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Unveiling the Role of Oligosaccharyltransferase STT3B in Colorectal Cancer Tissues: Clinical significance and Molecular Mechanisms Driving the Formation of Tertiary Lymphoid Structures
IF 2.5 4区 医学
Immunobiology Pub Date : 2025-03-04 DOI: 10.1016/j.imbio.2025.152886
Caixia Zhang , Bin Wang , Xiaofeng Bian , Youcai Zhao , Xiaobing Yang , Wei Zhao
{"title":"Unveiling the Role of Oligosaccharyltransferase STT3B in Colorectal Cancer Tissues: Clinical significance and Molecular Mechanisms Driving the Formation of Tertiary Lymphoid Structures","authors":"Caixia Zhang ,&nbsp;Bin Wang ,&nbsp;Xiaofeng Bian ,&nbsp;Youcai Zhao ,&nbsp;Xiaobing Yang ,&nbsp;Wei Zhao","doi":"10.1016/j.imbio.2025.152886","DOIUrl":"10.1016/j.imbio.2025.152886","url":null,"abstract":"<div><div>The role of tertiary lymphatic structures (TLS) in anti-tumor response has garnered increasing attention; however, the clinical implications and regulatory mechanisms of various TLS subtypes remain poorly understood. This study investigates the function of the oligosaccharyltransferase subunit STT3B in modulating TLS formation and B cell activity within colorectal cancer (CRC) tissues. Spatial morphology analysis was employed to accurately identify the localization of STT3B expression within TLS. By integrating clinical samples with bioinformatics analyses, we examined the expression levels and distribution patterns of STT3B in the CRC microenvironment and assessed its clinical significance. Transcriptome sequencing, combined with <em>in vitro</em> validation, was utilized to evaluate the effects of STT3B knockdown on B cell functionality. The findings indicated that CRC patients with a high density of STT3B expression in the TLS had a better prognosis. Multicolor fluorescence analysis further demonstrated that the density of STT3B<sup>+</sup>CD19<sup>+</sup> B cells correlated with pathological characteristics and lymph node metastasis status in CRC patients, with higher densities predicting longer disease-free survival. Transcriptome sequencing further demonstrated that STT3B knockdown predominantly impacts B cell metabolic functions. <em>In vitro</em> experiments confirmed that the downregulation of STT3B inhibits the metabolism and proliferation of B cells. These findings suggest that STT3B plays a crucial role in enhancing B cell metabolism and facilitating the development of mature TLS, which is associated with improved prognostic outcomes in patients with CRC.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 3","pages":"Article 152886"},"PeriodicalIF":2.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Renqing Changjue alleviates sepsis-induced acute lung injury by regulating renin-angiotensin system and inhibiting inflammatory response
IF 2.5 4区 医学
Immunobiology Pub Date : 2025-02-23 DOI: 10.1016/j.imbio.2025.152883
Minxia Zhu , Yaqi Lei , Zhaojun Zhang , Xu Guo , Jing Guo , Ruipeng Wu , Xiaofeng Li , Shibo Tian , Yuanhao Zhao
{"title":"Renqing Changjue alleviates sepsis-induced acute lung injury by regulating renin-angiotensin system and inhibiting inflammatory response","authors":"Minxia Zhu ,&nbsp;Yaqi Lei ,&nbsp;Zhaojun Zhang ,&nbsp;Xu Guo ,&nbsp;Jing Guo ,&nbsp;Ruipeng Wu ,&nbsp;Xiaofeng Li ,&nbsp;Shibo Tian ,&nbsp;Yuanhao Zhao","doi":"10.1016/j.imbio.2025.152883","DOIUrl":"10.1016/j.imbio.2025.152883","url":null,"abstract":"<div><div>Sepsis, with high morbidity and mortality, represents a systemic inflammatory response syndrome. A common consequence of sepsis is acute lung injury (ALI). Renqing Changjue (RQCJ), a renowned prescription in traditional Tibetan medicine, is reported to have anti-inflammatory effects. The present study was aimed at exploring whether RQCJ could mitigate sepsis-induced ALI and elucidating its underlying mechanism. The rat model of sepsis-induced ALI was established by intraperitoneal injection of lipopolysaccharide (LPS), and high, medium, and low doses of RQCJ were administered. The results indicated that the intervention of RQCJ improved septic symptoms, mitigated the murine sepsis score and pulmonary edema in LPS-induced septic rats, and decreased inflammatory cytokines in lung tissue such as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). Furthermore, RQCJ regulated the balance of renin-angiotensin system by enhancing the enzyme activity of angiotensin converting enzyme 2 (ACE2) while inhibiting ACE, thereby promoting the production of angiotensin 1–7 (Ang1–7). This study highlights the multiple protective effects of RQCJ on sepsis-induced ALI, providing a valuable reference for its further development and offering a novel perspective for the treatment of sepsis-induced ALI.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 3","pages":"Article 152883"},"PeriodicalIF":2.5,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CVB3 regulates Treg cell pyroptosis through the lncRNA XIST/miR-195-5p/caspase-1 molecular axis
IF 2.5 4区 医学
Immunobiology Pub Date : 2025-02-19 DOI: 10.1016/j.imbio.2025.152882
Yan Zhang , Lei Yang , Huiting Mu , Na Li , Xuejia Wang , Hualan Lei , Mingjie Pang
{"title":"CVB3 regulates Treg cell pyroptosis through the lncRNA XIST/miR-195-5p/caspase-1 molecular axis","authors":"Yan Zhang ,&nbsp;Lei Yang ,&nbsp;Huiting Mu ,&nbsp;Na Li ,&nbsp;Xuejia Wang ,&nbsp;Hualan Lei ,&nbsp;Mingjie Pang","doi":"10.1016/j.imbio.2025.152882","DOIUrl":"10.1016/j.imbio.2025.152882","url":null,"abstract":"<div><div>Viral myocarditis (VMC) is characterized by severe cardiac inflammation and is a major cause of congestive heart failure and sudden cardiac death in healthy young people. The lncRNA XIST plays an important regulatory role in myocardial injury, but its role in VMC caused by coxsackievirus B3 (CVB3) infection is unclear. In this study, we evaluated the effects of the lncRNA XIST on a CVB3-induced VMC mouse model and on pyroptosis in CVB3-exposed Treg cells. The results showed that in CVB3-infected VMC and Treg cells, the expression level of the lncRNA XIST was increased, whereas miR-195-5p expression was decreased. In CVB3-induced VMC mice, inflammation was elevated, whereas the Treg/Th17 ratio was reduced. Knocking down the lncRNA XIST suppressed pyroptosis in Treg cells caused by CVB3 infection and inhibited VMC progression in vivo. Studies on downstream mechanisms have shown that the lncRNA XIST targets miR-195-5p, induces caspase-1 expression through the inhibition of miR-195-5p, promotes the expression of the inflammatory factors IL-1β and IL-18 associated with pyroptosis, inhibits the secretion of the anti-inflammatory factors IL-10 and TGF-β1, and ultimately promotes pyroptosis in Treg cells. In conclusion, knocking down the lncRNA XIST inhibits CVB3-induced pyroptosis of Treg cells and VMC progression in mice induced by CVB3 infection. These findings provide a potential theoretical basis for the treatment of VMC.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 2","pages":"Article 152882"},"PeriodicalIF":2.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Preclinical models of immune checkpoint inhibitors-related interstitial pneumonia for anti-PD1 tumor immunotherapy
IF 2.5 4区 医学
Immunobiology Pub Date : 2025-02-17 DOI: 10.1016/j.imbio.2025.152884
Tingyue Luo , Weisheng Chen , Danhui Huang , Xiguang Liu , Junjie Xi , Zeyu Fu , Junwei Chen , Yuhan Du , Ruijun Cai , Qi Yu , Dongyu Liu , Jiangzhou Du , Laiyu Liu , Shaoxi Cai , Hangming Dong
{"title":"Preclinical models of immune checkpoint inhibitors-related interstitial pneumonia for anti-PD1 tumor immunotherapy","authors":"Tingyue Luo ,&nbsp;Weisheng Chen ,&nbsp;Danhui Huang ,&nbsp;Xiguang Liu ,&nbsp;Junjie Xi ,&nbsp;Zeyu Fu ,&nbsp;Junwei Chen ,&nbsp;Yuhan Du ,&nbsp;Ruijun Cai ,&nbsp;Qi Yu ,&nbsp;Dongyu Liu ,&nbsp;Jiangzhou Du ,&nbsp;Laiyu Liu ,&nbsp;Shaoxi Cai ,&nbsp;Hangming Dong","doi":"10.1016/j.imbio.2025.152884","DOIUrl":"10.1016/j.imbio.2025.152884","url":null,"abstract":"<div><div>Immune-related adverse reactions (irAEs) are common adverse reactions after immune checkpoint inhibitor treatment, impacting the universality and continued use of immunotherapy. Currently, preclinical models to investigate the mechanisms underlying these adverse effects are inadequate. This study aims to develop both in vitro and in vivo models of irAEs to advance basic research on these adverse reactions. For vitro models, we designed two co-culture systems: “Lung epithelial cells-PBMC” conditional co-culture model and “organoid-PBMCs” co-culture model. These involve culturing spheroids, patient-derived organoids and isolating, expanding, and co-culturing peripheral blood mononuclear cells (PBMCs). For vivo model, PD1 humanized mice were used to establish a lung carcinoma in situ model in offspring, with blocked immune checkpoints to induce systemic inflammatory responses. Mice without PD-1 blockade served as the control group. In both organoid and “lung epithelial cell-PBMC” models, compared with the control group, the PBMC+anti-PD1 group exhibited inflammatory injury, demonstrated by the worst activity, increased collagen deposition, elevated mRNA levels of αSMA and Vimentin, higher Fibronectin expression, and higher inflammatory factors (IL6, IL1β, MPO) in the culture supernatant (<em>p</em> &lt; 0.05). In vivo model also showed pulmonary inflammation, with slower weight gain of the affected mice, more obvious pulmonary interstitial thickening(Masson staining and α-SMA immunofluorescence staining), and increased immune cells and IL17A in alveolar lavage fluid and serum. This study successfully developed preclinical models of irAEs using organoid technology, conditioned co-culture and humanized mouse models, effectively reproducing inflammatory injury and offering valuable tools for irAE research.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 2","pages":"Article 152884"},"PeriodicalIF":2.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Shared pyroptosis pathways and crosstalk genes underpin inflammatory links between periodontitis and atherosclerosis
IF 2.5 4区 医学
Immunobiology Pub Date : 2025-02-13 DOI: 10.1016/j.imbio.2025.152880
Pinxin Zhan, Zhiying Feng, Xinqi Huang, Haoyang Xu, Shijun Xu, Shan Wang
{"title":"Shared pyroptosis pathways and crosstalk genes underpin inflammatory links between periodontitis and atherosclerosis","authors":"Pinxin Zhan,&nbsp;Zhiying Feng,&nbsp;Xinqi Huang,&nbsp;Haoyang Xu,&nbsp;Shijun Xu,&nbsp;Shan Wang","doi":"10.1016/j.imbio.2025.152880","DOIUrl":"10.1016/j.imbio.2025.152880","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to identify crosstalk genes shared between periodontitis (PD) and atherosclerosis (AS) and to investigate their potential connections with pyroptosis-related genes. The goal was to uncover common regulatory mechanisms underlying these two inflammatory conditions.</div></div><div><h3>Methods</h3><div>Gene expression datasets for PD (GSE10334) and AS (GSE43292) were retrieved from public databases. Following batch effect correction and normalization, differential expression analysis was conducted using the limma package in R. Functional enrichment analysis was performed with the clusterProfiler package to identify key pathways, while heatmaps and pathway networks were constructed to visualize the relationships among pyroptosis genes and crosstalk genes. Weighted gene co-expression network analysis (WGCNA) was applied to identify critical modules, and the diagnostic potential of core genes was evaluated via receiver operating characteristic (ROC) analysis. Protein-protein interaction (PPI) networks were also constructed to explore molecular interactions.</div></div><div><h3>Results</h3><div>A total of 28 downregulated and 105 upregulated genes were identified in the PD dataset, while the AS dataset revealed 55 downregulated and 56 upregulated genes. Thirteen crosstalk genes were identified between the two datasets. Enrichment analyses of these crosstalk genes highlighted their involvement in inflammation- and immune-related pathways. The observed association of pyrototic phenotypes with PD and AS indicated significant overexpression of pyroptosis-related genes such as CASP1, NLRP3, and GSDMD, suggesting the participation of pyroptosis in the progression of disease. The WGCNA suggested that pyroptosis genes are closely relevant to immune responses and cell death processes. Data up to October 2023 were used to perform receiver operating characteristics (ROC) curves to confirm the diagnostic value of the enriched core genes, and all of them presented AUC values &gt;0.8, which meant that they were key genes with effective diagnostic power.</div></div><div><h3>Conclusion</h3><div>We report a novel study that identifies differentially expressed genes and pyroptosis-related pathways in PD and AS with shared inflammatory mechanisms. These results underscore the crucial role of pyroptosis in disease progression, suggesting its potential as a focus of diagnostic and therapeutic strategies. These findings provide insights for dissecting the molecular basis of inflammatory diseases.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 2","pages":"Article 152880"},"PeriodicalIF":2.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143444425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Expression of human superoxide dismutase (SOD) 1 G93A and chlorovirus ATCV-1 SOD increases the response of macrophages to inflammatory stimulants, including ATCV-1 major capsid protein glycans
IF 2.5 4区 医学
Immunobiology Pub Date : 2025-02-12 DOI: 10.1016/j.imbio.2025.152881
Thomas M. Petro , Ahmed Esmael , Gary L. Pattee , Fiyad Al-Sarmi , Fabrizio Chiodo , Irina V. Agarkova , David D. Dunigan , James L. Van Etten
{"title":"Expression of human superoxide dismutase (SOD) 1 G93A and chlorovirus ATCV-1 SOD increases the response of macrophages to inflammatory stimulants, including ATCV-1 major capsid protein glycans","authors":"Thomas M. Petro ,&nbsp;Ahmed Esmael ,&nbsp;Gary L. Pattee ,&nbsp;Fiyad Al-Sarmi ,&nbsp;Fabrizio Chiodo ,&nbsp;Irina V. Agarkova ,&nbsp;David D. Dunigan ,&nbsp;James L. Van Etten","doi":"10.1016/j.imbio.2025.152881","DOIUrl":"10.1016/j.imbio.2025.152881","url":null,"abstract":"<div><div>One cause of familial Amyotrophic Lateral Sclerosis (ALS) is a mutation in Super Oxide Dismutase 1 (SOD1) whereby amino acid 93 is alanine instead of glycine (SOD1-G93A). Transgenic mice expressing human SOD1-G93A pathogenic variant develop motor neuron disease (MND), similar to ALS. Humans with ALS and SOD1-G93A mice have elevated production of inflammatory cytokines, such as IL-6, which may promote MND. We previously showed that infection with the Chlorovirus <em>Acanthocystis turfacea</em> chlorella virus 1 (ATCV-1), which encodes a SOD1, accelerates onset of MND in these mice and induces macrophages to produce high levels of IL-6. We confirm here that ALS patients compared with healthy controls have significantly elevated levels of plasma IL-6 and Interferon-gamma (IFN-γ), but not IL-17. To determine if expression of ATCV-1 SOD1 or SOD1-G93A in mouse macrophages elevates expression of inflammatory cytokines, we transfected the RAW264.7 mouse macrophage cell line with plasmids encoding ATCV-1 SOD1, wild-type human SOD1, SOD1-G93A, or an empty vector. RAW264.7 cells stably expressing wtSOD1 or G93A-SOD1 were stimulated with poly I:C and Interferon-gamma, alone, or in combination to induce inflammatory factors, such as IL-6 and Nitric Oxide (NO), anti-inflammatory factors, such as IL-10, or activation of Interferon Stimulated Response Elements (ISRE) promoters. After stimulation, production of IL-6 and NO, but not IL-10 or ISRE promoter activity was significantly higher in RAW264.7 cells expressing SOD1-G93A compared with wt SOD1. Moreover, RAW264.7 cells expressing SOD1-G93A compared with wt SOD1 produced higher levels of IL-6 and NO in response to ATCV-1 glycoproteins. Finally, transfection of plasmid encoding ATCV-1 SOD1 into RAW264.7 cells significantly increased expression of inflammatory factors in responses to poly I:C and IFN-γ, primarily in an Interferon regulatory factor 3 (IRF3) dependent fashion. These data clearly show that expression of G93A-SOD1 or ATCV-1 SOD1 in macrophages significantly elevates expression of inflammatory factors following stimulations that mimic virus infection, viral components, or T cell cytokines, thereby suggesting one mechanism by which atypical SOD1 in macrophages can contribute to ALS-MND.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 2","pages":"Article 152881"},"PeriodicalIF":2.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Regulation of FOXM1 by HDAC3 Inhibition Ameliorates Macrophage Endoplasmic Reticulum stress and Apoptosis in Mycobacterium tuberculosis Infection
IF 2.5 4区 医学
Immunobiology Pub Date : 2025-02-05 DOI: 10.1016/j.imbio.2025.152879
Jinqi Hao, Lan Zhang, Jiafu Qi, Yanqin Yu
{"title":"Regulation of FOXM1 by HDAC3 Inhibition Ameliorates Macrophage Endoplasmic Reticulum stress and Apoptosis in Mycobacterium tuberculosis Infection","authors":"Jinqi Hao,&nbsp;Lan Zhang,&nbsp;Jiafu Qi,&nbsp;Yanqin Yu","doi":"10.1016/j.imbio.2025.152879","DOIUrl":"10.1016/j.imbio.2025.152879","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (Mtb) infection may induce significant damage to the host lung tissues. Endoplasmic reticulum stress (ERS) and apoptosis of macrophages are considered key factors affecting the survival and pathogenicity of intracellular Mtb. Forkhead box M1 (FOXM1) is closely implicated in lung diseases. This study aimed to investigate the role of FOXM1 in Mtb infection and the involvement of histone deacetylase 3 (HDAC3) in this process. An in vitro Mtb infection model was established by infecting RAW264.7 macrophages with Mtb H37Ra. The results showed that RAW264.7 macrophages subjected to Mtb infection showed upregulated expressions of ERS markers and FOXM1. FOXM1 overexpression further elevated the levels of ERS and apoptosis markers, pro-inflammatory cytokines, and reactive oxygen species in Mtb-infected macrophages. FOXM1 could bind to the promoter of <em>TXNIP</em> and activate its transcription. Knockdown of TXNIP suppressed the effects of Mtb infection on macrophages, while upregulation of FOXM1 completely abolished the effects of TXNIP knockdown. HDAC3 inhibitor effectively diminished the effects of FOXM1 upregulation on Mtb-infected macrophages. In conclusion, inhibition of HDAC3 may reduce ERS and apoptosis of Mtb-infected macrophages by regulating the FOXM1/TXNIP axis.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 2","pages":"Article 152879"},"PeriodicalIF":2.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Autoimmune Profiles in the Etiopathogenesis of Granulomatous Lobular Mastitis
IF 2.5 4区 医学
Immunobiology Pub Date : 2025-01-31 DOI: 10.1016/j.imbio.2025.152878
Lu Xie, Jiamei Feng, Qingqian Gao, Wenchao Qu, Shijun Shao, Jiaye Sun, Xueqing Wu, Hua Wan
{"title":"The Autoimmune Profiles in the Etiopathogenesis of Granulomatous Lobular Mastitis","authors":"Lu Xie,&nbsp;Jiamei Feng,&nbsp;Qingqian Gao,&nbsp;Wenchao Qu,&nbsp;Shijun Shao,&nbsp;Jiaye Sun,&nbsp;Xueqing Wu,&nbsp;Hua Wan","doi":"10.1016/j.imbio.2025.152878","DOIUrl":"10.1016/j.imbio.2025.152878","url":null,"abstract":"<div><h3>Objectives</h3><div>Granulomatous lobular mastitis (GLM) is a chronic breast inflammation with low remission and high recurrence. This study aimed to investigate GLM patients' autoimmune profiles and their correlation with GLM etiopathogenesis.</div></div><div><h3>Methods</h3><div>Samples from GLM patients and fibroadenoma (FA) controls admitted to Shuguang Hospital between July 2021 and July 2022 were analyzed. Patients (107 GLM, 73 FA) underwent humoral immunity (C3, C4, IgG, IgM, IgE and IgA), cellular immunity (CD3<sup>+</sup>CD4<sup>+</sup> T cells, CD3<sup>+</sup>CD8<sup>+</sup> T cells, regulatory T cells and CD4/CD8 ratio) and cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12 and TNF-α) tests. Immunohistochemical staining (10 GLM, 10 FA normal tissues) detected IL-1β, IL-6, CD86 and CD206, and immunofluorescence (3 GLM, 3 FA normal tissues) evaluated CD86 and CD206 expression. Multivariate analysis was done using logistic regression.</div></div><div><h3>Results</h3><div>GLM featured granulomas with non-caseation necrosis and inflammatory cell infiltration. GLM patients showed higher C3 (<em>P</em> &lt; 0.001), C4 (<em>P</em> &lt; 0.001), IgE (<em>P</em> &lt; 0.05), IgA (<em>P</em> &lt; 0.05), IL-6 (<em>P</em> &lt; 0.001), and IL-8 levels (<em>P</em> &lt; 0.05). M1 (CD86) and M2 (CD206) macrophage markers were significantly higher in GLM than controls in both immunohistochemical and immunofluorescent staining (<em>P</em> &lt; 0.05). The multivariate logistic regression analysis revealed that reproductive history (OR = 7.011, <em>P</em> &lt; 0.01) and C3 expression level (OR = 5565.570, <em>P</em> &lt; 0.001) were independent factors of GLM.</div></div><div><h3>Conclusions</h3><div>The results highlighted the crucial role of elevated M1 and M2 macrophages in GLM inflammation. GLM was associated with reproductive history, C3, C4, IgE, IgA, IL-6, and IL-8, with reproductive history and C3 as independent risks.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 2","pages":"Article 152878"},"PeriodicalIF":2.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Integrated analyses uncover new features of atypical memory B cells and novel targets for intervention
IF 2.5 4区 医学
Immunobiology Pub Date : 2025-01-30 DOI: 10.1016/j.imbio.2025.152877
Fuli Fan , Shubei Liu , Bin Wang , Xiaojian Song , Wei Wang
{"title":"Integrated analyses uncover new features of atypical memory B cells and novel targets for intervention","authors":"Fuli Fan ,&nbsp;Shubei Liu ,&nbsp;Bin Wang ,&nbsp;Xiaojian Song ,&nbsp;Wei Wang","doi":"10.1016/j.imbio.2025.152877","DOIUrl":"10.1016/j.imbio.2025.152877","url":null,"abstract":"<div><h3>Background</h3><div>Atypical memory B (AMB) is a novel subset of B lymphocytes, but its immune features and pathogenetic roles in systemic rheumatic diseases are still largely elusive. This study aimed to characterize transcriptomic features, immune phenotypes and potential signaling pathways of AMB, and also to confirm its alternations in systemic rheumatic diseases via combined transcriptome analyses.</div></div><div><h3>Method</h3><div>B cell subsets and their transcriptomic signatures were identified via analyses of single cell RNA-sequencing (scRNA-seq) data. Functional characterization of AMB was performed with bioinformatics and CyTOF-based phenotyping. Alternation of AMB in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (SjS) was evaluated via bioinformatic approaches.</div></div><div><h3>Result</h3><div>A total of 11 B cell subsets including AMB were identified through scRNA-seq transcriptome analyses. Both transcriptome analyses and CyTOF-based immune phenotyping confirmed that AMB had increased levels of TBX21 (T-bet), ITGAX (CD11c), CD19, CD20 and CXCR3 (<em>P</em> &lt; 0.05), and it had decreased expressions of CD27, CD38, CXCR4, CXCR5 and CD62L (P &lt; 0.05). More than 50 % of T-bet<sup>+</sup> B cells did not express CD11c, and more than 30 % expressed CD27. AMB was characterized by activated mTORC1 signaling and increased p-P38 level (<em>P</em> &lt; 0.05). AMB transcriptional signature was significantly enriched in the peripheral blood and disease tissues of patients of SLE, RA and SjS (P &lt; 0.05), suggesting the expanded AMB cells in those patients.</div></div><div><h3>Conclusion</h3><div>This study defines the transcriptomic signature, immune phenotypes and potential signaling pathways of AMB, and also confirms the involvement of AMB in systemic rheumatic diseases including SLE, RA and SjS via transcriptomic approaches. mTORC1 signaling and P38/MAPK signaling are promising therapeutic targets for systemic rheumatic diseases mediated by AMB.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 2","pages":"Article 152877"},"PeriodicalIF":2.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibiting the alternative pathway of complement by reducing systemic complement factor B: Randomized, double-blind, placebo-controlled phase 1 studies with Sefaxersen
IF 2.5 4区 医学
Immunobiology Pub Date : 2025-01-28 DOI: 10.1016/j.imbio.2025.152876
Michael L. McCaleb , Steven G. Hughes , Tamar R. Grossman , Ashley Frazer-Abel , Bill Jung , Lixuan Yin , Scott P. Henry , Brett P. Monia , Eugene Schneider , Richard Geary , Gary T. Brice
{"title":"Inhibiting the alternative pathway of complement by reducing systemic complement factor B: Randomized, double-blind, placebo-controlled phase 1 studies with Sefaxersen","authors":"Michael L. McCaleb ,&nbsp;Steven G. Hughes ,&nbsp;Tamar R. Grossman ,&nbsp;Ashley Frazer-Abel ,&nbsp;Bill Jung ,&nbsp;Lixuan Yin ,&nbsp;Scott P. Henry ,&nbsp;Brett P. Monia ,&nbsp;Eugene Schneider ,&nbsp;Richard Geary ,&nbsp;Gary T. Brice","doi":"10.1016/j.imbio.2025.152876","DOIUrl":"10.1016/j.imbio.2025.152876","url":null,"abstract":"<div><div>An over-active alternative complement pathway has been implicated in the pathophysiology of multiple diseases, including IgA nephropathy and geographic atrophy secondary to age related macular degeneration. In first-in-human double-blind, placebo-controlled phase 1 studies, the safety and pharmacodynamic effects of sefaxersen (RO7434656), a GalNAc-conjugated 2’-MOE antisense oligonucleotide targeting the complement factor B mRNA, was investigated. Healthy volunteers received either single or repeated (for 6 weeks) subcutaneous administrations of investigational drug or placebo. Safety and plasma complement protein levels were assessed throughout the studies and during 90-day follow-up periods. All subjects (54) completed the studies and no safety signals or clinically meaningful changes in blood chemistry, urinalysis, hematology, ECG, vital signs or ocular endpoints were observed. Mean levels of systemic complement factor B (FB) were reduced up to 38 % after single administration and 69 % after repeated administration. Lowering of FB protein was paralleled by similar reductions of plasma Bb levels. There was a strong correlation between reduction of plasma levels of FB and alternative complement pathway activity (AH50), but no meaningful changes in classical complement pathway activity (CH50). The long duration of lowering of FB levels following the last dose supports monthly dosing in future clinical trials. These clinical results support the ongoing Phase 2 development for geographic atrophy secondary to age-related macular degeneration and Ph 2/3 development for IgA nephropathy.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 2","pages":"Article 152876"},"PeriodicalIF":2.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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