Pub Date : 2024-11-01DOI: 10.1016/j.molimm.2024.10.005
Huan Zhang , Zhentao Zhang , Kedi Fan , Yuxi Chen , Peng Xu , Yufan Guo , Xingbo Mo
Functional genes within genomic loci associated with systemic lupus erythematosus (SLE), as identified by genome-wide association studies, exhibit cell-specific characteristics. This study delves into the impact of genetic variants within SLE loci on gene expression in different types of immune cells, unraveling the complex interplay between genetics and immunopathogenesis. Through the integration of genetic association and single-cell transcriptomic sequencing data, we identified potential cell-specific susceptibility genes for SLE across diverse immune cell subsets. The single-cell eQTL analysis revealed 30,409 associations involving 3583 SLE-associated SNPs. These SNPs exhibited associations with expression levels of 147 genes across 14 distinct cell types. The single-cell summary data-based Mendelian randomization (SMR) analysis identified 119 significant associations between the expression levels of 44 genes and SLE. Notably, myeloid cells exhibited associations solely within the MHC region, while T, B, and natural killer cells showed associations with both MHC and non-MHC genes in relation to SLE. Analysis of single-cell transcriptomic data from 33 children SLE cases and 11 match controls (227,303 cells), as well as 7 adult SLE cases and 5 match controls (78,414 cells) highlights differential expression of key genes. Notably, genetic variants within HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, IRF7, IRF5, BLK and HLA-DPA1 play a pivotal role in mediating immune dysregulation in specific immune cell types. Our study contributes to a comprehensive understanding of the intricate relationships between genetics, gene expression and SLE susceptibility. The findings shed light on the cell-specific impacts of genetic variants within SLE-associated genomic loci.
{"title":"Deciphering cell-specific genetic insights: Unraveling the immunogenetic landscape of systemic lupus erythematosus","authors":"Huan Zhang , Zhentao Zhang , Kedi Fan , Yuxi Chen , Peng Xu , Yufan Guo , Xingbo Mo","doi":"10.1016/j.molimm.2024.10.005","DOIUrl":"10.1016/j.molimm.2024.10.005","url":null,"abstract":"<div><div>Functional genes within genomic loci associated with systemic lupus erythematosus (SLE), as identified by genome-wide association studies, exhibit cell-specific characteristics. This study delves into the impact of genetic variants within SLE loci on gene expression in different types of immune cells, unraveling the complex interplay between genetics and immunopathogenesis. Through the integration of genetic association and single-cell transcriptomic sequencing data, we identified potential cell-specific susceptibility genes for SLE across diverse immune cell subsets. The single-cell eQTL analysis revealed 30,409 associations involving 3583 SLE-associated SNPs. These SNPs exhibited associations with expression levels of 147 genes across 14 distinct cell types. The single-cell summary data-based Mendelian randomization (SMR) analysis identified 119 significant associations between the expression levels of 44 genes and SLE. Notably, myeloid cells exhibited associations solely within the MHC region, while T, B, and natural killer cells showed associations with both MHC and non-MHC genes in relation to SLE. Analysis of single-cell transcriptomic data from 33 children SLE cases and 11 match controls (227,303 cells), as well as 7 adult SLE cases and 5 match controls (78,414 cells) highlights differential expression of key genes. Notably, genetic variants within <em>HLA-DRB1</em>, <em>HLA-DRB5</em>, <em>HLA-DQA1</em>, <em>HLA-DQB1</em>, <em>IRF7</em>, <em>IRF5</em>, <em>BLK</em> and <em>HLA-DPA1</em> play a pivotal role in mediating immune dysregulation in specific immune cell types. Our study contributes to a comprehensive understanding of the intricate relationships between genetics, gene expression and SLE susceptibility. The findings shed light on the cell-specific impacts of genetic variants within SLE-associated genomic loci.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"175 ","pages":"Pages 165-175"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-21DOI: 10.1016/j.molimm.2024.10.001
Bin Wang , Shuqi Feng , Yixuan Jiang , Yufei Tang , Yi Man , Na Wei , Lin Xiang
Dental implants are considered a superior option for the replacement of missing teeth. However, the invasive nature of the surgical procedure often results in significant postoperative inflammation, and the prolonged healing period of 3–6 months presents a notable disadvantage. High mobility group box 1 (HMGB1) is a critical mediator of acute inflammation following surgical injury, which can hinder the onset of osseointegration. This study aims to examine whether the inhibition of HMGB1 can mitigate acute inflammation and subsequently enhance osseointegration. The findings indicate that HMGB1 inhibition markedly reduces inflammation and promotes bone repair in murine models. Further in vitro investigations into the regulatory mechanisms of HMGB1 in macrophages reveal its role in increasing Yes-associated protein (YAP) activity, which contributes to pro-inflammatory polarization. Additionally, conditioned media derived from macrophages influenced by HMGB1 significantly impair the migratory and osteogenic capabilities of bone marrow-derived mesenchymal stem cells, which are essential for bone regeneration. In vivo experiments further validate that the administration of exogenous HMGB1 exacerbates postoperative acute inflammation and obstructs osseointegration. The study concludes that inhibiting HMGB1 fosters an anti-inflammatory polarization of macrophages, leading to diminished postoperative acute inflammation and expedited osseointegration around dental implants in mice.
{"title":"Early anti-inflammatory polarization of macrophages ameliorates post-surgical inflammation and osseointegration around titanium implants in mice","authors":"Bin Wang , Shuqi Feng , Yixuan Jiang , Yufei Tang , Yi Man , Na Wei , Lin Xiang","doi":"10.1016/j.molimm.2024.10.001","DOIUrl":"10.1016/j.molimm.2024.10.001","url":null,"abstract":"<div><div>Dental implants are considered a superior option for the replacement of missing teeth. However, the invasive nature of the surgical procedure often results in significant postoperative inflammation, and the prolonged healing period of 3–6 months presents a notable disadvantage. High mobility group box 1 (HMGB1) is a critical mediator of acute inflammation following surgical injury, which can hinder the onset of osseointegration. This study aims to examine whether the inhibition of HMGB1 can mitigate acute inflammation and subsequently enhance osseointegration. The findings indicate that HMGB1 inhibition markedly reduces inflammation and promotes bone repair in murine models. Further in vitro investigations into the regulatory mechanisms of HMGB1 in macrophages reveal its role in increasing Yes-associated protein (YAP) activity, which contributes to pro-inflammatory polarization. Additionally, conditioned media derived from macrophages influenced by HMGB1 significantly impair the migratory and osteogenic capabilities of bone marrow-derived mesenchymal stem cells, which are essential for bone regeneration. In vivo experiments further validate that the administration of exogenous HMGB1 exacerbates postoperative acute inflammation and obstructs osseointegration. The study concludes that inhibiting HMGB1 fosters an anti-inflammatory polarization of macrophages, leading to diminished postoperative acute inflammation and expedited osseointegration around dental implants in mice.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"175 ","pages":"Pages 155-163"},"PeriodicalIF":3.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-21DOI: 10.1016/j.molimm.2024.10.002
Yanyan Liu , Yue Huang , Haotian Wei , Xinjun Liang , Jing Luo
Cyclic GMP–AMP (cGAMP) synthase (cGAS) senses DNA in a sequence-independent manner, triggering cGAMP synthesis, which activates stimulator of interferon genes (STING) and the subsequent expression of type I interferons, tumour necrosis factor alpha (TNF-α) and other proinflammatory factors in two downstream pathways. However, the function of the cGASSTING pathway in γδ T cells remains unclear. The γδ T-cell population differs from the innate-like lymphocyte population, particularly with respect to tissue distribution, indicating the unique potential of γδ T cells in treating infections and cancers. On the basis of accumulating evidence, cGAS activity is modulated by protein posttranslational modifications (PTMs), including phosphorylation, O-GlcNAcylation, acetylation, ubiquitylation and methylation, which affect multiple cGAS functions. Thus, here, we summarize recent research on PTMs of the cGAS protein that modulate γδ T-cell function. An understanding of cGAS features and modulation mechanisms may facilitate the design of therapies for γδ T-cell-related immune diseases and cancer.
环GMP-AMP(cGAMP)合成酶(cGAS)以序列无关的方式感知DNA,触发cGAMP的合成,从而激活干扰素基因刺激器(STING),随后在两条下游途径中表达I型干扰素、肿瘤坏死因子α(TNF-α)和其他促炎因子。然而,cGASSTING 通路在 γδ T 细胞中的功能仍不清楚。γδT细胞群不同于先天性类淋巴细胞群,特别是在组织分布方面,这表明γδT细胞在治疗感染和癌症方面具有独特的潜力。越来越多的证据表明,cGAS的活性受蛋白质翻译后修饰(PTM)的调节,包括磷酸化、O-GlcNA酰化、乙酰化、泛素化和甲基化,这些修饰影响着cGAS的多种功能。因此,我们在此总结了最近关于调控γδ T细胞功能的cGAS蛋白PTM的研究。了解 cGAS 的特征和调节机制可能有助于设计治疗与 γδ T 细胞相关的免疫疾病和癌症的疗法。
{"title":"The role of post-translational modifications of cGAS in γδ T cells","authors":"Yanyan Liu , Yue Huang , Haotian Wei , Xinjun Liang , Jing Luo","doi":"10.1016/j.molimm.2024.10.002","DOIUrl":"10.1016/j.molimm.2024.10.002","url":null,"abstract":"<div><div>Cyclic GMP–AMP (cGAMP) synthase (cGAS) senses DNA in a sequence-independent manner, triggering cGAMP synthesis, which activates stimulator of interferon genes (STING) and the subsequent expression of type I interferons, tumour necrosis factor alpha (TNF-α) and other proinflammatory factors in two downstream pathways. However, the function of the cGAS<img>STING pathway in γδ T cells remains unclear. The γδ T-cell population differs from the innate-like lymphocyte population, particularly with respect to tissue distribution, indicating the unique potential of γδ T cells in treating infections and cancers. On the basis of accumulating evidence, cGAS activity is modulated by protein posttranslational modifications (PTMs), including phosphorylation, O-GlcNAcylation, acetylation, ubiquitylation and methylation, which affect multiple cGAS functions. Thus, here, we summarize recent research on PTMs of the cGAS protein that modulate γδ T-cell function. An understanding of cGAS features and modulation mechanisms may facilitate the design of therapies for γδ T-cell-related immune diseases and cancer.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"175 ","pages":"Pages 146-154"},"PeriodicalIF":3.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1016/j.molimm.2024.09.012
Anne M. van der Leun
The immune make-up of human tumors is dynamic over the course of cancer progression. However, what factors drive spatiotemporal changes in the tumor-immune landscape is not well-known. In issue 3 of Cell Reports Medicine, Liu, You, Lan and Ren et al. demonstrate that the development of tertiary lymphoid structures (TLSs) is a stepwise process that co-occurs with tumor progression in patients with lung adenocarcinoma (LUAD).
{"title":"Tertiary lymphoid structure formation: A matter of tumor-immune co-evolution","authors":"Anne M. van der Leun","doi":"10.1016/j.molimm.2024.09.012","DOIUrl":"10.1016/j.molimm.2024.09.012","url":null,"abstract":"<div><div>The immune make-up of human tumors is dynamic over the course of cancer progression. However, what factors drive spatiotemporal changes in the tumor-immune landscape is not well-known. In issue 3 of Cell Reports Medicine, Liu, You, Lan and Ren et al. demonstrate that the development of tertiary lymphoid structures (TLSs) is a stepwise process that co-occurs with tumor progression in patients with lung adenocarcinoma (LUAD).</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"175 ","pages":"Pages 143-145"},"PeriodicalIF":3.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.molimm.2024.09.013
Nini Jia , Yun Meng , Jing Li , Mengyao Cui , Yaqing Li , Dayuan Jiang , Xiaoqin Chu
<div><h3>Objective</h3><div>To study the therapeutic effect and mechanism of Shaoyao Gancao Decoction (SGD) on ulcerative colitis (UC) mice based on the perspective of intestinal barrier, and this study provides a new consultation for the clinical application of SGD.</div></div><div><h3>Methods</h3><div>The chemical composition of SGD was characterized by HPLC. The UC mouse model was constructed by 3 % dextran sodium sulfate (DSS), which were randomly divided into the model group (DSS), the positive drug group (5-ASA), the Shaoyao group (SYD), Gancao group (GCD), and the Shaoyao Gancao Decoction group (SGD) at low, medium, and high dosages, respectively. The effects of each drug treatment group on UC were evaluated by the rate of body weight loss, disease activity index (DAI), colon length, spleen index, histopathological evaluations, and the levels of serum inflammatory factors (IL-1β, IL-6, IL-10, IL-21, and TNF-α). The goblet cell was observed by Alcian blue/periodic acid-Schiff (AB/PAS) straining, ELISA was used to detect the content of LPS in serum, and Western blot was used to detect the changes in the expression of tight junction proteins ZO-1, occludin, and the pathway proteins TLR4 and NF-κBp65 in the colonic tissues, to explore the protective effect of SGD on the intestinal barrier of UC mice. The vivo absorption process of the main active ingredients in the SG, SY and GC groups was determined by LC-MS.</div></div><div><h3>Results</h3><div>The contents of albiflorin, paeoniflorin, liquiritin apioside, liquiritin and glycyrrhetinic acid were 6.1227 mg/g, 20.8993 mg/g, 4.0054 mg/g, 3.6140 mg/g and 8.2515 mg/g, respectively. Compared with DSS group, SGD reduced weight loss(P<0.01) and DAI scores(P<0.05), prevented colon shortening(P<0.01), and ameliorated histopathological damage of the colon in UC mice(P<0.01). SGD also protected the intestinal barrier to alleviate UC by significantly reducing serum LPS and inflammatory factor levels, altering the number of goblet cells, promoting tight junction proteins (ZO-1 and occludin) and decreasing the expression of TLR4 and NF-κB in colonic tissues. Pharmacokinetic results showed that there was no significant difference in C<sub>max</sub>, AUC<sub>0-t (μg/L</sub><strong>.</strong><sub>h)</sub> and T<sub>max</sub> of albiflorin and paeoniflorin between the SY and SG groups, the T<sub>max</sub> was within 1 h; the AUC<sub>0-t (μg/L</sub><strong>.</strong><sub>h)</sub> of liquiritin and glycyrrhizic acid were about 1.6 and 1.9 times higher in the SG group compared to the GC group, respectively. The C<sub>max</sub>, T<sub>max</sub> and AUC<sub>0-t (μg/L</sub><strong>.</strong><sub>h)</sub> of glycyrrhizinic acid were significantly reduced to 0.73, 0.68 and 0.68 times of that of the GC group.</div></div><div><h3>Conclusion</h3><div>SGD may have a therapeutic effect on DSS-induced UC mice by repairing the damaged intestinal barrier through the TLR4/NF-κB pathway. The combination of Shaoyao a
{"title":"Pharmacodynamic and pharmacokinetic study of Shaoyao Gancao decoction for repairing intestinal barrier damage in ulcerative colitis","authors":"Nini Jia , Yun Meng , Jing Li , Mengyao Cui , Yaqing Li , Dayuan Jiang , Xiaoqin Chu","doi":"10.1016/j.molimm.2024.09.013","DOIUrl":"10.1016/j.molimm.2024.09.013","url":null,"abstract":"<div><h3>Objective</h3><div>To study the therapeutic effect and mechanism of Shaoyao Gancao Decoction (SGD) on ulcerative colitis (UC) mice based on the perspective of intestinal barrier, and this study provides a new consultation for the clinical application of SGD.</div></div><div><h3>Methods</h3><div>The chemical composition of SGD was characterized by HPLC. The UC mouse model was constructed by 3 % dextran sodium sulfate (DSS), which were randomly divided into the model group (DSS), the positive drug group (5-ASA), the Shaoyao group (SYD), Gancao group (GCD), and the Shaoyao Gancao Decoction group (SGD) at low, medium, and high dosages, respectively. The effects of each drug treatment group on UC were evaluated by the rate of body weight loss, disease activity index (DAI), colon length, spleen index, histopathological evaluations, and the levels of serum inflammatory factors (IL-1β, IL-6, IL-10, IL-21, and TNF-α). The goblet cell was observed by Alcian blue/periodic acid-Schiff (AB/PAS) straining, ELISA was used to detect the content of LPS in serum, and Western blot was used to detect the changes in the expression of tight junction proteins ZO-1, occludin, and the pathway proteins TLR4 and NF-κBp65 in the colonic tissues, to explore the protective effect of SGD on the intestinal barrier of UC mice. The vivo absorption process of the main active ingredients in the SG, SY and GC groups was determined by LC-MS.</div></div><div><h3>Results</h3><div>The contents of albiflorin, paeoniflorin, liquiritin apioside, liquiritin and glycyrrhetinic acid were 6.1227 mg/g, 20.8993 mg/g, 4.0054 mg/g, 3.6140 mg/g and 8.2515 mg/g, respectively. Compared with DSS group, SGD reduced weight loss(P<0.01) and DAI scores(P<0.05), prevented colon shortening(P<0.01), and ameliorated histopathological damage of the colon in UC mice(P<0.01). SGD also protected the intestinal barrier to alleviate UC by significantly reducing serum LPS and inflammatory factor levels, altering the number of goblet cells, promoting tight junction proteins (ZO-1 and occludin) and decreasing the expression of TLR4 and NF-κB in colonic tissues. Pharmacokinetic results showed that there was no significant difference in C<sub>max</sub>, AUC<sub>0-t (μg/L</sub><strong>.</strong><sub>h)</sub> and T<sub>max</sub> of albiflorin and paeoniflorin between the SY and SG groups, the T<sub>max</sub> was within 1 h; the AUC<sub>0-t (μg/L</sub><strong>.</strong><sub>h)</sub> of liquiritin and glycyrrhizic acid were about 1.6 and 1.9 times higher in the SG group compared to the GC group, respectively. The C<sub>max</sub>, T<sub>max</sub> and AUC<sub>0-t (μg/L</sub><strong>.</strong><sub>h)</sub> of glycyrrhizinic acid were significantly reduced to 0.73, 0.68 and 0.68 times of that of the GC group.</div></div><div><h3>Conclusion</h3><div>SGD may have a therapeutic effect on DSS-induced UC mice by repairing the damaged intestinal barrier through the TLR4/NF-κB pathway. The combination of Shaoyao a","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"175 ","pages":"Pages 132-142"},"PeriodicalIF":3.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.molimm.2024.09.005
Antônio Márcio Santana Fernandes , Eduardo Santos da Silva , Raphael Chagas Silva , Elisânia Fontes Silveira , Leonardo Freire Santiago , Emília Maria Medeiros de Andrade Belitardo , Vítor dos Santos Alves , Deise Souza Vilas Bôas , Luiz Antônio Rodrigues de Freitas , Fatima Ferreira , Alain Jacquet , Luis Gustavo Carvalho Pacheco , Neuza Maria Alcantara-Neves , Carina Silva Pinheiro
Background
The house-dust mite Dermatophagoides pteronyssinus is a key trigger of allergic asthma. Therefore, it is essential to develop new vaccines that can alter inflammatory processes and airway remodeling. The goal of this study was to test the hypoallergenic and immunogenic characteristics of the hypoallergen rDer p 2231 in a murine model of chronic asthma induced by D. pteronyssinus.
Methods
For this, we measured the levels of IgE, IgG1, IgG2a, and cytokines produced by mice receiving the rDer p 2231 protein. Histopathological parameters of the chronic inflammatory response were also investigated by assessing inflammation and airway remodeling.
Results
rDer p 2231 given as a therapeutic vaccine, led to a reduction in the production of IgE, eosinophils, and neutrophils, a lower activity of eosinophilic peroxidase in the airways, and an increase in the production of IgG1 and IgG2a antibodies. IgG antibodies blocked IgE binding to parental allergens in sera from atopic patients. Splenocytes, BALF, and lung from mice treated with rDer p 2231 secreted higher levels of Th1 and regulatory cytokines, as well as reduced levels of Th2 cytokines. Histopathological investigation of the lower airways demonstrated reductions in the thickness of the bronchiolar smooth muscle layer, in the subepithelial fibrosis, and in the goblet cells hyperplasia.
Conclusions
Our preclinical studies suggest that rDer p 2231 is a promising candidate for the treatment of D. pteronyssinus allergy, as the hypoallergen has demonstrated the ability to reduce IgE production, induce specific blocking antibodies, restore and balance Th1/Th2 immune responses, and significantly reduce airway remodeling factors. However, additional clinical studies are needed to more accurately assess the efficacy and safety of rDer p 2231 as a vaccine against D. pteronyssinus-induced allergy.
背景家尘螨 Dermatophagoides pteronyssinus 是过敏性哮喘的主要诱发因素。因此,开发能够改变炎症过程和气道重塑的新疫苗至关重要。本研究的目的是在翼尾螨诱发的慢性哮喘小鼠模型中测试低过敏原 rDer p 2231 的低过敏性和免疫原性。结果 rDer p 2231 作为治疗性疫苗接种后,IgE、嗜酸性粒细胞和中性粒细胞的产生量减少,气道中嗜酸性过氧化物酶的活性降低,IgG1 和 IgG2a 抗体的产生量增加。在特应性患者的血清中,IgG 抗体阻止了 IgE 与亲代过敏原的结合。经 rDer p 2231 处理的小鼠脾细胞、BALF 和肺分泌的 Th1 和调节性细胞因子水平较高,Th2 细胞因子水平较低。下呼吸道的组织病理学调查显示,支气管平滑肌层厚度、上皮下纤维化和鹅口疮细胞增生均有所减少。结论:我们的临床前研究表明,rDer p 2231 有希望成为治疗 D. pteronyssinus 过敏性疾病的候选药物,因为这种低过敏原已证明能够减少 IgE 的产生、诱导特异性阻断抗体、恢复和平衡 Th1/Th2 免疫反应,并显著减少气道重塑因子。然而,要更准确地评估 rDer p 2231 作为预防翼龙蝽引起的过敏的疫苗的有效性和安全性,还需要进行更多的临床研究。
{"title":"Therapeutic potential of a novel hybrid protein: Mitigating allergy and airway remodeling in chronic asthma models induced by Dermatophagoides pteronyssinus","authors":"Antônio Márcio Santana Fernandes , Eduardo Santos da Silva , Raphael Chagas Silva , Elisânia Fontes Silveira , Leonardo Freire Santiago , Emília Maria Medeiros de Andrade Belitardo , Vítor dos Santos Alves , Deise Souza Vilas Bôas , Luiz Antônio Rodrigues de Freitas , Fatima Ferreira , Alain Jacquet , Luis Gustavo Carvalho Pacheco , Neuza Maria Alcantara-Neves , Carina Silva Pinheiro","doi":"10.1016/j.molimm.2024.09.005","DOIUrl":"10.1016/j.molimm.2024.09.005","url":null,"abstract":"<div><h3>Background</h3><div>The house-dust mite <em>Dermatophagoides pteronyssinus</em> is a key trigger of allergic asthma. Therefore, it is essential to develop new vaccines that can alter inflammatory processes and airway remodeling. The goal of this study was to test the hypoallergenic and immunogenic characteristics of the hypoallergen rDer p 2231 in a murine model of chronic asthma induced by <em>D. pteronyssinus</em>.</div></div><div><h3>Methods</h3><div>For this, we measured the levels of IgE, IgG1, IgG2a, and cytokines produced by mice receiving the rDer p 2231 protein. Histopathological parameters of the chronic inflammatory response were also investigated by assessing inflammation and airway remodeling.</div></div><div><h3>Results</h3><div>rDer p 2231 given as a therapeutic vaccine, led to a reduction in the production of IgE, eosinophils, and neutrophils, a lower activity of eosinophilic peroxidase in the airways, and an increase in the production of IgG1 and IgG2a antibodies. IgG antibodies blocked IgE binding to parental allergens in sera from atopic patients. Splenocytes, BALF, and lung from mice treated with rDer p 2231 secreted higher levels of Th1 and regulatory cytokines, as well as reduced levels of Th2 cytokines. Histopathological investigation of the lower airways demonstrated reductions in the thickness of the bronchiolar smooth muscle layer, in the subepithelial fibrosis, and in the goblet cells hyperplasia.</div></div><div><h3>Conclusions</h3><div>Our preclinical studies suggest that rDer p 2231 is a promising candidate for the treatment of <em>D. pteronyssinus</em> allergy, as the hypoallergen has demonstrated the ability to reduce IgE production, induce specific blocking antibodies, restore and balance Th1/Th2 immune responses, and significantly reduce airway remodeling factors. However, additional clinical studies are needed to more accurately assess the efficacy and safety of rDer p 2231 as a vaccine against <em>D. pteronyssinus</em>-induced allergy.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"175 ","pages":"Pages 121-131"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142357706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cordyceps militaris, an entomopathogenic fungus, has been traditionally used in East Asian medicine. Recent research indicates that the fruit bodies of C. militaris are rich in bioactive compounds, such as polysaccharides and nucleosides, which may offer health benefits. However, the specific components responsible for its immunostimulatory effects and the mechanisms involved remain unclear. This study explored the immunomodulatory activity of a fruit body extract from C. militaris, named Ryukyu-kaso (RK), and examined the effect of the β-glucan receptor Dectin-1 on bone marrow-derived dendritic cells (BMDCs). Our results demonstrated that RK, which contains 1,3-β-glucan, effectively stimulated BMDCs to secrete pro-inflammatory and immunoregulatory cytokines and upregulated surface markers indicative of maturation and activation. Notably, these immunostimulatory effects were completely absent in BMDCs derived from Dectin-1-knockout mice, confirming that Dectin-1 is crucial for RK-induced immunomodulation. These findings provide new insights into the immunostimulatory mechanisms of C. militaris and underscore the potential of RK as a natural immunomodulatory agent for various therapeutic applications.
{"title":"Cordyceps militaris fruit body activates myeloid dendritic cells via a Dectin-1-mediated pathway","authors":"Takashi Kanno , Rui Tada , Toyokazu Nakasone , Shigemi Okamatsu , Yoichiro Iwakura , Kazuhiro Tamura , Hiroaki Miyaoka , Yoshiyuki Adachi","doi":"10.1016/j.molimm.2024.09.011","DOIUrl":"10.1016/j.molimm.2024.09.011","url":null,"abstract":"<div><div><em>Cordyceps militaris</em>, an entomopathogenic fungus, has been traditionally used in East Asian medicine. Recent research indicates that the fruit bodies of <em>C. militaris</em> are rich in bioactive compounds, such as polysaccharides and nucleosides, which may offer health benefits. However, the specific components responsible for its immunostimulatory effects and the mechanisms involved remain unclear. This study explored the immunomodulatory activity of a fruit body extract from <em>C. militaris</em>, named Ryukyu-kaso (RK), and examined the effect of the β-glucan receptor Dectin-1 on bone marrow-derived dendritic cells (BMDCs). Our results demonstrated that RK, which contains 1,3-β-glucan, effectively stimulated BMDCs to secrete pro-inflammatory and immunoregulatory cytokines and upregulated surface markers indicative of maturation and activation. Notably, these immunostimulatory effects were completely absent in BMDCs derived from Dectin-1-knockout mice, confirming that Dectin-1 is crucial for RK-induced immunomodulation. These findings provide new insights into the immunostimulatory mechanisms of <em>C. militaris</em> and underscore the potential of RK as a natural immunomodulatory agent for various therapeutic applications.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"175 ","pages":"Pages 112-120"},"PeriodicalIF":3.2,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.molimm.2024.09.010
Allanna C.E. MacKenzie , Mia P. Sams , Jane Lin , Carolina Reyes Batista , Michelle Lim , Chanpreet K. Riarh , Rodney P. DeKoter
Activation-induced cytidine deaminase (AID, encoded by Aicda) plays a key role in somatic hypermutation and class switch recombination in germinal center B cells. However, off-target effects of AID are implicated in human leukemia and lymphoma. A mouse model of precursor B cell acute lymphoblastic leukemia driven by deletion of the related transcription factors PU.1 and Spi-B revealed C->T transition mutations compatible with being induced by AID. Therefore, we hypothesized that PU.1 negatively regulates Aicda during B cell development. Aicda mRNA transcript levels were increased in leukemia cells and bone marrow pre-B cells lacking PU.1 and/or Spi-B, relative to wild type cells. Using chromatin immunoprecipitation, PU.1 was found to interact with a negative regulatory region (R2–1) within the first intron of Aicda. CRISPR-Cas9-induced mutagenesis of R2–1 in cultured pre-B cells resulted in upregulation of Aicda in response to lipopolysaccharide stimulation. Mutation of the PU.1 interaction site and neighboring sequences resulted in reduced repressive ability of R2–1 in transient transfection analysis followed by luciferase assays. These results show that a PU.1-interacting intronic region negatively regulates Aicda transcription in developing B cells.
激活诱导胞苷脱氨酶(AID,由 Aicda 编码)在生殖中心 B 细胞的体细胞超突变和类开关重组中发挥着关键作用。然而,AID 的脱靶效应与人类白血病和淋巴瘤有关。一个由相关转录因子 PU.1 和 Spi-B 缺失驱动的前体 B 细胞急性淋巴细胞白血病小鼠模型显示,C->T 转换突变与 AID 诱导的相符。因此,我们假设 PU.1 在 B 细胞发育过程中对 Aicda 起负向调节作用。与野生型细胞相比,缺乏 PU.1 和/或 Spi-B 的白血病细胞和骨髓前 B 细胞中 Aicda mRNA 转录水平升高。通过染色质免疫沉淀,发现PU.1与Aicda第一个内含子中的负调控区(R2-1)相互作用。在培养的前B细胞中,CRISPR-Cas9诱导的R2-1突变导致Aicda在脂多糖刺激下上调。在瞬时转染分析和荧光素酶检测中,PU.1相互作用位点和邻近序列的突变导致R2-1的抑制能力降低。这些结果表明,与 PU.1 相互作用的内含子区对发育中的 B 细胞中 Aicda 的转录具有负调控作用。
{"title":"Negative regulation of activation-induced cytidine deaminase gene transcription in developing B cells by a PU.1-interacting intronic region","authors":"Allanna C.E. MacKenzie , Mia P. Sams , Jane Lin , Carolina Reyes Batista , Michelle Lim , Chanpreet K. Riarh , Rodney P. DeKoter","doi":"10.1016/j.molimm.2024.09.010","DOIUrl":"10.1016/j.molimm.2024.09.010","url":null,"abstract":"<div><div>Activation-induced cytidine deaminase (AID, encoded by <em>Aicda</em>) plays a key role in somatic hypermutation and class switch recombination in germinal center B cells. However, off-target effects of AID are implicated in human leukemia and lymphoma. A mouse model of precursor B cell acute lymphoblastic leukemia driven by deletion of the related transcription factors PU.1 and Spi-B revealed C->T transition mutations compatible with being induced by AID. Therefore, we hypothesized that PU.1 negatively regulates <em>Aicda</em> during B cell development. <em>Aicda</em> mRNA transcript levels were increased in leukemia cells and bone marrow pre-B cells lacking PU.1 and/or Spi-B, relative to wild type cells. Using chromatin immunoprecipitation, PU.1 was found to interact with a negative regulatory region (R2–1) within the first intron of <em>Aicda</em>. CRISPR-Cas9-induced mutagenesis of R2–1 in cultured pre-B cells resulted in upregulation of <em>Aicda</em> in response to lipopolysaccharide stimulation. Mutation of the PU.1 interaction site and neighboring sequences resulted in reduced repressive ability of R2–1 in transient transfection analysis followed by luciferase assays. These results show that a PU.1-interacting intronic region negatively regulates <em>Aicda</em> transcription in developing B cells.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"175 ","pages":"Pages 103-111"},"PeriodicalIF":3.2,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.molimm.2024.09.002
J. Čelakovská , E. Čermákova , C. Andrýs , P. Boudkova , J. Krejsek
Aim of our study is to analyse the sensitisation profile to molecular components of latex and of food allergens with the use of ALEX2 Allergy Xplorer test and to compare these results with the anamnestical data after latex exposure and with the anamnestical data after exposure to food allergens in atopic dermatitis patients.
Methods
100 patients were included in the study (49 men and 51 women with the average age 40.6 years). The specific IgE was examined with the use of ALEX2 Allergy Xplorer test. A detailed personal history of allergic reaction to latex and allergic reaction to food allergens was taken in all included patients.
Results
The sensitisation to latex was recorded in 17 % of patients, majority of patients have positive results of specific IgE to Hev b 8 without clinical reaction to latex. In 7 % of patients with positive results of specific IgE to Hev b 1, Hev b 3, Hev b 5, Hev b 6.02 and Hev b 11 the contact urticaria or contact dermatitis were recorded. The latex fruit syndrome was recorded in 7 % of patients; in another 10 % of patients we recorded no clinical reaction to latex, but the positive results to molecular components of latex and the clinical symptoms after ingestion of different kinds of fruits.
Conclusion
The significant relation between the results of specific IgE to molecular components Hev b 3, Hev b 5 and Hev b 6.02 and the clinical reaction to latex was confirmed; these components significantly imply clinical reactivity to latex.
我们的研究旨在使用 ALEX2 Allergy Xplorer 测试分析特应性皮炎患者对乳胶和食物过敏原分子成分的过敏情况,并将这些结果与特应性皮炎患者接触乳胶后的过敏反应数据以及接触食物过敏原后的过敏反应数据进行比较。使用 ALEX2 Allergy Xplorer 检测仪检测特异性 IgE。结果有 17% 的患者对乳胶过敏,大多数患者对 Hev b 8 的特异性 IgE 呈阳性,但对乳胶没有临床反应。在对 Hev b 1、Hev b 3、Hev b 5、Hev b 6.02 和 Hev b 11 的特异性 IgE 呈阳性结果的患者中,有 7% 出现了接触性荨麻疹或接触性皮炎。有 7% 的患者出现了乳胶水果综合征;另有 10% 的患者对乳胶没有临床反应,但对乳胶分子成分的检测结果呈阳性,并且在摄入不同种类的水果后出现了临床症状。
{"title":"Sensitization to latex and food allergens in atopic dermatitis patients according to ALEX2 Allergy Xplorer test","authors":"J. Čelakovská , E. Čermákova , C. Andrýs , P. Boudkova , J. Krejsek","doi":"10.1016/j.molimm.2024.09.002","DOIUrl":"10.1016/j.molimm.2024.09.002","url":null,"abstract":"<div><div>Aim of our study is to analyse the sensitisation profile to molecular components of latex and of food allergens with the use of ALEX2 Allergy Xplorer test and to compare these results with the anamnestical data after latex exposure and with the anamnestical data after exposure to food allergens in atopic dermatitis patients.</div></div><div><h3>Methods</h3><div>100 patients were included in the study (49 men and 51 women with the average age 40.6 years). The specific IgE was examined with the use of ALEX2 Allergy Xplorer test. A detailed personal history of allergic reaction to latex and allergic reaction to food allergens was taken in all included patients.</div></div><div><h3>Results</h3><div>The sensitisation to latex was recorded in 17 % of patients, majority of patients have positive results of specific IgE to Hev b 8 without clinical reaction to latex. In 7 % of patients with positive results of specific IgE to Hev b 1, Hev b 3, Hev b 5, Hev b 6.02 and Hev b 11 the contact urticaria or contact dermatitis were recorded. The latex fruit syndrome was recorded in 7 % of patients; in another 10 % of patients we recorded no clinical reaction to latex, but the positive results to molecular components of latex and the clinical symptoms after ingestion of different kinds of fruits.</div></div><div><h3>Conclusion</h3><div>The significant relation between the results of specific IgE to molecular components Hev b 3, Hev b 5 and Hev b 6.02 and the clinical reaction to latex was confirmed; these components significantly imply clinical reactivity to latex.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"175 ","pages":"Pages 89-102"},"PeriodicalIF":3.2,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Freshwater snails of the genus Bulinus are critical hosts for Schistosoma haematobium, the causative agent of urogenital schistosomiasis. Among the 37 recognized Bulinus species, B. truncatus is a key vector. Using RNA sequencing (RNAseq), we investigated the genome-wide transcriptional responses of B. truncatus to S. haematobium infection. Our findings suggest that snails employ a complex defense strategy against the parasites by up-regulating genes involved in immune response, stress reaction, structural integrity, metabolism, and detoxification. In response, schistosome parasites appear to manipulate the snail’s defense system, as evidenced by the suppression of immune-related genes such as ficolin, peptidoglycan recognition protein, and C-type lectin domain-containing protein genes. The down-regulation of biomphalysin 9, compared to its function in Biomphalaria glabrata, indicates divergent immune strategies among snail hosts. Additionally, we compared transcriptome profiles between embryos and juveniles, providing insights into developmental processes. This study offers valuable genomic data for Bulinus snails, illuminating the molecular interactions between bulinids and schistosomes, and advancing our understanding of their developmental biology.
{"title":"Exploring the genome-wide transcriptomic responses of Bulinus truncatus to Schistosoma haematobium infection: An important host-parasite system involved in the transmission of human urogenital schistosomiasis","authors":"Mohamed R. Habib , Marijan Posavi , Abdelmalek Lekired , Si-Ming Zhang","doi":"10.1016/j.molimm.2024.09.006","DOIUrl":"10.1016/j.molimm.2024.09.006","url":null,"abstract":"<div><p>Freshwater snails of the genus <em>Bulinus</em> are critical hosts for <em>Schistosoma haematobium</em>, the causative agent of urogenital schistosomiasis. Among the 37 recognized <em>Bulinus</em> species, <em>B. truncatus</em> is a key vector. Using RNA sequencing (RNAseq), we investigated the genome-wide transcriptional responses of <em>B. truncatus</em> to <em>S. haematobium</em> infection. Our findings suggest that snails employ a complex defense strategy against the parasites by up-regulating genes involved in immune response, stress reaction, structural integrity, metabolism, and detoxification. In response, schistosome parasites appear to manipulate the snail’s defense system, as evidenced by the suppression of immune-related genes such as <em>ficolin</em>, <em>peptidoglycan recognition protein</em>, and <em>C-type lectin domain-containing protein</em> genes. The down-regulation of <em>biomphalysin 9</em>, compared to its function in <em>Biomphalaria glabrata</em>, indicates divergent immune strategies among snail hosts. Additionally, we compared transcriptome profiles between embryos and juveniles, providing insights into developmental processes. This study offers valuable genomic data for <em>Bulinus</em> snails, illuminating the molecular interactions between bulinids and schistosomes, and advancing our understanding of their developmental biology.</p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"175 ","pages":"Pages 74-88"},"PeriodicalIF":3.2,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142272936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}