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Genome-oriented treatment strategies for autoimmune diseases. 自身免疫性疾病的基因组导向治疗策略
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-09-23 DOI: 10.1186/s41232-021-00179-2
Yoshiya Tanaka
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引用次数: 0
Transition of clinical and basic studies on liver cirrhosis treatment using cells to seek the best treatment. 过渡临床与基础研究,利用细胞寻求肝硬化的最佳治疗方法。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-09-16 DOI: 10.1186/s41232-021-00178-3
Shuji Terai, Atsunori Tsuchiya, Yusuke Watanabe, Suguru Takeuchi

The liver is a highly regenerative organ; however, its regeneration potential is reduced by chronic inflammation with fibrosis accumulation, leading to cirrhosis. With an aim to tackle liver cirrhosis, a life-threatening disease, trials of autologous bone marrow cell infusion (ABMi) therapy started in 2003. Clinical studies revealed that ABMi attenuated liver fibrosis and improved liver function in some patients; however, this therapy has some limitations such as the need of general anesthesia. Following ABMi therapy, studies have focused on specific cells such as mesenchymal stromal cells (MSCs) from a variety of tissues such as bone marrow, adipose tissue, and umbilical cord tissues. Particularly, studies have focused on gaining mechanistic insights into MSC distribution and effects on immune cells, especially macrophages. Several basic studies have reported the use of MSCs for liver cirrhosis models, while a number of clinical studies have used autologous and allogeneic MSCs; however, there are only a few reports on the obvious substantial effect of MSCs in clinical studies. Since then, studies have analyzed and identified the important signals or components in MSCs that regulate immune cells, such as macrophages, under cirrhotic conditions and have revealed that MSC-derived exosomes are key regulators. Researchers are still seeking the best approach and filling the gap between basic and clinical studies to treat liver cirrhosis. This paper highlights the timeline of basic and clinical studies analyzing ABMi and MSC therapies for cirrhosis and the scope for future studies and therapy.

肝脏是一个高度再生的器官;然而,它的再生潜力因慢性炎症和纤维化积累而降低,导致肝硬化。为了治疗肝硬化这种危及生命的疾病,2003年开始了自体骨髓细胞输注(ABMi)疗法的试验。临床研究表明,ABMi减轻了一些患者的肝纤维化,改善了肝功能;然而,这种疗法有一些局限性,如需要全身麻醉。在ABMi治疗之后,研究集中在来自骨髓、脂肪组织和脐带组织等多种组织的特定细胞,如间充质间质细胞(MSCs)。特别是,研究集中于获得MSC分布和对免疫细胞,特别是巨噬细胞的作用的机制见解。一些基础研究报道了MSCs用于肝硬化模型,而一些临床研究使用了自体和异体MSCs;然而,在临床研究中,关于间充质干细胞具有明显实质性作用的报道很少。从那时起,研究分析并确定了MSCs中在肝硬化条件下调节免疫细胞(如巨噬细胞)的重要信号或成分,并揭示了MSCs衍生的外泌体是关键的调节因子。研究人员仍在寻找治疗肝硬化的最佳方法,填补基础研究和临床研究之间的空白。本文重点介绍了ABMi和MSC治疗肝硬化的基础和临床研究的时间表,以及未来研究和治疗的范围。
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引用次数: 4
Calcineurin-nuclear factor for activated T cells (NFAT) signaling in pathophysiology of wound healing. 活化T细胞(NFAT)信号传导在伤口愈合病理生理中的作用。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-08-18 DOI: 10.1186/s41232-021-00176-5
Takahiro Manabe, Heamin Park, Takashi Minami

Wound healing occurred with serial coordinated processes via coagulation-fibrinolysis, inflammation following to immune-activation, angiogenesis, granulation, and the final re-epithelization. Since the dermis forms critical physical and biological barriers, the repair system should be rapidly and accurately functioned to keep homeostasis in our body. The wound healing is impaired or dysregulated via an inappropriate microenvironment, which is easy to lead to several diseases, including fibrosis in multiple organs and psoriasis. Such a disease led to the dysregulation of several types of cells: immune cells, fibroblasts, mural cells, and endothelial cells. Moreover, recent progress in medical studies uncovers the significant concept. The calcium signaling, typically the following calcineurin-NFAT signaling, essentially regulates not only immune cell activations, but also various healing steps via coagulation, inflammation, and angiogenesis. In this review, we summarize the role of the NFAT activation pathway in wound healing and discuss its overall impact on future therapeutic ways.

伤口愈合发生一系列协调的过程,包括凝固-纤维蛋白溶解、免疫激活后的炎症、血管生成、肉芽形成和最终的再上皮化。由于真皮形成了关键的物理和生物屏障,修复系统应该迅速而准确地发挥作用,以保持我们体内的稳态。通过不适当的微环境导致伤口愈合受损或失调,容易导致多种疾病,包括多器官纤维化和牛皮癣。这种疾病导致几种类型的细胞失调:免疫细胞、成纤维细胞、壁细胞和内皮细胞。此外,医学研究的最新进展揭示了这一重要概念。钙信号,通常是钙调神经蛋白- nfat信号,本质上不仅调节免疫细胞激活,还调节凝血、炎症和血管生成等各种愈合步骤。在这篇综述中,我们总结了NFAT激活途径在伤口愈合中的作用,并讨论了其对未来治疗方法的总体影响。
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引用次数: 5
The role of lymphatics in intestinal inflammation. 淋巴管在肠道炎症中的作用。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-08-17 DOI: 10.1186/s41232-021-00175-6
Ryota Hokari, Akira Tomioka

The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.

淋巴血管系统将过滤后的间质动脉液和组织代谢物返回血液循环。它还在脂质吸收和免疫细胞运输中起主要作用。炎性疾病、克罗恩病、肥胖、心血管疾病、高血压、动脉粥样硬化和阿尔茨海默病中都发现了淋巴血管缺陷。在这篇综述中,我们讨论了肠道内淋巴的结构和功能,如饮食脂质吸收、抗原和免疫细胞到淋巴结的运输、外周耐受以及淋巴细胞从次级淋巴组织向淋巴和免疫系统的迁移。我们还讨论了这些淋巴管在炎症性肠病病理生理中的潜在作用,以及作为治疗管理的新靶点。
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引用次数: 8
Multi-omics approach to precision medicine for immune-mediated diseases. 免疫介导疾病精准医学的多组学方法。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-08-01 DOI: 10.1186/s41232-021-00173-8
Mineto Ota, Keishi Fujio

Recent innovation in high-throughput sequencing technologies has drastically empowered the scientific research. Consequently, now, it is possible to capture comprehensive profiles of samples at multiple levels including genome, epigenome, and transcriptome at a time. Applying these kinds of rich information to clinical settings is of great social significance. For some traits such as cardiovascular diseases, attempts to apply omics datasets in clinical practice for the prediction of the disease risk have already shown promising results, although still under way for immune-mediated diseases. Multiple studies have tried to predict treatment response in immune-mediated diseases using genomic, transcriptomic, or clinical information, showing various possible indicators. For better prediction of treatment response or disease outcome in immune-mediated diseases, combining multi-layer information together may increase the power. In addition, in order to efficiently pick up meaningful information from the massive data, high-quality annotation of genomic functions is also crucial. In this review, we discuss the achievement so far and the future direction of multi-omics approach to immune-mediated diseases.

最近高通量测序技术的创新极大地增强了科学研究的能力。因此,现在有可能一次捕获包括基因组、表观基因组和转录组在内的多个水平的样品的综合概况。将这些丰富的信息应用于临床,具有重要的社会意义。对于某些特征,如心血管疾病,在临床实践中应用组学数据集预测疾病风险的尝试已经显示出有希望的结果,尽管在免疫介导的疾病方面仍在进行中。多项研究试图利用基因组学、转录组学或临床信息预测免疫介导疾病的治疗反应,显示了各种可能的指标。为了更好地预测免疫介导性疾病的治疗反应或疾病结局,将多层信息结合在一起可能会增加能力。此外,为了从海量数据中高效提取有意义的信息,高质量的基因组功能标注也至关重要。本文综述了多组学方法在免疫介导性疾病研究中的进展及未来发展方向。
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引用次数: 12
Correction to: Renal complications in coronavirus disease 2019: a systematic review. 2019冠状病毒病肾脏并发症:系统综述
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-07-23 DOI: 10.1186/s41232-021-00171-w
Taichiro Minami, Yasunori Iwata, Takashi Wada
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引用次数: 0
Single-cell and spatial analyses of cancer cells: toward elucidating the molecular mechanisms of clonal evolution and drug resistance acquisition. 癌细胞的单细胞和空间分析:阐明克隆进化和耐药获得的分子机制。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-07-16 DOI: 10.1186/s41232-021-00170-x
Satoi Nagasawa, Yukie Kashima, Ayako Suzuki, Yutaka Suzuki

Even within a single type of cancer, cells of various types exist and play interrelated roles. Each of the individual cells resides in a distinct microenvironment and behaves differently. Such heterogeneity is the most cumbersome nature of cancers, which is occasionally uncountable when effective prevention or total elimination of cancers is attempted. To understand the heterogeneous nature of each cell, the use of conventional methods for the analysis of "bulk" cells is insufficient. Although some methods are high-throughput and compressive regarding the genes being detected, the obtained data would be from the cell mass, and the average of a large number of the component cells would no longer be measured. Single-cell analysis, which has developed rapidly in recent years, is causing a drastic change. Genome, transcriptome, and epigenome analyses at single-cell resolution currently target cancer cells, cancer-associated fibroblasts, endothelial cells of vessels, and circulating and infiltrating immune cells. In fact, surprisingly diverse features of clonal evolution of cancer cells, during the development of cancer or acquisition of drug resistance, accompanied by corresponding gene expression changes in the circumstantial stromal cells, appeared in recent single-cell analyses. Based on the obtained novel insights, better optimal drug selection and new drug administration sequences were started. Even a remaining concern of the single cell analyses is being addressed. Until very recently, it was impossible to obtain positional information of cells in cancer via single-cell analysis because such information is lost during preparation of single-cell suspensions. A new method, collectively called spatial transcriptome (ST) analysis, has been developed and rapidly applied to various clinical specimens. In this review, we first outline the recent achievements of single-cell cancer analysis in analyzing the molecular basis underlying the acquisition of drug resistance, particularly focusing on the latest anti-epidermal growth factor receptor tyrosine kinase inhibitor, osimertinib. Further, we review the currently available ST analysis methods and introduce our recent attempts regarding the respective topics.

即使在单一类型的癌症中,也存在各种类型的细胞并发挥相互关联的作用。每个单独的细胞都生活在不同的微环境中,行为也不同。这种异质性是癌症最麻烦的性质,当试图有效预防或完全消除癌症时,它有时是不可计数的。要了解每个细胞的异质性,使用传统方法分析“散装”细胞是不够的。虽然有些方法对于被检测的基因是高通量和压缩的,但所获得的数据将来自细胞团,并且不再测量大量组成细胞的平均值。单细胞分析近年来发展迅速,引起了巨大的变化。目前,单细胞分辨率下的基因组、转录组和表观基因组分析的目标是癌细胞、癌症相关成纤维细胞、血管内皮细胞、循环和浸润性免疫细胞。事实上,在最近的单细胞分析中,癌细胞克隆进化的惊人多样性特征,在癌症的发展或获得耐药性的过程中,伴随着环境基质细胞中相应的基因表达变化。基于获得的新见解,开始更好的优化药物选择和新的给药顺序。甚至单细胞分析的一个遗留问题也得到了解决。直到最近,还不可能通过单细胞分析获得癌症细胞的位置信息,因为这些信息在制备单细胞悬浮液的过程中会丢失。一种新的方法,统称为空间转录组(ST)分析,已经发展并迅速应用于各种临床标本。在这篇综述中,我们首先概述了单细胞肿瘤分析在分析耐药获得的分子基础方面的最新成就,特别关注最新的抗表皮生长因子受体酪氨酸激酶抑制剂奥希替尼。此外,我们回顾了目前可用的ST分析方法,并介绍了我们最近关于各自主题的尝试。
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引用次数: 15
Pathogenesis and management of gastrointestinal inflammation and fibrosis: from inflammatory bowel diseases to endoscopic surgery. 胃肠道炎症和纤维化的发病机制和治疗:从炎症性肠病到内镜手术。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-07-14 DOI: 10.1186/s41232-021-00174-7
Kentaro Iwata, Yohei Mikami, Motohiko Kato, Naohisa Yahagi, Takanori Kanai

Gastrointestinal fibrosis is a state of accumulated biological entropy caused by a dysregulated tissue repair response. Acute or chronic inflammation in the gastrointestinal tract, including inflammatory bowel disease, particularly Crohn's disease, induces fibrosis and strictures, which often require surgical or endoscopic intervention. Recent technical advances in endoscopic surgical techniques raise the possibility of gastrointestinal stricture after an extended resection. Compared to recent progress in controlling inflammation, our understanding of the pathogenesis of gastrointestinal fibrosis is limited, which requires the development of prevention and treatment strategies. Here, we focus on gastrointestinal fibrosis in Crohn's disease and post-endoscopic submucosal dissection (ESD) stricture, and we review the relevant literature.

胃肠道纤维化是一种由组织修复反应失调引起的生物熵累积状态。胃肠道的急性或慢性炎症,包括炎症性肠病,特别是克罗恩病,会引起纤维化和狭窄,通常需要手术或内窥镜干预。内镜手术技术的最新技术进步提高了扩大切除后胃肠道狭窄的可能性。与近年来在控制炎症方面的进展相比,我们对胃肠道纤维化发病机制的了解有限,这需要制定预防和治疗策略。在这里,我们主要关注克罗恩病和内镜下粘膜下夹层(ESD)狭窄的胃肠道纤维化,并回顾相关文献。
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引用次数: 4
Multiomic technologies for analyses of inborn errors of immunity: from snapshot of the average cell to dynamic temporal picture at single-cell resolution. 用于分析先天性免疫错误的多组学技术:从平均细胞快照到单细胞分辨率的动态时间图像。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-07-01 DOI: 10.1186/s41232-021-00169-4
Yusuke Kawashima, Ryuta Nishikomori, Osamu Ohara

Advances in DNA sequencing technology have significantly impacted human genetics; they have enabled the analysis of genetic causes of rare diseases, which are usually pathogenic variants in a single gene at the nucleotide sequence level. However, since the quantity of data regarding the relationship between genotype and phenotype is insufficient to diagnose some rare immune diseases definitively, genetic information alone cannot help obtain a mechanistic understanding of the disease etiology. For such cases, exploring the molecular phenotype using multiomic analyses could be the approach of choice. In this review, we first overview current technologies for multiomic analysis, particularly focusing on RNA and protein profiling of bulk cell ensembles. We then discuss the measurement modality and granularity issue because it is critical to design multiomic experiments properly. Next, we illustrate the importance of bioimaging by describing our experience with the analysis of an autoinflammatory disease, cryopyrin-associated periodic fever syndrome, which could be caused by low-frequency somatic mosaicism and cannot be well characterized only by multiomic snapshot analyses of an ensemble of many immune cells. We found it powerful to complement the multiomic data with bioimaging data that can provide us with indispensable time-specific dynamic information of every single cell in the "immune cell society." Because we now have many measurement tools in different modalities and granularity to tackle the etiology of rare hereditary immune diseases, we might gain a deeper understanding of the pathogenic mechanisms of these diseases by taking full advantage of these tools in an integrated manner.

DNA 测序技术的进步对人类遗传学产生了重大影响,使人们能够分析罕见疾病的遗传原因,这些原因通常是单个基因在核苷酸序列水平上的致病变异。然而,由于有关基因型和表型之间关系的数据量不足以明确诊断某些罕见免疫疾病,因此仅靠遗传信息无助于从机理上了解疾病的病因。在这种情况下,利用多组学分析探索分子表型可能是首选方法。在这篇综述中,我们首先概述了当前的多组学分析技术,尤其侧重于体细胞组合的 RNA 和蛋白质分析。然后,我们讨论测量模式和粒度问题,因为这对正确设计多组学实验至关重要。接下来,我们将介绍分析自身炎症性疾病--冰冻蛋白相关周期性发热综合征的经验,以此说明生物成像的重要性。这种疾病可能是由低频体细胞嵌合引起的,仅对许多免疫细胞的集合进行多组学快照分析无法很好地描述其特征。我们发现用生物成像数据来补充多组学数据非常有用,因为生物成像数据可以为我们提供 "免疫细胞社会 "中每个单细胞不可或缺的特定时间动态信息。由于我们现在拥有多种不同模式和粒度的测量工具来解决罕见遗传性免疫疾病的病因问题,因此,通过综合利用这些工具,我们可能会对这些疾病的致病机制有更深入的了解。
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引用次数: 0
Cardiac regeneration by direct reprogramming in this decade and beyond. 通过直接重编程实现心脏再生。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-07-01 DOI: 10.1186/s41232-021-00168-5
Hiroyuki Yamakawa, Masaki Ieda

Japan faces an increasing incidence of heart disease, owing to a shift towards a westernized lifestyle and an aging demographic. In cases where conventional interventions are not appropriate, regenerative medicine offers a promising therapeutic option. However, the use of stem cells has limitations, and therefore, "direct cardiac reprogramming" is emerging as an alternative treatment. Myocardial regeneration transdifferentiates cardiac fibroblasts into cardiomyocytes in situ.Three cardiogenic transcription factors: Gata4, Mef2c, and Tbx5 (GMT) can induce direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs), in mice. However, in humans, additional factors, such as Mesp1 and Myocd, are required. Inflammation and immune responses hinder the reprogramming process in mice, and epigenetic modifiers such as TET1 are involved in direct cardiac reprogramming in humans. The three main approaches to improving reprogramming efficiency are (1) improving direct cardiac reprogramming factors, (2) improving cell culture conditions, and (3) regulating epigenetic factors. miR-133 is a potential candidate for the first approach. For the second approach, inhibitors of TGF-β and Wnt signals, Akt1 overexpression, Notch signaling pathway inhibitors, such as DAPT ((S)-tert-butyl 2-((S)-2-(2-(3,5-difluorophenyl) acetamido) propanamido)-2-phenylacetate), fibroblast growth factor (FGF)-2, FGF-10, and vascular endothelial growth factor (VEGF: FFV) can influence reprogramming. Reducing the expression of Bmi1, which regulates the mono-ubiquitination of histone H2A, alters histone modification, and subsequently the reprogramming efficiency, in the third approach. In addition, diclofenac, a non-steroidal anti-inflammatory drug, and high level of Mef2c overexpression could improve direct cardiac reprogramming.Direct cardiac reprogramming needs improvement if it is to be used in humans, and the molecular mechanisms involved remain largely elusive. Further advances in cardiac reprogramming research are needed to bring us closer to cardiac regenerative therapy.

由于生活方式西化和人口老龄化,日本的心脏病发病率不断上升。在传统干预不合适的情况下,再生医学提供了一个有希望的治疗选择。然而,干细胞的使用有局限性,因此,“直接心脏重编程”正在成为一种替代治疗方法。心肌再生将心肌成纤维细胞原位转分化为心肌细胞。三种心源性转录因子:Gata4, Mef2c和Tbx5 (GMT)可以在小鼠中诱导成纤维细胞直接重编程为诱导心肌细胞(iCMs)。然而,在人类中,需要额外的因子,如Mesp1和心肌。炎症和免疫反应阻碍了小鼠的重编程过程,而TET1等表观遗传修饰因子参与了人类心脏的直接重编程。提高重编程效率的三个主要途径是:(1)改善直接心脏重编程因子,(2)改善细胞培养条件,(3)调节表观遗传因子。miR-133是第一种方法的潜在候选者。对于第二种方法,TGF-β和Wnt信号抑制剂、Akt1过表达、Notch信号通路抑制剂,如DAPT ((S)-叔丁基2-((S)-2-(2-(3,5-二氟苯基)乙酰氨基)丙胺)-2-苯乙酸)、成纤维细胞生长因子(FGF)-2、FGF-10和血管内皮生长因子(VEGF: FFV)可以影响重编程。第三种方法是降低Bmi1的表达,Bmi1调节组蛋白H2A的单泛素化,改变组蛋白修饰,进而改变重编程效率。此外,非甾体抗炎药双氯芬酸和Mef2c高水平过表达可改善心脏直接重编程。如果要将直接心脏重编程用于人类,则需要改进,而且涉及的分子机制在很大程度上仍然难以捉摸。心脏重编程研究的进一步进展需要使我们更接近心脏再生治疗。
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引用次数: 15
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