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Localization in vesicles, clusters and supramolecular complexes as key elements of LAT function 定位于囊泡、簇和超分子复合物是LAT功能的关键要素
Pub Date : 2023-04-27 DOI: 10.37349/ei.2023.00094
Laura E. McMillan, C. Wülfing
Linker for activation of T cells (LAT) is a central adaptor protein in proximal T cell activation. A key element of its adaptor function is the efficiency with which LAT interacts with its binding partners. Such efficiency is controlled by the local concentration of LAT as well as the vicinity to up- and downstream interaction partners, i.e. LAT localization. Several factors control LAT localization. LAT is a palmitoylated transmembrane protein and traffics between vesicular compartments and the plasma membrane. Membrane heterogeneity and protein-protein interactions can drive LAT clustering, at scales from a few to hundreds if not more molecules. LAT vesicular trafficking through the small, crowded cytoplasm of a T cell and the commonly nm scale clusters are difficult to access experimentally, in particular in the physiological interaction of T cells binding to antigen presenting cells (APCs) with a highly undulating interface. Only in recent years have technological advances begun to provide better access. Based on such advances, three elements of LAT localization are discussed in conjunction: vesicular trafficking as it regulates LAT transport towards, insertion into, and removal from the plasma membrane; LAT clustering as it increases local LAT concentrations; LAT-anchored supramolecular signaling complexes as they embed LAT in a dense network of interaction partners. Consistent with the important role of LAT localization for its function, each of these processes regulates LAT activity and the efficiency of T cell activation.
T细胞活化连接子(Linker for activation of T cells, LAT)是近端T细胞活化的中心接头蛋白。其适配器功能的一个关键要素是LAT与其绑定伙伴交互的效率。这种效率受局部LAT浓度以及上下游相互作用伙伴附近的控制,即LAT局域化。有几个因素控制着LAT定位。LAT是一种棕榈酰化的跨膜蛋白,在囊室和质膜之间运输。膜的非均质性和蛋白质之间的相互作用可以驱动LAT聚集,从几个到数百个甚至更多的分子。LAT通过T细胞小而拥挤的细胞质和通常纳米级的团簇进行囊泡运输在实验上是困难的,特别是在T细胞与抗原提呈细胞(APCs)结合的生理相互作用中具有高度波动的界面。直到最近几年,技术进步才开始提供更好的途径。基于这些进展,本文结合讨论了LAT定位的三个要素:囊泡运输,因为它调节LAT向质膜的运输、插入和从质膜中移除;LAT聚集增加了局部LAT浓度;laat锚定的超分子信号复合物,因为它们将LAT嵌入相互作用伙伴的密集网络中。与LAT定位对其功能的重要作用一致,这些过程中的每一个都调节LAT活性和T细胞活化的效率。
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引用次数: 0
Beyond MHC binding: immunogenicity prediction tools to refine neoantigen selection in cancer patients 超越MHC结合:免疫原性预测工具完善癌症患者新抗原选择
Pub Date : 2023-04-25 DOI: 10.37349/ei.2023.00091
I. Carri, Erika Schwab, Enrique Podaza, Heli M. Garcia Alvarez, J. Mordoh, M. Nielsen, M. M. Barrio
In the last years, multiple efforts have been made to accurately predict neoantigens derived from somatic mutations in cancer patients, either to develop personalized therapeutic vaccines or to study immune responses after cancer immunotherapy. In this context, the increasing accessibility of paired whole-exome sequencing (WES) of tumor biopsies and matched normal tissue as well as RNA sequencing (RNA-Seq) has provided a basis for the development of bioinformatics tools that predict and prioritize neoantigen candidates. Most pipelines rely on the binding prediction of candidate peptides to the patient’s major histocompatibility complex (MHC), but these methods return a high number of false positives since they lack information related to other features that influence T cell responses to neoantigens. This review explores available computational methods that incorporate information on T cell preferences to predict their activation after encountering a peptide-MHC complex. Specifically, methods that predict i) biological features that may increase the availability of a neopeptide to be exposed to the immune system, ii) metrics of self-similarity representing the chances of a neoantigen to break immune tolerance, iii) pathogen immunogenicity, and iv) tumor immunogenicity. Also, this review describes the characteristics of these tools and addresses their performance in the context of a novel benchmark dataset of experimentally validated neoantigens from patients treated with a melanoma vaccine (VACCIMEL) in a phase II clinical study. The overall results of the evaluation indicate that current tools have a limited ability to predict the activation of a cytotoxic response against neoantigens. Based on this result, the limitations that make this problem an unsolved challenge in immunoinformatics are discussed.
在过去的几年里,人们做出了多项努力来准确预测癌症患者体细胞突变产生的新抗原,或者开发个性化的治疗疫苗,或者研究癌症免疫疗法后的免疫反应。在这种情况下,肿瘤活检和匹配正常组织的配对全外显子组测序(WES)以及RNA测序(RNA-Seq)的可及性不断增加,为开发预测和优先考虑新抗原候选物的生物信息学工具提供了基础。大多数管道依赖于候选肽与患者主要组织相容性复合体(MHC)的结合预测,但这些方法返回大量假阳性,因为它们缺乏与影响T细胞对新抗原反应的其他特征相关的信息。这篇综述探索了现有的计算方法,这些方法结合了T细胞偏好的信息,以预测它们在遇到肽MHC复合物后的激活。具体而言,预测i)可能增加新肽暴露于免疫系统的可用性的生物学特征,ii)表示新抗原破坏免疫耐受的机会的自相似性指标,iii)病原体免疫原性和iv)肿瘤免疫原性的方法。此外,这篇综述描述了这些工具的特性,并在一个新的基准数据集的背景下讨论了它们的性能,该数据集是在一项II期临床研究中使用黑色素瘤疫苗(VACCIMEL)治疗的患者的实验验证的新抗原。评估的总体结果表明,目前的工具预测针对新抗原的细胞毒性反应激活的能力有限。基于这一结果,讨论了使这一问题成为免疫信息学中尚未解决的挑战的局限性。
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引用次数: 0
Inflammasomes driven inflammation in lung cancer revisited: a short review 肺癌中炎性小体驱动的炎症:简短回顾
Pub Date : 2023-03-14 DOI: 10.37349/ei.2023.00090
Vitor Rodrigues da Costa, O. F. Souza, Michelli Ramires Teixeira, A.L. Alievi, H. Vigerelli, R. P. Araldi
Lung cancer is the leading cause of cancer-related deaths worldwide. The main risk factor for lung cancer is exposure to chemicals present in cigarettes and atmospheric pollutants, which, among other mechanisms, can increase the risk of cancer by inducing pulmonary inflammation. Among the complex features of inflammatory processes, the role of inflammasomes has attracted increasing attention due to their role in different stages of carcinogenesis. Inflammasomes are intracellular multiprotein complexes that when activated promote the maturation of interleukin-1beta (IL-1β) and IL-18, pro-inflammatory cytokines involved in the promotion, progression, epithelial-mesenchymal transition, metastasis, and resistance to therapy of lung cancer. In this way, this review summarizes the recent findings of inflammasome research in different stages of lung cancer, with a focus on non-small cell lung carcinoma (NSCLC), and highlights these multiprotein complexes as promising targets for cancer therapy.
癌症是全球癌症相关死亡的主要原因。癌症的主要危险因素是暴露于香烟和大气污染物中的化学物质,除其他机制外,这些化学物质可通过诱导肺部炎症增加癌症的风险。在炎症过程的复杂特征中,炎症小体的作用因其在不同致癌阶段的作用而越来越受到关注。炎症小体是细胞内多蛋白复合物,当其被激活时,可促进白细胞介素-1β(IL-1β)和IL-18的成熟,这两种促炎细胞因子参与癌症的促进、进展、上皮-间质转化、转移和对治疗的抵抗。通过这种方式,本综述总结了癌症不同阶段炎症小体研究的最新发现,重点是非小细胞肺癌(NSCLC),并强调这些多蛋白复合物是癌症治疗的有前途的靶点。
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引用次数: 0
SARS-CoV-2 infection activates the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in the lung: a review SARS-CoV-2感染激活肺干扰素基因通路环鸟苷-腺苷-单磷酸合成酶刺激因子研究进展
Pub Date : 2023-02-28 DOI: 10.37349/ei.2023.00089
G. Aragão, S. G. Feitosa, H. Veras, Cícero Gilmário A. P. de Lima Filho, Karinne da S. Assunção, Luana M. Arrais, Sara Lívia M. Teixeira
The infection of COVID-19 is directly linked to the destruction of lung epithelial cells, and the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) system has been implicated in the pathology of respiratory infections. This study aimed to systematize the relationship between the pathophysiology of COVID-19 and the cGAS-STING system’s activation in the lungs. Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is an RNA virus that belongs to the Coronaviridae family whose genetic material is produced by a single positive RNA molecule (RNA+). The cGAS-STING signaling pathway has emerged as a key mediator of injury caused by infection and cellular or tissue stress. The cGAS-STING cyclic pathway is part of innate immunity and is activated from cytosolic DNA responses present in newly formed syncytia, by cell-to-cell fusion, in target of angiotensin-converting enzyme 2 (ACE2) expression and SARS-CoV-2 Spike protein. Although this pathway is canonically understood to be responsive to both pathogen-derived and host-derived DNA, it has been demonstrated to cross-communicate with the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). cGAS-STING activation is significant to interferon production, mainly type-I interferons (IFN-I), in a SARS-CoV-2 infection scenario, indicating a major antiviral role of the cGAS-STING pathway. It was identified that in SARS-CoV-2 the cGAS-STING axis is activated, but the inflammatory response could be specific for nuclear factor-κB (NF-κB) in infected cells, and that this axis is potentiated by a cytokine storm produced by the immune system’s cells.
COVID-19的感染与肺上皮细胞的破坏直接相关,而环鸟苷单磷酸腺苷单磷酸合成酶干扰素基因刺激因子(cGAS-STING)系统与呼吸道感染的病理有关。本研究旨在系统梳理COVID-19病理生理与肺部cGAS-STING系统激活之间的关系。严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)是一种属于冠状病毒科的RNA病毒,其遗传物质由单个阳性RNA分子(RNA+)产生。cGAS-STING信号通路已成为感染和细胞或组织应激引起的损伤的关键介质。cGAS-STING循环通路是先天免疫的一部分,在新形成的合胞体中,通过细胞间融合,以血管紧张素转换酶2 (ACE2)表达和SARS-CoV-2刺突蛋白为目标,在胞质DNA反应中被激活。虽然这一途径通常被认为对病原体来源和宿主来源的DNA都有反应,但它已被证明与视黄酸诱导基因I (RIG-I)样受体(rlr)交叉交流。在SARS-CoV-2感染情况下,cGAS-STING激活对干扰素(主要是i型干扰素(IFN-I))的产生具有重要意义,这表明cGAS-STING途径具有重要的抗病毒作用。研究发现,在SARS-CoV-2中,cGAS-STING轴被激活,但炎症反应可能针对感染细胞中的核因子-κB (NF-κB),并且该轴被免疫系统细胞产生的细胞因子风暴增强。
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引用次数: 0
Role of tumor necrosis factor receptor-associated factor 5 in B- and T-lymphocytes 肿瘤坏死因子受体相关因子5在B和t淋巴细胞中的作用
Pub Date : 2023-02-27 DOI: 10.37349/ei.2023.00088
Mari Hikosaka Kuniishi, N. Ishii, T. So
Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are a family of intracellular signaling adaptors that associate with the cytoplasmic tails of a diverse range of lymphocyte receptors, including members of the TNFR superfamily, the Toll-like receptor (TLR)/interleukin-1 (IL-1) receptor superfamily, and the IL-6 receptor family that are major targets for therapeutic intervention for inflammatory diseases. TRAF5 is one of the seven family members of the TRAF family and is highly expressed by B- and T-lymphocytes. As compared to other family members, the biological and pathophysiological functions of TRAF5 have remained ambiguous since its discovery. TRAF5 promotes lymphocyte signaling for the TNFR family molecules such as glucocorticoid-induced TNFR family-related protein (GITR), CD27, and CD40. In contrast, TRAF5 limits the activity of the common signaling receptor subunit glycoprotein 130 kDa (gp130) in CD4+ T cells that requires signaling by IL-6 and IL-27. TRAF5 also restrains TLR signaling in B cells. Thus, TRAF5 regulates lymphocyte signaling in both positive and negative ways. This review will summarize the findings of recent studies of TRAF5 in terms of how TRAF5 regulates signaling in lymphocytes and other cell types and how TRAF5 expression contributes to inflammatory and autoimmune diseases in mice and humans.
肿瘤坏死因子受体(TNFR)相关因子(TRAFs)是一个细胞内信号转接器家族,与多种淋巴细胞受体的细胞质尾部相关,包括TNFR超家族成员、toll样受体(TLR)/白细胞介素-1 (IL-1)受体超家族成员和IL-6受体家族,它们是炎症性疾病治疗干预的主要靶点。TRAF5是TRAF家族的7个成员之一,在B淋巴细胞和t淋巴细胞中高度表达。与其他家族成员相比,TRAF5的生物学和病理生理功能自发现以来一直不明确。TRAF5促进TNFR家族分子的淋巴细胞信号传导,如糖皮质激素诱导的TNFR家族相关蛋白(GITR)、CD27和CD40。相比之下,TRAF5限制了CD4+ T细胞中需要IL-6和IL-27信号传导的共同信号受体亚单位糖蛋白130 kDa (gp130)的活性。TRAF5也抑制B细胞中的TLR信号。因此,TRAF5以正、负两种方式调节淋巴细胞信号。本文将从TRAF5如何调节淋巴细胞和其他细胞类型的信号,以及TRAF5的表达如何参与小鼠和人类的炎症和自身免疫性疾病等方面对TRAF5的最新研究结果进行综述。
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引用次数: 0
Innate immune cell and severe acute respiratory syndrome coronavirus 2 interaction 先天免疫细胞与严重急性呼吸综合征冠状病毒2型的相互作用
Pub Date : 2023-02-26 DOI: 10.37349/ei.2023.00087
N. Cortes-Perez
Coronavirus disease caused by the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a major public health that has submerged the world into a crisis unprecedented in the modern era. A better understanding of the innate immune response could help to fight this pandemic and be better prepared for potential future outbreaks. Interestingly, innate immune cells can develop a non-specific memory termed trained immunity. This review details recent evidence concerning the interaction of SARS-CoV-2 with innate immune cells, in particular those in which the trained immunity activity has been demonstrated.
由最近出现的严重急性呼吸综合征冠状病毒2型(严重急性呼吸系统综合征冠状病毒冠状病毒2型)引起的冠状病毒疾病代表了一种重大的公共卫生,它使世界陷入了现代前所未有的危机。更好地了解先天免疫反应可能有助于抗击这一流行病,并为未来可能爆发的疫情做好更好的准备。有趣的是,先天免疫细胞可以产生一种称为训练免疫的非特异性记忆。这篇综述详细介绍了有关严重急性呼吸系统综合征冠状病毒2型与先天免疫细胞相互作用的最新证据,特别是那些已经证明具有训练免疫活性的细胞。
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引用次数: 0
Cytomegalovirus at the crossroads of immunosenescence and oncogenesis 处于免疫衰老和肿瘤发生十字路口的巨细胞病毒
Pub Date : 2023-02-24 DOI: 10.37349/ei.2023.00086
Fidaa Bouezzedine, Ranim El Baba, S. Morot-Bizot, M. Diab‐Assaf, G. Herbein
Human cytomegalovirus (HCMV), whose genome is around 235 kb, is a ubiquitous human herpesvirus that infects between 40% and 95% of the population. Though HCMV infection is commonly asymptomatic and leads to subtle clinical symptoms, it can promote robust immune responses and establish lifelong latency. In addition, in immunocompromised hosts, including individuals with acquired immunodeficiency syndrome (AIDS), transplant recipients, and developing fetuses it can lead to severe diseases. Immunosenescence, well-defined as the alterations in the immune system, is linked mainly to aging and has been recently gathering considerable attention. Senescence was characterized by an elevated inflammation and hence considered a powerful contributor to “inflammaging” that is measured mainly by tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) levels as well as latent viral infections, for instance, cytomegalovirus (CMV). Inflammaging resulted in a senescence-associated secretory phenotype (SASP). HCMV is markedly associated with accelerated aging of the immune system as well as several age-associated diseases that accumulate and subsequently deteriorate the immune responses, thus have been linked to mortality, declined vaccine efficacy, serious diseases, and tumors in the elderly. HCMV triggers or exacerbates immunosenescence; on the other hand, the weakened immune responses and inflammaging favor viral reactivation and highlight the role of HCMV in aging as well as viral-associated tumors. HCMV reactivation resulting in sequential lytic and latent viral cycles could contribute to HCMV genomic variability. Besides the oncomodulatory role and transforming capacities of HCMV, the immune-privileged tumor microenvironment has been considered the main element in tumor progression and aggressiveness. Therefore, the interplay between HCMV, immunosenescence, and cancer will aid in discovering new therapeutic approaches that target HCMV and act as immune response boosters mainly to fight cancers of poor prognosis, particularly in the elderly population.
人类巨细胞病毒(HCMV)的基因组约为235kb,是一种普遍存在的人类疱疹病毒,感染40%至95%的人群。尽管HCMV感染通常是无症状的,并会导致微妙的临床症状,但它可以促进强大的免疫反应并建立终身潜伏期。此外,在免疫功能低下的宿主中,包括艾滋病患者、移植受者和发育中的胎儿,它可能导致严重疾病。免疫衰老,定义为免疫系统的改变,主要与衰老有关,最近受到了相当大的关注。衰老的特征是炎症升高,因此被认为是“炎症”的有力因素,主要通过肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)和C反应蛋白(CRP)水平以及潜在的病毒感染(例如巨细胞病毒(CMV))来测量。炎症导致衰老相关分泌表型(SASP)。HCMV与免疫系统的加速衰老以及几种与年龄相关的疾病显著相关,这些疾病会积累并随后恶化免疫反应,因此与老年人的死亡率、疫苗效力下降、严重疾病和肿瘤有关。HCMV引发或加剧免疫衰老;另一方面,免疫反应减弱和炎症有利于病毒的再激活,并突出了HCMV在衰老和病毒相关肿瘤中的作用。HCMV再激活导致连续的裂解和潜伏病毒周期可能有助于HCMV基因组变异。除了HCMV的肿瘤调节作用和转化能力外,免疫特权肿瘤微环境被认为是肿瘤进展和侵袭性的主要因素。因此,HCMV、免疫衰老和癌症之间的相互作用将有助于发现新的治疗方法,这些方法靶向HCMV,并作为免疫反应增强剂,主要用于对抗预后不良的癌症,尤其是老年人群。
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引用次数: 0
Immunoinformatics and tick vaccinology 免疫信息学与蜱疫苗学
Pub Date : 2023-02-24 DOI: 10.37349/ei.2023.00085
R. Rosario-Cruz, D. Domínguez-García, Saúl López-Silva, Fernando Rosario-Domínguez
Immunoinformatics is an emerging area focused on development and applications of methods used to facilitate vaccine development. There is a growing interest in the field of vaccinology centered on the new omic science named ‘vaccinomics’. However, this approach has not succeeded to provide a solution against major infections affecting both animals and humans, since tick vaccines are still being developed based on conventional biochemical or immunological methods to dissect the molecular structure of the pathogen, looking for a candidate antigen. The availability of complete genomes and the novel advanced technologies, such as data mining, bioinformatics, microarrays, and proteomics, have revolutionized the approach to vaccine development and provided a new impulse to tick research. The aim of this review is to explore how modern vaccinology will contribute to the discovery of new candidate antigens and to understand the research process to improve existing vaccines. Under this concept, the omic age of ticks will make it possible to design vaccines starting from a prediction based on the in silico analysis of gene sequences obtained by data mining using computer algorithms, without the need to keep the pathogen growing in vitro. This new genome-based approach has been named “reverse vaccinology 3.0” or “vaccinomics 1.0” and can be applied to ticks.
免疫信息学是一个新兴领域,侧重于开发和应用用于促进疫苗开发的方法。人们对以名为“疫苗组学”的新基因组学为中心的疫苗学领域的兴趣日益浓厚。然而,这种方法还没有成功地提供一种针对影响动物和人类的重大感染的解决方案,因为蜱疫苗仍在基于传统的生化或免疫学方法开发,以解剖病原体的分子结构,寻找候选抗原。全基因组的可用性和新的先进技术,如数据挖掘、生物信息学、微阵列和蛋白质组学,已经彻底改变了疫苗开发的方法,并为蜱虫研究提供了新的动力。本综述的目的是探讨现代疫苗学如何有助于发现新的候选抗原,并了解改进现有疫苗的研究过程。根据这一概念,蜱虫的组学年龄将使设计疫苗成为可能,这一预测是基于计算机算法通过数据挖掘获得的基因序列的计算机分析,而无需让病原体在体外生长。这种新的基于基因组的方法被命名为“反向疫苗学3.0”或“疫苗组学1.0”,可以应用于蜱虫。
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引用次数: 0
The synergistic effects of the constant region and variable heavy chain families of multimeric immunoglobulin M on its interaction with Fc-mu receptor and antigen 多聚体免疫球蛋白M恒定区和可变重链家族对其与Fc-mu受体和抗原相互作用的协同作用
Pub Date : 2022-12-29 DOI: 10.37349/ei.2022.00083
Wei-Li Ling, S. Gan
Aim: As the primary response antibody with increasing use as a therapeutic immunoglobulin (Ig) format, IgM is also the largest antibody structure among the five major human isotypes. Spontaneously formed pentamers and hexamers of IgM have avidity effects that could compensate for weaker interactions in monomeric Igs. However, this advantage is counterbalanced by potential steric clashes when binding to multiple large antigens. Recent findings have challenged the expected canonical independence of Fc receptor (FcR) binding at the heavy chain constant (C)-region where the heavy chain C-region isotypes affected antigen binding at the variable (V)-regions, and the variable heavy (VH) families of the V-region affected FcR engagement at the antibody C-regions. With such effects found on other Ig isotypes, IgM candidates need to be investigated with regards to such effects, especially when considering its natural oligomerisation at the C-region that can amplify or modulate such allosteric effects.Methods: Through a panel of 14 recombinant complementarity determining regions (CDRs)-grafted trastuzumab and pertuzumab VH1-7 IgMs subjected to bio-layer interferometry measurements, the interactions with the antigen human epidermal growth factor receptor 2 (Her2), Fc-mu receptor (FcµR), and superantigen Protein L (PpL) were investigated.Results: Significant effects from the V-regions to mitigate FcµR binding and the IgM C-region bidirectional effect modulating Her2 antigen engagements at the V-regions were found. Additional modulatory effects from superantigen PpL binding on the V-region of the kappa chain (Vκ) mitigating antigen binding were also found, revealing possible novel mechanisms of antibody superantigens that can be moderated by the antibody VH frameworks.
目的:作为一种治疗性免疫球蛋白(Ig)形式的主要反应抗体,IgM也是人类五种主要同种型中最大的抗体结构。IgM的自发形成的五聚体和六聚体具有亲和力效应,可以补偿单体Ig中较弱的相互作用。然而,当与多种大抗原结合时,这种优势被潜在的空间冲突所抵消。最近的发现挑战了Fc受体(FcR)在重链恒定(C)区结合的预期规范独立性,其中重链C区同种型影响可变(V)区的抗原结合,并且V区的可变重(VH)家族影响FcR在抗体C区的结合。由于在其他Ig同种型上发现了这种影响,需要研究IgM候选物的这种影响,特别是当考虑到其在C区的天然寡聚作用时,该作用可以放大或调节这种变构效应。方法:通过一组由14个重组互补决定区(CDR)接枝的曲妥珠单抗和帕妥珠单抗VH1-7 IgM进行生物层干涉测量,研究其与抗原人表皮生长因子受体2(Her2)、Fcμ受体(FcµR)和超抗原L蛋白(PpL)的相互作用。结果:发现V区对减轻FcµR结合的显著作用,以及IgM C区对调节V区Her2抗原结合的双向作用。还发现了超抗原PpL结合在κ链V区(Vκ)上减轻抗原结合的额外调节作用,揭示了抗体超抗原可能的新机制,这些机制可以由抗体VH框架调节。
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引用次数: 0
Role of tyrosine kinase 2 signals during progression of psoriasis 酪氨酸激酶2信号在银屑病进展中的作用
Pub Date : 2022-12-27 DOI: 10.37349/ei.2022.00081
R. Muromoto, K. Oritani, T. Matsuda
Psoriasis is a skin disease characterized by scaly erythema, parakeratosis, and epidermal hyperplasia. Application of imiquimod (IMQ), a ligand for Toll-like receptor 7, produces a mouse model for psoriasis. IMQ application induces scaling, erythema, and thickness in skin lesions, and the symptoms are milder in interleukin-23 p19 (Il23p19)-deficient and Il17a-deficient mice than in wild-type mice; this suggests that the interleukin-23 (IL-23)/T helper 17 (Th17) axis and Th17 cell-secreting cytokines play essential roles in the IMQ-induced psoriasis model. It is notable that a genome-wide association study identified the human tyrosine kinase 2 (TYK2) gene within the psoriasis susceptibility locus. After IMQ application, mice lacking Tyk2, a mouse homologue of the human TYK2 gene, exhibited significantly lower symptom scores of psoriasis and diminished inflammatory cell infiltration in the skin lesions. Tyk2-deficient mice also failed to increase CD4+IL-17+ or CD4+ interferon-γ+ (IFN-γ+) T cells in the draining lymph nodes or to produce Th17 cell-related cytokines after IMQ application. Furthermore, Tyk2 deficiency led to diminished skin inflammation induced by IL-23 and IL-22 injections. These results indicate that Tyk2-mediated signals in mice contribute to multiple steps of immune and inflammatory responses during the development of psoriasis; therefore, TYK2 targeting may be a promising strategy to treat patients with psoriasis. Recent clinical trials have shown that TYK2 inhibitors have a high overall response rate with good tolerability in the management of psoriasis. This review describes the fundamental mechanisms of Tyk2 inhibition in immune/inflammatory diseases.
银屑病是一种以鳞状红斑、角化不良和表皮增生为特征的皮肤病。应用Toll样受体7的配体咪喹莫特(IMQ)产生银屑病小鼠模型。IMQ应用会在皮肤损伤中诱导结垢、红斑和厚度,白细胞介素-23 p19(Il23p19)缺陷和Il17a缺陷小鼠的症状比野生型小鼠轻;这表明白细胞介素-23(IL-23)/Th17(Th17)轴和分泌Th17细胞因子在IMQ诱导的银屑病模型中起重要作用。值得注意的是,一项全基因组关联研究在银屑病易感性基因座中鉴定了人酪氨酸激酶2(TYK2)基因。应用IMQ后,缺乏Tyk2(人类Tyk2基因的小鼠同源物)的小鼠表现出显著较低的银屑病症状评分,并减少了皮肤损伤中的炎症细胞浸润。Tyk2缺陷小鼠在IMQ应用后也未能增加引流淋巴结中的CD4+IL-17+或CD4+干扰素-γ+(IFN-γ+)T细胞,或产生Th17细胞相关细胞因子。此外,Tyk2缺乏导致IL-23和IL-22注射诱导的皮肤炎症减少。这些结果表明,在银屑病的发展过程中,小鼠中的Tyk2介导的信号有助于免疫和炎症反应的多个步骤;因此,TYK2靶向治疗银屑病可能是一种很有前途的策略。最近的临床试验表明,TYK2抑制剂在银屑病的治疗中具有高的总有效率和良好的耐受性。这篇综述描述了Tyk2抑制免疫/炎症疾病的基本机制。
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引用次数: 0
期刊
Exploration of immunology
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