Hang Zhou, Xin Zhao, Ru Chen, Tianqi Wang, Yi Zhuang, Yanying Liu
Objectives
To describe the first reported case of coexisting Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) syndrome and IgG4-related disease (IgG4-RD) and to evaluate the therapeutic response to Upadacitinib.
Methods
We described the clinical course, investigations, treatments, and outcomes of a 45-year-old woman initially diagnosed with SAPHO syndrome who subsequently developed IgG4-RD. Laboratory tests, imaging findings, and therapeutic responses were analyzed.
Results
The patient developed IgG4-RD-related organ involvement during the course of SAPHO syndrome. Although glucocorticoid therapy was initially effective, disease flares occurred upon tapering. Upadacitinib was initiated as an escalation therapy, leading to rapid improvement in clinical symptoms and normalization of inflammatory and IgG4-related serological markers. Sustained remission was maintained with continued treatment.
Conclusion
This case demonstrates that Upadacitinib may be an effective therapeutic option for patients with concurrent SAPHO syndrome and IgG4-RD. The observed clinical response supports the potential role of JAK-STAT pathway modulation in managing overlapping immune-mediated disorders.
{"title":"Coexistence of SAPHO syndrome and IgG4-related disease with Upadacitinib","authors":"Hang Zhou, Xin Zhao, Ru Chen, Tianqi Wang, Yi Zhuang, Yanying Liu","doi":"10.1002/cti2.70065","DOIUrl":"10.1002/cti2.70065","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To describe the first reported case of coexisting Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) syndrome and IgG4-related disease (IgG4-RD) and to evaluate the therapeutic response to Upadacitinib.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We described the clinical course, investigations, treatments, and outcomes of a 45-year-old woman initially diagnosed with SAPHO syndrome who subsequently developed IgG4-RD. Laboratory tests, imaging findings, and therapeutic responses were analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The patient developed IgG4-RD-related organ involvement during the course of SAPHO syndrome. Although glucocorticoid therapy was initially effective, disease flares occurred upon tapering. Upadacitinib was initiated as an escalation therapy, leading to rapid improvement in clinical symptoms and normalization of inflammatory and IgG4-related serological markers. Sustained remission was maintained with continued treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This case demonstrates that Upadacitinib may be an effective therapeutic option for patients with concurrent SAPHO syndrome and IgG4-RD. The observed clinical response supports the potential role of JAK-STAT pathway modulation in managing overlapping immune-mediated disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12626648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555890","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}
Jonathan Garnier, Anaïs Palen, Xavier Durand, Jacques Ewald, Amira Ben Amara, Marie Sarah Rouvière, Samuel Granjeaud, Gregoire Bellan, Benjamin Choisy, Franck Verdonk, Brice Gaudilliere, Caroline Gouarne, Olivier Turrini, Daniel Olive, Anne Sophie Chretien
Objectives
Despite advancements in surgical techniques and perioperative care, pancreatic surgery remains a high-risk procedure with significant morbidity and mortality. Furthermore, understanding its impact on the immune system is essential for designing strategies that interact with it. The aim of this study was to elucidate the immunomodulation that occurs following pancreatectomy.
Methods
Patients were recruited for the IMMUNOPANC trial (NCT03978702). We performed mass cytometry to analyse the circulating immune subpopulations and integrated the data using the hierarchical-stochastic neighbour embedding clustering analysis and Stabl algorithm.
Results
Among the enrolled 39 patients, 33 (84.5%) had undergone pancreatectomy for neoplasia including 13 (39%) with pancreatic ductal adenocarcinoma. Twelve (32%) patients developed pancreatic fistula with a 90-day mortality rate of 2.5%. We phenotyped 156 samples and observed a significant increase in myeloid cells (26% vs. 34%, P = 0.018) after pancreatectomy. Natural killer cell proportions decreased on postoperative day one (POD1) compared with the preoperative levels (7% vs. 12%, P < 0.001). Similarly, both CD8+ and CD4+ T-cell proportions decreased significantly post-surgery (25% and 40%, respectively, P < 0.001). During a narrow window, we observed the alteration of NK cells, contraction of CD8+ T cells, and increase in the proportion of naive CD4+ T cells. These changes may be a result of the immune response to surgery but could also reflect lymphoid organ demargination.
Conclusion
This study presents the first analysis of peripheral immune system trajectories following pancreatic surgery. Understanding these dynamics would facilitate the restoration of postoperative immunity, which is potentially crucial for recovery.
{"title":"Immediate variations in high-dimensional circulating immune cells following pancreatectomy","authors":"Jonathan Garnier, Anaïs Palen, Xavier Durand, Jacques Ewald, Amira Ben Amara, Marie Sarah Rouvière, Samuel Granjeaud, Gregoire Bellan, Benjamin Choisy, Franck Verdonk, Brice Gaudilliere, Caroline Gouarne, Olivier Turrini, Daniel Olive, Anne Sophie Chretien","doi":"10.1002/cti2.70059","DOIUrl":"10.1002/cti2.70059","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Despite advancements in surgical techniques and perioperative care, pancreatic surgery remains a high-risk procedure with significant morbidity and mortality. Furthermore, understanding its impact on the immune system is essential for designing strategies that interact with it. The aim of this study was to elucidate the immunomodulation that occurs following pancreatectomy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients were recruited for the IMMUNOPANC trial (NCT03978702). We performed mass cytometry to analyse the circulating immune subpopulations and integrated the data using the hierarchical-stochastic neighbour embedding clustering analysis and Stabl algorithm.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among the enrolled 39 patients, 33 (84.5%) had undergone pancreatectomy for neoplasia including 13 (39%) with pancreatic ductal adenocarcinoma. Twelve (32%) patients developed pancreatic fistula with a 90-day mortality rate of 2.5%. We phenotyped 156 samples and observed a significant increase in myeloid cells (26% vs. 34%, <i>P</i> = 0.018) after pancreatectomy. Natural killer cell proportions decreased on postoperative day one (POD1) compared with the preoperative levels (7% vs. 12%, <i>P <</i> 0.001). Similarly, both CD8<sup>+</sup> and CD4<sup>+</sup> T-cell proportions decreased significantly post-surgery (25% and 40%, respectively, <i>P <</i> 0.001). During a narrow window, we observed the alteration of NK cells, contraction of CD8<sup>+</sup> T cells, and increase in the proportion of naive CD4<sup>+</sup> T cells. These changes may be a result of the immune response to surgery but could also reflect lymphoid organ demargination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study presents the first analysis of peripheral immune system trajectories following pancreatic surgery. Understanding these dynamics would facilitate the restoration of postoperative immunity, which is potentially crucial for recovery.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12620249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547337","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}
Amal Elhage, Janna H Hadaya, Chloe Sligar, Debbie Watson, Sahil Adriouch, Ronald Sluyter
Objectives
Graft-versus-host disease (GVHD) is an inflammatory disorder that arises following allogeneic haematopoietic stem cell transplantation. P2X7 is an extracellular ATP-gated cation channel present on immune cells. P2X7 blockade with small molecule inhibitors impairs GVHD development in a humanised mouse model. This study investigated whether adeno-associated viral (AAV) vectors encoding nanobodies (Nbs) that block mouse P2X7 (mP2X7) or both mP2X7 and human P2X7 (m/hP2X7) impair GVHD development in this model.
Methods
On Day −21, NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice were injected intramuscularly with 10 × 1010 viral genomes encoding either green fluorescent protein (GFP), an anti-mP2X7 Nb or an anti-m/hP2X7 Nb, or with saline. On Day 0, mice were euthanised or injected intraperitoneally with 10 × 106 human peripheral blood mononuclear cells and monitored thrice weekly for signs of GVHD until the experiment or disease endpoint.
Results
The anti-m/hP2X7 and anti-mP2X7 Nbs reduced clinical GVHD and time to disease onset, as well as liver and lung GVHD. Both Nbs reduced liver human T helper (Th)17 cells. Sera collected at Day 0 and disease endpoint from treated mice, but not from control mice, completely blocked P2X7 activity in human RPMI 8226 and/or murine J774 cells, confirming circulating anti-P2X7 Nbs in mice from Day 0 to disease endpoint.
Conclusion
This study indicates that P2X7 blockade with an anti-m/hP2X7 and to a lesser extent an anti-mP2X7 Nb reduces GVHD progression in humanised mice. This supports the future testing of these P2X7 biologics as a prophylactic therapy for GVHD.
{"title":"Adeno-associated viral vectors encoding anti-P2X7 nanobodies reduce graft-versus-host disease in a humanised mouse model","authors":"Amal Elhage, Janna H Hadaya, Chloe Sligar, Debbie Watson, Sahil Adriouch, Ronald Sluyter","doi":"10.1002/cti2.70061","DOIUrl":"https://doi.org/10.1002/cti2.70061","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Graft-versus-host disease (GVHD) is an inflammatory disorder that arises following allogeneic haematopoietic stem cell transplantation. P2X7 is an extracellular ATP-gated cation channel present on immune cells. P2X7 blockade with small molecule inhibitors impairs GVHD development in a humanised mouse model. This study investigated whether adeno-associated viral (AAV) vectors encoding nanobodies (Nbs) that block mouse P2X7 (mP2X7) or both mP2X7 and human P2X7 (m/hP2X7) impair GVHD development in this model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>On Day −21, NOD.Cg-<i>Prkdc</i><sup><i>scid</i></sup><i>Il2rg</i><sup><i>tm1Wjl</i></sup>/SzJ (NSG) mice were injected intramuscularly with 10 × 10<sup>10</sup> viral genomes encoding either green fluorescent protein (GFP), an anti-mP2X7 Nb or an anti-m/hP2X7 Nb, or with saline. On Day 0, mice were euthanised or injected intraperitoneally with 10 × 10<sup>6</sup> human peripheral blood mononuclear cells and monitored thrice weekly for signs of GVHD until the experiment or disease endpoint.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The anti-m/hP2X7 and anti-mP2X7 Nbs reduced clinical GVHD and time to disease onset, as well as liver and lung GVHD. Both Nbs reduced liver human T helper (Th)17 cells. Sera collected at Day 0 and disease endpoint from treated mice, but not from control mice, completely blocked P2X7 activity in human RPMI 8226 and/or murine J774 cells, confirming circulating anti-P2X7 Nbs in mice from Day 0 to disease endpoint.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study indicates that P2X7 blockade with an anti-m/hP2X7 and to a lesser extent an anti-mP2X7 Nb reduces GVHD progression in humanised mice. This supports the future testing of these P2X7 biologics as a prophylactic therapy for GVHD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469775","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}
Yunus Kuijpers, M Liset Rietman, H Susan J Picavet, Peter Engelfriet, W M Monique Verschuren, Anne-Marie Buisman
Objectives
Older persons generally have weaker antibody responses to vaccines than younger individuals, but heterogeneity is large. We aimed to identify genetic variants associated with primary SARS-CoV-2 vaccine-induced antibody responses in older persons that might contribute to this heterogeneity.
Methods
Demographic and genotype data were collected in the Doetinchem Cohort Study prior to the COVID-19 pandemic. Antibody responses were measured 1 month after the first and second SARS-CoV-2 vaccinations, and genome-wide association analysis was performed in 842 and 890 individuals respectively. Polygenic scores were calculated and tested in an independent sample, and the variance explained by the scores was estimated using a bootstrap procedure. Genes were mapped to genome-wide suggestive (P < 1 × 10−5) loci, and gene set enrichment was performed using the hypergeometric test.
Results
Antibody responses 1 month after the first and second SARS-CoV-2 vaccinations were linked to genome-wide significant (P < 5 × 10−8) loci on Chromosome 5. Polygenic scores related to these antibody responses could explain 9% (95% CI P1: [−4% to 21%], 95% CI P2: [−4% to 24%]) of the variance. Genome-wide suggestive loci related to the responses after two vaccinations could be mapped to several genes in the human leukocyte antigen (HLA) region on chromosome 6p21.
Conclusion
Genetic variation is suggested to play a role in the primary vaccine-induced IgG antibody responses to SARS-CoV-2 in older persons. The most prominent source of variation was found to lie in HLA genes, which are enriched in several immune pathways and immune-mediated diseases.
目的：老年人对疫苗的抗体反应通常比年轻人弱，但异质性很大。我们的目的是确定与老年人原发性SARS-CoV-2疫苗诱导的抗体反应相关的遗传变异，这些变异可能导致这种异质性。方法：收集COVID-19大流行前Doetinchem队列研究的人口统计学和基因型数据。在第一次和第二次SARS-CoV-2疫苗接种1个月后测量抗体应答，并分别对842和890例个体进行全基因组关联分析。在独立样本中计算和测试多基因分数，并使用自举程序估计分数解释的方差。基因被定位到全基因组暗示（P -5）位点，并使用超几何测试进行基因集富集。结果：第一次和第二次SARS-CoV-2疫苗接种1个月后的抗体应答与5号染色体上全基因组显著（P -8）位点相关。与这些抗体反应相关的多基因评分可以解释9%的方差（95% CI P1:[-4%至21%]，95% CI P2:[-4%至24%]）。在全基因组范围内，与两次接种后的应答相关的暗示性位点可以定位到6p21染色体上人类白细胞抗原（HLA）区域的几个基因。结论：遗传变异可能在老年人一次疫苗诱导的SARS-CoV-2 IgG抗体应答中起作用。最突出的变异来源是HLA基因，它在几种免疫途径和免疫介导的疾病中富集。
{"title":"Genetic differences in the HLA region contribute to the variability in SARS-CoV-2 vaccine responsiveness of older persons: the Doetinchem Cohort Study","authors":"Yunus Kuijpers, M Liset Rietman, H Susan J Picavet, Peter Engelfriet, W M Monique Verschuren, Anne-Marie Buisman","doi":"10.1002/cti2.70058","DOIUrl":"10.1002/cti2.70058","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Older persons generally have weaker antibody responses to vaccines than younger individuals, but heterogeneity is large. We aimed to identify genetic variants associated with primary SARS-CoV-2 vaccine-induced antibody responses in older persons that might contribute to this heterogeneity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Demographic and genotype data were collected in the Doetinchem Cohort Study prior to the COVID-19 pandemic. Antibody responses were measured 1 month after the first and second SARS-CoV-2 vaccinations, and genome-wide association analysis was performed in 842 and 890 individuals respectively. Polygenic scores were calculated and tested in an independent sample, and the variance explained by the scores was estimated using a bootstrap procedure. Genes were mapped to genome-wide suggestive (<i>P</i> < 1 × 10<sup>−5</sup>) loci, and gene set enrichment was performed using the hypergeometric test.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Antibody responses 1 month after the first and second SARS-CoV-2 vaccinations were linked to genome-wide significant (<i>P</i> < 5 × 10<sup>−8</sup>) loci on Chromosome 5. Polygenic scores related to these antibody responses could explain 9% (95% CI P1: [−4% to 21%], 95% CI P2: [−4% to 24%]) of the variance. Genome-wide suggestive loci related to the responses after two vaccinations could be mapped to several genes in the human leukocyte antigen (HLA) region on chromosome 6p21.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Genetic variation is suggested to play a role in the primary vaccine-induced IgG antibody responses to SARS-CoV-2 in older persons. The most prominent source of variation was found to lie in HLA genes, which are enriched in several immune pathways and immune-mediated diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12588338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457273","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}
The skin is a vital organ that protects organisms from external insults, providing a barrier to the outside environment. The cellular system of the skin consists of highly specialised immune and non-immune cells, which are equipped to respond promptly, providing effective immunity and restoring tissue homeostasis. Well-coordinated cellular communication involves cells and soluble factors, which are essential for maintaining the balance and protecting the skin from inflammatory skin diseases, impaired tissue repair and recurring infections. In this review, we will focus on the recent development of understanding how cellular networks orchestrate skin immunity via a coordinated communication system of soluble factors and their signalling pathways, with a focus on psoriasis as a model of inflammatory skin disease.
{"title":"Skin immunity and inflammation: cellular interactions and communication","authors":"Divyaa Narayanan, Seen Ling Sim, Snehlata Kumari","doi":"10.1002/cti2.70053","DOIUrl":"10.1002/cti2.70053","url":null,"abstract":"<p>The skin is a vital organ that protects organisms from external insults, providing a barrier to the outside environment. The cellular system of the skin consists of highly specialised immune and non-immune cells, which are equipped to respond promptly, providing effective immunity and restoring tissue homeostasis. Well-coordinated cellular communication involves cells and soluble factors, which are essential for maintaining the balance and protecting the skin from inflammatory skin diseases, impaired tissue repair and recurring infections. In this review, we will focus on the recent development of understanding how cellular networks orchestrate skin immunity via a coordinated communication system of soluble factors and their signalling pathways, with a focus on psoriasis as a model of inflammatory skin disease.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12581170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443571","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}
Alba Díaz Herrero, Phuong-Ha Le, Loic Renaud, Véronique Meignin, Catherine Thieblemont, Véronique Blanc, Vassili Soumelis, Pierre Tonnerre
Objectives
Diffuse large B-cell lymphoma (DLBCL) constitutes 30–40% of non-Hodgkin lymphoma cases. Despite therapeutic advances, persistence of relapsed cases has been linked to the complex tumor microenvironment (TME) and its interactions with lymphoma cells. In particular, characterising T-cell subsets, including rare cell types, and their interplay with the remaining TME is crucial for unravelling DLBCL pathogenesis and refining therapeutic strategies.
Methods
Using flow and spectral cytometry with unsupervised analysis, we investigated T-cell subpopulations across DLBCL biopsies and control lymph nodes (LN). We also inferred communication pathways between T cells and other immune cells in the TME based on the correlation of ligand–receptor expression.
Results
Our analysis revealed a higher frequency of CD8+ follicular regulatory T (Tfr) cells in DLBCL biopsies compared to control LN. These cells exhibited an effector-memory phenotype (CD45RA− CCR7−), expressed follicular markers (PD-1+ CXCR5+) and had a regulatory profile (CD127− CD25+) along with an activation/co-stimulatory signature (HLA-DR+, ICOS+, CD95+). Correlation analysis highlighted a co-stimulatory interaction between lymphoma B cells and CD8+ Tfr cells through the ICOS/ICOSL pathway, which may contribute to a protumor effect. Validation in independent scRNAseq and flow cytometry datasets confirmed the notable prevalence of CD8+ Tfr cells in DLBCL biopsies.
Conclusions
Our study highlights the utility of high-dimensional computational cytometry in elucidating T-cell subpopulations, including an increased frequency of CD8+ follicular regulatory T cells and their communication patterns within the DLBCL TME. This unbiased approach sheds light on novel cellular mechanisms in DLBCL, uncovering potential targets and biomarkers for immunotherapy.
{"title":"High-dimensional spectral cytometry identifies follicular regulatory CD8+ T cells in diffuse large B-cell lymphoma","authors":"Alba Díaz Herrero, Phuong-Ha Le, Loic Renaud, Véronique Meignin, Catherine Thieblemont, Véronique Blanc, Vassili Soumelis, Pierre Tonnerre","doi":"10.1002/cti2.70062","DOIUrl":"10.1002/cti2.70062","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Diffuse large B-cell lymphoma (DLBCL) constitutes 30–40% of non-Hodgkin lymphoma cases. Despite therapeutic advances, persistence of relapsed cases has been linked to the complex tumor microenvironment (TME) and its interactions with lymphoma cells. In particular, characterising T-cell subsets, including rare cell types, and their interplay with the remaining TME is crucial for unravelling DLBCL pathogenesis and refining therapeutic strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using flow and spectral cytometry with unsupervised analysis, we investigated T-cell subpopulations across DLBCL biopsies and control lymph nodes (LN). We also inferred communication pathways between T cells and other immune cells in the TME based on the correlation of ligand–receptor expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our analysis revealed a higher frequency of CD8<sup>+</sup> follicular regulatory T (Tfr) cells in DLBCL biopsies compared to control LN. These cells exhibited an effector-memory phenotype (CD45RA<sup>−</sup> CCR7<sup>−</sup>), expressed follicular markers (PD-1<sup>+</sup> CXCR5<sup>+</sup>) and had a regulatory profile (CD127<sup>−</sup> CD25<sup>+</sup>) along with an activation/co-stimulatory signature (HLA-DR<sup>+</sup>, ICOS<sup>+</sup>, CD95<sup>+</sup>). Correlation analysis highlighted a co-stimulatory interaction between lymphoma B cells and CD8<sup>+</sup> Tfr cells through the ICOS/ICOSL pathway, which may contribute to a protumor effect. Validation in independent scRNAseq and flow cytometry datasets confirmed the notable prevalence of CD8<sup>+</sup> Tfr cells in DLBCL biopsies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study highlights the utility of high-dimensional computational cytometry in elucidating T-cell subpopulations, including an increased frequency of CD8<sup>+</sup> follicular regulatory T cells and their communication patterns within the DLBCL TME. This unbiased approach sheds light on novel cellular mechanisms in DLBCL, uncovering potential targets and biomarkers for immunotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12581182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443425","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}
Romy Böttcher-Loschinski, Franziska Karl, Diana Drettwan, Johannes Wittmann, Benedikt Jacobs, Simon Völkl, Heiko Bruns, Andreas Mackensen, Dimitrios Mougiakakos
Objectives
Allogeneic stem cell transplantation (allo-SCT) is the only curative treatment option for several haematologic malignancies. Its therapeutic principle is based on the donor T cells' ability to eliminate any residual malignant cells. Despite its success, challenges such as graft-versus-host disease (GvHD) and disease relapse persist. Recent studies emphasise the role of the metabolic environment in shaping T-cell responses. This study investigates the impact of serum metabolites on T-cell responses following allo-SCT.
Methods
Metabolite levels in serum samples from 55 allo-SCT patients transplanted between November 2015 and October 2018 were analysed by nuclear magnetic resonance (NMR) spectroscopy for six time points after transplantation. These metabolite profiles were correlated with clinical data and T-cell characteristics obtained by flow cytometry-based immunomonitoring. High-density lipoprotein (HDL) emerged as a key factor of interest. To explore the potential relationship between T-cell-related differences and HDL levels, healthy donor T-cell cultures supplemented with HDL were performed.
Results
Elevated HDL levels were associated with acute GvHD (aGvHD) and relapse. Patients with high HDL serum levels exhibited a delayed normalisation of T-cell frequencies and increased effector-memory CD8+ T-cell frequencies. In vitro experiments revealed reduced proliferation and expression of activation/effector molecules after exposure to HDL. Effects of HDL on memory T-cell subset formation resembled the in situ findings in patients.
Conclusions
AGvHD was linked to elevated HDL levels, potentially affecting T-cell-mediated graft-versus-leukaemia (GvL) activity and promoting relapse. HDL could therefore be a potential biomarker for the success of allo-SCT and a lever for improving patients' outcomes.
{"title":"Elevated high-density lipoprotein levels following acute graft-versus-host disease onset: a potential link to T-cell dysfunction and increased relapse risk","authors":"Romy Böttcher-Loschinski, Franziska Karl, Diana Drettwan, Johannes Wittmann, Benedikt Jacobs, Simon Völkl, Heiko Bruns, Andreas Mackensen, Dimitrios Mougiakakos","doi":"10.1002/cti2.70060","DOIUrl":"10.1002/cti2.70060","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Allogeneic stem cell transplantation (allo-SCT) is the only curative treatment option for several haematologic malignancies. Its therapeutic principle is based on the donor T cells' ability to eliminate any residual malignant cells. Despite its success, challenges such as graft-versus-host disease (GvHD) and disease relapse persist. Recent studies emphasise the role of the metabolic environment in shaping T-cell responses. This study investigates the impact of serum metabolites on T-cell responses following allo-SCT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Metabolite levels in serum samples from 55 allo-SCT patients transplanted between November 2015 and October 2018 were analysed by nuclear magnetic resonance (NMR) spectroscopy for six time points after transplantation. These metabolite profiles were correlated with clinical data and T-cell characteristics obtained by flow cytometry-based immunomonitoring. High-density lipoprotein (HDL) emerged as a key factor of interest. To explore the potential relationship between T-cell-related differences and HDL levels, healthy donor T-cell cultures supplemented with HDL were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Elevated HDL levels were associated with acute GvHD (aGvHD) and relapse. Patients with high HDL serum levels exhibited a delayed normalisation of T-cell frequencies and increased effector-memory CD8<sup>+</sup> T-cell frequencies. <i>In vitro</i> experiments revealed reduced proliferation and expression of activation/effector molecules after exposure to HDL. Effects of HDL on memory T-cell subset formation resembled the <i>in situ</i> findings in patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>AGvHD was linked to elevated HDL levels, potentially affecting T-cell-mediated graft-versus-leukaemia (GvL) activity and promoting relapse. HDL could therefore be a potential biomarker for the success of allo-SCT and a lever for improving patients' outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12581179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443464","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}
Yuxi Chen, Hengmo Rong, Ting Li, Chao Zhang, Huqin Yang, Han Sun, Dong Wang, Xiaoxia Zhou, Kan Zhai, Zhaohui Tong
Pneumocystis pneumonia (PCP), caused by the opportunistic fungal pathogen Pneumocystis, remains a common fungal infection among immunosuppressed individuals. T cells are known to play a critical role in host defences against Pneumocystis. Two functional groups of T cells exist: CD4+ T and CD8+ T. Distinct subsets of CD4+ and CD8+ T cells have been shown to participate in PCP development through specific cytokines and interactions with other immune cells, significantly influencing the pulmonary fungal burden and disease severity. However, the host T-cell responses required for an effective adaptive immune response to PCP remain incompletely defined. In this review, we explore how an in-depth understanding of the integrated and well-defined functions of different T-cell subsets in the immune defence against Pneumocystis could provide insights into facilitating the development of anti-Pneumocystis treatment.
{"title":"T-cell subsets in Pneumocystis pneumonia","authors":"Yuxi Chen, Hengmo Rong, Ting Li, Chao Zhang, Huqin Yang, Han Sun, Dong Wang, Xiaoxia Zhou, Kan Zhai, Zhaohui Tong","doi":"10.1002/cti2.70055","DOIUrl":"10.1002/cti2.70055","url":null,"abstract":"<p><i>Pneumocystis</i> pneumonia (PCP), caused by the opportunistic fungal pathogen <i>Pneumocystis</i>, remains a common fungal infection among immunosuppressed individuals. T cells are known to play a critical role in host defences against <i>Pneumocystis</i>. Two functional groups of T cells exist: CD4<sup>+</sup> T and CD8<sup>+</sup> T. Distinct subsets of CD4<sup>+</sup> and CD8<sup>+</sup> T cells have been shown to participate in PCP development through specific cytokines and interactions with other immune cells, significantly influencing the pulmonary fungal burden and disease severity. However, the host T-cell responses required for an effective adaptive immune response to PCP remain incompletely defined. In this review, we explore how an in-depth understanding of the integrated and well-defined functions of different T-cell subsets in the immune defence against <i>Pneumocystis</i> could provide insights into facilitating the development of anti-<i>Pneumocystis</i> treatment.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 10","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12560118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399398","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}
Maria-Danae Jessel, Owen McGreevy, Lauryn McReynolds, Lekh N Dahal, Timothy Gilbert, Hassan Z Malik, Christopher E Goldring, Laura E Randle
Cholangiocarcinoma is a malignancy of significant unmet clinical need with limited therapeutic options. Most patients are diagnosed at advanced or metastatic stages, where surgical resection with curative intent is no longer an option. Gemcitabine-cisplatin chemotherapy has been the standard of care for these patients, remaining unchanged for over a decade. Recently, the addition of the programmed death ligand 1 inhibitor, durvalumab, to this regimen demonstrated an objective response rate of 26.7% in a phase III trial, becoming the new standard of care for advanced cholangiocarcinoma. Although considered a success in cholangiocarcinoma treatment, the results indicate that only a small proportion of patients respond to treatment with immune checkpoint inhibitors. Emerging evidence suggests that many cholangiocarcinoma tumors exhibit an immunologically ‘cold’ tumor microenvironment, characterised by predominance of immunosuppressive immune populations and limited infiltration of cytotoxic T cells, which contributes to their resistance to immune checkpoint inhibitors. This review provides a comprehensive overview of the research studies that have employed immunomodulatory strategies in cholangiocarcinoma aimed at priming the tumor microenvironment for a more effective response to immune checkpoint inhibitors. This update will also evaluate the strengths and limitations of current pre-clinical models of cholangiocarcinoma, with emphasis on more advanced translational models. These complex models remain underutilised, hindering the development of novel therapeutic approaches. We suggest that these complex preclinical models may help translation of therapies into clinical practice.
{"title":"Targeting the tumor microenvironment in cholangiocarcinoma to improve immune checkpoint blockade: potential strategies and translational pre-clinical models","authors":"Maria-Danae Jessel, Owen McGreevy, Lauryn McReynolds, Lekh N Dahal, Timothy Gilbert, Hassan Z Malik, Christopher E Goldring, Laura E Randle","doi":"10.1002/cti2.70057","DOIUrl":"https://doi.org/10.1002/cti2.70057","url":null,"abstract":"<p>Cholangiocarcinoma is a malignancy of significant unmet clinical need with limited therapeutic options. Most patients are diagnosed at advanced or metastatic stages, where surgical resection with curative intent is no longer an option. Gemcitabine-cisplatin chemotherapy has been the standard of care for these patients, remaining unchanged for over a decade. Recently, the addition of the programmed death ligand 1 inhibitor, durvalumab, to this regimen demonstrated an objective response rate of 26.7% in a phase III trial, becoming the new standard of care for advanced cholangiocarcinoma. Although considered a success in cholangiocarcinoma treatment, the results indicate that only a small proportion of patients respond to treatment with immune checkpoint inhibitors. Emerging evidence suggests that many cholangiocarcinoma tumors exhibit an immunologically ‘cold’ tumor microenvironment, characterised by predominance of immunosuppressive immune populations and limited infiltration of cytotoxic T cells, which contributes to their resistance to immune checkpoint inhibitors. This review provides a comprehensive overview of the research studies that have employed immunomodulatory strategies in cholangiocarcinoma aimed at priming the tumor microenvironment for a more effective response to immune checkpoint inhibitors. This update will also evaluate the strengths and limitations of current pre-clinical models of cholangiocarcinoma, with emphasis on more advanced translational models. These complex models remain underutilised, hindering the development of novel therapeutic approaches. We suggest that these complex preclinical models may help translation of therapies into clinical practice.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 10","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367143","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}
Pei Dai, Oliver Skinner, Xufeng Lin, Aiden Telfser, Stephanie Ruiz-Diaz, Rohit G Saldanha, Katie Frith, Ming-Wei Lin, Kahn Preece, Paul E Gray, Alberto Pinzon-Charry, Anna Sullivan, Stephen Adelstein, Winnie WY Tong, Matthew JS Parker, Laila Girgis, Brynn Wainstein, Samar Ojami, Elissa K Deenick, Leonard D Goldstein, Michael J Rogers, Tri Giang Phan
Objective
To develop a rapid functional assay to validate variants of uncertain significance (VUS) in the MEFV gene.
Methods
Overactivity of the pyrin inflammasome pathway and ASC speck oligomerisation in response to stimulation with low concentrations of Clostridium difficile toxin A was directly visualised by immunofluorescence microscopy. A semi-automated algorithm was developed to count cells and ASC specks.
Results
The semi-automated ASC speck assay is able to discriminate between healthy controls and patients with familial Mediterranean fever (FMF) and pyrin inflammasome overactivity with high sensitivity. It is also able to discriminate pyrin inflammasome overactivity from other autoinflammatory disease controls with high specificity.
Conclusion
The semi-automated ASC speck assay may be a useful test to functionally validate VUS in the MEFV gene and screen for pyrin inflammasome overactivity.
{"title":"A semi-automated ASC speck assay to evaluate pyrin inflammasome activation","authors":"Pei Dai, Oliver Skinner, Xufeng Lin, Aiden Telfser, Stephanie Ruiz-Diaz, Rohit G Saldanha, Katie Frith, Ming-Wei Lin, Kahn Preece, Paul E Gray, Alberto Pinzon-Charry, Anna Sullivan, Stephen Adelstein, Winnie WY Tong, Matthew JS Parker, Laila Girgis, Brynn Wainstein, Samar Ojami, Elissa K Deenick, Leonard D Goldstein, Michael J Rogers, Tri Giang Phan","doi":"10.1002/cti2.70054","DOIUrl":"https://doi.org/10.1002/cti2.70054","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To develop a rapid functional assay to validate variants of uncertain significance (VUS) in the <i>MEFV</i> gene.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Overactivity of the pyrin inflammasome pathway and ASC speck oligomerisation in response to stimulation with low concentrations of <i>Clostridium difficile</i> toxin A was directly visualised by immunofluorescence microscopy. A semi-automated algorithm was developed to count cells and ASC specks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The semi-automated ASC speck assay is able to discriminate between healthy controls and patients with familial Mediterranean fever (FMF) and pyrin inflammasome overactivity with high sensitivity. It is also able to discriminate pyrin inflammasome overactivity from other autoinflammatory disease controls with high specificity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The semi-automated ASC speck assay may be a useful test to functionally validate VUS in the <i>MEFV</i> gene and screen for pyrin inflammasome overactivity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 10","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145366859","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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