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Signal-transducing adaptor protein-2 modulates T-cell functions 信号转导衔接蛋白-2调节T细胞功能
Pub Date : 2022-12-27 DOI: 10.37349/ei.2022.00082
T. Matsuda, Yuto Sasaki, Kota Kagohashi, Kodai Saitoh, Y. Sekine, J. Kashiwakura, K. Oritani
Immune responses are orchestrated by controlling the initiation, magnitude, and duration of various signaling pathways. Adaptor proteins act as positive or negative regulators by targeting critical molecules of signaling cascades. Signal-transducing adaptor protein-2 (STAP-2) contains typical features of adaptor proteins, like a pleckstrin homology (PH) domain in the N-terminal region and a Src homology 2 (SH2) domain in the central region. STAP-2 binds to a variety of signaling or transcriptional molecules to control multiple steps of inflammatory/immune responses. STAP-2 enhances T-cell receptor (TCR)-mediated signaling via the association with TCR-proximal CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) and lymphocyte-specific protein tyrosine kinase (Lck). STAP-2 decreases adherence of T-cells to fibronectin (FN) through an association with focal adhesion kinase (Fak) and Casitas B-lineage Lymphoma (c-Cbl), and increases chemotaxis of T-cells toward stromal cell-derived factor-1α (SDF-1α) through interactions with Vav1 and Ras-related C3 botulinum toxin substrate 1 (Rac1). STAP-2 positively regulates activation-induced cell deathrough the association with Fas and caspase-8. This review describes the current knowledge of the roles of STAP-2 in T-cell-dependent immune responses and the possible clinical utility of STAP-2-targeting therapies.
免疫反应是通过控制各种信号通路的启动、大小和持续时间来协调的。衔接蛋白通过靶向信号级联的关键分子起到阳性或阴性调节因子的作用。信号转导衔接蛋白-2(STAP-2)包含衔接蛋白的典型特征,如N末端区域的pleckstring同源性(PH)结构域和中心区域的Src同源性2(SH2)结构域。STAP-2与多种信号传导或转录分子结合,以控制炎症/免疫反应的多个步骤。STAP-2通过与TCR近端CD3ζ免疫受体酪氨酸基激活基序(ITAMs)和淋巴细胞特异性蛋白酪氨酸激酶(Lck)的结合,增强T细胞受体(TCR)介导的信号传导。STAP-2通过与粘着斑激酶(Fak)和Casitas B系淋巴瘤(c-Cbl)的结合降低T细胞对纤连蛋白(FN)的粘附,并通过与Vav1和Ras相关的C3肉毒杆菌毒素底物1(Rac1)的相互作用增加T细胞对基质细胞衍生因子-1α(SDF-1α)的趋化性。STAP-2通过与Fas和胱天蛋白酶-8的结合正向调节活化诱导的细胞死亡。这篇综述描述了STAP-2在T细胞依赖性免疫反应中的作用以及STAP-2靶向疗法的可能临床应用的最新知识。
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引用次数: 0
Distributing human leukocyte antigen (HLA) database in histocompatibility: a shift in HLA data governance 在组织相容性中分布人类白细胞抗原(HLA)数据库:HLA数据管理的转变
Pub Date : 2022-11-01 DOI: 10.37349/ei.2022.00080
Sirine Sayadi, Venceslas Douillard, N. Vince, Mario Südholt, P. Gourraud
Aim: Human leukocyte antigen (HLA) population genetics has been a historical field centralizing data resource. HLA genetics databases typically facilitate access to frequencies of allele, haplotype, and genotype format information. Among many resources, the Allele Frequency Net Database (AFND) is a typical centralized repository that allows users to research and analyze immune gene frequencies in different populations around the world. With the massive increase in medical data and the strengthening of data governance laws, the proposal for a new distributed and secure model for the historical centralization method in population genetics has become important. In this paper, a new model of HLA population genetic resources, an alternative distributed version of HLA databases has been developed. It allows users to perform the same research and analysis with other remote sites without sharing their original data and monitoring data access.Methods: This new version uses the Master/Worker distributed model and offers distributed algorithms for the calculation of allelic frequencies, haplotypic frequencies and for individual genotypic calculations. The new model was evaluated on a distributed testbed for experiment-driven research Grid’5000 and has obtained good results of accuracy and execution time compared to the original centralized scheme used by researchers.Results: The results show that distributed algorithm applied to HLA population genetics resources enables usage control and enables enforcing the security framework of the data-owning institution. It gives the same results for all counting methods in population immunogenetics. With the same frequencies’ estimations, it yields a much quicker computation time in many cases, in particular for large samples.Conclusions: Distributing previously centralized resources is an interesting perspective enhancing better control of data sharing.
目的:人类白细胞抗原(HLA)群体遗传学是一个历史领域的集中数据资源。HLA遗传数据库通常有助于获取等位基因、单倍型和基因型格式信息的频率。在众多资源中,等位基因频率网络数据库(AFND)是一个典型的集中式存储库,允许用户研究和分析世界各地不同人群的免疫基因频率。随着医疗数据的大量增加和数据治理法规的加强,为群体遗传学中的历史集中式方法提出一种新的分布式和安全模型变得非常重要。本文提出了一种新的HLA群体遗传资源模型,即HLA数据库的替代分布式版本。它允许用户在不共享原始数据和监控数据访问的情况下与其他远程站点执行相同的研究和分析。方法:新版本采用Master/Worker分布模型,提供了计算等位基因频率、单倍型频率和个体基因型计算的分布式算法。在实验驱动研究网格5000的分布式测试平台上对新模型进行了评估,与研究人员使用的原始集中式方案相比,在精度和执行时间方面取得了良好的效果。结果:将分布式算法应用于HLA群体遗传资源,实现了对资源使用的控制,增强了数据拥有机构的安全框架。对群体免疫遗传学中各种计数方法给出了相同的结果。对于相同频率的估计,它在许多情况下产生更快的计算时间,特别是对于大样本。结论:分配以前集中的资源是一个有趣的视角,可以更好地控制数据共享。
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引用次数: 0
Fight fire with fire: the need for a vaccine based on intrinsic disorder and structural flexibility 以毒攻毒:需要一种基于内在无序和结构灵活性的疫苗
Pub Date : 2022-10-31 DOI: 10.37349/ei.2022.00079
V. Uversky
The absence of advancement in finding efficient vaccines for several human viruses, such as hepatitis C virus (HCV), human immunodeficiency virus type 1 (HIV-1), and herpes simplex viruses (HSVs) despite 30, 40, and even 60 years of research, respectively, is unnerving. Among objective reasons for such failure are the highly glycosylated nature of proteins used as primary vaccine targets against these viruses and the presence of neotopes and cryptotopes, as well as high mutation rates of the RNA viruses HCV and HIV-1 and the capability to establish latency by HSVs. However, the lack of success in utilization of the structure-based reverse vaccinology for these viruses is likely to be related to the presence of highly flexible and intrinsically disordered regions in human antibodies (Abs) and the major immunogens of HIV-1, HCV, and HSVs, their surface glycoproteins. This clearly calls for moving from the rational structure-based vaccinology to the unstructural vaccinology based on the utilization of tools designed for the analysis of disordered and flexible proteins, while looking at intrinsically disordered viral antigens and their interactions with intrinsically disordered/flexible Abs.
几种人类病毒,如丙型肝炎病毒(HCV)、人类免疫缺陷病毒1型(HIV-1)和单纯疱疹病毒(hsv),尽管分别进行了30年、40年甚至60年的研究,但在寻找有效疫苗方面缺乏进展,这令人不安。造成这种失败的客观原因包括:作为这些病毒的初级疫苗靶点的蛋白质的高度糖基化性质、新位体和隐位体的存在、HCV和HIV-1 RNA病毒的高突变率以及单纯疱疹病毒建立潜伏期的能力。然而,基于结构的反向疫苗学在这些病毒的应用上缺乏成功,可能与人抗体(Abs)和HIV-1、HCV和hsv的主要免疫原及其表面糖蛋白中存在高度灵活和内在无序的区域有关。这显然需要从基于合理结构的疫苗学转向基于利用分析无序和柔性蛋白的工具的非结构疫苗学,同时研究内在无序的病毒抗原及其与内在无序/柔性抗体的相互作用。
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引用次数: 0
Utilization of formalin-fixed paraffin-embedded specimens for microbiota characterization in cancer: utility and concern 利用甲醛固定石蜡包埋标本对癌症微生物群进行鉴定:实用性和关注点
Pub Date : 2022-10-31 DOI: 10.37349/ei.2022.00078
L. Di Gloria, E. Niccolai
Microbiome research has enormous potential in cancer research and the use of formalin-fixed paraffin-embedded (FFPE) tissues could offer many advantages. The tumor microenvironment represents a suitable niche for specific microbes and evidence proves the presence of an endogenous tumor microbiota, here referred to as oncobiota. Awareness of the oncobiota role in tumorigenesis could have a large influence on cancer care, in terms of diagnosis, prevention, and treatment. Moreover, understanding the microbial-related tumor microenvironment, and its influence on tumor immune response and cancer cells will help define important pathogenetic mechanisms in cancer starting or progression. Routine collection of histopathological FFPE samples provides a large availability of specimens essential for affordable and impactful retrospective analyses and for getting robust statistical results. The FFPE tissues are common in the analysis of tumor biopsies including the tumor microbiota characterization which has an important role in the modulation of our immune system and consequently of tumor cells. However, the microbiota analysis starting from FFPE tissues presents methodological pitfalls and limits that may negatively affect the oncobiota research. After examining the methodological and analytical difficulties of this approach, this work seeks to offer workable solutions to promote that research area.
微生物组研究在癌症研究中具有巨大的潜力,使用甲醛固定石蜡包埋(FFPE)组织可以提供许多优势。肿瘤微环境代表了特定微生物的合适生态位,有证据证明存在内源性肿瘤微生物群,这里称为肿瘤生物群。认识到肿瘤生物群在肿瘤发生中的作用可能会对癌症的诊断、预防和治疗产生重大影响。此外,了解微球相关的肿瘤微环境及其对肿瘤免疫反应和癌症细胞的影响,将有助于确定癌症开始或发展的重要发病机制。组织病理学FFPE样本的常规收集提供了大量样本,这对于负担得起且有影响力的回顾性分析和获得可靠的统计结果至关重要。FFPE组织在肿瘤活检的分析中很常见,包括肿瘤微生物群的特征,这在我们的免疫系统以及肿瘤细胞的调节中起着重要作用。然而,从FFPE组织开始的微生物群分析存在方法上的缺陷和局限性,可能会对肿瘤生物群研究产生负面影响。在研究了这种方法的方法和分析困难后,这项工作试图提供可行的解决方案来促进这一研究领域。
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引用次数: 1
Natural killer cell-mediated immunopathology in recurrent pregnancy losses 自然杀伤细胞介导的免疫病理在复发性妊娠损失
Pub Date : 2022-10-30 DOI: 10.37349/ei.2022.00077
T. Luu, L. Alsubki, Katherine Wolf, Amy Thees, U. Ganieva, S. Dambaeva, K. Beaman, J. Kwak‐Kim
Natural killer (NK) cells have a dual role in human reproduction for maternal-fetal tolerance and protection from infection. During the ovarian cycle and pregnancy, peripheral NK (pNK) and uterine NK (uNK) cells dynamically change their proportions and cytotoxicities to prepare and accommodate invading trophoblast and maintain pregnancy. However, dysregulated pNK and uNK cell proportions and cytotoxic activities have been associated with aberrant spiral artery remodeling and trophoblast invasion, leading to implantation failures and recurrent pregnancy losses (RPLs). This review will focus on the role of NK cells in RPLs reviewing the ontogeny of NK cells, changes in pNK and uNK cell levels, and activities during the ovarian cycle, normal pregnancy, and RPL. In addition, the immunopathological role of NK cells in endometrial/decidual vascular development and killer immunoglobin-like receptor (KIR) and human leukocyte antigen (HLA)-C interactions are discussed.
自然杀伤细胞(NK)在人类生殖中具有母婴耐受和保护免受感染的双重作用。在卵巢周期和妊娠期间,外周NK(pNK)和子宫NK(uNK)细胞动态改变其比例和细胞毒性,以准备和适应入侵的滋养层并维持妊娠。然而,pNK和uNK细胞比例失调和细胞毒性活性与异常的螺旋动脉重塑和滋养层侵袭有关,导致植入失败和复发性妊娠损失(RPL)。这篇综述将集中于NK细胞在RPL中的作用,回顾NK细胞的个体发生、pNK和uNK细胞水平的变化以及卵巢周期、正常妊娠和RPL期间的活动。此外,还讨论了NK细胞在子宫内膜/蜕膜血管发育中的免疫病理作用以及杀伤性免疫球蛋白样受体(KIR)和人类白细胞抗原(HLA)-C相互作用。
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引用次数: 0
Do endometrial immune changes with age prior to menopause compromise fertility in women? 更年期前子宫内膜免疫随年龄的变化会影响女性的生育能力吗?
Pub Date : 2022-10-29 DOI: 10.37349/ei.2022.00076
Mickey V. Patel, Zheng Shen, C. Wira
Menopause signals the end of the reproductive period in women. However, fertility and fecundity decrease with increasing age prior to menopause demonstrating that changes in the premenopausal female reproductive tract (FRT) are already occurring that negatively impact reproductive success. The effects of age on the endometrium are poorly understood, in contrast to the ovary where changes occur with increasing age that negatively affect successful reproduction. The endometrial immune system is essential for generating a receptive endometrium, but the link between the immune and reproductive systems in the endometrium in the years prior to menopause has not been well-defined. Since the endometrial immune system is tightly regulated to maximize reproductive success and pathogen protection, changes in immune function with increasing premenopausal age have the potential to impact reproduction.
更年期标志着女性生殖期的结束。然而,随着绝经前年龄的增加,生育能力和繁殖力下降,这表明绝经前女性生殖道(FRT)的变化已经发生,对生殖成功产生了负面影响。年龄对子宫内膜的影响尚不清楚,而卵巢则随着年龄的增长而发生变化,从而对成功繁殖产生负面影响。子宫内膜免疫系统对产生接受性子宫内膜至关重要,但更年期前几年子宫内膜的免疫系统和生殖系统之间的联系尚不明确。由于子宫内膜免疫系统受到严格调节,以最大限度地提高生殖成功率和病原体保护,因此随着绝经前年龄的增加,免疫功能的变化有可能影响生殖。
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引用次数: 1
The progression of sepsis from physiologic systemic inflammatory response to immune dysregulation due to life-threatening infections 脓毒症的进展,从生理性全身炎症反应到免疫失调,由于危及生命的感染
Pub Date : 2022-10-25 DOI: 10.37349/ei.2022.00075
Nicholas J Daering, M. Al-Hasan
Sepsis was defined in 1991 by the systemic inflammatory response syndrome (SIRS) criteria which consisted mostly of physiologic responses to infection or inflammation (fever, tachycardia, tachypnea, and leukocytosis). These criteria were initially proposed to identify patients with gram-negative bloodstream infection (BSI). However, most patients with BSI are not critically ill at initial presentation using objective clinical scores for acute severity of illness, such as the Pitt bacteremia score (PBS). Lack of specificity and low positive predictive value (PPV) are other pitfalls of the SIRS criteria. Moreover, the implementation of sepsis interventions based on this outdated definition failed to improve patients’ outcomes and in some settings was associated with increased use of broad-spectrum antibiotics and Clostridioides difficile (C. difficile) infection. In 2016, sepsis was redefined as a dysregulatory host response to life-threatening infections using quick sequential organ failure assessment (qSOFA) score. The presence of two of three bedside clinical variables (hypotension, respiratory distress, and altered mental status) that have consistently predicted mortality in patients with infections now constitutes sepsis. The scientific debate continues in the medical literature regarding the performance of the new criteria. Some medical professionals and quality organizations consider these changes to the sepsis definition too revolutionary and are resistant to altering existing medical practice. This narrative review presents infection as a continuum from localized to systemic infection (pre-sepsis) with the potential progression into sepsis and septic shock if appropriate antibiotic therapy and source control are delayed. The review assesses host and microbial factors that may influence the rate of progression through the sepsis cascade and proposes diagnostic considerations and management decisions at each step of the way. It emphasizes the need to utilize precision medicine concepts in selecting empirical antibiotic therapy based on patient-specific risk factors for infections due to resistant bacteria and potential benefits from appropriate therapy across the sepsis spectrum.
1991年,全身性炎症反应综合征(SIRS)标准定义了脓毒症,该标准主要包括对感染或炎症的生理反应(发烧、心动过速、呼吸急促和白细胞增多)。这些标准最初被提出用于识别革兰氏阴性血流感染(BSI)患者。然而,大多数BSI患者在首次就诊时,使用客观的临床急性严重程度评分,如皮特菌血症评分(PBS),并不是危重症。缺乏特异性和低阳性预测值(PPV)是SIRS标准的其他缺陷。此外,基于这一过时定义的脓毒症干预措施的实施未能改善患者的预后,在某些情况下还与广谱抗生素的使用增加和艰难梭菌(C. difficile)感染有关。2016年,使用快速顺序器官衰竭评估(qSOFA)评分,败血症被重新定义为对危及生命的感染的失调宿主反应。三个床边临床变量中的两个(低血压、呼吸窘迫和精神状态改变)一直预测感染患者的死亡率,现在构成败血症。关于新标准的表现,医学文献中的科学争论仍在继续。一些医疗专业人员和质量组织认为这些对败血症定义的改变过于革命性,并且抵制改变现有的医疗实践。这篇叙述性综述认为感染是一个连续体,从局部感染到全身性感染(脓毒症前),如果延迟适当的抗生素治疗和源控制,可能会进展为脓毒症和感染性休克。该综述评估了宿主和微生物因素,这些因素可能会影响脓毒症级联的进展速度,并在每个步骤中提出诊断考虑和管理决策。它强调在选择经验性抗生素治疗时,需要利用精确医学概念,根据耐药细菌引起的感染的患者特异性风险因素和脓毒症范围内适当治疗的潜在益处。
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引用次数: 0
Immune responses to SARS-CoV-2 infection and COVID-19 vaccines 对SARS-CoV-2感染和新冠肺炎疫苗的免疫反应
Pub Date : 2022-09-21 DOI: 10.37349/ei.2022.00074
B. R. Sharma, P. Ravindra
Coronavirus disease 2019 (COVID-19) is currently a major public health concern causing devastating sociological, economic, and psychological damage to livelihood all over the world. The most intense severity of COVID-19 is not only acute respiratory distress syndrome (ARDS), it also causes multi-organ failure, the post-infection secondary effect as well as death. The fast-mutating ability and high transmissibility rate of the virus cause emergence of the new variants and also the occurrence of breakthrough infections. Evidence suggests that vaccination against COVID-19 has been effective at preventing the severity of illness, hospitalization, and death. The efficacy of vaccines depends on multiple factors including the host’s ability to mount a robust and sustainable immune response, the virus’s ability to mutate its genome, and programmatic factors such as vaccine dose, storage, dosing schedules, etc. In this article, an overview of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, its pathogenesis, host immune responses to infection, and different type of COVID-19 vaccines, including vaccine efficacy and adverse effects are described.
2019冠状病毒病(新冠肺炎)目前是一个主要的公共卫生问题,对世界各地的生计造成了毁灭性的社会、经济和心理损害。新冠肺炎最严重的不仅是急性呼吸窘迫综合征(ARDS),它还导致多器官衰竭、感染后的继发性影响以及死亡。病毒的快速变异能力和高传播率导致了新变种的出现,也导致了突破性感染的发生。有证据表明,接种新冠肺炎疫苗可有效预防疾病、住院和死亡的严重程度。疫苗的效力取决于多种因素,包括宿主产生强大和可持续免疫反应的能力、病毒基因组突变的能力,以及疫苗剂量、储存、给药时间表等程序性因素,描述了宿主对感染的免疫反应,以及不同类型的新冠肺炎疫苗,包括疫苗效力和不良反应。
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引用次数: 1
Chemokines and nanomaterials: interaction for useful immune-applications 趋化因子和纳米材料:用于免疫应用的相互作用
Pub Date : 2022-08-31 DOI: 10.37349/ei.2022.00073
G. Bardi
Chemokines are homeostatic or inflammatory small proteins regulating immune cell migration and are structurally characterized by cysteine disulfide bridges. Around 50 human chemokines binding almost 20 seven-transmembrane G-protein coupled receptors have been discovered. The finding that two of them were the main human immunodeficiency virus (HIV) co-receptors intensified the research on the binding mechanism to block the viral entrance. Blockade of chemokine/chemokine receptor signaling ultimately modulates cell migration, then immune responses. Particular nanotechnologies can be designed to interfere with chemokine signaling or to exploit the ligand-receptor interaction. Surface chemical modification of nanomaterials with chemokines or specific peptides can find several applications in bio-medicine, from tissue-specific drug delivery to reduced cell migration in pathological conditions. Recent highlights on peculiar chemokine-nanoparticle design and their potential to modulate immune responses will be discussed.
趋化因子是调节免疫细胞迁移的稳态或炎性小蛋白,其结构特征为半胱氨酸二硫桥。已发现约50种人类趋化因子结合近20种七跨膜g蛋白偶联受体。发现其中两种是人类免疫缺陷病毒(HIV)的主要共受体,加强了对阻断病毒进入的结合机制的研究。趋化因子/趋化因子受体信号的阻断最终调节细胞迁移,进而调节免疫应答。可以设计特定的纳米技术来干扰趋化因子信号传导或利用配体-受体相互作用。用趋化因子或特定肽对纳米材料进行表面化学修饰可以在生物医学中找到几种应用,从组织特异性药物递送到病理条件下减少细胞迁移。将讨论最近在特殊趋化因子纳米颗粒设计及其调节免疫反应的潜力方面的亮点。
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引用次数: 1
A non-redundant role of complement protein C1q in normal and adverse pregnancy 补体蛋白C1q在正常和不良妊娠中的非冗余作用
Pub Date : 2022-08-31 DOI: 10.37349/ei.2022.00072
C. Agostinis, A. Mangogna, A. Balduit, U. Kishore, R. Bulla
Complement component 1q (C1q) is the recognition molecule of the classical pathway of the complement system that can bind to an array of closely spaced antigen-bound immunoglobulin G (IgG) and IgM antibodies. In addition to its involvement in defence against a range of pathogens and clearance of apoptotic and necrotic cells, C1q has also been implicated in immune and non-immune homeostasis. C1q is locally produced by immune cells such as monocytes, macrophages, and dendritic cells. C1q is also synthesized by decidual endothelial cells, thus acting as a link between decidual cells and trophoblasts, as well as contributing to the remodelling of spiral arteries. Furthermore, C1q is produced by the extravillous trophoblasts (EVTs) invading the decidua. As a pro-angiogenic molecule, C1q is also important for normal placentation processes as it favors the active angiogenesis in the developing decidua. These observations have been validated by C1q gene knock-out mice which showed pre-eclampsia (PE)-like symptoms, characterized by hypertension, proteinuria, glomerular endotheliosis, and increased soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, and increased oxidative stress. The role of C1q in normal and adverse human pregnancy is being studied extensively due to its absence or low level as a likely precipitating factor for the development of PE.
补体成分1q (C1q)是补体系统经典途径的识别分子,可以结合一系列紧密间隔的抗原结合免疫球蛋白G (IgG)和IgM抗体。除了参与防御一系列病原体和清除凋亡和坏死细胞外,C1q还与免疫和非免疫稳态有关。C1q由免疫细胞如单核细胞、巨噬细胞和树突状细胞局部产生。C1q也可由蜕膜内皮细胞合成,作为蜕膜细胞与滋养层细胞之间的纽带,参与螺旋动脉的重塑。此外,C1q是由侵入蜕膜的胞外滋养细胞(evt)产生的。作为一种促血管生成分子,C1q对正常胎盘过程也很重要,因为它有利于发育中的蜕膜中活跃的血管生成。这些观察结果被C1q基因敲除的小鼠证实,这些小鼠表现出先兆子痫(PE)样症状,其特征是高血压、蛋白尿、肾小球内皮增生、可溶性膜样酪氨酸激酶-1 (sFlt-1)/胎盘生长因子(PlGF)比例增加,氧化应激增加。C1q在正常和不良妊娠中的作用正在被广泛研究,因为它缺乏或低水平可能是PE发展的促成因素。
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引用次数: 0
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Exploration of immunology
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