. Momnougui,&nbsp;Cabirou Mounchili Shintouo,&nbsp;Robert Adamu Shey,&nbsp;Rene Bilingwe Ayiseh,&nbsp;Fidele Ntie-Kang,&nbsp;Stephen Mbigha Ghogomu","doi":"10.1002/cti2.70114","DOIUrl":"10.1002/cti2.70114","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Onchocerciasis, caused by the filarial worm <i>Onchocerca volvulus</i>, remains a major public health challenge because of the limitations of ivermectin-based control strategies, thereby highlighting the need for more innovative tools such as vaccines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study investigated the safety and immunogenicity of a novel multi-epitope chimeric antigen, <i>Ov</i>MANE1 formulated with Freund's adjuvant, in BALB/c mice. Mice were immunised at three time points of 2-week intervals, with blood collected at each point to measure antibody levels and immune cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Adjuvanted-<i>Ov</i>MANE1 exhibited a promising safety profile, revealing neither any physical signs of toxicity nor behavioural abnormalities. Immunological assays showed significant increases in total IgG absorbance (OD 450 nm) after the first (<i>P</i> = 0.0260) and final booster doses (<i>P</i> = 0.026). Total IgG (<i>P</i> = 0.0086) and IgG1 (<i>P</i> = 0.0465) absorbances also increased significantly over the study period, suggesting sustained humoral immunity. Moreover, cellular responses were significantly enhanced, with elevated leucocyte count (<i>P</i> = 0.0190) and increased lymphocyte activity (<i>P</i> = 0.0397) observed in the adjuvanted-<i>Ov</i>MANE1 group compared to the control. Indeed, total leucocytes increased progressively from Day 0 to Day 39, with significant differences recorded in the test group between doses: Days 0–14 (<i>P</i> = 0.0043) and Days 14–28 (<i>P</i> = 0.0079). The pronounced production of relevant antibodies and induction of cellular immunity is indicative of a mixed Th1/Th2 response and antibody-dependent cellular cytotoxicity (ADCC) targeting <i>O. volvulus</i> L3 and/or other larval stages of the parasite.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These results position <i>Ov</i>MANE1 as a promising vaccine candidate against human onchocerciasis. However, further <i>in vivo</i> studies are needed to confirm and expand these findings.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148358653","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":"Early brain-penetrant immunotherapy reverses interferon signature and improves motor outcome in a case of ADAR1-related Aicardi-Goutières syndrome","authors":"Russell C Dale,&nbsp;Jessica Hayes,&nbsp;Velda X Han,&nbsp;Ruwani Dissanayake,&nbsp;Xianzhong Lau,&nbsp;Michelle Farrar,&nbsp;Brian Gloss,&nbsp;Markus Hofer,&nbsp;Esther Tantsis,&nbsp;Michelle Lorentzos,&nbsp;Safiyyah Abbas,&nbsp;Yanick J Crow,&nbsp;Shekeeb Mohammad,&nbsp;Shrujna Patel","doi":"10.1002/cti2.70113","DOIUrl":"https://doi.org/10.1002/cti2.70113","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy resulting from defects in nucleic acid metabolism and subsequent enhanced type I interferon signalling. We report how an expedited genomic diagnosis in conjunction with natural history data can enable a long-term brain-penetrant anti-inflammatory regimen to optimise neurodevelopmental outcomes in genetic autoinflammatory brain disorders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Expedited genomic testing identified compound heterozygous <i>ADAR1</i> mutations. Published natural history data from 33 patients with biallelic <i>ADAR1</i> mutations reported severe disability (GMFCS V) or death in 79%. To reduce neuroinflammation, we commenced a long-term pulsed oral dexamethasone protocol (20 mg/m² for 3 days every 3 weeks) from the age of 11 months, plus ruxolitinib, a Janus Kinase (JAK) inhibitor (5 mg per day).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At the age of 24 months, the patient was crawling and walking a few steps unaided, with a GMFCS level of II. Single-cell RNA sequencing of 41 164 leukocytes, taken before and after 3 months of treatment and compared to three age matched male controls, showed a reversal of upregulated pan-cellular interferon pathways, with most differentially expressed genes observed in monocytes. On treatment, there was statistically significant downregulation of key autoinflammatory genes, including nucleic acid sensing (<i>CGAS, IFIH1, SAMHD1</i>), interferon-stimulated genes (<i>ISG15 and IFIF44L</i>) and signalling (<i>JAK1</i>). Given the dual immune therapy, it was not possible to define whether the biological effect was related to dexamethasone or JAK inhibitor, or both.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Compared with natural history data, our data suggest that early diagnosis, and the use of early brain-penetrant immune suppressants (dexamethasone), may improve outcomes in <i>ADAR1</i> AGS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70113","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343318","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":"Effect of CXCR5, PD-1 and ICOS on B-cell responses and relevance to myasthenia gravis","authors":"Merve Çebi,&nbsp;Arman Çakar,&nbsp;Hacer Durmuş,&nbsp;Yeşim Parman,&nbsp;Güher Saruhan-Direskeneli","doi":"10.1002/cti2.70112","DOIUrl":"10.1002/cti2.70112","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>T follicular helper (Tfh) cells regulate B-cell responses within germinal centres primarily via programmed cell death protein 1 (PD-1) and inducible T-cell costimulator (ICOS), whereas CXC chemokine receptor type 5 (CXCR5)-negative T peripheral helper (Tph) cells provide similar support extra-follicularly. Both subsets contribute to the pathogenesis of acetylcholine receptor-antibody-positive myasthenia gravis (AChR-MG). This study investigated the roles of PD-1, ICOS and CXCR5 in T-cell-mediated B-cell activation to identify therapeutic targets for MG.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CD4 T cells from 10 healthy controls and six untreated AChR-MG patients were sorted by CXCR5, PD-1 and ICOS expression, stimulated with anti-CD3/CD28, and co-cultured with autologous CD19 B cells. Plasmablast differentiation, total AChR-IgG and cytokine productions were measured.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In healthy donors, PD-1⁺ or ICOS⁺ Tph cells modestly enhanced plasmablasts and IgG production, while CXCR5⁺ Tfh cells co-expressing PD-1 or ICOS induced significantly stronger B-cell responses. In AChR-MG patients, PD-1 expressing T cells promoted plasmablasts, antibody production and cytokine secretion regardless of CXCR5, with amplified effects in CXCR5⁺ co-cultures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>PD-1 expression on CD4⁺ T cells is associated with increased B-cell helper capacity. This effect is more pronounced in Tfh-related contexts and is linked to dysregulated humoral immune responses in MG. PD-1 appears to play a central role in the pathogenesis of MG, primarily through Tfh cell activity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13283754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300297","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":"Development and functional adaptation of intestinal macrophages across the lifespan","authors":"Baha Mustafa,&nbsp;Elisa L Hill-Yardin,&nbsp;Sarah J Spencer","doi":"10.1002/cti2.70111","DOIUrl":"10.1002/cti2.70111","url":null,"abstract":"<p>Macrophages of the gastrointestinal system are central regulators of gut development, homeostasis and disease, yet their origin, functional diversification and life stage-specific roles remain incompletely integrated. This review aimed to provide a comprehensive synthesis of current knowledge on intestinal macrophage ontogeny, heterogeneity and function from prenatal development through adulthood and into the aging phase. We highlight emerging evidence defining embryonic and monocyte-derived macrophage populations, their specialised roles in tissue remodelling, immune regulation, vascular and neural support, and their dynamic turnover across the lifespan. The review also examines how disruption of key regulatory pathways, including those relating to interleukin 10 (IL10), transforming growth factor (TGFβ) and metabolic signalling, contributes to macrophage dysfunction in inflammatory bowel disease, as an example of a gastrointestinal disorder with macrophage involvement. By integrating findings from lineage-tracing, single-cell transcriptomics and functional studies, this review provides a unified framework for understanding intestinal macrophage biology across life stages. This review provides a strengthened understanding of intestinal macrophage biology and establishes a knowledge base for translational therapies that can modify macrophage function to target inflammatory disorders and maintain gut health.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13270256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148269567","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":"Single-cell and repertoire profiling reveals immune remodelling in paediatric upper airway: insights from adenoid hypertrophy","authors":"Chao Wang,&nbsp;Yufei Pan,&nbsp;Xiao Han,&nbsp;Kai Sun,&nbsp;Jing Li,&nbsp;Yuanyuan Lu,&nbsp;Zhenkun Yu","doi":"10.1002/cti2.70101","DOIUrl":"https://doi.org/10.1002/cti2.70101","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To characterise the immune cellular landscape and paired B-cell and T-cell receptor repertoires of hypertrophic adenoids in children with obstructive sleep apnoea.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed 10x Genomics 5′ single-cell RNA sequencing with paired V(D)J profiling on adenoid tissues from children (AH, <i>n</i> = 4; control, <i>n</i> = 4) and analysed 72 076 high-quality cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with controls, AH adenoids exhibited an expanded B-cell compartment (62.26% vs 51.94%, <i>P</i> = 0.029) and a modest increase in plasmacytoid dendritic cells (0.37% vs 0.15%, <i>P</i> = 0.029), accompanied by reduced T-cell representation (34.19% vs 44.54%, <i>P</i> = 0.029). Within the B-cell compartment, GC B cell populations were expanded in AH, particularly Cycling B cells (15.07% vs 2.86%, <i>P</i> = 0.029), whereas memory B cells were reduced (21.48% vs 32.18%, <i>P</i> = 0.029). B-cell receptor analysis demonstrated reduced somatic hypermutation frequencies across multiple mature B-cell subsets in AH, accompanied by an isotype distribution skewed towards IgM with reduced class-switched fractions. Although CD8⁺ tissue-resident memory T-cell (TRM) frequencies were similar between groups, CD8⁺ TRM in AH adenoids displayed interferon-polarised and antigen-processing signatures, and T-cell clonal expansion occurred predominantly within this subset.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest that AH is not merely an anatomic cause of upper airway obstruction but also an immunologically active mucosal state associated with ongoing immune remodelling and antiviral defence.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 6","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148174302","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":"Control of poorly immunogenic tumors with systemic STING agonist-loaded liposomes targeting cross-presenting dendritic cells","authors":"Bijun Zeng,&nbsp;Meghna Talekar,&nbsp;Thais Aragao-Horoiwa,&nbsp;Amy Cameron,&nbsp;Guangzu Zhao,&nbsp;Yulia Zybina,&nbsp;Wendy Blumenschein,&nbsp;Karyn van de Mark,&nbsp;Wittaya Suwakulsiri,&nbsp;Gretchen A Baltus,&nbsp;Riccardo Dolcetti,&nbsp;Ranjeny Thomas","doi":"10.1002/cti2.70110","DOIUrl":"https://doi.org/10.1002/cti2.70110","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Cancer vaccines combine tumor antigen and adjuvant to drive an anti-tumor immune response. Clec9A-targeted nanoparticles directing CD4 and CD8 neo-epitopes to cross-presenting dendritic cells (DCs) stimulate adjuvant-free therapeutically effective tumor-specific immunity. However, personalised neo-epitopes limit the scalability of Clec9A nanoparticles for clinical translation. Since Clec9A⁺ DCs constitutively present relevant neoepitopes in tumors but are suppressed in tumor microenvironments, we developed Clec9A-targeted STING or RIG-I liposomes to enhance endogenous tumor immunity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Liposomes encapsulating RIG-I or the STING agonist MSA-1 and functionalised with Clec9A binding peptide WH were optimised for uptake by Clec9A⁺ conventional and plasmacytoid DCs <i>in vivo</i>. Biodistribution after i.v. administration was determined with <i>in vivo</i> imaging and cellular uptake and activation with flow cytometry. Plasma was analysed for type 1 interferon (IFN) by ELISA and liver, spleen, tumor, blood, kidney, heart and tumor draining lymph node transcriptomes were analysed with Nanostring. Effects on tumor growth and survival, and tumor-specific T cells were evaluated using the B16 melanoma model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Clec9A-targeting liposomes administered i.v. were distributed to spleen, liver and tumor and were taken up by cross-presenting and plasmacytoid DCs. Type 1 IFN production and DC, B- and T-cell activation were more effective with i.v. Clec9A-STING than Clec9A-RIG-I liposomes. Intravenous Clec9A-STING liposomes stimulated IFN-dependent transcription in blood, lung, tumor, and draining lymph nodes. Intravenous Clec9A-STING liposomes, or intra-tumoral Clec9A-RIG-I liposomes significantly suppressed B16-F10 melanoma growth and induced neo-epitope and survivin-specific CD4⁺ and CD8⁺ T-cell responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Clec9A-STING liposomes are a scalable, translatable tumor-targeted immunotherapy platform.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 6","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148173681","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":"Alterations of circulating innate lymphoid cells in recent-onset type 1 diabetes","authors":"Ariadna Roig,&nbsp;David Perna-Barrull,&nbsp;Eva Aguilera,&nbsp;Sebastián Pérez,&nbsp; Marta Vives-Pi,&nbsp;Raquel Planas","doi":"10.1002/cti2.70109","DOIUrl":"https://doi.org/10.1002/cti2.70109","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Type 1 diabetes (T1D) is driven by autoreactive T lymphocytes with contributions from innate immune compartments, yet early innate immune alterations associated with autoimmune amplification remain incompletely defined. We aimed at investigating whether circulating innate lymphoid cells (ILCs) contribute to these processes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Circulating ILCs from patients with recent-onset T1D (<i>n</i> = 12) and age-matched healthy donors were analysed by spectral flow cytometry and targeted gene-expression profiling of purified ILC progenitors (ILCP). Metabolic and inflammatory modulation of ILC activation was assessed in vitro. Antigen presentation to autologous memory CD4 T cells was functionally evaluated. Findings were examined across disease progression in NOD mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Total ILC frequencies were comparable between groups; however, ILC1 and ILCP from T1D patients displayed increased activation markers (CD69, HLA-DR). ILCP exhibited reduced expression of migratory (CCR7, CCR6) and regulatory-associated genes (ICOS, CD58). Glycolytic inhibition selectively attenuated ILCP activation, supporting a metabolic contribution. IL-1β, and to a lesser extent IFNγ, enhanced antigen presentation-associated phenotypes in human circulating ILCs. Upon inflammatory pre-activation, insulin peptide-loaded circulating ILCs upregulated MHC class II–associated markers and induced antigen-specific activation of autologous CD4⁺ memory T cells. NOD mice recapitulated ILC activation and MHC class II expression patterns during diabetes progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Circulating ILCs in recent-onset T1D display a pre-activated, metabolically regulated phenotype with functional antigen-presenting capacity, supporting a potential role in autoimmune amplification. The findings of this exploratory study provide translational insight into innate immune dysregulation associated with recent-onset T1D.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 6","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148173680","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":"Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet-induced obesity","authors":"Yizhuo Wang,&nbsp;Divya Ramnath,&nbsp;Kaustav Das Gupta,&nbsp;P Prakrithi,&nbsp;Kavita Bisht,&nbsp;Gregory C Miller,&nbsp;Zherui Xiong,&nbsp;Yujun Wan,&nbsp;Ellen N Tejo,&nbsp;James EB Curson,&nbsp;Rishika Abrol,&nbsp;Sahar Keshvari,&nbsp;Kimberley S Gunther,&nbsp;Jordan D Atkinson,&nbsp;Zhixuan Loh,&nbsp;Jessica A Engel,&nbsp;Christian R Engwerda,&nbsp;Sabrina Sofia Burgener,&nbsp;Kate Schroder,&nbsp;David P Fairlie,&nbsp;Andrew D Clouston,&nbsp;Elizabeth E Powell,&nbsp;Katharine M Irvine,&nbsp;Mitchell A Sullivan,&nbsp;Jean-Pierre Lévesque,&nbsp;Quan Nguyen,&nbsp;Matthew J Sweet,&nbsp;Denuja Karunakaran","doi":"10.1002/cti2.70100","DOIUrl":"https://doi.org/10.1002/cti2.70100","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Histone deacetylase 7 (HDAC7), a classical HDAC family member, promotes LPS-inducible glycolysis and inflammatory mediator production in macrophages, innate immune cells that contribute to pathology in metabolic diseases. Here, we investigated myeloid HDAC7 functions in obesity-driven metabolic disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used gain- and loss-of-function genetic approaches in mice to investigate myeloid HDAC7 functions in hepatic inflammation and metabolic disease, as well as associations with hepatic gene signatures characteristic of advanced chronic liver disease (CLD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Transgenic expression of <i>Hdac7</i> in myeloid cells increased liver inflammation and liver mRNA levels of <i>Ccl2</i> and <i>Il1b</i>, key inflammatory mediators linked to CLD. Liver glycogen levels were also decreased, another feature of CLD. Transgenic expression of <i>Hdac7</i> in myeloid cells mimicked the hepatic inflammatory phenotype that was observed in mice fed a high fat, high cholesterol and high sucrose (HFHCHS) diet, an obesity model that mimics some features of metabolic dysfunction-associated steatotic liver disease. In myeloid <i>Hdac7</i> transgenic mice fed a HFHCHS diet, relative weight gain was increased, fasted glucose levels were elevated, and glucose tolerance was dysregulated by comparison to control mice. Conversely, fasted blood glucose levels were reduced and glucose tolerance was improved in myeloid <i>Hdac7</i>-deleted mice on a HFHCHS diet. <i>HDAC7</i> mRNA levels were also elevated in the livers of people with advanced CLD and spatial transcriptomics revealed that myeloid HDAC7 directs hepatic gene signatures characteristic of advanced CLD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Myeloid HDAC7 contributes to hepatic inflammation and systemic glucose dysregulation in a mouse model of obesity and liver inflammation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 6","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148099952","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148077795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant intra-epithelial lymphocytes cause enterocyte cell death in refractory celiac disease by CD103-β7-receptor-mediated granzyme-B degranulation which can be restored by etrolizumab.","authors":"Daan A R Castelijn, Jolanda M W van de Water, Laura R de Baaij, Bridget S McGlinchy, Michelle van Leeuwen, Sander P J Joosten, Nikita Alberts, Margherita Rossi, Martine Reijm, Jolien C Hollander, Petra Bonnet, Yvonne M C Kooy-Winkelaar, Frits Koning, Steven T Pals, Gerd Bouma, Chris J L M Meijer, Hetty J Bontkes, Chris J J Mulder, Saskia A G M Cillessen","doi":"10.1002/cti2.70099","DOIUrl":"10.1002/cti2.70099","url":null,"abstract":"<p><strong>Objectives: </strong>Refractory celiac disease type II (RCDII) is an intestinal tumor of aberrant intra-epithelial T-lymphocytes (IEL). The severe enteropathy found in RCDII is caused by aberrant IEL that exert cytotoxicity against enterocytes. In this study, we investigated the cell death mechanism responsible for villous atrophy in RCDII.</p><p><strong>Methods: </strong>Aberrant IEL were isolated from duodenal biopsies of RCDII patients. Enterocyte and RCDII patient-derived cell lines and human small intestinal organoids were used. mRNA expression was determined with reverse transcriptase-multiplex ligation-dependent probe amplification. Protein expression, degranulation and enterocyte killing were measured using flow cytometry, immunofluorescence or bright field microscopy. Secretion of granzyme-B was detected by enzyme immunoassay.</p><p><strong>Results: </strong>Levels of granzyme-B expression were significantly upregulated in aberrant IEL of RCDII patients compared to patients with celiac disease (CD) on gluten-free diet (<i>P</i> = 0.0001) and correlated with severity of villous atrophy and clinical response to therapy. Killing of intestinal epithelial cells was caused by granzyme-B. For granzyme-B degranulation and subsequent cytotoxicity, cell-cell binding via the CD103-receptor, which was upregulated on aberrant IEL, was essential. In a preclinical model, aberrant IEL migrated to the intestinal organoids and induced organoid disintegration and CD103-dependent cell death. Targeting CD103-heterodimeric partner β7 with therapeutic monoclonal antibody etrolizumab prevented enterocyte cell killing and resulted in survival of organoids.</p><p><strong>Conclusion: </strong>Killing of enterocytes in RCDII patients depends on degranulation of granzyme-B by aberrant IEL through CD103-β7 binding. By blocking this interaction, etrolizumab restores the intestinal epithelium and therefore should be considered as potential therapy for RCDII patients.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 ","pages":"e70099"},"PeriodicalIF":3.4,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13175919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961504","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}