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The role of the skin in the atopic march. 皮肤在特应性进展中的作用。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-13 DOI: 10.1093/intimm/dxae053
Xin Tang,Mei Li
Atopic diseases, including atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are closely related to inflammatory diseases involving different body sites (i.e. the skin, airway, and digestive tract) with characteristic features including specific IgE to allergens (so-called 'atopy') and Th2 cell-mediated inflammation. It has been recognized that AD often precedes the development of other atopic diseases. The progression from AD during infancy to FA or asthma/AR in later childhood is referred as the 'atopic march' (AM). Clinical, genetic and experimental studies have provided evidence that allergen sensitization occurring through AD skin could be the origin of the AM. Here, we provide an updated review focusing on the role of the skin in the AM, from genetic mutations and environmental factors associated with epidermal barrier dysfunction in AD and the AM, to immunological mechanisms for skin sensitization, particularly recent progress on the function of key cytokines produced by epidermal keratinocytes or by immune cells infiltrating the skin during AD. We also highlight the importance of developing strategies that target AD skin to prevent and attenuate the AM.
特应性疾病,包括特应性皮炎(AD)、食物过敏(FA)、哮喘和过敏性鼻炎(AR)与涉及不同身体部位(即皮肤、气道和消化道)的炎症性疾病密切相关,其特征包括对过敏原的特异性 IgE(所谓的 "特应性")和 Th2 细胞介导的炎症。人们已经认识到,渐冻人症往往先于其他特应性疾病的发生。从婴儿期的过敏性鼻炎发展到儿童后期的过敏性鼻炎或哮喘/过敏性鼻炎被称为 "特应性进展"(AM)。临床、遗传和实验研究已经提供了证据,证明通过 AD 皮肤发生的过敏原致敏可能是特应性哮喘的起源。在此,我们对皮肤在特应性哮喘中的作用进行了最新综述,从与 AD 和特应性哮喘中表皮屏障功能障碍相关的基因突变和环境因素,到皮肤过敏的免疫学机制,特别是最近在研究 AD 期间表皮角质形成细胞或浸润皮肤的免疫细胞产生的关键细胞因子的功能方面取得的进展。我们还强调了制定针对 AD 皮肤的策略以预防和减轻 AM 的重要性。
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引用次数: 0
Regnase-1 D141N mutation induces CD4+ T cell-mediated lung granuloma formation via upregulation of Pim2. Regnase-1 D141N突变通过上调Pim2诱导CD4+ T细胞介导的肺肉芽肿形成。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-10 DOI: 10.1093/intimm/dxae026
Thin Sandi Htun, Hiroki Tanaka, Shailendra Kumar Singh, Diego Diez, Shizuo Akira

Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory messenger RNAs (mRNAs). Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of the RNase activity of Regnase-1 in developing inflammatory diseases. We have constructed mice with a single point mutation at the catalytic center of the Regnase-1 RNase domain, which lacks endonuclease activity. D141N mutant mice demonstrated systemic inflammation, immune cell infiltration into various organs, and progressive development of lung granuloma. CD4+ T cells, mainly affected by this mutation, upregulated the mTORC1 pathway and facilitated the autoimmune trait in the D141N mutation. Moreover, serine/threonine kinase Pim2 contributed to lung inflammation in this mutation. Inhibition of Pim2 kinase activity ameliorated granulomatous inflammation, immune cell infiltration, and proliferation in the lungs. Additionally, Pim2 inhibition reduced the expression of adhesion molecules on CD4+ T cells, suggesting a role for Pim2 in facilitating leukocyte adhesion and migration to inflamed tissues. Our findings provide new insights into the role of Regnase-1 RNase activity in controlling immune functions and underscore the therapeutic relevance of targeting Pim2 to modulate abnormal immune responses.

Regnase-1 是一种 RNase,它通过破坏炎症 mRNA 的稳定性,在负向调节免疫反应方面发挥着关键作用。Regnase-1 的功能障碍可能是导致组织损伤和免疫细胞浸润器官的各种炎症性疾病的主要原因。本研究主要探讨 Regnase-1 的 RNase 活性在炎症性疾病发生中的作用。我们构建了Regnase-1 RNase结构域催化中心单点突变的小鼠,该突变缺乏内切酶活性。D141N突变小鼠表现出全身性炎症、免疫细胞浸润各器官以及肺肉芽肿的进行性发展。主要受该突变影响的 CD4+ T 细胞上调了 mTORC1 通路,促进了 D141N 突变小鼠的自身免疫特征。此外,丝氨酸/苏氨酸激酶Pim2也导致了这种突变的肺部炎症。抑制 Pim2 激酶的活性可改善肺部肉芽肿性炎症、免疫细胞浸润和增殖。此外,抑制 Pim2 还能减少 CD4+ T 细胞上粘附分子的表达,这表明 Pim2 在促进白细胞粘附和向炎症组织迁移方面发挥了作用。我们的研究结果为了解 Regnase-1 RNase 活性在控制免疫功能中的作用提供了新的视角,并强调了靶向 Pim2 以调节异常免疫反应的治疗意义。
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引用次数: 0
Humoral responses are enhanced by facilitating B cell viability by Fcrl5 overexpression in B cells. B 细胞中 Fcrl5 的过表达可促进 B 细胞的活力,从而增强体液反应。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-10 DOI: 10.1093/intimm/dxae028
Chisato Ono, Yuta Kochi, Yoshihiro Baba, Shinya Tanaka

B cell initial activity is regulated through a balance of activation and suppression mediated by regulatory molecules expressed in B cells; however, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the function of the Fc receptor-like (Fcrl) family molecule Fcrl5, which is constitutively expressed in naive B cells, in humoral immune responses. Our study demonstrated that B cell-specific overexpression of Fcrl5 enhanced antibody (Ab) production in both T cell-independent type 1 (TI1) and T cell-dependent (TD) responses. Additionally, it promoted effector B cell formation under competitive conditions in TD responses. Mechanistically, in vitro ligation of Fcrl5 by agonistic Abs reduced cell death and enhanced proliferation in lipopolysaccharide-stimulated B cells. In the presence of anti-CD40 Abs and IL-5, the Fcrl5 ligation not only suppressed cell death but also enhanced differentiation into plasma cells. These findings reveal a novel role of Fcrl5 in promoting humoral immune responses by enhancing B cell viability and plasma cell differentiation.

B细胞的初始活性是通过B细胞中表达的调控分子介导的激活和抑制的平衡来调节的;然而,这一过程的分子机制仍不完全清楚。在这项研究中,我们研究了 Fc 受体样(Fcrl)家族分子 Fcrl5 在体液免疫反应中的功能。我们的研究表明,B细胞特异性过表达Fcrl5能增强T细胞依赖型1(TI1)和T细胞依赖型(TD)反应中抗体(Ab)的产生。此外,在 TD 反应的竞争条件下,它还能促进效应 B 细胞的形成。从机理上讲,体外激动性 Abs 与 Fcrl5 连接可减少细胞死亡,并增强脂多糖(LPS)刺激下 B 细胞的增殖。在抗CD40 Abs和IL-5存在的情况下,Fcrl5结扎不仅能抑制细胞死亡,还能促进分化成浆细胞。这些发现揭示了 Fcrl5 在通过增强 B 细胞活力和浆细胞分化促进体液免疫反应中的新作用。
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引用次数: 0
Lipid metabolism: a central modulator of RORγt-mediated Th17 cell differentiation. 脂质代谢:RORt 介导的 Th17 细胞分化的核心调节器。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-10 DOI: 10.1093/intimm/dxae031
Toshio Kanno, Keisuke Miyako, Yusuke Endo

Among the T helper cell subsets, Th17 cells contribute to the development of various inflammatory and autoimmune diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Retinoid-related orphan receptor gamma t (RORγt), a nuclear hormone receptor, serves as a master transcription factor for Th17 cell differentiation. Recent findings have shown that modulating the metabolic pathway is critical for Th17 cell differentiation, particularly through the engagement of de novo lipid biosynthesis. Suppression of lipid biosynthesis, either through the pharmacological inhibition or gene deletion of related enzymes in CD4+ T cells, results in significant impairment of Th17 cell differentiation. Mechanistic studies indicate that metabolic fluxes through both the fatty acid and cholesterol biosynthetic pathways have a pivotal role in the regulation of RORγt activity through the generation of endogenous RORγt lipid ligands. This review discusses recent discoveries highlighting the importance of lipid metabolism in Th17 cell differentiation and function, as well as exploring specific molecular pathways involved in RORγt activation through cellular lipid metabolism. We further elaborate on a pioneering therapeutic approach to improve inflammatory and autoimmune disorders via the inhibition of RORγt.

在 T 辅助细胞亚群中,Th17 细胞是导致牛皮癣、类风湿性关节炎、炎症性肠病、类固醇耐药哮喘和多发性硬化症等各种炎症和自身免疫性疾病的病因。视黄醇相关孤儿受体γt(RORγt)是一种核激素受体,是 Th17 细胞分化的主转录因子。最近的研究结果表明,调节新陈代谢途径对 Th17 细胞的分化至关重要,特别是通过参与脂质的从头生物合成。通过药物抑制或基因缺失 CD4+ T 细胞中的相关酶来抑制脂质生物合成,会导致 Th17 细胞分化明显受损。机理研究表明,脂肪酸和胆固醇生物合成途径的代谢通量通过生成内源性 RORγt 脂质配体在调节 RORγt 活性方面起着关键作用。这篇综述讨论了最近的发现,强调了脂质代谢在 Th17 细胞分化和功能中的重要性,并探讨了通过细胞脂质代谢激活 RORγt 所涉及的特定分子途径。我们进一步阐述了通过抑制 RORγt 改善炎症和自身免疫性疾病的开创性治疗方法。
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引用次数: 0
Altering the competitive environment of B cell epitopes significantly extends the duration of antibody production. 改变 B 细胞表位的竞争环境可大大延长抗体的产生时间。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-10 DOI: 10.1093/intimm/dxae027
Hongke Xu, Yanfei Chen, Jingzhi Li, Mengyu Li, Miao Sun, Jian Chen, Ling Li, Qinghong Xue, Hongwei Ma

Persistent immunoglobulin G (IgG) production (PIP) provides long-term vaccine protection. While variations in the duration of protection have been observed with vaccines prepared from different pathogens, little is known about the factors that determine PIP. Here, we investigated the impact of three parameters on the duration of anti-peptide IgG production, namely amino acid sequences, protein carriers, and immunization programs. We show that anti-peptide IgG production can be transformed from transient IgG production (TIP) to PIP, by placing short peptides (Pi) containing linear B cell epitopes in different competitive environments using bovine serum albumin (BSA) conjugates instead of the original viral particles. When goats were immunized with the peste des petits ruminants (PPR) live-attenuated vaccine (containing Pi as the constitutive component) and BSA-Pi conjugate, anti-Pi IgG production exhibited TIP (duration < 60 days) and PIP (duration > 368 days), respectively. Further, this PIP was unaffected by subsequent immunization with the PPR live-attenuated vaccine in the same goat. When goats were coimmunized with PPR live-attenuated vaccine and BSA-Pi, the induced anti-Pi IgG production showed a slightly extended TIP (from ~60 days to ~100 days). This discovery provides new perspectives for studying the fate of plasma cells in humoral immune responses and developing peptide vaccines related to linear neutralizing epitopes from various viruses.

持续产生免疫球蛋白 G (IgG) (PIP) 可提供长期疫苗保护。虽然从不同病原体制备的疫苗在保护持续时间上存在差异,但人们对决定 PIP 的因素知之甚少。在这里,我们研究了氨基酸序列、蛋白载体和免疫程序这三个参数对抗肽 IgG 生成持续时间的影响。我们的研究表明,通过使用牛血清白蛋白(BSA)共轭物代替原始病毒颗粒,将含有线性 B 细胞表位的短肽(Pi)置于不同的竞争环境中,抗肽 IgGs 的产生可从瞬时 IgG 产生(TIP)转变为 PIP。用小反刍兽疫(PPR)减毒活疫苗(含有 Pi 作为组成成分)和 BSA-Pi 结合物对山羊进行免疫,抗 Pi IgGs 的产生分别表现出 TIP(持续时间为 368 天)。此外,这种 PIP 不受同一只山羊随后接种 PPR 减毒活疫苗的影响。当山羊同时接种 PPR 减毒活疫苗和 BSA-Pi 时,诱导产生的抗 Pi IgG 的 TIP 稍有延长(从 ~60 天延长到 ~100 天)。这一发现为研究体液免疫反应中浆细胞的命运以及开发与各种病毒线性中和表位相关的多肽疫苗提供了新的视角。
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引用次数: 0
Blockade of CCR5 and CXCR3 attenuates murine acute graft-versus-host disease through modulating donor-derived T-cell distribution and function. 通过调节供体源性 T 细胞的分布和功能,阻断 CCR5 和 CXCR3 可减轻小鼠急性移植物抗宿主疾病。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-10 DOI: 10.1093/intimm/dxae033
Bo Tang, Chenchen Qin, Huihui Liu, Shengchao Miao, Chao Xue, Zhenhua Wang, Yang Zhang, Yujun Dong, Wei Liu, Hanyun Ren

Lymphocyte trafficking via chemokine receptors such as C-C chemokine receptor 5 (CCR5) and CXCR3 plays a critical role in the pathogenesis of acute graft-versus-host disease (aGVHD). Our previous studies showed that the addition of CCR5 or CXCR3 antagonists could only slightly alleviate the development of aGVHD. Given the specificity of T lymphocytes bearing CXCR3 and CCR5, we investigated whether combined CCR5 and CXCR3 blockade could further attenuate murine aGVHD. A mouse model of aGVHD was established to assess the efficacy of CCR5 and/or CXCR3 blockade on the development of aGVHD. The distribution of lymphocytes was calculated by quantification of immunostaining cells. The immunomodulatory effect on T cells was assessed by evaluating T-cell proliferation, viability, and differentiation. Using the murine allogeneic hematopoietic stem cell transplantation model, we demonstrated that blockade of both CCR5 and CXCR3 could efficiently alleviate the development of aGVHD. Further investigation on the immune mechanisms for this prophylactic effect showed that more T cells were detained into secondary lymphoid organs (SLOs), which may lead to reduced infiltration of T cells into GVHD target organs. Our study also showed that T cells detained in SLOs dampened the activation, suppressed the polarization toward T helper type 1 (Th1) and T cytotoxic type 1 (Tc1) cells, and induced the production of Treg cells. These data suggest that concurrent blockade of CCR5 and CXCR3 attenuates murine aGVHD through modulating donor-derived T-cell distribution and function, and this might be applicable for aGVHD prophylaxis in clinical settings.

背景:淋巴细胞通过趋化因子受体(如 CCR5 和 CXCR3)的迁移在 aGVHD 的发病机制中起着至关重要的作用。我们之前的研究表明,添加 CCR5 或 CXCR3 拮抗剂只能轻微缓解 aGVHD 的发展。鉴于携带 CXCR3 和 CXCR5 的 T 淋巴细胞的特异性,我们研究了联合阻断 CXCR5 和 CXCR3 是否能进一步减轻小鼠 aGVHD:方法:我们建立了小鼠 aGVHD 模型,以评估 CCR5 或/和 CXCR3 阻断对 aGVHD 发病的疗效。通过免疫染色细胞的定量计算淋巴细胞的分布。通过评估 T 细胞的增殖、活力和分化,评估对 T 细胞的免疫调节作用:结果:我们利用小鼠异体 HSCT 模型证明,阻断 CCR5 和 CXCR3 可有效缓解 aGVHD 的发生。对这种预防作用的免疫机制的进一步研究表明,更多的 T 细胞被阻滞在继发性淋巴器官(SLO)中,这可能会导致 T 细胞向 GVHD 靶器官的浸润减少。我们的研究还表明,滞留在SLO中的T细胞抑制了Th1和Tc1的活化,抑制了Th1和Tc1的极化,并诱导了Treg细胞的产生:这些数据表明,同时阻断 CCR5 和 CXCR3 可通过调节供体源性 T 细胞的分布和功能来减轻小鼠 aGVHD,这可能适用于临床环境中的 aGVHD 预防。
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引用次数: 0
Mechanisms and Effects of Activation of Innate Immunity by Mitochondrial Nucleic Acids. 线粒体核酸激活先天性免疫的机制和影响
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-30 DOI: 10.1093/intimm/dxae052
Prashant Rai, Michael B Fessler

In recent years, a growing number of roles have been identified for mitochondria in innate immunity. One principal mechanism is that translocation of mitochondrial nucleic acid species from the mitochondrial matrix to the cytosol and endolysosomal lumen in response to an array of microbial and non-microbial environmental stressors has been found to serve as a second messenger event in the cell signaling of the innate immune response. Thus, mitochondrial DNA and RNA have been shown to access the cytosol through several regulated mechanisms involving remodeling of the mitochondrial inner and outer membranes and to access lysosomes via vesicular transport, thereby activating cytosolic (e.g., cyclic GMP-AMP synthase [cGAS]; retinoic acid-inducible gene-I [RIG-I]-like receptors) and endolysosomal (Toll-like Receptor [TLR]7, -9) nucleic acid receptors that induce type I interferons and pro-inflammatory cytokines. In this mini-review, we discuss these molecular mechanisms of mitochondrial nucleic acid mislocalization and their roles in host defense, autoimmunity, and auto-inflammatory disorders. The emergent paradigm is one in which host-derived DNA interestingly serves as a signal amplifier in the innate immune response and also as an alarm signal for disturbances in organellar homeostasis. The apparent vast excess of mitochondria and mitochondrial DNA nucleoids per cell may thus serve to sensitize the cell response to stressors while ensuring an underlying reserve of intact mitochondria to sustain cellular metabolism. An improved understanding of these molecular mechanisms will hopefully afford future opportunities for therapeutic intervention in human disease.

近年来,线粒体在先天性免疫中发挥的作用越来越多。其中一个主要机制是,线粒体核酸物种在应对一系列微生物和非微生物环境压力时从线粒体基质转位到细胞膜和溶酶体内腔,被认为是先天性免疫反应细胞信号传递过程中的第二信使事件。因此,线粒体 DNA 和 RNA 已被证明可通过涉及线粒体内外膜重塑的多种调节机制进入细胞膜,并通过囊泡运输进入溶酶体,从而激活细胞膜(如环状 GMP-AMP 合成酶)、环 GMP-AMP 合成酶 [cGAS];视黄酸诱导基因-I [RIG-I]样受体)和溶酶体内(Toll 样受体 [TLR]7, -9)核酸受体,从而诱导 I 型干扰素和促炎细胞因子。在这篇微型综述中,我们将讨论线粒体核酸错位的分子机制及其在宿主防御、自身免疫和自身炎症性疾病中的作用。新出现的模式是,宿主衍生 DNA 在先天性免疫反应中有趣地充当了信号放大器,同时也是细胞器平衡紊乱的警报信号。因此,每个细胞中明显过量的线粒体和线粒体 DNA 核苷酸可能会使细胞对应激反应更加敏感,同时确保完整线粒体的基本储备,以维持细胞的新陈代谢。对这些分子机制的进一步了解有望为未来干预人类疾病的治疗提供机会。
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引用次数: 0
Spatial diversity of in vivo tissue immunity. 体内组织免疫的空间多样性。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-23 DOI: 10.1093/intimm/dxae051
Yu Miyamoto, Masaru Ishii

The immune system exhibits spatial diversity in in vivo tissues. Immune cells are strategically distributed within tissues to maintain the organ integrity. Advanced technologies such as intravital imaging and spatial transcriptomics have revealed the spatial heterogeneity of immune cell distribution and function within organs such as the liver, kidney, intestine, and lung. In addition, these technologies visualize nutrient and oxygen environments across tissues. Recent spatial analyses have suggested that a functional immune niche is determined by interactions between immune and non-immune cells in an appropriate nutrient and oxygen environment. Understanding the spatial communication between immune cells, environment, and surrounding non-immune cells is crucial for developing strategies to control immune responses and effectively manage inflammatory diseases.

免疫系统在体内组织中表现出空间多样性。免疫细胞在组织内呈策略性分布,以保持器官的完整性。显微成像和空间转录组学等先进技术揭示了免疫细胞在肝、肾、肠和肺等器官内分布和功能的空间异质性。此外,这些技术还能将各组织的营养和氧气环境可视化。最近的空间分析表明,功能性免疫龛是由免疫细胞和非免疫细胞在适当的营养和氧气环境中的相互作用决定的。了解免疫细胞、环境和周围非免疫细胞之间的空间沟通对于制定控制免疫反应和有效控制炎症性疾病的策略至关重要。
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引用次数: 0
Identification and characterization of putative enhancer regions that direct Il6 transcription in murine macrophages. 小鼠巨噬细胞中指导 Il6 转录的推定增强子区域的鉴定和特征描述
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-13 DOI: 10.1093/intimm/dxae024
Norisuke Kano, Takeo Miki, Yurina Uehara, Daisuke Ori, Taro Kawai

Interleukin-6 (IL-6) plays a crucial role in various cellular functions, including innate and adaptive immune responses. Dysregulated expression of IL-6 is associated with hyperinflammation and chronic inflammatory diseases. In this study, we aimed to identify the enhancer regions responsible for robust Il6 mRNA expression in murine macrophages. Through comprehensive genome-wide ChIP- and ATAC-seq analyses, we identified two distinct clusters, termed E1 and E2 regions, located at -144 to -163 kb relative to the Il6 transcription start site in lipopolysaccharide (LPS)-activated murine macrophages. These clusters exhibited an accumulation of histone modification marks (H3K27ac and H3K4me1), as well as open chromatin, and were found to contain binding sites for the transcription factors PU.1, NF-κB, C/EBPβ, and JunB. Upregulation of non-coding RNA (ncRNA) transcripts from the E1 and E2 regions was observed upon LPS stimulation, and repression of these ncRNAs resulted in abrogation of Il6 expression. Additionally, deletion of either E1 or E2 region significantly impaired Il6 expression, while CRISPR/dCas9 activation-mediated recruitment of the co-activator p300 to the E1 and E2 regions facilitated Il6 expression. Collectively, our findings suggest that the E1 and E2 regions serve as putative enhancers for Il6 expression.

白细胞介素-6(IL-6)在包括先天性和适应性免疫反应在内的各种细胞功能中发挥着至关重要的作用。IL-6表达失调与炎症亢进和慢性炎症性疾病有关。在这项研究中,我们旨在确定小鼠巨噬细胞中负责Il6 mRNA强表达的增强子区域。通过全面的全基因组 ChIP-seq 和 ATAC-seq 分析,我们在脂多糖(LPS)激活的小鼠巨噬细胞中发现了两个不同的簇,称为 E1 和 E2 区,分别位于 Il6 转录起始位点的 -144 kb 至 -163 kb 处。这些集群显示出组蛋白修饰标记(H3K27ac 和 H3K4me1)的积累以及染色质的开放,并发现它们包含转录因子 PU.1、NF-κB、C/EBPβ 和 JunB 的结合位点。在 LPS 刺激下,观察到来自 E1 和 E2 区域的非编码 RNA(ncRNA)转录本上调,这些 ncRNA 的抑制导致 Il6 表达减弱。此外,E1 或 E2 区域的缺失会显著影响 Il6 的表达,而 CRISPR/dCas9 激活介导的共激活剂 p300 招募到 E1 和 E2 区域会促进 Il6 的表达。总之,我们的研究结果表明,E1和E2区是Il6表达的假定增强子。
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引用次数: 0
"A Splice of Life: The Discovery, Function, and Clinical Implications of FOXP3 Isoforms in Autoimmune Disease". "生命的剪接:FOXP3 同工酶在自身免疫性疾病中的发现、功能和临床意义"。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-13 DOI: 10.1093/intimm/dxae049
Kristin N Weinstein, Phillip P Domeier, Steven F Ziegler

Regulatory T cells (Tregs) are a specialized subset of CD4+ T cells essential for the maintenance of immune homeostasis and prevention of autoimmunity. Treg lineage and functions are programmed by the X-chromosome encoded transcription factor Forkhead box P3 (FOXP3). In humans, multiple FOXP3 isoforms are generated through alternative splicing. A full-length isoform containing all coding exons (FOXP3-FL) and a version lacking the second exon (FOXP3-ΔE2) are the predominant FOXP3 isoforms. Additionally, there are two minor isoforms lacking either exon 7 (FOXP3-ΔE7) and both exons 2 and 7 (FOXP3-ΔE2ΔE7). Although healthy humans express approximately equal levels of the FOXP3-FL and FOXP3-ΔE2 isoforms, sole expression of FOXP3-ΔE2 results in development of a systemic autoimmune disease that resembles immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. These clinical observations strongly suggest functional defects in suppression by Tregs programmed by the FOXP3-ΔE2 isoform. Work from the past two decades has provided phenotypic and functional evidence of differences between Tregs programmed by the FOXP3-FL, FOXP3-ΔE2, and FOXP3-ΔE7 isoforms. In this review, we discuss the discovery of the FOXP3 isoforms, differences in the phenotype and function of Tregs programmed by different FOXP3 isoforms, and the role that these isoforms are known to play in autoimmunity.

调节性 T 细胞(Tregs)是 CD4+ T 细胞的一个特化亚群,对维持免疫平衡和预防自身免疫至关重要。Treg的血统和功能由X染色体编码的转录因子叉头盒P3(FOXP3)编程。在人类中,通过替代剪接产生了多种 FOXP3 异构体。包含所有编码外显子的全长异构体(FOXP3-FL)和缺少第二个外显子的异构体(FOXP3-ΔE2)是主要的 FOXP3 异构体。此外,还有两种次要的异构体,分别缺乏第 7 号外显子(FOXP3-ΔE7)和同时缺乏第 2 号和第 7 号外显子(FOXP3-ΔE2ΔE7)。虽然健康人表达的 FOXP3-FL 和 FOXP3-ΔE2 同工酶的水平大致相同,但只表达 FOXP3-ΔE2 会导致全身性自身免疫性疾病的发生,这种疾病类似于免疫调节失调、多内分泌病、肠病、X-连锁(IPEX)综合征。这些临床观察强烈表明,由 FOXP3-ΔE2 同工型编程的集落抑制功能存在缺陷。过去二十年的研究提供了表型和功能证据,证明由 FOXP3-FL、FOXP3-ΔE2 和 FOXP3-ΔE7 异构体编程的 Tregs 之间存在差异。在这篇综述中,我们将讨论 FOXP3 同工酶的发现、不同 FOXP3 同工酶编程的 Tregs 表型和功能的差异以及这些同工酶在自身免疫中的作用。
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引用次数: 0
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