Frontiers in ImmunologyPub Date : 2025-10-03eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1651819
Lyna-Nour Hamidi, Jack Christopher Drda, Meriem Belhocine, Hannah-Laure Elfassy, Stéphanie Ducharme-Bénard, Maxime Chayer-Lanthier, Bushra Sultana, Sylvain Lanthier
{"title":"Case Report: Mevalonate kinase deficiency: an underdiagnosed cause of ischemic stroke-characterization of a novel genetic variant.","authors":"Lyna-Nour Hamidi, Jack Christopher Drda, Meriem Belhocine, Hannah-Laure Elfassy, Stéphanie Ducharme-Bénard, Maxime Chayer-Lanthier, Bushra Sultana, Sylvain Lanthier","doi":"10.3389/fimmu.2025.1651819","DOIUrl":"10.3389/fimmu.2025.1651819","url":null,"abstract":"<p><p>Mevalonate kinase deficiency (MKD) is an inherited autoinflammatory syndrome resulting from impaired isoprenoid biosynthesis due to biallelic mevalonate kinase (<i>MVK</i>) mutations. This metabolic defect leads to dysregulated innate immunity, particularly excessive interleukin-1β release. While typically presenting in childhood with periodic fevers, expanding evidence links MKD to heterogeneous adult phenotypes with immune-mediated end-organ damage. We report an adult male presenting with leg pain and finger cyanosis followed by acute ischemic stroke, macular rash, and lymphadenopathies. He exhibited classical markers of innate immune activation, including persistent elevation of C-reactive protein. Genetic testing identified compound heterozygosity for the known <i>MVK</i> pathogenic variant c.1129G>A (V377I) and a novel missense variant, c.1049A>C (Q350P). Structural modeling of Q350P revealed disruption of the GHMP kinase domain, predicted to destabilize mevalonate kinase conformation and impair its function. The measurement of mevalonate kinase activity in lymphocytes was at 55% (normal >60%). Interleukin-1β blockade with canakinumab was initiated, and the blood markers of inflammation normalized, further supporting a central role for innate immune dysregulation. This case highlights a novel <i>MVK</i> missense variant (Q350P) with subnormal mevalonate kinase activity. The patient's compound heterozygous state with partially preserved mevalonate kinase activity may explain the attenuated systemic features and the delayed clinical onset. Remarkably, ischemic stroke was part of the initial presentation, suggesting that mevalonate kinase deficiency can manifest primarily through thrombo-inflammatory complications in adulthood, even in the absence of recurrent febrile episodes. This expands the phenotypic spectrum of MKD and underscores the need to consider adult-onset autoinflammatory syndromes in the differential diagnosis of cryptogenic ischemic strokes with markers of systemic inflammation. It also supports the utility of cytokine-targeted therapies in such contexts.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1651819"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Iptacopan for cold agglutinin disease: a case report with literature review.","authors":"Baozhi Fang, Hongbin Lu, Xiao Yu, Peng Wang, Yifei Zhou, Qiudan Shen, Muzhi Yuan, Mingen Lyu, Guangsheng He","doi":"10.3389/fimmu.2025.1672590","DOIUrl":"10.3389/fimmu.2025.1672590","url":null,"abstract":"<p><p>This study reports a case of cold agglutinin disease (CAD) secondary to lymphoplasmacytic lymphoma in a patient intolerant to rituximab plus bendamustine and with persistent uncontrolled hemolysis following zanubrutinib therapy. The addition of the complement C3 inhibitor iptacopan to a cyclophosphamide and dexamethasone regimen successfully controlled hemolysis and improved hemoglobin levels. Within one week of treatment, the patient achieved transfusion independence, with hemoglobin increasing from 67 g/L to 90 g/L by week 3 and 101 g/L by week 7, alongside normalized bilirubin levels and no adverse events. The follow-up period was 4 months, during which the patient showed sustained remission. These findings suggest that iptacopan can rapidly ameliorate hemolysis in CAD, warranting further investigation into its therapeutic potential.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1672590"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328903","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}
Frontiers in ImmunologyPub Date : 2025-10-03eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1688699
Xiaodong Wang, Jing He, Gouping Ding, Yixuan Tang, Qianqian Wang
{"title":"Overcoming resistance to PD-1 and CTLA-4 blockade mechanisms and therapeutic strategies.","authors":"Xiaodong Wang, Jing He, Gouping Ding, Yixuan Tang, Qianqian Wang","doi":"10.3389/fimmu.2025.1688699","DOIUrl":"10.3389/fimmu.2025.1688699","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 have achieved groundbreaking clinical success in multiple cancers; however, a large proportion of patients experience primary or acquired resistance. This review synthesizes the complex mechanisms underlying resistance to PD-1/CTLA-4 blockade and surveys emerging strategies to overcome them. Resistance arises from multifaceted interactions among tumor-intrinsic alterations (e.g., epigenetic silencing of antigen presentation machinery via EZH2/PRC2, oncogenic pathway-driven upregulation of PD-L1, genetic loss of IFNγ pathway components such as JAK1/2 or B2M), immune cell dysfunction (e.g., T cell exhaustion with co-expression of inhibitory receptors including PD-1, TIM-3, and LAG-3, metabolic and epigenetic T cell reprogramming, suppressive regulatory T cells), and stromal microenvironmental factors (e.g., hypoxia-inducible factors, immunosuppressive metabolites like IDO-mediated kynurenine, tumor-associated macrophages and MDSCs, aberrant angiogenesis). To counteract these diverse resistance mechanisms, a spectrum of novel therapeutic approaches is under development. Mechanism-targeted monotherapies include agents that restore tumor immunogenicity (e.g., epigenetic modulators to upregulate MHC expression), reinvigorate exhausted T cells (e.g., blockade of alternative checkpoints such as LAG-3), and reprogram the suppressive tumor microenvironment (e.g., inhibitors of immunosuppressive myeloid pathways). In parallel, rational combination therapies are being explored, pairing ICIs with chemotherapy (to induce immunogenic cell death and enhance T cell infiltration), molecularly targeted drugs (to disrupt oncogenic immune-evasion signals), or immune modulators (e.g., IL-2 or IL-18 variants to boost effector T cell function). Furthermore, emerging predictive biomarkers and machine learning-based signatures (e.g., soluble checkpoint levels, inflammatory indices, tumor transcriptomic scores) are improving the ability to anticipate ICI resistance and guide personalized escalation of therapy. Overall, this synthesis highlights the recent insights into resistance biology and promising avenues to extend the durable benefits of PD-1/CTLA-4 blockade to a larger proportion of patients.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1688699"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"HMGB1-dependent signaling in the regulation of mast cell activity during inflammation.","authors":"Justyna Agier, Sylwia Różalska, Magdalena Wiktorska, Elżbieta Kozłowska, Magdalena Jurczak, Monika Nowak, Paulina Żelechowska","doi":"10.3389/fimmu.2025.1643427","DOIUrl":"10.3389/fimmu.2025.1643427","url":null,"abstract":"<p><strong>Background: </strong>Damaged cells release endogenous molecules known as alarmins into the extracellular space following cellular injury. Alarmins may function as adjuvants by interacting with PRRs to indicate danger and initiate a localized sterile inflammatory response, which facilitates tissue regeneration. A pivotal alarmin is HMGB1, which is internalized through the RAGE to notify adjacent cells about compromised homeostasis. Given the significant role of mast cells (MCs) in inflammatory processes and the critical nature of alarmins as indicators of danger, this study evaluates the hypothesis that MCs serve as essential sensors of cellular injury. The present study investigates whether HMGB1 affects the expression levels of specific PRRs in mature MCs. These receptors include Dectin-1 and Dectin-2, TLR2, NOD1, and RIG-I. Furthermore, this study aims to determine whether HMGB1 modulates the inflammatory response of these cells, which encompasses the production of cytokines, chemokines, ROS, histamine, and cysLTs, as well as their migration patterns. Moreover, the research aims to investigate the role of RAGE and the involvement of signaling molecules in the activation of MCs mediated by HMGB1.</p><p><strong>Methods: </strong>All experiments were carried out using <i>in vivo</i> differentiated, mature tissue MCs freshly isolated from the rat peritoneal cavity. The potency of HMGB1 to provoke MC PRR expression, generation, and/or release of a panel of mediators and migration was investigated.</p><p><strong>Results: </strong>HMGB1 markedly enhances the expression of Dectin-1, RIG-I, and NOD1, while simultaneously stimulating MCs to produce CCL3, IL-1β, TNF, cysLTs, histamine, and ROS. This protein acts as a potent chemoattractant for MCs. The administration of RAGE antagonist to MCs significantly attenuated the generation of mediators and the migratory response, thereby confirming the receptor's involvement in the response of HMGB1-treated cells. Intracellular signaling in MCs activated by HMGB1 involves ERK1/2, p38 MAPK, PI3K, NF-κB, and, in part, JAK2.</p><p><strong>Conclusions: </strong>The data robustly support the notion that HMGB1 is an important endogenous alarmin that promotes and enhances MC activity in inflammatory processes. These insights highlight HMGB1 as a potential therapeutic target for regulating MC-driven inflammatory disorders, which encompass allergy, autoimmune diseases, and chronic conditions.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1643427"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328910","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}
Frontiers in ImmunologyPub Date : 2025-10-03eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1642482
Adriana Navas, Jéssica C Dos Santos, Bram van Cranenbroek, Nadira Vadaq, Albert L Groenendijk, Wilhelm A J W Vos, Marc J T Blaauw, Louise van Eekeren, Casper Rokx, Janneke E Stalenhoef, Marvin A H Berrevoets, Mihai G Netea, Leo A B Joosten, Andre J A M van der Ven, Hans J P M Koenen
{"title":"Circulating immune landscape and immune signatures in spontaneous HIV controllers.","authors":"Adriana Navas, Jéssica C Dos Santos, Bram van Cranenbroek, Nadira Vadaq, Albert L Groenendijk, Wilhelm A J W Vos, Marc J T Blaauw, Louise van Eekeren, Casper Rokx, Janneke E Stalenhoef, Marvin A H Berrevoets, Mihai G Netea, Leo A B Joosten, Andre J A M van der Ven, Hans J P M Koenen","doi":"10.3389/fimmu.2025.1642482","DOIUrl":"10.3389/fimmu.2025.1642482","url":null,"abstract":"<p><p>A subset of people with HIV, termed HIV controllers (HIC), maintain low viral loads without antiretroviral therapy. To identify the immune cell architecture of HIV control, we profiled peripheral blood from 54 HIC (including 21 elite controllers, EC) and 1,044 non-controllers (non-HIC) in the 2000HIV study (NCT03994835) using high-dimensional cytometry and confounder-adjusted regression analysis. Both HIC and EC exhibited distinct innate immune profiles compared to non-HIC, marked by reduced frequencies of CCR5<sup>+</sup> NKT and TCRγδ1<sup>+</sup> cells. EC further showed increased neutrophils and TCRγδ2<sup>+</sup> cells, and reduced eosinophils. Unsupervised clustering revealed elevated CD11c and CD1c expression on TCRγδ2<sup>+</sup> cells in EC, correlating with IFNγ production, suggesting a proinflammatory γδ T cell program unique to EC. Adaptive immune profiling showed shared features between HIC and EC: increased CD4<sup>+</sup> naïve and Th1/17 cells, reduced Th17 and Tfh cells, and higher CD8<sup>+</sup> TEMRA and Tc1/17 cells with reduced memory subsets. Both groups showed increased naïve and immature B cells and decreased switched memory and plasma cells. EC uniquely exhibited increased IgA<sup>+</sup> memory B cells -a feature consistent with enhanced mucosal immunity- and decreased IgG<sup>+</sup> memory B cells and CD307d expression, suggestive of mucosal imprinting and reduced exhaustion. Comparison of HIC and EC revealed divergent CCR5 and CXCR4 expression: EC had higher frequencies of CCR5<sup>+</sup> and CXCR4<sup>+</sup> CD4<sup>+</sup> and CD8<sup>+</sup> T cells. These elevations correlated with circulating chemokines, notably MIF for CXCR4, implying protective ligand occupancy. HIC instead showed overall lower co-receptor expression and ligand correlations. In conclusion, while HIC and EC share a core immune phenotype linked to viral control, EC-specific features- γδ T cell activation, IgA<sup>+</sup> memory enrichment, and chemokine receptor regulation-may underlie more robust or distinct immune control mechanisms. This profiling resource offers new avenues for HIV cure-focused strategies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1642482"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12532132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328953","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}
Frontiers in ImmunologyPub Date : 2025-10-03eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1677801
Jian Mei, Nicole Schäfer, Penghui Wei, Zhiheng Kong, Shushan Li, Patrick Pann, Marianne Ehrnsperger, Brian Johnstone, Eva Matalova, Susanne Grässel
{"title":"Targeting Caspase-1 in osteoarthritis: multi-omics insights into the effects of VX-765 on human chondrocyte function and phenotype.","authors":"Jian Mei, Nicole Schäfer, Penghui Wei, Zhiheng Kong, Shushan Li, Patrick Pann, Marianne Ehrnsperger, Brian Johnstone, Eva Matalova, Susanne Grässel","doi":"10.3389/fimmu.2025.1677801","DOIUrl":"10.3389/fimmu.2025.1677801","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) progression involves chronic inflammation, chondrocyte senescence, and extracellular matrix (ECM) degradation affecting all synovial joint tissues. To date, no regenerative OA drugs have been approved. Caspase-1, a core effector of the inflammasome, may contribute to OA via both canonical inflammatory and non-canonical functions, but its therapeutic value remains unclear.</p><p><strong>Methods: </strong>We combined transcriptomic, proteomic, functional, and Mendelian randomization (MR) approaches. Using GSE168505 data, we analyzed CASP1, CARD gene family members (CARD16/17/18/8), and OA-related genes in OA- versus non-OA chondrocytes. We established an <i>in vitro</i> OA model by treating human chondrocytes with TNF-α ± VX-765 and assessed Caspase-1 activity, cell metabolism, and MMP secretion. We further conducted LC-MS/MS proteomic profiling, molecular docking, and MR analysis to identify molecular mechanisms and causal links.</p><p><strong>Results: </strong>CASP1 and inflammatory/ECM-degrading genes (e.g., IL1B, MMP13) were upregulated in OA chondrocytes, whereas SOX9 was downregulated. CASP1 gene expression correlated positive with genes involved in senescence, inflammation, oxidative stress and ECM remodeling. Inhibitor VX-765 significantly inhibited Caspase-1 activity, reduced senescence, and enhanced migration in non-OA- and OA chondrocytes, with donor-dependent effects in OA chondrocytes. It also suppressed MMP13 secretion in OA chondrocytes. Integrated transcriptomic and proteomic analysis showed that VX-765 reprogrammed OA-activated signaling, significantly downregulating pathways related to senescence, inflammation, complement activation, and ECM organization, while upregulating interferon-α/γ responses. Moreover, in silico performed molecular docking analyses suggest that caspase-1 may directly bind MMP13, CTSD, ABL1, MRPS11, POLR21, SMAD2 and SOX9. MR analysis supported a causal link between increased CARD17/18/8 gene expression and reduced OA risk; several CASP1 SNPs (e.g., rs61751523) showed negative OA associations, suggesting a protective role.</p><p><strong>Conclusions: </strong>This study demonstrates that Caspase-1 contributes to OA pathogenesis through both canonical and non-canonical mechanisms, and that VX-765 can alleviate chondrocyte dysfunction. The combined evidence supports VX-765 as a potential disease-modifying target for OA therapy. However, further investigation is warranted to clarify Caspase-1's physiological roles, including possible off-target effects of its inhibitors, in cartilage and other joint tissues and the clinical relevance of inter-individual variability, with genomic variants (e.g., rs61751523) as one potential contributor, for therapeutic application.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1677801"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12532135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328921","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}
Frontiers in ImmunologyPub Date : 2025-10-03eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1636782
Xin Pei, Minghui Yu, Yijia Wang, Shi Zong, Fei Qi, Kaichen Wang
{"title":"What is the relationship between microorganisms in the human body and upper tract urothelial carcinoma?","authors":"Xin Pei, Minghui Yu, Yijia Wang, Shi Zong, Fei Qi, Kaichen Wang","doi":"10.3389/fimmu.2025.1636782","DOIUrl":"10.3389/fimmu.2025.1636782","url":null,"abstract":"<p><p>Upper Tract Urothelial Carcinoma (UTUC) is a highly malignant tumor originating from the epithelium of the upper urinary tract with diverse pathogenesis, but currently available diagnostic and therapeutic strategies have some limitations. In recent years, human microbiome-related studies have provided new ideas for the exploration of the pathogenesis and treatment of UTUC. In this paper, we review the research progress of human microbiome related to UTUC. Focusing on the urinary microbiome, the role of the microbiome in the pathogenesis of UTUC is investigated through the mechanisms of chronic inflammation, genotoxic damage, immune microenvironmental imbalance and metabolic reprogramming. The pyelo-ureteric microbiome of healthy populations is dominated by commensal bacteria such as Lactobacillus and Streptococcus, whereas pathogenic bacteria such as Escherichia coli (E. coli) and Enterococcus faecalis are significantly enriched in patients with UTUC, which results in the development of DNA damage, inflammatory response and immunosuppression. In addition, microbiome metabolites (e.g., short-chain fatty acids, tryptophan derivatives) can influence tumor progression by modulating immune checkpoints (e.g., PD-1/PD-L1, B7-H4) and metabolic pathways (e.g., Warburg effect). In diagnostic and therapeutic applications, urinary microbial markers (e.g., E. coli-specific gene clusters) can be combined with circulating tumor DNA (ctDNA) assays to improve diagnostic sensitivity and specificity, and indices of intestinal flora diversity (e.g., Simpson's index) are significantly correlated with the response rate to chemotherapy and prognostic course. In the future, we need to overcome the challenges of difficult sample acquisition, unknown causal mechanisms, and etiologic heterogeneity interference, and promote multi-omics joint modeling as well as cross-ethnicity and geographic research, and bidirectional regulation mechanisms of the gut-kidney axis in order to develop more accurate UTUC diagnosis and treatment strategies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1636782"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328852","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}
Frontiers in ImmunologyPub Date : 2025-10-03eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1679071
Luana Filippi Xavier, Ranko Gacesa, Gustavo Henrique Oliveira da Rocha, Milena Fronza Broering, Pablo Scharf, Fabiana da Silva Lima, Klaas Nico Faber, Hermie Harmsen, Christian Hoffmann, Sandra Helena Poliselli Farsky
{"title":"Annexin A1 levels affect microbiota in health and DSS-induced colitis/inflammatory bowel disease development.","authors":"Luana Filippi Xavier, Ranko Gacesa, Gustavo Henrique Oliveira da Rocha, Milena Fronza Broering, Pablo Scharf, Fabiana da Silva Lima, Klaas Nico Faber, Hermie Harmsen, Christian Hoffmann, Sandra Helena Poliselli Farsky","doi":"10.3389/fimmu.2025.1679071","DOIUrl":"10.3389/fimmu.2025.1679071","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory Bowel Diseases (IBDs) are characterized by intestinal dysbiosis and immune dysregulation. Annexin A1 (AnxA1) promotes epithelial repair and inhibits immune responses during IBD. However, AnxA1's impact on gut microbiota during IBD remains unclear. Here, we experimentally investigated the microbiota profile during colitis in wild-type (WT) and AnxA1-deficient mice (AnxA1<sup>-/-</sup>), and evaluated an observational cohort in IBD patients with high or low AnxA1 expression.</p><p><strong>Methods: </strong>Colitis was induced in C57BL/6 WT and AnxA1 <sup><sup>-</sup>/<sup>-</sup></sup> mice via oral administration of 2% DSS for six days. Fecal samples were collected at baseline, peak inflammation (day 6), and during the recovery phase (day 10) for 16S rRNA sequencing. Human microbiota data from the Lifelines Dutch Microbiome Project cohort, including IBD and healthy subjects, were analyzed for AnxA1 expression using R software.</p><p><strong>Results: </strong>Healthy AnxA1<sup>-/-</sup> mice exhibited reduced microbial richness and a distinct gut microbiota composition, marked by increased <i>Proteobacteria</i> and <i>Parasutterella</i>, and reduced <i>Deferribacterota</i>, <i>Campylobacterota</i>, and <i>Verrucomicrobiota.</i> During DSS-induced colitis, AnxA1<sup>-/-</sup> mice showed greater weight loss and heightened inflammation, displaying earlier and more pronounced microbial shifts, including increased <i>Proteobacteria</i>, <i>Cyanobacteria</i>, <i>Parabacteroides</i>, <i>Bacteroides</i>, and <i>Escherichia-Shigella</i>. In contrast, WT mice exhibited delayed changes, with expansion of <i>Alloprevotella</i>, <i>Akkermansia</i>, and <i>Faecalibaculum</i> after day 6. In human IBD samples, Crohn's disease (CD) patients with low AnxA1 expression and active inflammation presented an altered microbiota enriched in <i>Lachnoclostridium</i> and <i>Parabacteroides</i>, while ulcerative colitis (UC) patients showed phylum-level shifts modulated by AnxA1 levels. Notably, non-inflamed CD and UC patients with low AnxA1 differed significantly in microbiota composition. Moreover, inflamed CD patients with high AnxA1 expression showed microbial profiles resembling those of healthy controls, while low AnxA1 expression was associated with a more pronounced dysbiotic state.</p><p><strong>Conclusion: </strong>AnxA1 is implicated in microbiota control under healthy and IBD conditions. Accordingly, the microbiota of healthy AnxA1<sup>-/-</sup> mice, colitic AnxA1<sup>-/-</sup> mice, and IBD patients with low AnxA1 expression exhibit dysbiosis compared to their respective controls. Together, these unprecedented findings reveal AnxA1 as a potential regulatory protein in the immune-microbiota axis involved in IBD pathogenesis.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1679071"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328860","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}
Frontiers in ImmunologyPub Date : 2025-10-03eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1640024
Chu Zhang, Lu Wang, Qihong Fan, Yan Pan
{"title":"Polymorphism-driven immune disruptions in Kawasaki disease across populations: decoding the role of T and B-cells.","authors":"Chu Zhang, Lu Wang, Qihong Fan, Yan Pan","doi":"10.3389/fimmu.2025.1640024","DOIUrl":"10.3389/fimmu.2025.1640024","url":null,"abstract":"<p><p>Kawasaki disease (KD) is a self-limiting, systemic vasculitic syndrome of unknown etiology that primarily affects children under the age of five, with notably high incidence in Asian populations. Although initial treatment with high-dose intravenous immunoglobulin (IVIG) and aspirin can reduce acute symptoms of KD and the risk of coronary artery lesions (CALs), diagnosis remains challenging due to the absence of specific biomarkers and the incomplete understanding of disease pathogenesis, often resulting in misdiagnosis or delayed intervention. Genetic predisposition and immune dysregulation, particularly involving B-cell and T-cell pathways, have been implicated in KD susceptibility and the development of CAL. This review summarizes current evidence on immune-regulatory gene polymorphisms, with a focus on how T-cell and B-cell-related genetic variations may contribute to disease onset and vascular complications. These insights may help inform improved diagnostic accuracy-particularly for incomplete KD-and support personalized treatment strategies, such as corticosteroids or anti-TNF agents in genetically high-risk patients.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1640024"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12532134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328908","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}
Frontiers in ImmunologyPub Date : 2025-10-03eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1675429
Haotian Li, Congmin Xia, Yuewei Song, Jin Chen, Yanjun Liu
{"title":"Unveiling the mechanisms of American ginseng and achyranthes in treatment of primary Sjogren's syndrome via mtDNA-cGAS-STING pathway insights from network pharmacology, molecular dynamics, and experimental validation.","authors":"Haotian Li, Congmin Xia, Yuewei Song, Jin Chen, Yanjun Liu","doi":"10.3389/fimmu.2025.1675429","DOIUrl":"10.3389/fimmu.2025.1675429","url":null,"abstract":"<p><strong>Objective: </strong>With the aim of clarifying the therapeutic mechanisms of the American Ginseng-Achyranthes bidentata (AG&A) herbal pair in primary Sjögren's syndrome (pSS), this study employs an integrated approach combining network pharmacology, molecular docking, molecular dynamics simulations, and animal experiments.</p><p><strong>Methods: </strong>Network pharmacology & LC-MS/MS was utilized to identify the active components and potential targets of A&A. Molecular docking and dynamics simulations were performed to evaluate binding affinity and complex stability with key targets. Animal experiments using non-obese diabetic (NOD) mice were conducted to validate symptom improvement by critical active components.</p><p><strong>Results: </strong>Network pharmacology identified baicalin and quercetin as key active components. Molecular docking revealed strong binding affinities (binding energy ≤ -8.0 kcal/mol) between these compounds and apoptosis-related proteins, BAX and CASP3. Molecular dynamics simulations confirmed the stability of these complexes. Animal experiments demonstrated that baicalin can significantly reduce inflammatory cytokines of IL-18, TNF-α, IFN-α, and IFN-β,CXCL-10 (p < 0.05), decrease mtDNA release, and downregulate cGAS-STING pathway-related proteins including cGAS, STING, CASP3, ZBP1, TBK1, p-STING, p-TBK1, IRF3, p-IRF3 and BAX.</p><p><strong>Conclusion: </strong>The critical components baicalin and quercetin from AG&A, particularly in aqueous extracts, exhibit therapeutic efficacy against pSS. This study provides experimental evidence for their action mechanism through modulating the mtDNA-cGAS-STING pathway. While highlighting their therapeutic potential, additional <i>in vivo</i> and clinical studies are warranted to validate these findings.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1675429"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328929","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}