Pub Date : 2025-02-04eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1515602
Jie Zhao, Yan Bao, Ying Gao, Keliang Xie
A case report highlights the challenges faced in managing a 66-year-old Chinese woman diagnosed with anti-MDA5 antibody-positive dermatomyositis (MDA5-DM) complicated by rapidly progressive interstitial lung disease (RP-ILD). Despite aggressive therapeutic interventions, her condition rapidly deteriorated, emphasizing the severity and devastating nature of this subtype of DM. A salient feature of her clinical presentation was the marked elevation of interferon (IFN)-γ and IFN-α levels, underscoring the pivotal role that IFNs play in driving the pathogenesis and progression of MDA5-DM-related RP-ILD. In an attempt to stem the relentless progression, tofacitinib, a Janus kinase (JAK) inhibitor, was applied into her treatment regimen. This therapeutic intervention led to a transient decrease in IFN-related cytokines, offering a glimpse of hope that JAK inhibition could modulate the exaggerated IFN response implicated in the disease. Other four similar cases underscore the critical importance of early and aggressive intervention in MDA5-DM patients, as well as the potential therapeutic avenues involving IFN blockers by JAK inhibitors. Urgent and well-designed clinical trials are imperative to unravel the intricate interplay between RP-ILD and the IFN signature in MDA5-DM, and to evaluate novel therapeutic targets that promise long-term efficacy and safety.
{"title":"Case report: Exploring efficacy of tofacitinib in modulating interferon response in five case of anti-MDA5+ dermatomyositis with interstitial lung disease.","authors":"Jie Zhao, Yan Bao, Ying Gao, Keliang Xie","doi":"10.3389/fimmu.2025.1515602","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1515602","url":null,"abstract":"<p><p>A case report highlights the challenges faced in managing a 66-year-old Chinese woman diagnosed with anti-MDA5 antibody-positive dermatomyositis (MDA5-DM) complicated by rapidly progressive interstitial lung disease (RP-ILD). Despite aggressive therapeutic interventions, her condition rapidly deteriorated, emphasizing the severity and devastating nature of this subtype of DM. A salient feature of her clinical presentation was the marked elevation of interferon (IFN)-γ and IFN-α levels, underscoring the pivotal role that IFNs play in driving the pathogenesis and progression of MDA5-DM-related RP-ILD. In an attempt to stem the relentless progression, tofacitinib, a Janus kinase (JAK) inhibitor, was applied into her treatment regimen. This therapeutic intervention led to a transient decrease in IFN-related cytokines, offering a glimpse of hope that JAK inhibition could modulate the exaggerated IFN response implicated in the disease. Other four similar cases underscore the critical importance of early and aggressive intervention in MDA5-DM patients, as well as the potential therapeutic avenues involving IFN blockers by JAK inhibitors. Urgent and well-designed clinical trials are imperative to unravel the intricate interplay between RP-ILD and the IFN signature in MDA5-DM, and to evaluate novel therapeutic targets that promise long-term efficacy and safety.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1515602"},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448812","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}
Pub Date : 2025-02-04eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1524781
Eduardo López-Collazo, Laura Hurtado-Navarro
Numerous studies have investigated the molecular mechanisms and signalling pathways underlying cancer metastasis, as there is still no effective treatment for this terminal stage of the disease. However, the exact processes that enable primary cancer cells to acquire a metastatic phenotype remain unclear. Increasing attention has been focused on the fusion of cancer cells with myeloid cells, a phenomenon that may result in hybrid cells, so-called Tumour Hybrid Cells (THCs), with enhanced migratory, angiogenic, immune evasion, colonisation, and metastatic properties. This process has been shown to potentially drive tumour progression, drug resistance, and cancer recurrence. In this review, we explore the potential mechanisms that govern cancer cell fusion, the molecular mediators involved, the metastatic characteristics acquired by fusion-derived hybrids, and their clinical significance in human cancer. Additionally, we discuss emerging pharmacological strategies aimed at targeting fusogenic molecules as a means to prevent metastatic dissemination.
{"title":"Cell fusion as a driver of metastasis: re-evaluating an old hypothesis in the age of cancer heterogeneity.","authors":"Eduardo López-Collazo, Laura Hurtado-Navarro","doi":"10.3389/fimmu.2025.1524781","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1524781","url":null,"abstract":"<p><p>Numerous studies have investigated the molecular mechanisms and signalling pathways underlying cancer metastasis, as there is still no effective treatment for this terminal stage of the disease. However, the exact processes that enable primary cancer cells to acquire a metastatic phenotype remain unclear. Increasing attention has been focused on the fusion of cancer cells with myeloid cells, a phenomenon that may result in hybrid cells, so-called Tumour Hybrid Cells (THCs), with enhanced migratory, angiogenic, immune evasion, colonisation, and metastatic properties. This process has been shown to potentially drive tumour progression, drug resistance, and cancer recurrence. In this review, we explore the potential mechanisms that govern cancer cell fusion, the molecular mediators involved, the metastatic characteristics acquired by fusion-derived hybrids, and their clinical significance in human cancer. Additionally, we discuss emerging pharmacological strategies aimed at targeting fusogenic molecules as a means to prevent metastatic dissemination.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1524781"},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448831","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}
Pub Date : 2025-02-04eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1496046
Ruohua Li, Cuixia Zhou, Kejun Ye, Haihui Chen, Mengjia Peng
Background: Preeclampsia is a complex pregnancy condition marked by hypertension and organ dysfunction, posing significant risks to maternal and fetal health. This study investigates the role of energy metabolism-associated genes in preeclampsia development and identifies potential early diagnostic biomarkers.
Methods: Preeclampsia datasets from Gene Expression Omnibus were analyzed for batch correction, normalization, and differential expression. Enrichment analyses using gene ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment were performed. Protein-protein interaction networks were constructed to identify key genes, and regulatory networks involving transcription factors, miRNAs, and RNA-binding proteins were established. Differential expression was validated with receiver operating characteristic curve analyses, and immune infiltration was assessed.
Results: Six energy metabolism-related genes were identified. Enrichment analyses revealed their involvement in glycolysis, gluconeogenesis, lipid transport, bone remodeling, and glucagon secretion. Key differentially expressed genes included CRH(Corticotropin-Releasing Hormone), LEP(Leptin), PDK4(Pyruvate Dehydrogenase Kinase Isozyme 4), SPP1(Secreted Phosphoprotein 1), and SST(Somatostatin). PDK4 exhibited moderate accuracy in receiver operating characteristic analysis. Immune infiltration analysis indicated significant differences between preeclampsia and control samples. qRT-PCR confirmed LEP and CRH increased, while SPP1 expression in preeclampsia samples.
Conclusion: Dysregulated energy metabolism-related genes may contribute to preeclampsia through metabolic and immune changes. Identifying these genes aids in understanding preeclampsia's molecular basis and early diagnosis. Future studies should validate these markers in larger cohorts and explore targeted treatments.
{"title":"Identification of genes involved in energy metabolism in preeclampsia and discovery of early biomarkers.","authors":"Ruohua Li, Cuixia Zhou, Kejun Ye, Haihui Chen, Mengjia Peng","doi":"10.3389/fimmu.2025.1496046","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1496046","url":null,"abstract":"<p><strong>Background: </strong>Preeclampsia is a complex pregnancy condition marked by hypertension and organ dysfunction, posing significant risks to maternal and fetal health. This study investigates the role of energy metabolism-associated genes in preeclampsia development and identifies potential early diagnostic biomarkers.</p><p><strong>Methods: </strong>Preeclampsia datasets from Gene Expression Omnibus were analyzed for batch correction, normalization, and differential expression. Enrichment analyses using gene ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment were performed. Protein-protein interaction networks were constructed to identify key genes, and regulatory networks involving transcription factors, miRNAs, and RNA-binding proteins were established. Differential expression was validated with receiver operating characteristic curve analyses, and immune infiltration was assessed.</p><p><strong>Results: </strong>Six energy metabolism-related genes were identified. Enrichment analyses revealed their involvement in glycolysis, gluconeogenesis, lipid transport, bone remodeling, and glucagon secretion. Key differentially expressed genes included <i>CRH(Corticotropin-Releasing Hormone)</i>, <i>LEP(Leptin), PDK4(Pyruvate Dehydrogenase Kinase Isozyme 4)</i>, <i>SPP1(Secreted Phosphoprotein 1)</i>, <i>and SST(Somatostatin)</i>. <i>PDK4</i> exhibited moderate accuracy in receiver operating characteristic analysis. Immune infiltration analysis indicated significant differences between preeclampsia and control samples. qRT-PCR confirmed <i>LEP</i> and <i>CRH</i> increased, while <i>SPP1</i> expression in preeclampsia samples.</p><p><strong>Conclusion: </strong>Dysregulated energy metabolism-related genes may contribute to preeclampsia through metabolic and immune changes. Identifying these genes aids in understanding preeclampsia's molecular basis and early diagnosis. Future studies should validate these markers in larger cohorts and explore targeted treatments.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1496046"},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448870","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}
Pub Date : 2025-02-04eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1431066
Dongkai Li, Jiahui Zhang, Wei Cheng, Guoyu Zhao, Xianli Lei, Yawen Xie, Na Cui, Hao Wang
Background: Sepsis induces profound derangements in the immune system, including lymphopenia, which correlates with immunosuppression and poor prognosis. However, most evaluations of immunosuppression in sepsis patients rely on static, sporadic lymphocyte counts, lacking dynamic modeling over the disease course. This study aimed to apply latent class mixed modeling on longitudinal lymphocyte counts to uncover heterogeneous trajectory phenotypes in sepsis patients and assess their predictive value for clinical outcomes.
Results: Four lymphocyte trajectory phenotypes were identified in the retrospective cohort (n=2,149) and externally validated (n=2,388): high-declining (α, 3.8%), stable-medium (β, 69.3%), high-increasing (γ, 3.2%), and stable-low (δ, 23.8%). The α phenotype exhibited the highest disease severity and mortality (25.9%) compared with other phenotypes in both cohorts. In the prospective cohort (n=1,056), all lymphocyte subset counts differed among phenotypes on admission (P <.001) and were lower in non-survivors (P<.05). Multivariable regression demonstrated that age, Acute Physiology and Chronic Health Evaluation-II score, heart rate, natural killer cell count, infection source, and lymphocyte trajectory phenotype were independent predictors of 28-day mortality. A nomogram combining these variables provided individualized risk estimations.
Conclusions: The lymphocyte trajectories delineated novel dynamic phenotypes associated with divergent sepsis outcomes. Incorporating longitudinal trajectory modeling and lymphocyte subsets may improve prognostic risk assessment and guide the selection of immunotherapies tailored to specific immune phenotypes in sepsis patients.
{"title":"Dynamic changes in peripheral blood lymphocyte trajectory predict the clinical outcomes of sepsis.","authors":"Dongkai Li, Jiahui Zhang, Wei Cheng, Guoyu Zhao, Xianli Lei, Yawen Xie, Na Cui, Hao Wang","doi":"10.3389/fimmu.2025.1431066","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1431066","url":null,"abstract":"<p><strong>Background: </strong>Sepsis induces profound derangements in the immune system, including lymphopenia, which correlates with immunosuppression and poor prognosis. However, most evaluations of immunosuppression in sepsis patients rely on static, sporadic lymphocyte counts, lacking dynamic modeling over the disease course. This study aimed to apply latent class mixed modeling on longitudinal lymphocyte counts to uncover heterogeneous trajectory phenotypes in sepsis patients and assess their predictive value for clinical outcomes.</p><p><strong>Results: </strong>Four lymphocyte trajectory phenotypes were identified in the retrospective cohort (n=2,149) and externally validated (n=2,388): high-declining (α, 3.8%), stable-medium (β, 69.3%), high-increasing (γ, 3.2%), and stable-low (δ, 23.8%). The α phenotype exhibited the highest disease severity and mortality (25.9%) compared with other phenotypes in both cohorts. In the prospective cohort (n=1,056), all lymphocyte subset counts differed among phenotypes on admission (P <.001) and were lower in non-survivors (P<.05). Multivariable regression demonstrated that age, Acute Physiology and Chronic Health Evaluation-II score, heart rate, natural killer cell count, infection source, and lymphocyte trajectory phenotype were independent predictors of 28-day mortality. A nomogram combining these variables provided individualized risk estimations.</p><p><strong>Conclusions: </strong>The lymphocyte trajectories delineated novel dynamic phenotypes associated with divergent sepsis outcomes. Incorporating longitudinal trajectory modeling and lymphocyte subsets may improve prognostic risk assessment and guide the selection of immunotherapies tailored to specific immune phenotypes in sepsis patients.</p><p><strong>Clinical trial registration: </strong>https://www.chictr.org.cn/showproj.aspx?proj=18277, identifier ChiCTR-40 ROC-17010750.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1431066"},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448913","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}
Pub Date : 2025-02-04eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1552112
Yi Wang, Ang Li, Yaozhong Hu
{"title":"Editorial: Immunomodulatory effect of nutrients on intestinal disorders and immunity.","authors":"Yi Wang, Ang Li, Yaozhong Hu","doi":"10.3389/fimmu.2025.1552112","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1552112","url":null,"abstract":"","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1552112"},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448926","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}
Pub Date : 2025-02-04eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1491448
Yuan Yao, Yiyi Yan, Vera J Suman, Allan B Dietz, Courtney L Erskine, Anastasios Dimou, Svetomir N Markovic, Robert R McWilliams, Heather N Montane, Matthew S Block
Background: Immune checkpoint inhibitors (ICIs) have been transformative in the treatment of patients with metastatic melanoma, but primary and secondary resistance to ICI treatment is common. One key mechanism for ICI resistance is the skewing of the immune response from a cytotoxic (Th1) to a chronic inflammatory (Th2) profile. The small molecule ibrutinib is a dual-target agent that inhibits Bruton's Tyrosine Kinase (BTK) and Interleukin-2-inducible T-cell Kinase (ITK), a key regulator of Th2 immunity. Therefore, combining ibrutinib and pembrolizumab could potentially induce an increase in Th1 immune polarity in melanoma patients. We hypothesize that the combination would be well-tolerated and might result in clinical benefit for patients with metastatic melanoma. The primary aim of this phase I study was to evaluate the safety, tolerability, and determine the maximum tolerated dose (MTD) of ibrutinib in combination with pembrolizumab in patients with metastatic melanoma.
Methods: A 3 + 3 phase I clinical trial was conducted in patients with unresectable Stage III or metastatic melanoma (stage IV) not amenable to local therapy. Pembrolizumab (200 mg/kg every 3 weeks) was combined with ibrutinib, administered orally at the dose assigned at the time of registration (140 mg daily, 280 mg daily, and 420 mg daily). Patients were treated until disease progression, intolerability, or patient decision to discontinue. Blood samples were collected after each cycle of treatment for immunophenotyping and Th1/Th2 polarity assessment based on immune response markers.
Results: Between January 31, 2017 and January 9, 2023, 17 patients were enrolled. The MTD of ibrutinib in combination with pembrolizumab was determined to be 420 mg daily. The adverse events leading to discontinuation included: grade 4 ALT and AST increase (1 pt, DL0); grade 4 ALT increase with grade 3 AST increase (1 pt, DL1); and grade 3 hyponatremia, hypoxia, and maculo-papular rash (1 pt, DL1). Three of the 16 patients treated had objective responses (2 partial responses, 1 complete response) lasting over 8 months. The median progression-free survival was 3 months, and median and overall survival was 1.8 years. The combination treatment did not result in consistent increase in Th1 immune polarity.
Conclusion: In conclusion, the maximum tolerated dose of ibrutinib in combination with pembrolizumab in patients with advanced or metastatic melanoma was established at 420 mg by mouth once daily. The combination was well-tolerated but did not result in a consistent increase in Th1 immune polarity; further investigation is needed to assess the relative clinical efficacy of this approach. (Funded by Pharmacyclics; ClinicalTrials.gov number: NCT03021460).
{"title":"Phase I study of pembrolizumab in combination with ibrutinib for the treatment of unresectable or metastatic melanoma.","authors":"Yuan Yao, Yiyi Yan, Vera J Suman, Allan B Dietz, Courtney L Erskine, Anastasios Dimou, Svetomir N Markovic, Robert R McWilliams, Heather N Montane, Matthew S Block","doi":"10.3389/fimmu.2025.1491448","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1491448","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have been transformative in the treatment of patients with metastatic melanoma, but primary and secondary resistance to ICI treatment is common. One key mechanism for ICI resistance is the skewing of the immune response from a cytotoxic (Th1) to a chronic inflammatory (Th2) profile. The small molecule ibrutinib is a dual-target agent that inhibits Bruton's Tyrosine Kinase (BTK) and Interleukin-2-inducible T-cell Kinase (ITK), a key regulator of Th2 immunity. Therefore, combining ibrutinib and pembrolizumab could potentially induce an increase in Th1 immune polarity in melanoma patients. We hypothesize that the combination would be well-tolerated and might result in clinical benefit for patients with metastatic melanoma. The primary aim of this phase I study was to evaluate the safety, tolerability, and determine the maximum tolerated dose (MTD) of ibrutinib in combination with pembrolizumab in patients with metastatic melanoma.</p><p><strong>Methods: </strong>A 3 + 3 phase I clinical trial was conducted in patients with unresectable Stage III or metastatic melanoma (stage IV) not amenable to local therapy. Pembrolizumab (200 mg/kg every 3 weeks) was combined with ibrutinib, administered orally at the dose assigned at the time of registration (140 mg daily, 280 mg daily, and 420 mg daily). Patients were treated until disease progression, intolerability, or patient decision to discontinue. Blood samples were collected after each cycle of treatment for immunophenotyping and Th1/Th2 polarity assessment based on immune response markers.</p><p><strong>Results: </strong>Between January 31, 2017 and January 9, 2023, 17 patients were enrolled. The MTD of ibrutinib in combination with pembrolizumab was determined to be 420 mg daily. The adverse events leading to discontinuation included: grade 4 ALT and AST increase (1 pt, DL0); grade 4 ALT increase with grade 3 AST increase (1 pt, DL1); and grade 3 hyponatremia, hypoxia, and maculo-papular rash (1 pt, DL1). Three of the 16 patients treated had objective responses (2 partial responses, 1 complete response) lasting over 8 months. The median progression-free survival was 3 months, and median and overall survival was 1.8 years. The combination treatment did not result in consistent increase in Th1 immune polarity.</p><p><strong>Conclusion: </strong>In conclusion, the maximum tolerated dose of ibrutinib in combination with pembrolizumab in patients with advanced or metastatic melanoma was established at 420 mg by mouth once daily. The combination was well-tolerated but did not result in a consistent increase in Th1 immune polarity; further investigation is needed to assess the relative clinical efficacy of this approach. (Funded by Pharmacyclics; ClinicalTrials.gov number: NCT03021460).</p><p><strong>Clinical trial registration: </strong>www.clinicaltrials.gov, identifier NCT03021460.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1491448"},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449028","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}
Pub Date : 2025-02-04eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1487284
Leandro Junqueira Moragas, Laíza Vianna Arruda, Lucca de Lima Siqueira Oliveira, Felipe de Andrade Vieira Alves, Natália Gedeão Salomão, Jemima Fuentes Ribeiro da Silva, Carlos Alberto Basílio-de-Oliveira, Rodrigo Panno Basílio-de-Oliveira, Ronaldo Mohana-Borges, Caio Gonçalves Azevedo, Gabriela Xavier de Oliveira, Jorge José de Carvalho, Fernando Colonna Rosman, Marciano Viana Paes, Kíssila Rabelo
Introduction: The dengue virus (DENV) is the etiological agent that causes dengue fever illness, an arbovirus with a major endemic potential that has become increasingly prevalent in Brazil and has already been associated with fatal cases in children. DENV has tropism for several organs, including lungs causing pulmonary complications. The aim of this article was to evaluate the inflammatory and histopathological profile of the lung tissue of three fatal cases of children infected with DENV, which represents a group more susceptible to fatality due to its incomplete development.
Methods: Histopathological analysis was carried out using Hematoxylin and Eosin staining and special stains. While the characterization of the inflammatory response and cellular expression was done by marking the viral protein, macrophages, lymphocytes and pro-inflammatory cytokines.
Results and discussion: The results confirm that vascular dysfunctions such as hemorrhage, vascular congestion and edema associated with a mononuclear infiltrate were observed in all three cases. In addition, the presence of viral replication and increased expression of inflammatory markers were also observed. Such findings contribute to the study and description of dengue, especially its effects on lung tissue.
{"title":"Detection of viral antigen and inflammatory mediators in fatal pediatric dengue: a study on lung immunopathogenesis.","authors":"Leandro Junqueira Moragas, Laíza Vianna Arruda, Lucca de Lima Siqueira Oliveira, Felipe de Andrade Vieira Alves, Natália Gedeão Salomão, Jemima Fuentes Ribeiro da Silva, Carlos Alberto Basílio-de-Oliveira, Rodrigo Panno Basílio-de-Oliveira, Ronaldo Mohana-Borges, Caio Gonçalves Azevedo, Gabriela Xavier de Oliveira, Jorge José de Carvalho, Fernando Colonna Rosman, Marciano Viana Paes, Kíssila Rabelo","doi":"10.3389/fimmu.2025.1487284","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1487284","url":null,"abstract":"<p><strong>Introduction: </strong>The dengue virus (DENV) is the etiological agent that causes dengue fever illness, an arbovirus with a major endemic potential that has become increasingly prevalent in Brazil and has already been associated with fatal cases in children. DENV has tropism for several organs, including lungs causing pulmonary complications. The aim of this article was to evaluate the inflammatory and histopathological profile of the lung tissue of three fatal cases of children infected with DENV, which represents a group more susceptible to fatality due to its incomplete development.</p><p><strong>Methods: </strong>Histopathological analysis was carried out using Hematoxylin and Eosin staining and special stains. While the characterization of the inflammatory response and cellular expression was done by marking the viral protein, macrophages, lymphocytes and pro-inflammatory cytokines.</p><p><strong>Results and discussion: </strong>The results confirm that vascular dysfunctions such as hemorrhage, vascular congestion and edema associated with a mononuclear infiltrate were observed in all three cases. In addition, the presence of viral replication and increased expression of inflammatory markers were also observed. Such findings contribute to the study and description of dengue, especially its effects on lung tissue.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1487284"},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448896","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}
Pub Date : 2025-02-04eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1535427
Benshuai You, Yang Yang, Jing Wei, Chenglin Zhou, Surong Dong
Sepsis is a systemic injury resulting in vascular dysfunction, which can lead to multiple organ dysfunction, even shock and death. Extracellular vesicles (EVs) released by mammalian cells and bacteria have been shown to play important roles in intercellular communication and progression of various diseases. In past decades, the functional role of EVs in sepsis and its complications has been well explored. EVs are one of the paracrine components of cells. By delivering bioactive materials, EVs can promote immune responses, particularly the development of inflammation. In addition, EVs can serve as beneficial tools for delivering therapeutic cargos. In this review, we discuss the dual role of EVs in the progression and treatment of sepsis, exploring their intricate involvement in both inflammation and tissue repair processes. Specifically, the remarkable role of engineered strategies based on EVs in the treatment of sepsis is highlighted. The engineering EVs-mediated drug delivery and release strategies offer broad prospects for the effective treatment of sepsis. EVs-based approaches provide a novel avenue for diagnosing sepsis and offer opportunities for more precise intervention.
{"title":"Pathogenic and therapeutic roles of extracellular vesicles in sepsis.","authors":"Benshuai You, Yang Yang, Jing Wei, Chenglin Zhou, Surong Dong","doi":"10.3389/fimmu.2025.1535427","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1535427","url":null,"abstract":"<p><p>Sepsis is a systemic injury resulting in vascular dysfunction, which can lead to multiple organ dysfunction, even shock and death. Extracellular vesicles (EVs) released by mammalian cells and bacteria have been shown to play important roles in intercellular communication and progression of various diseases. In past decades, the functional role of EVs in sepsis and its complications has been well explored. EVs are one of the paracrine components of cells. By delivering bioactive materials, EVs can promote immune responses, particularly the development of inflammation. In addition, EVs can serve as beneficial tools for delivering therapeutic cargos. In this review, we discuss the dual role of EVs in the progression and treatment of sepsis, exploring their intricate involvement in both inflammation and tissue repair processes. Specifically, the remarkable role of engineered strategies based on EVs in the treatment of sepsis is highlighted. The engineering EVs-mediated drug delivery and release strategies offer broad prospects for the effective treatment of sepsis. EVs-based approaches provide a novel avenue for diagnosing sepsis and offer opportunities for more precise intervention.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1535427"},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449024","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}
Pub Date : 2025-02-04eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1501307
Ahmed Rakib, Mousumi Mandal, Md Abdullah Al Mamun, Sonia Kiran, Nelufar Yasmen, Lexiao Li, Daniel M Collier, Jianxiong Jiang, Frank Park, Udai P Singh
Background: Obesity is associated with dysregulated metabolism and low-grade chronic inflammation in adipose tissue (AT). Immune cells, including macrophages, T cells, and neutrophils, infiltrate the AT and secrete proinflammatory cytokines to exacerbate the AT inflammation. RNA-Seq analysis of AT immune cells isolated from mice fed a high-fat diet (HFD) versus normal fat diet (ND) identified a panel of genes that were markedly downregulated, including sialic acid-binding Ig-like lectin E (siglec-E), in HFD compared to ND mice.
Methods: A series of experiments in wild-type (WT) and siglec-E knockout (siglec-E KO) mice was designed to investigate the effect of HFD on the functional role of siglec-E in the regulation of AT inflammation and adipogenesis. We analyzed the changes in immune phenotypes, inflammatory response, adipogenesis, and levels of cytokines and chemokines after HFD and ND feeding.
Results: HFD consumption significantly increased the body weight and blood glucose levels in siglec-E KO mice relative to those of WT mice. This was associated with an increased infiltration of macrophages, CXCR3 expressing CD8 T cells, and monocytic myeloid-derived suppressor cells (M-MDSCs) with a concomitant decrease in numbers of dendritic cells (DCs), in the AT of siglec-E KO fed HFD versus the WT HFD counterparts. The HFD-fed siglec-E KO mice also exhibited elevated expression of intracellular Akt and TNF receptor-associated factor 3 (TRAF3) signaling, inducing C/EBPα, FASN, PPARγ, and resistin in suprascapular AT compared to WT HFD-fed mice. Taken together, these results suggest that a genetic deficiency of siglec-E plays a key role in inducing AT inflammation by differentially altering M-MDSCs and CD8+CXCR3+ T cell function and adipogenesis by TRAF3 and Akt signaling in AT.
Conclusion: Our findings strongly suggest that modulation of siglec-E pathways might have a protective effect at least in part against AT inflammation and metabolic disorders.
{"title":"Siglec-E augments adipose tissue inflammation by modulating TRAF3 signaling and monocytic myeloid-derived suppressor cells during obesity.","authors":"Ahmed Rakib, Mousumi Mandal, Md Abdullah Al Mamun, Sonia Kiran, Nelufar Yasmen, Lexiao Li, Daniel M Collier, Jianxiong Jiang, Frank Park, Udai P Singh","doi":"10.3389/fimmu.2025.1501307","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1501307","url":null,"abstract":"<p><strong>Background: </strong>Obesity is associated with dysregulated metabolism and low-grade chronic inflammation in adipose tissue (AT). Immune cells, including macrophages, T cells, and neutrophils, infiltrate the AT and secrete proinflammatory cytokines to exacerbate the AT inflammation. RNA-Seq analysis of AT immune cells isolated from mice fed a high-fat diet (HFD) versus normal fat diet (ND) identified a panel of genes that were markedly downregulated, including sialic acid-binding Ig-like lectin E (siglec-E), in HFD compared to ND mice.</p><p><strong>Methods: </strong>A series of experiments in wild-type (WT) and siglec-E knockout (siglec-E KO) mice was designed to investigate the effect of HFD on the functional role of siglec-E in the regulation of AT inflammation and adipogenesis. We analyzed the changes in immune phenotypes, inflammatory response, adipogenesis, and levels of cytokines and chemokines after HFD and ND feeding.</p><p><strong>Results: </strong>HFD consumption significantly increased the body weight and blood glucose levels in siglec-E KO mice relative to those of WT mice. This was associated with an increased infiltration of macrophages, CXCR3 expressing CD8 T cells, and monocytic myeloid-derived suppressor cells (M-MDSCs) with a concomitant decrease in numbers of dendritic cells (DCs), in the AT of siglec-E KO fed HFD versus the WT HFD counterparts. The HFD-fed siglec-E KO mice also exhibited elevated expression of intracellular Akt and TNF receptor-associated factor 3 (TRAF3) signaling, inducing C/EBPα, FASN, PPARγ, and resistin in suprascapular AT compared to WT HFD-fed mice. Taken together, these results suggest that a genetic deficiency of siglec-E plays a key role in inducing AT inflammation by differentially altering M-MDSCs and CD8<sup>+</sup>CXCR3<sup>+</sup> T cell function and adipogenesis by TRAF3 and Akt signaling in AT.</p><p><strong>Conclusion: </strong>Our findings strongly suggest that modulation of siglec-E pathways might have a protective effect at least in part against AT inflammation and metabolic disorders.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1501307"},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449042","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}
Pub Date : 2025-02-04eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1443932
Saravanan Subramaniam, Asha Jose, Devin Kenney, Aoife K O'Connell, Markus Bosmann, Florian Douam, Nicholas Crossland
{"title":"Challenging the notion of endothelial infection by SARS-CoV-2: insights from the current scientific evidence.","authors":"Saravanan Subramaniam, Asha Jose, Devin Kenney, Aoife K O'Connell, Markus Bosmann, Florian Douam, Nicholas Crossland","doi":"10.3389/fimmu.2025.1443932","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1443932","url":null,"abstract":"","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1443932"},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448845","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}