Clinical and experimental immunology最新文献

{"title":"Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus.","authors":"Anna Radziszewska, Hannah Peckham, Restuadi Restuadi, Melissa Kartawinata, Dale Moulding, Nina M de Gruijter, George A Robinson, Maryam Butt, Claire T Deakin, Meredyth G Ll Wilkinson, Lucy R Wedderburn, Elizabeth C Jury, Elizabeth C Rosser, Coziana Ciurtin","doi":"10.1093/cei/uxae127","DOIUrl":"10.1093/cei/uxae127","url":null,"abstract":"<p><p>Juvenile systemic lupus erythematosus (JSLE) is an autoimmune condition which causes significant morbidity in children and young adults and is more severe in its presentation than adult-onset SLE. While many aspects of immune dysfunction have been studied extensively in adult-onset SLE, there is limited and contradictory evidence of how cytotoxic CD8+ T cells contribute to disease pathogenesis and studies exploring cytotoxicity in JSLE are virtually non-existent. Here, we report that CD8+ T cell cytotoxic capacity is reduced in JSLE versus healthy controls, irrespective of treatment or disease activity. Transcriptomic and serum metabolomic analysis identified that this reduction in cytotoxic CD8+ T cells in JSLE was associated with upregulated type I interferon (IFN) signalling, mitochondrial dysfunction, and metabolic disturbances when compared to controls. Greater interrogation of the influence of these pathways on altered cytotoxic CD8+ T cell function demonstrated that JSLE CD8+ T cells had enlarged mitochondria and enhanced sensitivity to IFN-α leading to selective apoptosis of effector memory (EM) CD8+ T cells, which are enriched for cytotoxic mediator-expressing cells. This process ultimately contributes to the observed reduction in CD8+ T cell cytotoxicity in JSLE, reinforcing the growing evidence that mitochondrial dysfunction is a key pathogenic factor affecting multiple immune cell populations in type I IFN-driven rheumatic diseases.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced response to SARS-CoV-2 vaccination is associated with impaired immunoglobulin class switch recombination in SLE patients.","authors":"Guillem Montamat, Claire E Meehan, Hannah F Bradford, Reşit Yıldırım, Francisca Guimarães, Marina Johnson, David Goldblatt, David A Isenberg, Claudia Mauri","doi":"10.1093/cei/uxae119","DOIUrl":"10.1093/cei/uxae119","url":null,"abstract":"<p><strong>Introduction: </strong>Systemic lupus erythematosus (SLE) patients exhibit B-cell abnormalities. Although there are concerns about reduced antibody responses to SARS-CoV-2 vaccines, detailed data on B-cell-specific responses in SLE remain scarce. Understanding the responsiveness to novel vaccine antigens, and boosters number, is important to avoid unnecessarily prolonged isolation of immunocompromised individuals. We assessed humoral and antigen-specific B-cell subset responses, including changes in isotype switching, prior to and after several doses of SARS-CoV-2 vaccines.</p><p><strong>Methods: </strong>Blood samples were obtained prior to and after SARS-CoV-2 vaccination from cross-sectional and longitudinal cohorts of previously uninfected patients with SLE (n = 93). Healthy participants receiving SARS-CoV-2 vaccines were recruited as controls (n = 135). We measured serum antibody titres, their neutralizing capacity, and vaccine-specific memory B-cell subsets.</p><p><strong>Results: </strong>Impaired IgG, IgA, and neutralizing responses against the original and various SARS-CoV-2 variants were observed following two doses of vaccine in SLE patients. Follow-up booster doses increased humoral responses compared to baseline, but they remained lower, with poorer neutralisation capacity against most strains, compared to healthy individuals after three or more doses. Analysis of memory B-cell subsets in SLE patients revealed an increase of SARS-CoV-2-specific isotype unswitched IgM+ over SARS-CoV-2-specific isotype switched IgG+/IgA+ memory B-cells compared to healthy individuals. Culturing healthy naive B-cells with high levels of IFNα, a hallmark of SLE pathogenesis, prevented B-cells from switching to IgG under IgG-polarizing conditions.</p><p><strong>Conclusion: </strong>SLE patients' protection against SARS-CoV-2 is overall impaired compared to healthy individuals and is associated with a class switch defect possibly due to chronic exposure of B-cells to IFNα.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-depth immune profiling of a patient with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 caused by a novel mutation in ZBTB24.","authors":"Colleen M Roark, Diana Ramírez-Vásquez, Jenniffer Yissel Giron Martinez, Xin Zhen, Alexa N Del Bene, Shannon E Gibson, Megan M Dobrose, Natasha B Halasa, Lizbeth Blancas-Galicia, Ruben Martinez-Barricarte","doi":"10.1093/cei/uxaf016","DOIUrl":"10.1093/cei/uxaf016","url":null,"abstract":"<p><p>Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare genetic disorder characterized by recurrent, severe infections. Mutations in DNA methylation genes such as DNMT3B (ICF1), ZBTB24 (ICF2), CDCA7 (ICF3), and HELLS (ICF4) cause ICF. ICF2 syndrome has been previously described, yet the extent of its clinical presentation and immunological consequences needs to be further elucidated. We describe a patient with a novel homozygous mutation in ZBTB24 (Q375Hfs*3). While infections with extracellular pathogens are frequent in other reported ICF2 patients, our patient also displays infections by intracellular pathogens. At the molecular level, we showed that the novel mutation results in a truncated ZBTB24 protein that disrupts its function in DNA methylation. We thoroughly characterized the immunological consequences of ZBTB24 deficiency using mass cytometry coupled with state-of-the-art computational methods. Our analysis revealed reduced frequencies of natural killer cells and class-switched memory B cell populations in our patient, along with low levels of the immunoglobulin isotypes IgG4 and IgM. Despite observing normal cell frequencies within the T and myeloid compartments, the clinical presentation of this patient suggests a functional defect in immune cells known to be critical to combat intracellular pathogens. Overall, this study expands the clinical and immunological features of ZBTB24 deficiency and highlights the importance of ZBTB24 to the human immune response.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Antibody-mediated glomerulonephritis in mice: the role of endotoxin, complement and genetic background.","authors":"","doi":"10.1093/cei/uxaf004","DOIUrl":"10.1093/cei/uxaf004","url":null,"abstract":"","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":"219 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pneumococcal serotype-specific antibodies in children with recurrent oto-sinopulmonary infections.","authors":"Hanadys Ale, Jose G Calderon, Joshua Gruber, Thomas Taylor, William R Blouin, Vivian P Hernández-Trujillo","doi":"10.1093/cei/uxae086","DOIUrl":"10.1093/cei/uxae086","url":null,"abstract":"<p><p>Low titers to pneumococcal vaccine are a frequent finding in pediatric patients with recurrent oto-sinopulmonary infections. To characterize the pre- and post-immunization antibody trend for each serotype included in the pneumococcal 13-valent conjugate vaccine, in a cohort of pediatric patients with recurrent oto-sinopulmonary infections, this retrospective review identified 182 patients with recurrent oto-sinopulmonary infections (131 required an immune workup and 99 had low pneumococcal titers leading to a pneumococcal 13-valent conjugate vaccine booster). Baseline pneumococcal serotype-specific antibody titers at the initial visit and 6 weeks after the vaccine booster were obtained. An adequate response to the pneumococcal conjugate vaccine was deemed to be a 4-fold increase over baseline and/or a post-immunization titer of 1.3 µg/ml or greater. Overall, The pneumococcal 13-valent conjugate vaccine booster provided a significant improvement in the number of protective titers, increasing from 3.6 serotypes at baseline to 11.1 serotypes at 6 weeks (P < 0.001). This increase correlated with improved clinical outcomes (81% showed no signs of recurrent infection after the first booster and 94% after a second booster). Post-immunization antibody concentrations were significantly higher than at baseline for all serotypes (P < 0.05), and only 8, 9N, and 12F did not exhibit a greater than 4-fold increase (P > 0.05) 6 weeks following booster. There were no differences between patients at different ages in post-immunization titer levels for all serotypes. In pediatric patients with recurrent oto-sinopulmonary infections, an additional pneumococcal booster proved to be effective in the protection of these children against further infections, across all age groups.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic changes of host immune response during Helicobacter pylori-induced gastric cancer development.","authors":"Weiwei Fu, Xiurui Han, Xinyu Hao, Jing Zhang, Hejun Zhang, Chao Ma, Miao Xu, Jing Zhang, Shigang Ding","doi":"10.1093/cei/uxae109","DOIUrl":"10.1093/cei/uxae109","url":null,"abstract":"<p><strong>Introduction: </strong>Helicobacter pylori infection is the main risk factor for gastric cancer (GC). Chronic inflammation is usually induced by H. pylori infection and is accompanied by inherent immune disorders. However, the dynamic changes in the host immune response associated with the transition from normal to metaplasia, dysplasia, and GC are largely undefined.</p><p><strong>Method: </strong>We established the H. pylori-induced GC mice model. The gastric mucosa of H. pylori-infected mice was subjected to RNA-sequencing analysis at different stages. We analyzed systemic immune disturbances in the spleen and changes in serum inflammatory cytokines during GC development, including gastritis, premalignant lesions (pre-GC), and GC stages.</p><p><strong>Results: </strong>RNA-sequencing analysis of the gastric mucosa of H. pylori-infected mice highlighted the important role of immune-associated pathways (especially inflammatory pathways) during GC development. Immune cell proportion analysis revealed the stage-dependent involvement of key immune cell types, including increased Th17 cells in early gastritis and pre-GC stages and decreased central memory CD4+ and CD8+ T cells during GC transition. Serum inflammatory cytokine analysis showed that IL-6 and IL-10 levels significantly increased, whereas IL-23 levels decreased during the GC stage.</p><p><strong>Conclusion: </strong>In summary, we illustrated systemic immune disturbances in the spleen and changes in serum inflammatory cytokines during GC development. Th17 cells were involved in early gastritis and premalignant processes, while central memory T cells participated in GC transition. Our findings provide valuable insights into identifying key inflection points and associated biomarkers for the early detection, diagnosis, and treatment of GC.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pathophysiology of hemophagocytic lympho-histiocytosis (HLH) syndrome and insights from animal models.","authors":"Sayan Mukherjee, Puneet Kumar","doi":"10.1093/cei/uxaf036","DOIUrl":"10.1093/cei/uxaf036","url":null,"abstract":"<p><p>Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by an aberrant immune response against host tissues. It can arise from diverse triggers like infection, inflammation, malignancy, genetic defects, or therapy-related factors. Cytokine storm, capillary leak syndrome, cytokine release syndrome, and macrophage activation syndrome are the different faces of this chimera, and each of them displays significant clinical variability associated with high mortality. The pathogenesis of both primary and secondary HLH generally follows a similar pattern, involving excessive activation of macrophages and uncontrolled destruction of reticuloendothelial tissues. Environmental triggers cause exaggerated activation of innate immune cells in genetically predisposed individuals. This process is further driven by the release of multiple cytokines and soluble mediators that sustain ongoing inflammation and cause subsequent target organ damage. Biomarkers, including cytokines and inflammatory mediators, are crucial for early detection and monitoring treatment response. Persistent immune activation and inadequate resolution mechanisms result in a destructive inflammatory cascade or \"immunological massacre\". Animal models of HLH and MAS elucidate the roles of impaired cytotoxicity, IFN-γ, TLR signaling, and inflammatory cytokines in disease pathogenesis. Trigger-specific differences highlight the involvement of CD8+ T cells, NK cells, macrophages, and cytokines. Therapeutic strategies include cytokine neutralization, adoptive T-cell transfer, and mTOR inhibition. Timely diagnosis and prompt initiation of therapy are essential to mitigate the serious consequences of HLH and improve long-term outcomes.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An atypical adolescent case of leukocyte adhesion deficiency I caused by a novel ITGB2 splicing variant with successful immune reconstitution following hematopoietic stem cell transplantation.","authors":"Guanghua Zhu, Honghong Yue, Jianxin He, Caisheng Wang, Chen Xu, Chenguang Jia, Xiaolin Wang, Yan Yan, Bin Wang, Hui Zhang, Xi Chen, Jianping Qiu, Liwei Gao, Jie Zheng, Ge Lv, Jun Yang, Yanhui Luo, Maoquan Qin, Jingang Gui, Wenjun Mou","doi":"10.1093/cei/uxaf024","DOIUrl":"10.1093/cei/uxaf024","url":null,"abstract":"<p><p>Leukocyte adhesion deficiency I (LAD-I) is an autosomal recessive immunodeficiency caused by mutations in the ITGB2 gene, characterized by recurrent severe infections, impaired pus formation, and delayed wound healing. In this study, we describe a late-onset presentation of LAD-I in a 22-year-old male who initially exhibited marked leukocytosis and neonatal omphalitis, followed by recurrent upper respiratory tract infections from 9 months of age. At age 13, the patient developed abdominal and left iliac fossa abscesses, which progressed to a vesicocutaneous fistula after a prolonged febrile episode. Extended catheterization and antibiotic treatment led to the formation of characteristic tin foil-like scarring. Recurrent purulent skin and soft tissue infections led to widespread scarring and pigmentary changes. Next-generation sequencing (NGS) identified a novel homozygous splice-site mutation in ITGB2 (NM_000211.5, c.1225-1G > A, IVS10-1G > A). In silico analysis predicted disruption of the acceptor site, while a minigene assay demonstrated two aberrant splicing events, namely a 12-bp deletion and complete skipping of exon 11 (188 bp). Flow cytometry analysis at age 13 showed CD18 expression reduced to less than 1% across granulocytes, monocytes, and lymphocytes, with concomitant decreases in β2-integrin α subunits (CD11a, CD11b, and CD11c). At 15 years of age, the patient underwent hematopoietic stem cell transplantation (HSCT) from a fully HLA-matched (10/10) heterozygous sister donor following a modified myeloablative conditioning regimen. Although initial chimerism fluctuated, full donor chimerism was ultimately achieved, restoring CD18 expression and normalizing ɑ-integrin levels. This study highlights the therapeutic efficacy of HSCT in correcting the molecular defects associated with LAD-I.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":"219 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Discrepancy in clinical and laboratory profiles of NMOSD patients between AQP4 antibody positive and negative: can NMOSD be diagnosed without AQP4 antibody?","authors":"","doi":"10.1093/cei/uxaf033","DOIUrl":"10.1093/cei/uxaf033","url":null,"abstract":"","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":"219 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 analysis of lung epithelial cells reveals age and cell population-specific responses to SARS-CoV-2 infection in ciliated cells.","authors":"Raven M Osborn, Christopher S Anderson, Justin R Leach, Chin Yi Chu, Stephen Dewhurst, Thomas J Mariani, Juilee Thakar","doi":"10.1093/cei/uxae118","DOIUrl":"https://doi.org/10.1093/cei/uxae118","url":null,"abstract":"<p><strong>Introduction: </strong>The ability of SARS-CoV-2 to evade antiviral immune signaling in the airway contributes to the severity of COVID-19 disease. Additionally, COVID-19 is influenced by age and has more severe presentations in older individuals. This raises questions about innate immune signaling as a function of lung development and age.</p><p><strong>Method: </strong>Therefore, we investigated the transcriptome of different cell populations of the airway epithelium using pediatric and adult lung tissue samples from the LungMAP Human Tissue Core Biorepository. Specifically, lung lobes were digested and cultured into a biomimetic model of the airway epithelium on an air-liquid interface. Cells were then infected with SARS-CoV-2 and subjected to single-cell RNA sequencing. Transcriptional profiling and differential expression analysis were carried out using Seurat.</p><p><strong>Results: </strong>The clustering analysis identified several cell populations: club cells, proliferating epithelial cells, multiciliated precursor cells, ionocytes, and two biologically distinct clusters of ciliated cells (FOXJ1high and FOXJ1low). Interestingly, the two ciliated cell clusters showed different infection rates and enrichment of processes involved in ciliary biogenesis and function; we observed a cell-type-specific suppression of innate immunity in infected cells from the FOXJ1low subset. We also identified a significant number of genes that were differentially expressed in lung cells derived from children as compared to adults, suggesting the differential pathogenesis of SARS-CoV-2 infection in children versus adults.</p><p><strong>Conclusion: </strong>We discuss how this work can be used to identify drug targets to modulate molecular signaling cascades that mediate an innate immune response and begin to understand differences in COVID-19 outcomes for pediatric vs. adult populations.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}