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Understanding sepsis-induced immunosuppression and organ dysfunctions: from immunosuppression to immunotherapy 了解败血症诱导的免疫抑制和器官功能障碍:从免疫抑制到免疫治疗
Pub Date : 2022-08-29 DOI: 10.37349/ei.2022.00070
D. Gupta, T. Sinha, Richa Pathak, S. Bhoi, D. Rao
Sepsis is a life-threatening condition caused by dysregulated host immune response to infection, leading to persistent inflammation followed by immunosuppression. Sepsis represents a substantial global health problem owing to protracted inflammation, immune suppression, and susceptibility to nosocomial infections. Despite continuing progress in the development of antibiotics, fluid resuscitation, and other supportive care therapies, no specific immunomodulatory drugs or immunotherapeutic adjuncts for the treatment of sepsis are available to date. The advances in tertiary care facilities and patient care have improved the survival of sepsis patients in the initial hyper-inflammatory phase of sepsis. However, the majority of sepsis patients succumb later due to prolong immunosuppression. The sepsis-induced immune dysregulation and its long-term effects on mortality are under meticulous investigations that are still poorly defined. Sepsis leads to the impaired functions of the innate and adaptive immune systems. The exhaustion of T cells, reduced expression of human leukocytes antigen (HLA)-DR on monocytes, and induced uncontrolled apoptosis of immune cells have been reported as hallmark features of sepsis. Sepsis-induced immune cell apoptosis of immune cells is a primary contributing factor to the immunosuppression in sepsis. Preclinical studies have identified several new therapeutic targets for therapy in sepsis, including monoclonal antibodies (Abs) and anti-apoptotic agents to reduce T cells exhaustion, immune cells apoptosis, and restoring immune cells functions. Recent studies have centered on immune-modulatory therapy. The review article will focus solely on sepsis’ effects on innate and adaptive cells functions that contribute to immunosuppression. Finally, it is discussed how immune cells responsible for immunosuppression might be directly targeted to provide potential therapeutic benefits in treating sepsis and improving long-term survival.
脓毒症是一种危及生命的疾病,由宿主对感染的免疫反应失调引起,导致持续的炎症,随后是免疫抑制。脓毒症是一个严重的全球性健康问题,原因是长期炎症、免疫抑制和对医院感染的易感性。尽管抗生素、液体复苏和其他支持性护理疗法的发展不断取得进展,但迄今为止还没有用于治疗败血症的特异性免疫调节药物或免疫治疗辅助药物。三级医疗设施和患者护理的进步提高了脓毒症患者在脓毒症初始高炎症期的生存率。然而,大多数败血症患者由于免疫抑制延长而死亡。败血症引起的免疫失调及其对死亡率的长期影响正在进行细致的研究,但仍然没有明确的定义。脓毒症导致先天和适应性免疫系统功能受损。T细胞的衰竭,单核细胞上人类白细胞抗原(HLA)-DR的表达减少,以及诱导免疫细胞不受控制的凋亡已被报道为败血症的标志特征。脓毒症诱导的免疫细胞凋亡是脓毒症免疫抑制的主要因素。临床前研究已经确定了几种新的败血症治疗靶点,包括单克隆抗体(Abs)和抗凋亡药物,以减少T细胞衰竭,免疫细胞凋亡,恢复免疫细胞功能。最近的研究集中在免疫调节疗法上。这篇综述文章将只关注脓毒症对先天和适应性细胞功能的影响,这些功能有助于免疫抑制。最后,讨论了如何直接靶向免疫抑制细胞,以提供治疗败血症和提高长期生存率的潜在治疗效益。
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引用次数: 0
The human microbiome and the tumor microenvironment 人类微生物组与肿瘤微环境
Pub Date : 2022-08-27 DOI: 10.37349/ei.2022.00069
Joseph F. Murphy
The human microbiome has emerged as an intriguing field of scientific research. Its role in human physiology impacts both health and disease, contributing to the enhancement or impairment of metabolic and immune functions. Sometimes referred to as our body’s “second genome”, the alteration of the microbiome’s bacterial ecology (dysbiosis), is linked to increasing numbers of illnesses, including cancer. The tumor microenvironment (TME) is the environment in which tumors grow and modulate the tumorigenic process depending on a myriad of distinct factors, including cell types, vascular system, and cytokines. Given the emerging relationship between the microbiome and the TME, this perspective aims to distill some of the key factors regulating the crosstalk between the microbiome and the TME. It also outlines why manipulating the microbiome may be a feasible strategy for anti-cancer therapy.
人类微生物组已经成为一个有趣的科学研究领域。它在人体生理中的作用影响健康和疾病,有助于增强或损害代谢和免疫功能。微生物群细菌生态的改变(生态失调)有时被称为我们身体的“第二基因组”,与包括癌症在内的越来越多的疾病有关。肿瘤微环境(tumor microenvironment, TME)是肿瘤生长和调节肿瘤发生过程的环境,这取决于无数不同的因素,包括细胞类型、血管系统和细胞因子。鉴于微生物组和TME之间的新兴关系,本观点旨在提炼出调节微生物组和TME之间串扰的一些关键因素。它还概述了为什么操纵微生物组可能是抗癌治疗的可行策略。
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引用次数: 0
γδ T cells: a sparkling star for clinical immunotherapy γδ T细胞:临床免疫治疗中一颗闪亮的明星
Pub Date : 2022-08-26 DOI: 10.37349/ei.2022.00066
Jiamian Zheng, Xuan Jiang, Haotian Zhao, Wandi Wang, Xiuli Wu, Zhenyi Jin
Human γδ T cells are unconventional lymphocytes that function in innate and adaptive immune responses and immunosurveillance. These cells show potent cytotoxicity against tumor cells in a major histocompatibility complex unrestricted manner and have recently gained considerable attention as a sparkling star for clinical immunotherapy. Clinical immunotherapy trials with activated γδ T cells are tolerated well. However, clinical benefits are still unsatisfactory. Therefore, anti-tumor effects need to further increase the cytotoxicity of γδ T cells via several mechanisms, including the novel nitrogen-containing bisphosphonate products, adjuvant use with a bispecific antibody and chimeric antigen receptor, co-immunotherapy with γδ T cells plus immune checkpoint inhibitors, and adoptive immunotherapy with Vδ1 T cells and T cells engineered to express a defined γδ T cell receptor. Here, this article describes the crucial role of γδ T cells in anti-tumor immunity, concludes transduction strategies and summarizes the different development of novel approaches for clinical applications and cancer immunotherapy, which may be effective in overcoming current therapeutic limitations.
人γδ T细胞是一种非常规淋巴细胞,在先天性和适应性免疫反应和免疫监视中起作用。这些细胞以一种主要的组织相容性复合物不受限制的方式对肿瘤细胞表现出强大的细胞毒性,最近作为临床免疫治疗的一颗闪亮的明星受到了相当大的关注。活化γδ T细胞的临床免疫治疗试验耐受性良好。然而,临床疗效仍不令人满意。因此,抗肿瘤作用需要通过多种机制进一步提高γδ T细胞的细胞毒性,包括新型含氮双膦酸盐产物、双特异性抗体和嵌合抗原受体的辅助使用、γδ T细胞加免疫检查点抑制剂的联合免疫治疗、Vδ1 T细胞和表达特定γδ T细胞受体的T细胞的过继免疫治疗。本文介绍了γδ T细胞在抗肿瘤免疫中的重要作用,总结了转导策略,并总结了临床应用和癌症免疫治疗新方法的不同发展,这些新方法可能有效地克服当前治疗的局限性。
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引用次数: 0
Immune network operations in COVID-19 COVID-19中的免疫网络操作
Pub Date : 2022-08-26 DOI: 10.37349/ei.2022.00068
J. Burgos-Salcedo
The immune system, whose nature lies in being a complex network of interactions, lends itself well to being represented and studied using graph theory. However, it should be noted that although the formalization of models of the immune system is relatively recent, the medical use of its signaling network structure has been carried out empirically for centuries in vaccinology, immunopathology, and clinical immunology, as evidenced by the development of effective vaccines, the management of transplant rejection, the management of allergies, and the treatment of certain types of cancer and autoimmune diseases. A network optimization analogy is proposed through the employment of the system dynamic formalism of causal loop diagrams (CLDs), where current network operations (also known as NetOps) in information technology (IT), are interpreted as immune NetOps in coronavirus disease 2019 (COVID-19) treatment. Traffic shaping corresponds to signaling pathway modulation by immunosuppressors. Data caching corresponds to the activation of innate immunity by application of Bacillus Calmette-Guerin (BCG) and other vaccines. Data compression corresponds with the activation of adaptative immune response by vaccination with the actual approved COVID-19 vaccines. Buffer tuning corresponds with concurrent activation of innate and adaptative or specialized immune cells and antibodies that attack and destroy foreign invaders by trained immunity-based vaccines to develop. The present study delineates some experimental extensions and future developments. Given the complex communication architecture of signal transduction in the immune system, it is apparent that multiple parallel pathways influencing and regulating each other are not the exception but the norm. Thus, the transition from empirical immune NetOps to analytical immune NetOps is a goal for the near future in biomedicine.
免疫系统的本质是一个复杂的相互作用网络,它很适合用图论来表示和研究。然而,应该指出的是,尽管免疫系统模型的形式化是相对较新的,但其信号网络结构的医学应用已经在疫苗学、免疫病理学和临床免疫学中进行了几个世纪的经验,如有效疫苗的开发、移植排斥反应的管理、过敏的管理以及某些类型的癌症和自身免疫性疾病的治疗。通过使用因果循环图(CLDs)的系统动态形式化,提出了一个网络优化类比,其中信息技术(IT)中的当前网络操作(也称为NetOps)被解释为2019冠状病毒病(COVID-19)治疗中的免疫NetOps。交通整形对应于免疫抑制因子对信号通路的调节。数据缓存对应于应用卡介苗和其他疫苗激活先天免疫。数据压缩与接种实际批准的COVID-19疫苗激活适应性免疫反应相对应。缓冲调节与先天和适应性或特化免疫细胞和抗体的同时激活相对应,这些细胞和抗体通过训练有素的免疫疫苗来攻击和摧毁外来入侵者。本研究描述了一些实验的扩展和未来的发展。鉴于免疫系统中信号转导的复杂通信结构,很明显,多个平行通路相互影响和调节不是例外,而是常态。因此,从经验性免疫NetOps过渡到分析性免疫NetOps是生物医学不久的将来的目标。
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引用次数: 0
Contribution of immunology to build precision medicine in reproduction: present and future 免疫学对生殖精准医学建设的贡献:现在和未来
Pub Date : 2022-08-26 DOI: 10.37349/ei.2022.00067
A. Kazhalawi, M. Petitbarat, M. Rahmati, N. Lédée
Infertility affects millions of people of reproductive age. The failure of a blastocyst to implant is a leading cause of psychological distress. It became increasingly evident that an effective immune dialogue occurs at each step in the fluids surrounding the oocyte, the spermatozoa, the embryo, or the endometrium. Exploring and deciphering this dialogue could potentially help understand why 50% of healthy euploid blastocysts fail to implant. Introducing immunology into reproductive medicine requires a change of mindset to bring immune hypothesis to clinical applications. Implantation of an embryo requires a prepared uterus in order to dialogue with the embryo, which is able to express and repair itself. Exploring the uterine immune profile of patients with previous implantation failures (IF) or recurrent miscarriages (RM) has already been developed and is under evaluation as a precision tool to equilibrate the uterine environment before implantation to increase the subsequent live birth rate after the embryo transfer. Immunology may also be fundamental in the future to identify through non-invasive procedure the competence of oocytes or embryos through reliable immune biomarkers quantified in follicular fluids or embryo supernatants during the in vitro fertilization (IVF) process. Non-invasive biomarkers would allow physicians to identify competent oocytes or embryos based on their ability to communicate with the mother and their energetic potential for all the self-repair processes that should occur during the preimplantation and the implantation period. This area of research is only beginning.
不孕不育影响着数以百万计的育龄人口。囊胚植入失败是造成心理困扰的主要原因。越来越明显的是,在卵母细胞、精子、胚胎或子宫内膜周围的液体中,每一步都发生了有效的免疫对话。探索和破译这种对话可能有助于理解为什么50%的健康整倍体囊胚不能植入。将免疫学引入生殖医学需要转变观念,将免疫假说引入临床应用。胚胎的植入需要一个准备好的子宫,以便与能够表达和自我修复的胚胎对话。探索既往着床失败(IF)或复发性流产(RM)患者的子宫免疫特征已经被开发出来,并且正在评估作为一种精确工具来平衡着床前的子宫环境,以增加胚胎移植后的后续活产率。在体外受精(IVF)过程中,通过在卵泡液或胚胎上清液中量化可靠的免疫生物标志物,通过无创程序识别卵母细胞或胚胎的能力,免疫学也可能是基础。非侵入性生物标志物将使医生能够根据卵母细胞与母亲的沟通能力以及它们在着床前和着床期间应该发生的所有自我修复过程中的能量潜力来识别有能力的卵母细胞或胚胎。这一领域的研究才刚刚开始。
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引用次数: 0
Uterine natural killer cells and successful pregnancy: from mouse experiments to human physiology 子宫自然杀伤细胞与成功妊娠:从小鼠实验到人体生理学
Pub Date : 2022-08-25 DOI: 10.37349/ei.2022.00065
M. Faas
Uterine natural killer (uNK) cells, a specific type of natural killer (NK) cells, are important cells at the foeto-maternal interface in humans as well as in mice. uNK cells are part of the innate lymphoid cells group 1. Especially in the mouse, but also in the rat, many in vivo studies have been performed to evaluate the role of uNK cells in placental development. These studies have shown that uNK cells are not indispensable to pregnancy, but that they play an important role in optimal decidual angiogenesis in early pregnancy, trophoblast invasion and spiral artery remodelling in the mouse placenta. Based on the mouse studies, various in vitro studies, as well as immunohistological studies of the human placenta from elective abortions, have shown that uNK cells have similar functions in the human placenta. In the present narrative review, the role of the uNK cells in the development of the mouse and rat placenta will be discussed first. Thereafter, studies on the role of human uNK cells in the human placenta will be reviewed and these studies will be discussed in the light of the knowledge on mouse uNK cells.
子宫自然杀伤细胞(uNK)是一种特殊类型的自然杀伤细胞(NK),是人类和小鼠胎母界面的重要细胞。uNK细胞是先天淋巴样细胞组1的一部分。特别是在小鼠和大鼠中,已经进行了许多体内研究来评估uNK细胞在胎盘发育中的作用。这些研究表明,uNK细胞并非妊娠不可缺少的细胞,但它们在妊娠早期最佳蜕膜血管生成、滋养细胞侵袭和小鼠胎盘螺旋动脉重构中发挥着重要作用。基于小鼠研究,各种体外研究以及选择性流产人胎盘的免疫组织学研究表明,uNK细胞在人胎盘中具有类似的功能。在目前的叙述回顾中,uNK细胞在小鼠和大鼠胎盘发育中的作用将首先讨论。接下来,我们将回顾关于人类uNK细胞在人胎盘中的作用的研究,并结合小鼠uNK细胞的知识对这些研究进行讨论。
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引用次数: 1
Pathogenesis of the obstetric antiphospholipid syndrome: the key role of beta 2 glycoprotein I 产科抗磷脂综合征的发病机制:β2糖蛋白I的关键作用
Pub Date : 2022-08-19 DOI: 10.37349/ei.2022.00064
P. Meroni, C. Grossi, F. Tedesco
Antiphospholipid syndrome (APS) is defined by recurrent pregnancy morbidity and/or vascular thrombosis associated with the persistent presence of antibodies against anionic phospholipid-binding proteins. Beta 2 glycoprotein I (β2GPI) and prothrombin (PT) are the major antigens for antiphospholipid antibodies (aPL) detectable by functional coagulation [lupus anticoagulant (LA)] or solid-phase assays [anti-β2GPI-dependent cardiolipin (aCL) and anti-β2GPI]. β2GPI-dependent aPL are responsible for the positivity of the three classification laboratory criteria. While medium/high titers of antibodies against β2GPI are risk factors for both the vascular and the obstetric manifestations of APS, persistent low titers are also associated with pregnancy complications. There is evidence from animal models of aPL-dependent fetal loss and from in vitro systems that β2GPI-dependent aPL can be pathogenic. β2GPI is physiologically found in large quantities at the placental level being available for the specific antibodies circulating in the maternal blood. Once bound to the protein, the antibodies trigger a local inflammation via the activation of the complement cascade and affect trophoblast and decidual function. The final result is represented by defective placentation, while thrombotic events are apparently less important. β2GPI is a pleiotropic molecule with scavenging properties towards several molecules including apoptotic material and displays anti-oxidant activity. These functions may explain the β2GPI placental localization in an area of intensive tissue remodeling and low oxygen tension. Since β2GPI interacts also with the complement and the coagulation cascade, its binding with specific antibodies may affect the physiology of placentation in several ways.
抗磷脂综合征(APS)是指与持续存在抗阴离子磷脂结合蛋白抗体相关的复发性妊娠发病率和/或血管血栓形成。β2糖蛋白I(β2GPI)和凝血酶原(PT)是通过功能性凝血[狼疮抗凝血剂(LA)]或固相分析[抗β2GPI依赖性心磷脂(aCL)和抗β2GPI]检测到的抗磷脂抗体(aPL)的主要抗原。β2GPI依赖性aPL是三种分类实验室标准阳性的原因。虽然针对β2GPI的中/高滴度抗体是APS血管和产科表现的危险因素,但持续的低滴度抗体也与妊娠并发症有关。来自aPL依赖性胎儿丢失的动物模型和体外系统的证据表明,β2GPI依赖性aPL可能具有致病性。在生理学上,β2GPI在胎盘水平上大量存在,可用于母体血液中循环的特异性抗体。一旦与蛋白质结合,抗体就会通过激活补体级联反应引发局部炎症,并影响滋养层和蜕膜功能。最后的结果是胎盘形成缺陷,而血栓事件显然不那么重要。β2GPI是一种多效性分子,对包括凋亡物质在内的多种分子具有清除作用,并表现出抗氧化活性。这些功能可能解释了β2GPI胎盘在组织重塑和低氧紧张区域的定位。由于β2GPI还与补体和凝血级联反应相互作用,其与特异性抗体的结合可能以多种方式影响胎盘形成的生理学。
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引用次数: 0
Small molecules targeting endolysosomal acidification and signaling in sepsis and severe SARS-CoV-2 infection/COVID-19 脓毒症和严重SARS-CoV-2感染/新冠肺炎中靶向内溶酶体酸化和信号传导的小分子
Pub Date : 2022-08-11 DOI: 10.37349/ei.2022.00063
M. Blaess, O. Sommerfeld, R. Csuk, H. Deigner
Sepsis and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and its severe form coronavirus disease 2019 (COVID-19), represent the major medical challenges of the modern era. Therapeutic options are limited, mostly symptomatic, partially relying on antibodies and corticosteroids and, in the case of SARS-CoV-2 infection, supplemented by the antiviral drug remdesivir, and more recently by molnupiravir, nirmatrelvir/ritonavir, and the Janus kinase (JAK) inhibitors tofacitinib and baricitinib. Sepsis and severe SARS-CoV-2 infection/COVID-19 share many features at the level of pathophysiology and pro-inflammatory mediators, thus enabling a common disease management strategy. New ideas in successfully targeting the prognostic severity and mortality marker pentraxin 3 (PTX3) in sepsis and severe SARS-CoV-2 infection/COVID-19; the complement (C3/C3a/C3aR and C5/C5a/C5aR axis); tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 expression; IL-6-triggered expression of C5aR receptor in vascular endothelial cells; and release of anti-inflammatory IL-10 are still missing. Small molecules with lysosomotropic characteristics such as the approved drugs amitriptyline, desloratadine, fluvoxamine, azelastine, and ambroxol have demonstrated their clinical benefits in rodent models of sepsis or clinical trials in COVID-19; however, their exact mode of action remains to be fully elucidated. Addressing disease-relevant targets such as viral infection of host cells, shedding of toll-like receptors (TLRs), expression of pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, PTX3, and the complement receptor C5aR, highlight the advantages of this multi-target approach in comparison to current standards. Rational drug repurposing of approved drugs or screening for active compounds with virtually exclusively lysosomotropic pharmacologic effects is a major opportunity to improve prophylaxis and treatment of sepsis and/or SARS-CoV-2 infection, and its severe form COVID-19.
脓毒症和严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染及其严重形式的2019冠状病毒病(新冠肺炎)是现代医学的主要挑战。治疗选择有限,大多是有症状的,部分依赖抗体和皮质类固醇,在严重急性呼吸系统综合征冠状病毒2型感染的情况下,辅以抗病毒药物瑞德西韦,以及最近的莫努匹拉韦、尼马特雷韦/利托那韦和Janus激酶(JAK)抑制剂托法替尼和巴里西替尼。脓毒症和严重的SARS-CoV-2感染/新冠肺炎在病理生理学和促炎介质水平上有许多共同特征,因此能够制定共同的疾病管理策略。成功靶向脓毒症和严重SARS-CoV-2感染/新冠肺炎的预后严重性和死亡率标志物五唑菌素3(PTX3)的新想法;补体(C3/C3a/C3aR和C5/C5a/C5aR轴);肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β和IL-6的表达;IL-6触发血管内皮细胞中C5aR受体的表达;以及抗炎IL-10的释放仍然缺失。具有溶酶运动特征的小分子,如已批准的药物阿米替林、地氯雷他定、氟伏沙明、氮卓斯汀和氨溴索,已在败血症啮齿类动物模型或新冠肺炎临床试验中证明其临床益处;然而,它们的确切作用方式还有待充分阐明。针对疾病相关靶点,如宿主细胞的病毒感染、toll样受体(TLRs)的脱落、促炎介质如TNF-α、IL-1β、IL-6、PTX3和补体受体C5aR的表达,突出了这种多靶点方法与当前标准相比的优势。合理调整已批准药物的用途或筛选几乎完全具有溶酶运动药理作用的活性化合物是改善败血症和/或SARS-CoV-2感染及其严重形式新冠肺炎的预防和治疗的重要机会。
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引用次数: 0
Endometriosis through an immunological lens: a pathophysiology based in immune dysregulation 从免疫角度看子宫内膜异位症:一种基于免疫失调的病理生理学
Pub Date : 2022-07-26 DOI: 10.37349/ei.2022.00062
Alison McCallion, Danielle J. Sisnett, Katherine B. Zutautas, Donya Hayati, Katherine G. Spiess, Stanimira Aleksieva, Harshavardhan Lingegowda, M. Koti, C. Tayade
Endometriosis (EMS) is an inflammatory, gynaecologic disease characterized by the growth of endometrial tissues outside the uterus. With no satisfactory therapies or non-invasive diagnostics available, a shift in perspectives on EMS pathophysiology is overdue. The implication of immune dysregulation in EMS pathogenesis and disease progression has been an evolving area of research, with numerous immune and inflammatory pathways identified. Traditional theories regarding the establishment of endometriotic lesions have lacked mechanistic explanations for their proliferation and survival until recent research unearthed the involvement of mesenchymal stem cell (MSC) and myeloid-derived suppressor cells (MDSCs) in a complex network of immune-endocrine signaling. The unique immunology of EMS is likely owing to estrogen dominance, as endocrine imbalance reliably cultivates immune dysregulation. Many of the phenomena observed in EMS parallel immune biology seen in various cancers, including accelerated somatic mutations in endometrial epithelial cells. Here, the high mutational load leads to EMS neoantigen development which potentially contributes to the lesion immune microenvironment. As well, EMS manifests comorbidity with several chronic inflammatory diseases that share common dysregulation of the interleukin-23 (IL-23)/IL-17 pathway (as seen in inflammatory bowel disease, psoriasis, and rheumatoid arthritis). EMS is especially relevant to the study of chronic pelvic pain (CPP) as 60% of EMS patients experience this symptom and chronic inflammation is believed to be central to the process of pain sensitization. Since the onset of the disease usually occurs in adolescence, and diagnosis only occurs years later once moderate to severe symptoms have developed, it is vital to innovate non-invasive diagnostic tools for earlier detection. Several potential biomarkers are being studied, including some cytokines, gene signatures, and extracellular vesicle (EV) signatures. By incorporating the immune perspectives of EMS into our research, approaches to diagnosis, and treatment solutions, the field has more promising avenues to clearly define EMS and offer patients relief.
子宫内膜异位症(EMS)是一种炎症性妇科疾病,其特征是子宫外子宫内膜组织生长。由于没有令人满意的治疗方法或非侵入性诊断方法,EMS病理生理学的观点早就应该转变了。免疫失调在EMS发病机制和疾病进展中的意义一直是一个不断发展的研究领域,已经确定了许多免疫和炎症途径。关于子宫内膜异位病变建立的传统理论缺乏对其增殖和存活的机制解释,直到最近的研究发现间充质干细胞(MSC)和骨髓源性抑制细胞(MDSCs)参与了免疫内分泌信号的复杂网络。EMS独特的免疫学可能是由于雌激素的优势,因为内分泌失衡确实会导致免疫失调。EMS中观察到的许多现象与各种癌症中的免疫生物学相似,包括子宫内膜上皮细胞的体细胞突变加速。在这里,高突变负荷导致EMS新抗原的发展,这可能有助于损伤免疫微环境。此外,EMS表现出与几种慢性炎症性疾病的共病,这些疾病共有白细胞介素-23(IL-23)/IL-17通路的失调(如炎症性肠病、银屑病和类风湿性关节炎中所见)。EMS与慢性盆腔疼痛(CPP)的研究尤其相关,因为60%的EMS患者都有这种症状,而慢性炎症被认为是疼痛致敏过程的核心。由于该疾病的发病通常发生在青春期,而只有在出现中度至重度症状后几年才能进行诊断,因此创新非侵入性诊断工具以进行早期检测至关重要。一些潜在的生物标志物正在研究中,包括一些细胞因子、基因特征和细胞外小泡(EV)特征。通过将EMS的免疫观点纳入我们的研究、诊断方法和治疗解决方案,该领域有了更有希望的途径来明确定义EMS并为患者提供缓解。
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引用次数: 0
In COVID-19, antigen size lower or larger than 70 kDa modulates the sepsis and memory B cells 在新冠肺炎中,低于或大于70kDa的抗原大小调节败血症和记忆B细胞
Pub Date : 2022-07-17 DOI: 10.37349/ei.2022.00061
Francisco Javier Martín Oncina
This review pretends to shed light on the immune processes occurring in the coronavirus disease 2019 (COVID-19) from a perspective based on the antigens size, lower or larger than 70 kDa. This cutoff size point explains the host type of immune response against the antigenic proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to the development of the memory B cells or, conversely, the immune suppression, apoptosis, viral escape, and sepsis. Here, based on previous experimental work and the review of related literature, the following is proposed: antigens < 70 kDa can access the germinal center through the follicular conduits, where the activated B cells can present the processed antigen to specific naive CD4+ T cells that, in interaction with the major histocompatibility complex class II (MHC-II), trigger the immune response T helper type 2 (Th2). Conversely, antigens > 70 kDa cannot circulate through the narrow follicular conduits network and might be captured within the subcapsular sinus by the macrophages and dendritic follicular cells. Then, these cognate antigens are presented, via complement receptors, to the B cells that acquire and present them through the MHC-II to the specific naive CD4+ T cells, triggering the immune response Th1. The sustained infected cells lysis can overfeed high levels of unassembled viral proteins < 70 kDa, which can lead to a strong and persistent B cell receptor (BCR) activation, enhancing the Th2 immune response, releasing interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) that may lead to the immune paralysis, apoptosis, sepsis, and death. Finally, it is suggested that the polymerization of the viral antigens < 70 kDa into an antigenic polymer > 70 kDa could shift the immune response type from Th2 to Th1, developing the memory B cells and immunoglobulin G2 (IgG2) production, and avoiding the sepsis.
这篇综述试图从抗原大小(小于或大于70 kDa)的角度来揭示2019冠状病毒病(COVID-19)发生的免疫过程。这一截断点解释了宿主对严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)抗原蛋白的免疫反应,这可能导致记忆B细胞的发育,或者相反,导致免疫抑制、细胞凋亡、病毒逃逸和败血症。在此,基于以往的实验工作和对相关文献的回顾,我们提出以下建议:< 70 kDa的抗原可以通过滤泡导管进入生发中心,在那里,活化的B细胞可以将加工后的抗原呈递给特异性的幼稚CD4+ T细胞,这些细胞与主要组织相容性复合体II类(MHC-II)相互作用,触发免疫反应T辅助型2 (Th2)。相反,抗原>70kda不能通过狭窄的滤泡导管网络循环,可能被囊下窦内的巨噬细胞和树突状滤泡细胞捕获。然后,这些同源抗原通过补体受体呈递给B细胞,B细胞获得抗原并通过MHC-II呈递给特定的初始CD4+ T细胞,触发免疫反应Th1。持续的感染细胞裂解可过量供给高水平的< 70 kDa的未组装病毒蛋白,导致强烈和持续的B细胞受体(BCR)激活,增强Th2免疫应答,释放白细胞介素-10 (IL-10)和转化生长因子-β (TGF-β),可能导致免疫瘫痪、细胞凋亡、败血症和死亡。最后,我们认为将病毒抗原< 70 kDa聚合成抗原聚合物> 70 kDa可以将免疫反应类型从Th2转变为Th1,促进记忆B细胞和免疫球蛋白G2 (IgG2)的产生,从而避免败血症的发生。
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Exploration of immunology
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