Autoimmune Diseases

自身免疫性疾病
  • 文章类型: Journal Article
    间充质干细胞(MSCs)具有诱人的再生医学治疗潜力,然而,关于他们的临床移植,仍有争议。这篇全面的评论浏览了MSC争议的错综复杂的景观,利用15年的临床经验和研究。我们深入研究了MSCs的基本性质,探索其独特的免疫调节能力和表面标记。我们探究的核心在于MSC移植的有争议的应用,包括自体和同种异体来源之间的长期争论,对功效的担忧,和挥之不去的安全忧虑。此外,我们解开围绕MSC移植的神秘机制,比如归巢,一体化,以及分化和旁分泌效应之间的微妙平衡。我们还评估了临床试验的现状和不断变化的监管环境。当我们展望未来时,我们研究新兴趋势,设想个性化医疗和创新的交付方法。我们的评论为争议提供了一个平衡和知情的观点,为读者提供对复杂性的清晰理解,挑战,和MSC移植的潜在解决方案。
    Mesenchymal stem cells (MSCs) have tantalized regenerative medicine with their therapeutic potential, yet a cloud of controversies looms over their clinical transplantation. This comprehensive review navigates the intricate landscape of MSC controversies, drawing upon 15 years of clinical experience and research. We delve into the fundamental properties of MSCs, exploring their unique immunomodulatory capabilities and surface markers. The heart of our inquiry lies in the controversial applications of MSC transplantation, including the perennial debate between autologous and allogeneic sources, concerns about efficacy, and lingering safety apprehensions. Moreover, we unravel the enigmatic mechanisms surrounding MSC transplantation, such as homing, integration, and the delicate balance between differentiation and paracrine effects. We also assess the current status of clinical trials and the ever-evolving regulatory landscape. As we peer into the future, we examine emerging trends, envisioning personalized medicine and innovative delivery methods. Our review provides a balanced and informed perspective on the controversies, offering readers a clear understanding of the complexities, challenges, and potential solutions in MSC transplantation.
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  • 文章类型: Journal Article
    隐球菌是一种机会性真菌病原体,可在免疫力低下的患者中引起播散性感染,主要涉及中枢神经系统。生物制剂越来越多地用于治疗肿瘤和自身免疫性/炎症性疾病以及预防移植排斥,这可能会影响人类对隐球菌病的防御机制。在这次审查中,我们全面调查隐球菌病与各种生物制剂之间的关联,强调他们感染的风险,临床表现,和临床结果。临床医生应该对接受影响Th1/巨噬细胞激活途径的生物制剂的患者发生隐球菌病的风险保持警惕。如肿瘤坏死因子α拮抗剂,布鲁顿酪氨酸激酶抑制剂,芬戈莫德,JAK/STAT抑制剂(Janus激酶/信号转导和转录激活因子),和抗CD52的单克隆抗体。其他风险因素,如年龄,潜在条件,同时使用免疫抑制剂,尤其是皮质类固醇-在风险分层时也应考虑。
    Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification.
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  • 文章类型: Systematic Review
    小说的鉴定,然而,容易测量的炎症和氧化应激的生物标志物可能有助于风湿性疾病(RD)患者的诊断和治疗.我们对研究胆红素循环浓度的研究进行了系统评价和荟萃分析,血红素代谢的最终产物和具有抗炎特性的有效内源性抗氧化剂,在患有RD和健康对照的患者中。电子数据库PubMed,Scopus,和WebofScience从成立到2023年12月31日进行了相关文章的搜索。我们使用JoannaBriggs清单和建议等级评估了偏见的风险和证据的确定性,评估,发展,和评估工作组系统,分别。在17项符合条件的研究中,所有的偏见风险都很低,与对照组相比,患有RD的患者的总胆红素浓度明显降低(标准平均差,SMD=-0.68,95%CI-0.91至-0.44,p<0.001;I2=92.5%,p<0.001;证据确定性低),直接(结合)胆红素(SMD=-0.67,95%CI-0.92至-0.41,p<0.001;I2=81.7%,p<0.001;证据的确定性非常低),和活性抗氧化剂和抗炎间接(未结合)形式的胆红素(SMD=-0.71,95%CI-1.18至-0.24,p=0.003;I2=95.1%,p<0.001;证据的确定性非常低)。在敏感性分析中,荟萃分析结果稳定。在元回归中,总胆红素的SMD与一些临床和人口统计学特征之间没有显着关联,包括年龄,男女比例,参与人数,肝酶和红细胞沉降率。在亚组分析中,总胆红素的SMD在一系列RD中显著,包括类风湿性关节炎,系统性红斑狼疮,原发性干燥综合征,和肌炎。因此,我们的系统评价和荟萃分析的结果表明,在患有RDs的患者中观察到的胆红素浓度降低反映了由于胆红素消耗导致的抗氧化和抗炎防御受损的状态,并突出了这种内源性产物作为RDs生物标志物的有希望的作用.
    https://www.crd.约克。AC.英国/普华永道/,标识符CRD42023500649。
    The identification of novel, yet easily measurable biomarkers of inflammation and oxidative stress might assist in the diagnosis and management of patients with rheumatic diseases (RDs). We conducted a systematic review and meta-analysis of studies investigating the circulating concentrations of bilirubin, the end product of heme metabolism and a potent endogenous antioxidant with anti-inflammatory properties, in patients with RDs and healthy controls. The electronic databases PubMed, Scopus, and Web of Science were searched from inception to 31 December 2023 for relevant articles. We evaluated the risk of bias and the certainty of evidence using the Joanna Briggs Checklist and the Grades of Recommendation, Assessment, Development, and Evaluation Working Group system, respectively. In 17 eligible studies, all with low risk of bias, compared to controls, patients with RDs had significantly lower concentrations of total bilirubin (standard mean difference, SMD=-0.68, 95% CI -0.91 to -0.44, p<0.001; I2 = 92.5%, p<0.001; low certainty of evidence), direct (conjugated) bilirubin (SMD=-0.67, 95% CI -0.92 to -0.41, p<0.001; I2 = 81.7%, p<0.001; very low certainty of evidence), and the active antioxidant and anti-inflammatory indirect (unconjugated) form of bilirubin (SMD=-0.71, 95% CI -1.18 to -0.24, p=0.003; I2 = 95.1%, p<0.001; very low certainty of evidence). The results of the meta-analysis were stable in sensitivity analysis. In meta-regression, there were no significant associations between the SMD of total bilirubin and several clinical and demographic characteristics, including age, male to female ratio, number of participants, liver enzymes and erythrocyte sedimentation rate. In subgroup analysis, the SMD of total bilirubin was significant across a range of RDs, including rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren syndrome, and myositis. Therefore, the results of our systematic review and meta-analysis suggests that the reductions in bilirubin concentrations observed in patients with RDs reflect a state of impaired antioxidant and anti-inflammatory defence due to bilirubin consumption and highlight the promising role of this endogenous product as a biomarker of RDs.
    UNASSIGNED: https://www.crd.york.ac.uk/prospero/, identifier CRD42023500649.
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  • 文章类型: Journal Article
    Az autoimmun betegségek az immuntolerancia károsodása következtében létrejövő kórállapotok, melyeknek szervspecifikus és szisztémás formáit különítjük el. Az autoimmun kórképek krónikus lefolyásuk, sokszor szervet vagy életet veszélyeztető megjelenésük, valamint növekvő incidenciájuk miatt komoly kihívást jelentenek mind a betegek, mind pedig az egészségügyi ellátórendszer számára. Mivel az alkalmazott terápiákra a betegek egy része nem vagy csak kevéssé reagál, az újabb potenciális gyógyszercélpontok feltérképezése és hatóanyagok kifejlesztése elengedhetetlen. Ehhez ugyanakkor jobban meg kell ismerni a betegségek hátterében álló folyamatokat. Jelen közleményünkben néhány autoimmun betegség példáján keresztül szeretnénk a teljesség igénye nélkül betekintést nyújtani abba, hogy milyen lehetőségek állnak rendelkezésre e kórképek patomechanizmusának részletesebb megismerésére. A kutatásban gyakran alkalmazunk az autoimmun betegségek vizsgálatára állatmodelleket vagy páciensek vér- és szövetmintáit, amelyek segítségével a patogenezis jobban feltárható, illetve a klinikumban még nem törzskönyvezett, célzott inhibitorok preklinikai vizsgálatai is elvégezhetők. Célunk, hogy rövid betekintést adjunk az autoimmun betegségek transzlációs szemléletű, izgalmas kutatási lehetőségeibe. Orv Hetil. 2024; 165(26): 983–996.
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  • 文章类型: Journal Article
    区域免疫监视依赖于不同记忆T细胞群体的共同努力。其中,组织驻留记忆T(TRM)细胞被策略性地定位在屏障组织中,在那里他们能够有效的前线防御感染和癌症。然而,这些细胞的长期持久性与多种免疫介导的病理有关。因此,调节TRM细胞群体代表了针对基于组织的疾病的新型疫苗接种和治疗性干预的有吸引力的策略。这里,我们提供了跨组织和疾病状态的TRM细胞异质性和功能的最新概述.我们讨论了TRM细胞介导的免疫保护机制及其对自身免疫性疾病的潜在贡献。最后,我们研究了TRM细胞反应如何持久增强或抑制治疗增益。
    Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (TRM) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating TRM cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of TRM cell heterogeneity and function across tissues and disease states. We discuss mechanisms of TRM cell-mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how TRM cell responses might be durably boosted or dampened for therapeutic gain.
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  • 文章类型: Journal Article
    系统性硬化症(SSc)和冷冻比林相关的周期性综合征(CAPS)是属于自身免疫性和自身炎症性疾病的不同临床实体,分别。这两个实体的共存很少有报道,而且特征不明确。这里,我们描述了一例38岁的日本女性,诊断为携带NLRP3基因致病突变的抗着丝粒抗体阳性SSc和CAPS,通过覆盖约90%的人类转录组的高通量综合蛋白质阵列,具有详细的自身抗体谱。患者的临床表现为典型的SSc和CAPS。综合自身抗体谱分析确定了患者血清中的65种自身抗体和患有CAPS的女儿血清中的78种自身抗体,与患者携带相同的NLRP3突变。SSc相关自身抗体(抗DBT,反CENP-B,和抗CENP-A)和抗CD320抗体仅在患者血清中检测到高水平,同时在患者及其女儿的血清中检测到以下四种蛋白质的自身抗体:TRIM21,LIMS1,CLIP4和KAT2A。TRRUST富集分析确定NF-κB1和RelA是重叠的关键转录因子,它们调节在患者和她的女儿中检测到自身抗体的编码蛋白的基因。因此,患者的自身抗体谱不能完全归因于SSc,但也可能受到CAPS的影响。虽然自身免疫性疾病和自身炎症性疾病被认为是在免疫谱的两端,详细的自身抗体谱分析可能会在两个实体重叠的情况下揭示独特的免疫学景观。
    Systemic sclerosis (SSc) and cryopyrin-associated periodic syndrome (CAPS) are distinct clinical entities belonging to the autoimmune and autoinflammatory diseases, respectively. The coexistence of the two entities has rarely been reported and is poorly characterized. Here, we described a case of a 38-year-old Japanese woman diagnosed with anti-centromere antibody-positive SSc and CAPS carrying the pathogenic mutation in the NLRP3 gene, with a detailed autoantibody profile by a high-throughput comprehensive protein array covering approximately 90% of the human transcriptome. The clinical manifestations of the patient were typical of both SSc and CAPS. Comprehensive autoantibody profiling identified 65 autoantibodies in the patient\'s serum and 78 autoantibodies in the serum of her daughter with CAPS, who carried the same NLRP3 mutation as the patient. SSc-associated autoantibodies (anti-DBT, anti- CENP-B, and anti-CENP-A) and anti-CD320 antibody were detected at high levels only in the patient\'s serum, while autoantibodies to the following four proteins were detected in the sera of both the patient and her daughter: TRIM21, LIMS1, CLIP4, and KAT2A. The TRRUST enrichment analysis identified NF-κB1 and RelA as overlapping key transcription factors that regulate the genes encoding proteins to which autoantibodies were detected in the patient and her daughter, therefore the autoantibody profile of the patient cannot be solely attributed to SSc, but may also be influenced by CAPS. Although autoimmune and autoinflammatory diseases are considered to be at opposite ends of the immunological spectrum, detailed autoantibody profiling may reveal a unique immunological landscape in an overlapping case of the two entities.
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  • 文章类型: Journal Article
    目的:系统性红斑狼疮(SLE)在患病率上显示出明显的女性偏倚。X染色体失活(XCI)是随机沉默一条X染色体以平衡46,XX雌性和46,XY雄性之间的基因表达的机制。尽管XCI预计会导致跨组织的镶嵌现象的随机模式,一些女性在免疫细胞中表现出明显的偏差,称为XCI-偏斜。我们测试了SLE女性的XCI是否异常,从而导致性二态性。
    方法:我们检测了181例女性SLE患者全血DNA中的XCI,796名女性健康对照和10对双胞胎不一致的SLE。使用回归模型和孪生内比较,我们评估了SLE对XCI的影响,细胞和遗传数据通过多基因评分来探索潜在的机制。
    结果:适应年龄的强大混杂因素,与对照组相比,SLE女性的XCI偏斜减少(p=1.3×10-5),在那些患有更严重疾病的人中效果最大。应用>80%的XCI阈值,我们在6.6%的SLE病例中观察到XCI-偏斜,而对照组为22%.这种差异不能用白细胞计数的差异来解释,SLE的药物或遗传易感性。相反,XCI偏斜与I型干扰素调节基因表达的生物标志物相关。
    结论:这些结果驳斥了目前关于自身免疫中XCI-偏斜的观点,并建议,在狼疮中,免疫细胞的XCI模式反映了疾病状态的影响,特别是干扰素信号,它们来源的造血干细胞。
    OBJECTIVE: Systemic lupus erythematosus (SLE) shows a marked female bias in prevalence. X chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to equalise gene expression between 46, XX females and 46, XY males. Though XCI is expected to result in a random pattern of mosaicism across tissues, some females display a significantly skewed ratio in immune cells, termed XCI-skew. We tested whether XCI was abnormal in females with SLE and hence contributes to sexual dimorphism.
    METHODS: We assayed XCI in whole blood DNA in 181 female SLE cases, 796 female healthy controls and 10 twin pairs discordant for SLE. Using regression modelling and intra-twin comparisons, we assessed the effect of SLE on XCI and combined clinical, cellular and genetic data via a polygenic score to explore underlying mechanisms.
    RESULTS: Accommodating the powerful confounder of age, XCI-skew was reduced in females with SLE compared with controls (p=1.3×10-5), with the greatest effect seen in those with more severe disease. Applying an XCI threshold of >80%, we observed XCI-skew in 6.6% of SLE cases compared with 22% of controls. This difference was not explained by differential white cell counts, medication or genetic susceptibility to SLE. Instead, XCI-skew correlated with a biomarker for type I interferon-regulated gene expression.
    CONCLUSIONS: These results refute current views on XCI-skew in autoimmunity and suggest, in lupus, XCI patterns of immune cells reflect the impact of disease state, specifically interferon signalling, on the haematopoietic stem cells from which they derive.
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  • 文章类型: Journal Article
    荨麻疹性血管炎是一种罕见的自身免疫性疾病,其特征是皮肤上持续的水肿丘疹和斑块持续超过24小时,常伴有关节疼痛和发热等全身症状。与普通荨麻疹不同,这种情况涉及小血管的炎症,导致更严重和持久的皮肤损伤,并倾向于留下瘀血样的外观。诊断具有挑战性,可能需要皮肤活检。与潜在的自身免疫性疾病相关,治疗包括使用抗组胺药和皮质类固醇等药物控制症状,解决免疫系统的功能障碍,并治疗任何并发的自身免疫性疾病。
    Urticarial vasculitis is a rare autoimmune disorder characterized by persistent edematous papules and plaques on the skin that last longer than 24 hours, often accompanied by systemic symptoms such as joint pain and fever. Unlike common urticaria, this condition involves inflammation of small blood vessels, leading to more severe and long-lasting skin lesions with a tendency to leave a bruiselike appearance. Diagnosis is challenging and may require a skin biopsy. Associated with underlying autoimmune diseases, treatment involves managing symptoms with medications such as antihistamines and corticosteroids, addressing the immune system\'s dysfunction, and treating any concurrent autoimmune conditions.
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  • 文章类型: Journal Article
    背景:尽管JAK3在各种自身免疫性疾病中具有重要作用,包括移植物抗宿主病(GVHD),一直缺乏专门研究用于GVHD的有效和选择性的JAK3抑制剂.在我们的临床前调查中,我们评估了一种名为CS12192的新型JAK3抑制剂,该抑制剂已经在自身免疫性疾病的临床研究中。
    方法:我们通过小鼠和人类细胞的混合淋巴细胞反应(MLR)评估了CS12192在GVHD中的功效,以及小鼠模型中的同种异体骨髓移植(BMT)。
    结果:CS12192,起始浓度为0.5μM,剂量依赖性地降低了小鼠同种异体MLR测定期间CD4+T细胞(p<0.05至p<0.0001)和CD8+T细胞(p<0.01至p<0.0001)中细胞因子TNF-α和IFN-γ的细胞内阳性。对于细胞因子的单阳性和双阳性都观察到了这种作用。此外,在三个不同的人类供体的MLR测定中,CS12192还显示出IFN-γ阳性CD4+T细胞(p<0.0001)和CD8+T细胞(p<0.01至p<0.0001)比例的剂量依赖性降低。此外,它抑制了小鼠MLR中的T细胞增殖(p<0.05至p<0.0001),但这种效应仅在一个人供体中观察到(p<0.001至p<0.0001)。此外,CS12192以40和80mg/kgBID的剂量显著提高了BMT模型的存活率,累计62天生存率为88.89%(p<0.01)和100%(p<0.001),分别,与泼尼松龙相比(p<0.05)。
    结论:CS12192是一部小说,有效和选择性的JAK3抑制剂显示出缓解急性GVHD的巨大潜力。
    BACKGROUND: Despite the significant role of JAK3 in various autoimmune diseases, including graft-versus-host disease (GVHD), there has been a lack of potent and selective JAK3 inhibitors specifically studied for GVHD. In our preclinical investigations, we evaluated a novel JAK3 inhibitor called CS12192, which is already undergoing clinical investigation in autoimmune diseases.
    METHODS: We evaluated the efficacy of CS12192 in GVHD through mixed lymphocyte reaction (MLR) in both mouse and human cells, as well as allogeneic bone marrow transplantation (BMT) in a murine model.
    RESULTS: CS12192, starting at a concentration of 0.5 μM, dose-dependently reduced the intracellular positivity for cytokines TNF-α and IFN-γ in CD4+ T cells (p < 0.05 to p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001) during mouse allogeneic MLR assays. This effect was observed for both single and double positivity of the cytokines. Moreover, In MLR assays with three different human donors, CS12192 also demonstrated a dose-dependent reduction in the proportion of IFN-γ positive CD4+ T cells (p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001). Additionally, it suppressed T cell proliferation in the mouse MLR (p < 0.05 to p < 0.0001), but this effect was observed in only one human donor (p < 0.001 to p < 0.0001). Furthermore, the administration of CS12192 at 40 and 80 mg/kg BID significantly improved the survival rate in the BMT model, resulting in cumulative 62-day survival rates of 88.89% (p < 0.01) and 100% (p < 0.001), respectively, compared with prednisolone (p < 0.05).
    CONCLUSIONS: CS12192 is a novel, potent and selective JAK3 inhibitor demonstrating great potential to mitigate acute GVHD.
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  • 文章类型: Journal Article
    背景:T辅助(Th)9细胞是独立于Th2细胞发育的Th细胞的新型亚群,其特征在于白细胞介素(IL)-9的分泌。研究表明Th9细胞参与各种疾病,如过敏性和肺部疾病(例如,哮喘,慢性阻塞性气道疾病,慢性鼻-鼻窦炎,鼻息肉,和肺发育不全),代谢性疾病(如,急性白血病,粒细胞白血病,乳腺癌,肺癌,黑色素瘤,胰腺癌),神经精神疾病(例如,阿尔茨海默病),自身免疫性疾病(例如,Graves病,克罗恩病,结肠炎,牛皮癣,系统性红斑狼疮,系统性硬皮病,类风湿性关节炎,多发性硬化症,炎症性肠病,特应性皮炎,湿疹),和传染病(例如,结核病,肝炎)。然而,关于它参与其他代谢的信息缺乏,神经精神病学,和传染病。
    目的:本研究旨在鉴定Th2向Th9细胞转化过程中显著差异改变的基因,和它们的调节microRNAs(miRs)来自公开可用的小鼠模型的基因表达综合数据集,使用计算机分析来解开疾病过程中涉及的各种致病途径。
    方法:使用从2个公开数据集(GSE99166和GSE123501)中鉴定的差异表达基因(DEGs),我们进行了功能富集和网络分析,以鉴定通路,蛋白质-蛋白质相互作用,miR-信使RNA关联,以及与Th2向Th9细胞转化相关的显著差异改变基因相关的疾病基因关联。
    结果:我们提取了260个常见的下调,236共同上调,和来自数据集GSE99166和GSE123501的表达谱的634个常见DEGs。共差异表达的IL,细胞因子,受体,和转录因子(TFs)富集在7个关键的京都百科全书的基因和基因组途径和基因本体论。我们构建了蛋白质-蛋白质相互作用网络,并预测了参与Th2至Th9分化途径的顶级调控miRs。我们还确定了各种代谢,过敏和肺部,神经精神病学,自身免疫,和传染病以及Th2到Th9的分化可能起关键作用的癌。
    结论:本研究确定了迄今为止尚未探索的Th9与疾病状态之间的可能关联。一些重要的IL,包括CCL1(趋化因子[C-C基序]配体1),CCL20(趋化因子[C-C基序]配体20),IL-13,IL-4,IL-12A,和IL-9;受体,包括IL-12RB1,IL-4RA(白介素9受体α),CD53(分化簇53),CD6(分化簇6),CD5(分化簇5),CD83(分化簇83),CD197(分化簇197),IL-1RL1(白细胞介素1受体样1),CD101(分化簇101),CD96(分化簇96),CD72(分化簇72),CD7(分化簇7),CD152(细胞毒性T淋巴细胞相关蛋白4),CD38(分化簇38),CX3CR1(趋化因子[C-X3-C基序]受体1),CTLA2A(细胞毒性T淋巴细胞相关蛋白2α),CTLA28和CD196(分化簇196);和TFs,包括FOXP3(叉头箱P3),IRF8(干扰素调节因子8),FOXP2(叉头箱P2),RORA(RAR相关孤儿受体α),AHR(芳烃受体),MAF(禽类肌膜膜纤维肉瘤癌基因同源物),SMAD6(SMAD家族成员6),JUN(Jun原癌基因),JAK2(Janus激酶2),EP300(E1A结合蛋白p300),ATF6(激活转录因子6),BTAF1(B-TFIIDTATA盒结合蛋白相关因子1),BAFT(碱性亮氨酸拉链转录因子),NOTCH1(神经源性位点缺口同源蛋白1),GATA3(GATA结合蛋白3),SATB1(富含AT的特殊序列结合蛋白1),BMP7(骨形态发生蛋白7),和PPARG(过氧化物酶体增殖物激活受体γ,能够在Th2向Th9细胞的转化中鉴定出显著的差异改变的基因。我们确定了一些可以针对DEG的常见miR。Th9在代谢性疾病中的作用研究的匮乏凸显了该领域的空白。我们的研究为探索Th9在各种代谢紊乱如糖尿病中的作用提供了理论基础。糖尿病肾病,高血压疾病,缺血性卒中,脂肪性肝炎,肝纤维化,肥胖,腺癌,胶质母细胞瘤和神经胶质瘤,胃恶性肿瘤,黑色素瘤,神经母细胞瘤,骨肉瘤,胰腺癌,前列腺癌,还有胃癌.
    BACKGROUND: T helper (Th) 9 cells are a novel subset of Th cells that develop independently from Th2 cells and are characterized by the secretion of interleukin (IL)-9. Studies have suggested the involvement of Th9 cells in variable diseases such as allergic and pulmonary diseases (eg, asthma, chronic obstructive airway disease, chronic rhinosinusitis, nasal polyps, and pulmonary hypoplasia), metabolic diseases (eg, acute leukemia, myelocytic leukemia, breast cancer, lung cancer, melanoma, pancreatic cancer), neuropsychiatric disorders (eg, Alzheimer disease), autoimmune diseases (eg, Graves disease, Crohn disease, colitis, psoriasis, systemic lupus erythematosus, systemic scleroderma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atopic dermatitis, eczema), and infectious diseases (eg, tuberculosis, hepatitis). However, there is a dearth of information on its involvement in other metabolic, neuropsychiatric, and infectious diseases.
    OBJECTIVE: This study aims to identify significant differentially altered genes in the conversion of Th2 to Th9 cells, and their regulating microRNAs (miRs) from publicly available Gene Expression Omnibus data sets of the mouse model using in silico analysis to unravel various pathogenic pathways involved in disease processes.
    METHODS: Using differentially expressed genes (DEGs) identified from 2 publicly available data sets (GSE99166 and GSE123501) we performed functional enrichment and network analyses to identify pathways, protein-protein interactions, miR-messenger RNA associations, and disease-gene associations related to significant differentially altered genes implicated in the conversion of Th2 to Th9 cells.
    RESULTS: We extracted 260 common downregulated, 236 common upregulated, and 634 common DEGs from the expression profiles of data sets GSE99166 and GSE123501. Codifferentially expressed ILs, cytokines, receptors, and transcription factors (TFs) were enriched in 7 crucial Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology. We constructed the protein-protein interaction network and predicted the top regulatory miRs involved in the Th2 to Th9 differentiation pathways. We also identified various metabolic, allergic and pulmonary, neuropsychiatric, autoimmune, and infectious diseases as well as carcinomas where the differentiation of Th2 to Th9 may play a crucial role.
    CONCLUSIONS: This study identified hitherto unexplored possible associations between Th9 and disease states. Some important ILs, including CCL1 (chemokine [C-C motif] ligand 1), CCL20 (chemokine [C-C motif] ligand 20), IL-13, IL-4, IL-12A, and IL-9; receptors, including IL-12RB1, IL-4RA (interleukin 9 receptor alpha), CD53 (cluster of differentiation 53), CD6 (cluster of differentiation 6), CD5 (cluster of differentiation 5), CD83 (cluster of differentiation 83), CD197 (cluster of differentiation 197), IL-1RL1 (interleukin 1 receptor-like 1), CD101 (cluster of differentiation 101), CD96 (cluster of differentiation 96), CD72 (cluster of differentiation 72), CD7 (cluster of differentiation 7), CD152 (cytotoxic T lymphocyte-associated protein 4), CD38 (cluster of differentiation 38), CX3CR1 (chemokine [C-X3-C motif] receptor 1), CTLA2A (cytotoxic T lymphocyte-associated protein 2 alpha), CTLA28, and CD196 (cluster of differentiation 196); and TFs, including FOXP3 (forkhead box P3), IRF8 (interferon regulatory factor 8), FOXP2 (forkhead box P2), RORA (RAR-related orphan receptor alpha), AHR (aryl-hydrocarbon receptor), MAF (avian musculoaponeurotic fibrosarcoma oncogene homolog), SMAD6 (SMAD family member 6), JUN (Jun proto-oncogene), JAK2 (Janus kinase 2), EP300 (E1A binding protein p300), ATF6 (activating transcription factor 6), BTAF1 (B-TFIID TATA-box binding protein associated factor 1), BAFT (basic leucine zipper transcription factor), NOTCH1 (neurogenic locus notch homolog protein 1), GATA3 (GATA binding protein 3), SATB1 (special AT-rich sequence binding protein 1), BMP7 (bone morphogenetic protein 7), and PPARG (peroxisome proliferator-activated receptor gamma, were able to identify significant differentially altered genes in the conversion of Th2 to Th9 cells. We identified some common miRs that could target the DEGs. The scarcity of studies on the role of Th9 in metabolic diseases highlights the lacunae in this field. Our study provides the rationale for exploring the role of Th9 in various metabolic disorders such as diabetes mellitus, diabetic nephropathy, hypertensive disease, ischemic stroke, steatohepatitis, liver fibrosis, obesity, adenocarcinoma, glioblastoma and glioma, malignant neoplasm of stomach, melanoma, neuroblastoma, osteosarcoma, pancreatic carcinoma, prostate carcinoma, and stomach carcinoma.
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