Allergy is a complex array of diseases influenced by innate and adaptive immunity, genetic polymorphisms, and environmental triggers. Atopic dermatitis is a chronic inflammatory skin disease characterized by barrier defects and immune dysregulation, sometimes leading to asthma and food allergies because of the atopic march. During atopic skin inflammation, Langerhans cells and dendritic cells (DCs) in the skin capture and deliver allergen information to local lymph nodes. DCs are essential immune sensors coordinating immune reactions by capturing and presenting antigens to T cells. In the context of allergic responses, DCs play a crucial role in instructing two types of helper T cells-type 2 helper T (Th2) cells and follicular helper T (TFH) cells-in allergic responses and IgE antibody responses. In skin sensitization, the differentiation and function of Th2 cells and TFH cells are influenced by skin-derived factors, including epithelial cytokines, chemokines, and signalling pathways to modify the function of migratory DCs and conventional DCs. In this review, we aim to understand the specific mechanisms involving DCs in allergic responses to provide insights into the pathogenesis of allergic diseases and potential therapeutic strategies.
过敏是受先天性免疫和适应性免疫、基因多态性和环境诱因影响的一系列复杂疾病。特应性皮炎(AD)是一种慢性炎症性皮肤病,其特点是屏障缺陷和免疫调节失调,有时会因特应性进展而导致哮喘和食物过敏。在特应性皮肤炎症期间,皮肤中的朗格汉斯细胞和树突状细胞(DC)会捕捉过敏原信息并将其传递到局部淋巴结。DC 是重要的免疫传感器,通过捕捉抗原并将其呈现给 T 细胞来协调免疫反应。在过敏反应中,DC 在指导两种辅助性 T 细胞(2 型辅助性 T 细胞(Th2)和滤泡辅助性 T 细胞(TFH))的过敏反应和 IgE 抗体反应中发挥着至关重要的作用。在皮肤过敏中,Th2 细胞和 TFH 细胞的分化和功能受皮肤衍生因子的影响,包括上皮细胞因子、趋化因子和信号通路,从而改变迁移性 DC 和传统 DC 的功能。在这篇综述中,我们旨在了解 DCs 参与过敏反应的具体机制,以便深入了解过敏性疾病的发病机制和潜在的治疗策略。
{"title":"The role of dendritic cells in the instruction of helper T cells in the allergic march.","authors":"Masato Kubo, Yasuyo Harada, Takanori Sasaki","doi":"10.1093/intimm/dxae050","DOIUrl":"10.1093/intimm/dxae050","url":null,"abstract":"<p><p>Allergy is a complex array of diseases influenced by innate and adaptive immunity, genetic polymorphisms, and environmental triggers. Atopic dermatitis is a chronic inflammatory skin disease characterized by barrier defects and immune dysregulation, sometimes leading to asthma and food allergies because of the atopic march. During atopic skin inflammation, Langerhans cells and dendritic cells (DCs) in the skin capture and deliver allergen information to local lymph nodes. DCs are essential immune sensors coordinating immune reactions by capturing and presenting antigens to T cells. In the context of allergic responses, DCs play a crucial role in instructing two types of helper T cells-type 2 helper T (Th2) cells and follicular helper T (TFH) cells-in allergic responses and IgE antibody responses. In skin sensitization, the differentiation and function of Th2 cells and TFH cells are influenced by skin-derived factors, including epithelial cytokines, chemokines, and signalling pathways to modify the function of migratory DCs and conventional DCs. In this review, we aim to understand the specific mechanisms involving DCs in allergic responses to provide insights into the pathogenesis of allergic diseases and potential therapeutic strategies.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Atopic dermatitis (AD), a prevalent Th2-dominant skin disease, involves complex genetic and environmental factors, including mutations in the Filaggrin gene and dysbiosis of skin microbiota characterized by an increased abundance of Staphylococcus aureus. Our recent findings emphasize the pivotal role of the skin barrier's integrity and microbial composition in infantile AD and allergic diseases. Early skin dysbiosis predisposes infants to AD, suggesting targeted skincare practices as a preventive strategy. The effects of skincare interventions, particularly the application of moisturizers with the appropriate molar concentration of ceramides, cholesterol, and fatty acids, play a crucial role in restoring the skin barrier. Notably, our study revealed that appropriate skincare can reduce Streptococcus abundance while supporting Cutibacterium acnes presence, thus directly linking skincare practices to microbial modulation in neonatal skin. Despite the mixed outcomes of previous Randomized Controlled Trials on the efficacy of moisturizers in AD prevention, our research points to the potential of skincare intervention as a primary preventive method against AD by minimizing the impact of genetic and environmental factors. Furthermore, our research supports the notion that early aggressive management of eczema may reduce the incidence of food allergies, highlighting the necessity for multifaceted prevention strategies that address both the skin barrier and immune sensitization. By focusing on repairing the skin barrier and adjusting the skin's microbiome from birth, we propose a novel perspective on preventing infantile AD and allergic diseases, opening new avenues for future studies, and practices in allergy prevention.
特应性皮炎(AD)是一种流行的 Th2 主导型皮肤病,涉及复杂的遗传和环境因素,包括 Filaggrin 基因突变和以金黄色葡萄球菌增多为特征的皮肤微生物群失调。我们最近的研究结果强调了皮肤屏障的完整性和微生物组成在婴儿 AD 和过敏性疾病中的关键作用。早期皮肤菌群失调容易导致婴儿过敏性鼻炎,这表明有针对性的护肤方法是一种预防策略。护肤干预的效果,尤其是使用含有适当摩尔浓度神经酰胺、胆固醇和脂肪酸的保湿剂,对恢复皮肤屏障起着至关重要的作用。值得注意的是,我们的研究表明,适当的护肤品可以减少链球菌的数量,同时支持痤疮棒状杆菌的存在,从而将护肤方法与新生儿皮肤的微生物调节直接联系起来。尽管之前的随机对照试验对保湿剂在预防AD方面的功效结果不一,但我们的研究表明,护肤干预可最大限度地减少遗传和环境因素的影响,从而有可能成为预防AD的主要方法。此外,我们的研究还支持这样一种观点,即早期积极治疗湿疹可降低食物过敏的发病率,这突出说明了同时解决皮肤屏障和免疫致敏问题的多方面预防策略的必要性。通过关注从出生开始修复皮肤屏障和调整皮肤的微生物群,我们提出了预防婴幼儿AD和过敏性疾病的新观点,为过敏预防的未来研究和实践开辟了新途径。
{"title":"The skin barrier and microbiome in infantile atopic dermatitis development: can skincare prevent onset?","authors":"Tomoka Ito, Yuumi Nakamura","doi":"10.1093/intimm/dxae038","DOIUrl":"10.1093/intimm/dxae038","url":null,"abstract":"<p><p>Atopic dermatitis (AD), a prevalent Th2-dominant skin disease, involves complex genetic and environmental factors, including mutations in the Filaggrin gene and dysbiosis of skin microbiota characterized by an increased abundance of Staphylococcus aureus. Our recent findings emphasize the pivotal role of the skin barrier's integrity and microbial composition in infantile AD and allergic diseases. Early skin dysbiosis predisposes infants to AD, suggesting targeted skincare practices as a preventive strategy. The effects of skincare interventions, particularly the application of moisturizers with the appropriate molar concentration of ceramides, cholesterol, and fatty acids, play a crucial role in restoring the skin barrier. Notably, our study revealed that appropriate skincare can reduce Streptococcus abundance while supporting Cutibacterium acnes presence, thus directly linking skincare practices to microbial modulation in neonatal skin. Despite the mixed outcomes of previous Randomized Controlled Trials on the efficacy of moisturizers in AD prevention, our research points to the potential of skincare intervention as a primary preventive method against AD by minimizing the impact of genetic and environmental factors. Furthermore, our research supports the notion that early aggressive management of eczema may reduce the incidence of food allergies, highlighting the necessity for multifaceted prevention strategies that address both the skin barrier and immune sensitization. By focusing on repairing the skin barrier and adjusting the skin's microbiome from birth, we propose a novel perspective on preventing infantile AD and allergic diseases, opening new avenues for future studies, and practices in allergy prevention.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Translocator protein (TSPO) is a mitochondrial outer membrane protein expressed on a variety of immune cells, including macrophages, dendritic cells, and T cells, in addition to neurons and steroid-producing cells. Previous studies of TSPO ligands have suggested that TSPO is involved in multiple cellular functions, including steroidogenesis, immunomodulation, and cell proliferation. Currently, there are limited reports on the effects of TSPO or TSPO ligands on T cell-mediated immune responses. We here investigated the involvement of TSPO/TSPO ligand in T cell responses using a 2,4-dinitro-1-fluorobenzene (DNFB)-induced contact hypersensitivity (CH) model. Treatment with Ro5-4864, a TSPO ligand, during DNFB sensitization reduced the number and activation status of CD4+ and CD8+ T cells in draining lymph nodes and alleviated skin inflammation after DNFB challenge. Adoptive transfer of Ro5-4864-treated mouse-derived DNFB-sensitized T cells to naïve mice inhibited CH responses after DNFB challenge. Ro5-4864-treated sensitized T cells showed lower proliferative responses when stimulated with DNFB-pulsed antigen-presenting cells compared to control-treated sensitized T cells. Ro5-4864 also suppressed cell proliferation, as well as adenosine triphosphate and lactate production, during T cell activation. Moreover, the inhibitory effects of Ro5-4864 on T cell responses were conserved in TSPO-deficient cells. Our results suggest that Ro5-4864 inhibits CH responses by suppressing energy metabolism, at least via glycolysis, to reduce the T cell primary response in a TSPO-independent manner.
转运蛋白(TSPO)是一种线粒体外膜蛋白,表达于多种免疫细胞,包括巨噬细胞、树突状细胞和 T 细胞,以及神经元和类固醇生成细胞。以往对 TSPO 配体的研究表明,TSPO 参与多种细胞功能,包括类固醇生成、免疫调节和细胞增殖。目前,有关 TSPO 或 TSPO 配体对 T 细胞介导的免疫反应的影响的报道有限。我们在此使用 2,4-二硝基-1-氟苯(DNFB)诱导的接触过敏(CH)模型研究了 TSPO/TSPO 配体参与 T 细胞反应的情况。在DNFB致敏过程中使用TSPO配体Ro5-4864可减少引流淋巴结中CD4+和CD8+T细胞的数量和活化状态,并减轻DNFB挑战后的皮肤炎症。将经过 Ro5-4864 处理的小鼠 DNFB 致敏 T 细胞收养转移到幼稚小鼠体内可抑制 DNFB 挑战后的 CH 反应。与对照组相比,Ro5-4864处理过的致敏T细胞在受到DNFB脉冲抗原递呈细胞刺激时显示出较低的增殖反应。Ro5-4864 还能抑制 T 细胞活化过程中的细胞增殖以及三磷酸腺苷和乳酸的产生。此外,Ro5-4864 对 T 细胞反应的抑制作用在 TSPO 缺陷细胞中保持不变。我们的研究结果表明,Ro5-4864 通过抑制能量代谢(至少通过糖酵解)来抑制 CH 反应,从而以独立于 TSPO 的方式降低 T 细胞的初级反应。
{"title":"Ro5-4864, a translocator protein ligand, regulates T cell-mediated inflammatory responses in skin.","authors":"Yuka Sendai, Kazuyoshi Takeda, Keisuke Ohta, Susumu Nakae, Kyotaro Koshika, Kei Kitamura, Makoto Higuchi, Tatsuya Ichinohe, Toshifumi Azuma, Ko Okumura, Tatsukuni Ohno","doi":"10.1093/intimm/dxae065","DOIUrl":"https://doi.org/10.1093/intimm/dxae065","url":null,"abstract":"<p><p>Translocator protein (TSPO) is a mitochondrial outer membrane protein expressed on a variety of immune cells, including macrophages, dendritic cells, and T cells, in addition to neurons and steroid-producing cells. Previous studies of TSPO ligands have suggested that TSPO is involved in multiple cellular functions, including steroidogenesis, immunomodulation, and cell proliferation. Currently, there are limited reports on the effects of TSPO or TSPO ligands on T cell-mediated immune responses. We here investigated the involvement of TSPO/TSPO ligand in T cell responses using a 2,4-dinitro-1-fluorobenzene (DNFB)-induced contact hypersensitivity (CH) model. Treatment with Ro5-4864, a TSPO ligand, during DNFB sensitization reduced the number and activation status of CD4+ and CD8+ T cells in draining lymph nodes and alleviated skin inflammation after DNFB challenge. Adoptive transfer of Ro5-4864-treated mouse-derived DNFB-sensitized T cells to naïve mice inhibited CH responses after DNFB challenge. Ro5-4864-treated sensitized T cells showed lower proliferative responses when stimulated with DNFB-pulsed antigen-presenting cells compared to control-treated sensitized T cells. Ro5-4864 also suppressed cell proliferation, as well as adenosine triphosphate and lactate production, during T cell activation. Moreover, the inhibitory effects of Ro5-4864 on T cell responses were conserved in TSPO-deficient cells. Our results suggest that Ro5-4864 inhibits CH responses by suppressing energy metabolism, at least via glycolysis, to reduce the T cell primary response in a TSPO-independent manner.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The concept of immune cell exhaustion/dysfunction has developed mainly to understand impaired type 1 immune responses, especially by CD8 T-cells against tumors or virus-infected cells, and has been applied to other lymphocytes. Natural killer (NK) cells and CD4 T cells support the efficient activation of CD8 T cells but exhibit dysfunctional phenotypes in tumor microenvironments and in chronic viral infections. In contrast, the concept of type 2 immune cell exhaustion/dysfunction is poorly established. Group 2 innate lymphoid cells (ILC2s) and T-helper 2 (Th2) cells are the major lymphocyte subsets that initiate and expand type 2 immune responses for antiparasitic immunity or allergy. In mouse models of chronic parasitic worm infections, Th2 cells display impaired type 2 immune responses. Chronic airway allergy induces exhausted-like ILC2s that quickly fall into activation-induced cell death to suppress exaggerated inflammation. Thus, the modes of exhaustion/dysfunction are quite diverse and rely on the types of inflammation and the cells. In this review, we summarize current knowledge of lymphocyte exhaustion/dysfunction in the context of type 1 and type 2 immune responses and discuss ILC2-specific regulatory mechanisms during chronic allergy.
免疫细胞衰竭/功能障碍的概念主要是为了理解受损的第一类免疫反应,尤其是 CD8 T 细胞对肿瘤或病毒感染细胞的反应,这一概念也被应用于其他淋巴细胞。自然杀伤(NK)细胞和 CD4 T 细胞支持 CD8 T 细胞的有效激活,但在肿瘤微环境和慢性病毒感染中表现出功能失调的表型。相比之下,第 2 类免疫细胞衰竭/功能失调的概念尚未确立。第 2 组先天性淋巴细胞(ILC2s)和 T 辅助细胞 2(Th2)是启动和扩大 2 型免疫反应的主要淋巴细胞亚群,可用于抗寄生虫免疫或过敏。在慢性寄生蠕虫感染的小鼠模型中,Th2 细胞显示出受损的 2 型免疫反应。慢性气道过敏会诱导类似衰竭的 ILC2,这些 ILC2 会迅速陷入活化诱导的细胞死亡,以抑制夸张的炎症反应。因此,衰竭/功能障碍的模式多种多样,取决于炎症类型和细胞。在这篇综述中,我们总结了目前在 1 型和 2 型免疫反应背景下有关淋巴细胞衰竭/功能障碍的知识,并讨论了慢性过敏过程中 ILC2 的特异性调节机制。
{"title":"Dysfunction of type 1 and type 2 immune cells: a lesson from exhausted-like ILC2s and their activation-induced cell death.","authors":"Takashi Ebihara, Toshiki Yamada, Akane Fuchimukai, Shunsuke Takasuga, Tentaro Endo, Takechiyo Yamada, Megumi Tatematsu","doi":"10.1093/intimm/dxae032","DOIUrl":"10.1093/intimm/dxae032","url":null,"abstract":"<p><p>The concept of immune cell exhaustion/dysfunction has developed mainly to understand impaired type 1 immune responses, especially by CD8 T-cells against tumors or virus-infected cells, and has been applied to other lymphocytes. Natural killer (NK) cells and CD4 T cells support the efficient activation of CD8 T cells but exhibit dysfunctional phenotypes in tumor microenvironments and in chronic viral infections. In contrast, the concept of type 2 immune cell exhaustion/dysfunction is poorly established. Group 2 innate lymphoid cells (ILC2s) and T-helper 2 (Th2) cells are the major lymphocyte subsets that initiate and expand type 2 immune responses for antiparasitic immunity or allergy. In mouse models of chronic parasitic worm infections, Th2 cells display impaired type 2 immune responses. Chronic airway allergy induces exhausted-like ILC2s that quickly fall into activation-induced cell death to suppress exaggerated inflammation. Thus, the modes of exhaustion/dysfunction are quite diverse and rely on the types of inflammation and the cells. In this review, we summarize current knowledge of lymphocyte exhaustion/dysfunction in the context of type 1 and type 2 immune responses and discuss ILC2-specific regulatory mechanisms during chronic allergy.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Basic-leucine zipper transcription factor ATF-like (BATF) and interferon regulatory factor 4 (IRF4) are crucial transcription factors for generation of cytotoxic effector and memory CD8+ T cells. JunB is required for expression of genes controlled by BATF and IRF4 in CD4+ T cell responses, but the role of JunB in CD8+ T cells remains unknown. Here, we demonstrate that JunB is essential for cytotoxic CD8+ T cell responses. JunB expression is transiently induced, depending on T cell receptor (TCR) signal strength. JunB deficiency severely impairs clonal expansion of effector CD8+ T cells in response to acute infection with Listeria monocytogenes. Junb-deficient CD8+ T cells fail to control transcription and chromatin accessibility of a specific set of genes regulated by BATF and IRF4, resulting in impaired cell survival, glycolysis, and cytotoxic CD8+ T cell differentiation. Furthermore, JunB deficiency enhances expression of coinhibitory receptors, including programmed death receptor 1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM3) upon activation of naïve CD8+ T cells. These results indicate that JunB, in collaboration with BATF and IRF4, promotes multiple key events in the early stage of cytotoxic CD8+ T cell responses.
碱性亮氨酸拉链转录因子 ATF 样(BATF)和干扰素调节因子 4(IRF4)是产生细胞毒性效应细胞和记忆 CD8+ T 细胞的关键转录因子。在 CD4+ T 细胞反应中,由 BATF 和 IRF4 控制的基因的表达需要 JunB,但 JunB 在 CD8+ T 细胞中的作用仍然未知。在这里,我们证明了 JunB 对于细胞毒性 CD8+ T 细胞反应至关重要。JunB的表达是瞬时诱导的,取决于T细胞受体(TCR)的信号强度。在李斯特菌急性感染时,缺乏JunB会严重影响效应CD8+ T细胞的克隆扩增。Junb缺陷的CD8+ T细胞无法控制由BATF和IRF4调控的一组特定基因的转录和染色质可及性,导致细胞存活、糖酵解和细胞毒性CD8+ T细胞分化受损。此外,在激活幼稚 CD8+ T 细胞时,缺乏 JunB 会增强共抑制受体的表达,包括程序性死亡受体 1(PD-1)和 T 细胞免疫球蛋白粘蛋白-3(TIM3)。这些结果表明,JunB 与 BATF 和 IRF4 合作,促进了细胞毒性 CD8+ T 细胞反应早期的多个关键事件。
{"title":"JunB is required for CD8+ T cell responses to acute infections.","authors":"Shukla Sarkar, Naoyuki Taira, Tsung-Han Hsieh, Hsiao-Chiao Chien, Masato Hirota, Shin-Ichi Koizumi, Daiki Sasaki, Miho Tamai, Yu Seto, Mio Miyagi, Hiroki Ishikawa","doi":"10.1093/intimm/dxae063","DOIUrl":"https://doi.org/10.1093/intimm/dxae063","url":null,"abstract":"<p><p>Basic-leucine zipper transcription factor ATF-like (BATF) and interferon regulatory factor 4 (IRF4) are crucial transcription factors for generation of cytotoxic effector and memory CD8+ T cells. JunB is required for expression of genes controlled by BATF and IRF4 in CD4+ T cell responses, but the role of JunB in CD8+ T cells remains unknown. Here, we demonstrate that JunB is essential for cytotoxic CD8+ T cell responses. JunB expression is transiently induced, depending on T cell receptor (TCR) signal strength. JunB deficiency severely impairs clonal expansion of effector CD8+ T cells in response to acute infection with Listeria monocytogenes. Junb-deficient CD8+ T cells fail to control transcription and chromatin accessibility of a specific set of genes regulated by BATF and IRF4, resulting in impaired cell survival, glycolysis, and cytotoxic CD8+ T cell differentiation. Furthermore, JunB deficiency enhances expression of coinhibitory receptors, including programmed death receptor 1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM3) upon activation of naïve CD8+ T cells. These results indicate that JunB, in collaboration with BATF and IRF4, promotes multiple key events in the early stage of cytotoxic CD8+ T cell responses.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bruno Marques Vieira, Beatriz Fernandes Almeida, Marcelo Pelajo Machado
The milky spots are structures found in the omentum of humans and other vertebrates, representing a fraction of the lymphomyeloid tissue associated with the celom. They majorly consist of B lymphocytes, T lymphocytes, and macrophages. Also found in smaller quantities are mesothelial, stromal, dendritic, and rare mast cells. In an experimental model of Schistosoma mansoni infection, there is significant activation of the omentum and milky spots, which exhibit numerous eosinophils. Despite being described for many years, the complete profile of cells found in milky spots and their functions remains largely unexplored. Here, we evaluate the leukocyte populations of the milky spots in homeostasis and a murine model of Schistosoma mansoni infection. The histopathological characterizations, phenotypic profile analysis, and characterization of the eosinophilic potential of progenitors and precursors comparing the milky spots with the spleen and bone marrow showed significant activation of milky spots in infected mice, with changes in the profile over the analyzed times, showing signs of migration and activation of eosinophils, with local eosinopoiesis and maintenance of the eosinophilic population. In naive mice, B1a and B1b cells comprise only a small fraction of B lymphocytes. However, B1b cells expand significantly during infection, peaking at 60 DPI before stabilizing by 90 DPI. B1a cells also increase initially but decrease over time. The behavior of milky spots differs from other primary and secondary lymphoid organs, acting as a central lymphoid organ in cavity immunity.
乳斑是在人类和其他脊椎动物的网膜中发现的结构,是与腹腔相关的淋巴细胞组织的一部分。它们主要由 B 淋巴细胞、T 淋巴细胞和巨噬细胞组成。此外,还有少量间皮细胞、基质细胞、树突状细胞和罕见的肥大细胞。在曼氏血吸虫感染的实验模型中,网膜和乳斑被明显激活,出现大量嗜酸性粒细胞。尽管嗜酸性粒细胞已被描述多年,但乳斑中发现的细胞的完整特征及其功能在很大程度上仍未被探索。在这里,我们评估了乳斑中白细胞群的平衡状态以及曼氏血吸虫感染的小鼠模型。组织病理学特征、表型轮廓分析以及嗜酸性粒细胞祖细胞和前体细胞的嗜酸性粒细胞潜能特征显示,嗜酸性粒细胞祖细胞和前体细胞与脾脏和骨髓进行比较后发现,在感染小鼠体内,嗜酸性粒细胞乳斑显著活化,其轮廓在分析时间内发生了变化,显示出嗜酸性粒细胞迁移和活化的迹象,并伴有局部嗜酸性粒细胞生成和嗜酸性粒细胞群的维持。在幼稚小鼠体内,B1a 和 B1b 细胞只占 B 淋巴细胞的一小部分。然而,B1b 细胞在感染期间会显著增大,在 60 DPI 时达到峰值,到 90 DPI 时趋于稳定。B1a 细胞最初也会增加,但随着时间的推移会减少。乳斑的表现不同于其他初级和次级淋巴器官,它是空腔免疫的核心淋巴器官。
{"title":"Eosinophil and B cell dynamics in the milky spots from Schistosoma mansoni-infected mice - Comparison with spleen and bone marrow, and extramedullary eosinopoiesis.","authors":"Bruno Marques Vieira, Beatriz Fernandes Almeida, Marcelo Pelajo Machado","doi":"10.1093/intimm/dxae064","DOIUrl":"https://doi.org/10.1093/intimm/dxae064","url":null,"abstract":"<p><p>The milky spots are structures found in the omentum of humans and other vertebrates, representing a fraction of the lymphomyeloid tissue associated with the celom. They majorly consist of B lymphocytes, T lymphocytes, and macrophages. Also found in smaller quantities are mesothelial, stromal, dendritic, and rare mast cells. In an experimental model of Schistosoma mansoni infection, there is significant activation of the omentum and milky spots, which exhibit numerous eosinophils. Despite being described for many years, the complete profile of cells found in milky spots and their functions remains largely unexplored. Here, we evaluate the leukocyte populations of the milky spots in homeostasis and a murine model of Schistosoma mansoni infection. The histopathological characterizations, phenotypic profile analysis, and characterization of the eosinophilic potential of progenitors and precursors comparing the milky spots with the spleen and bone marrow showed significant activation of milky spots in infected mice, with changes in the profile over the analyzed times, showing signs of migration and activation of eosinophils, with local eosinopoiesis and maintenance of the eosinophilic population. In naive mice, B1a and B1b cells comprise only a small fraction of B lymphocytes. However, B1b cells expand significantly during infection, peaking at 60 DPI before stabilizing by 90 DPI. B1a cells also increase initially but decrease over time. The behavior of milky spots differs from other primary and secondary lymphoid organs, acting as a central lymphoid organ in cavity immunity.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The transcription factor T-bet is essential for the anti-tumor effector function of NK cells, but the mechanism regulating its expression in NK cells remains unclear. In this study, we aimed to identify an NK cell intrinsic regulator that controls T-bet expression. Using T-bet-luciferase reporter assay screening, we identified a protein phosphatase inhibitor as a potential activator of T-bet expression. A series of PP2A-specific inhibitors (PP2Ai) or PP2A siRNA induced the expression of T-bet. In PP2Ai-treated mice, the expressions of T-bet and its downstream effector molecules, granzyme B and IFN-γ, were also upregulated in NK cells. Mechanistically, PP2Ai increased the phosphorylation of mTOR and ribosomal protein S6 in NK cells, and mTOR inhibitor canceled the effects of PP2Ai in NK cells. Importantly, NK cells isolated from PP2Ai-treated mice showed higher cytotoxicity and IFN-γ production; therefore, they increased the anti-tumor effector function of NK cells. Accordingly, PP2Ai treatment inhibited lung metastasis of B16 melanoma by NK cell- and mTOR-dependent mechanisms. These results suggest that PP2A negatively regulates NK cell T-bet expression and effector function by an mTOR-dependent mechanism.
转录因子 T-bet 对 NK 细胞的抗肿瘤效应功能至关重要,但其在 NK 细胞中的表达调控机制仍不清楚。在这项研究中,我们的目的是找出一种控制T-bet表达的NK细胞内在调节因子。通过T-bet-荧光素酶报告实验筛选,我们发现一种蛋白磷酸酶抑制剂是T-bet表达的潜在激活剂。一系列 PP2A 特异性抑制剂(PP2Ai)或 PP2A siRNA 诱导了 T-bet 的表达。在 PP2Ai 处理的小鼠中,T-bet 及其下游效应分子颗粒酶 B 和 IFN-γ 在 NK 细胞中的表达也上调。从机理上讲,PP2Ai增加了NK细胞中mTOR和核糖体蛋白S6的磷酸化,而mTOR抑制剂消除了PP2Ai对NK细胞的影响。重要的是,从经 PP2Ai 处理的小鼠体内分离出的 NK 细胞显示出更高的细胞毒性和 IFN-γ 生成,因此增强了 NK 细胞的抗肿瘤效应功能。因此,PP2Ai通过NK细胞和mTOR依赖机制抑制了B16黑色素瘤的肺转移。这些结果表明,PP2A通过mTOR依赖性机制负向调节NK细胞T-bet的表达和效应功能。
{"title":"PP2A negatively regulates NK cell T-bet expression and anti-tumor effector function.","authors":"Yui Shinzawa, Daisuke Hara, Yuki Shinguryo, Satoru Yokoyama, Manabu Kawada, Yoshihiro Hayakawa","doi":"10.1093/intimm/dxae057","DOIUrl":"https://doi.org/10.1093/intimm/dxae057","url":null,"abstract":"<p><p>The transcription factor T-bet is essential for the anti-tumor effector function of NK cells, but the mechanism regulating its expression in NK cells remains unclear. In this study, we aimed to identify an NK cell intrinsic regulator that controls T-bet expression. Using T-bet-luciferase reporter assay screening, we identified a protein phosphatase inhibitor as a potential activator of T-bet expression. A series of PP2A-specific inhibitors (PP2Ai) or PP2A siRNA induced the expression of T-bet. In PP2Ai-treated mice, the expressions of T-bet and its downstream effector molecules, granzyme B and IFN-γ, were also upregulated in NK cells. Mechanistically, PP2Ai increased the phosphorylation of mTOR and ribosomal protein S6 in NK cells, and mTOR inhibitor canceled the effects of PP2Ai in NK cells. Importantly, NK cells isolated from PP2Ai-treated mice showed higher cytotoxicity and IFN-γ production; therefore, they increased the anti-tumor effector function of NK cells. Accordingly, PP2Ai treatment inhibited lung metastasis of B16 melanoma by NK cell- and mTOR-dependent mechanisms. These results suggest that PP2A negatively regulates NK cell T-bet expression and effector function by an mTOR-dependent mechanism.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Onco-immunotherapy via blocking checkpoint-inhibitors has revolutionized the treatment-landscape of several malignancies, though not in the metastatic castration-resistant prostate cancer (PCa) owing to immunosuppressive and poorly immunogenic "cold" tumor microenvironment (TME). Turning up the heat of such cold TME via triggering innate immunity is now of increasing interest to restore immune-surveillance. Retinoic acid-inducible gene- I (RIG-I)-like receptors (RLRs) are cytosolic innate-sensors that can detect exogenous RNAs and induce type-I interferons and other pro-inflammatory signaling. RIG-I activation is suggested to be a valuable addition to the treatment approaches for several cancers. However, the knowledge about RIG-I signaling in PCa remains elusive. The present study evaluated the expression of two important RLRs, RIG-I and melanoma differentiation-associated protein 5 (MDA5) along with their downstream partners, mitochondrial antiviral-signaling protein (MAVS) and ERA G-protein-like 1 (ERAL1) during PCa progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The early stage of PCa revealed a significant increment in the expression of RLRs, but not MAVS. However, the advanced stage showed downregulated RLR signaling. Further, the therapeutic implication of 5'ppp-dsRNA, a synthetic RIG-I agonist and Bcl2 gene silencer has been investigated in vitro and in vivo. Intra-tumoral delivery of 5'ppp-dsRNA regressed tumor growth via triggering tumor cells apoptosis, immunomodulation, and inducing phagocytic "eat me" signals. These findings highlight that, for the first time, RIG-I activation and Bcl-2 silencing with 5'ppp-dsRNA can serve as a potent tumor-suppressor strategy in PCa and has a significant clinical implication in transforming "cold" TME into immunogenic "hot" TME of PCa.
{"title":"Intra-tumoral delivery of 5'ppp-dsRNA induces robust anti-tumor response via RIG-I activation and Bcl-2 gene downregulation in murine model of prostate cancer.","authors":"Kasturi Ganguly, Siddhanath M Metkari, Barnali Biswas, Rambhadur Subedi, Taruna Madan","doi":"10.1093/intimm/dxae061","DOIUrl":"https://doi.org/10.1093/intimm/dxae061","url":null,"abstract":"<p><p>Onco-immunotherapy via blocking checkpoint-inhibitors has revolutionized the treatment-landscape of several malignancies, though not in the metastatic castration-resistant prostate cancer (PCa) owing to immunosuppressive and poorly immunogenic \"cold\" tumor microenvironment (TME). Turning up the heat of such cold TME via triggering innate immunity is now of increasing interest to restore immune-surveillance. Retinoic acid-inducible gene- I (RIG-I)-like receptors (RLRs) are cytosolic innate-sensors that can detect exogenous RNAs and induce type-I interferons and other pro-inflammatory signaling. RIG-I activation is suggested to be a valuable addition to the treatment approaches for several cancers. However, the knowledge about RIG-I signaling in PCa remains elusive. The present study evaluated the expression of two important RLRs, RIG-I and melanoma differentiation-associated protein 5 (MDA5) along with their downstream partners, mitochondrial antiviral-signaling protein (MAVS) and ERA G-protein-like 1 (ERAL1) during PCa progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The early stage of PCa revealed a significant increment in the expression of RLRs, but not MAVS. However, the advanced stage showed downregulated RLR signaling. Further, the therapeutic implication of 5'ppp-dsRNA, a synthetic RIG-I agonist and Bcl2 gene silencer has been investigated in vitro and in vivo. Intra-tumoral delivery of 5'ppp-dsRNA regressed tumor growth via triggering tumor cells apoptosis, immunomodulation, and inducing phagocytic \"eat me\" signals. These findings highlight that, for the first time, RIG-I activation and Bcl-2 silencing with 5'ppp-dsRNA can serve as a potent tumor-suppressor strategy in PCa and has a significant clinical implication in transforming \"cold\" TME into immunogenic \"hot\" TME of PCa.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and increase of CD26+ T cells in inflamed tissues and peripheral blood has been reported in diverse autoimmune diseases. In contrast, our group has previously shown that levels of circulating CD26+ T cells are decreased in patients with systemic lupus erythematosus (SLE), although the role of reduced CD26 T cell surface expression in SLE pathology remains to be elucidated. In the present study, we conducted CD26-based T cell subset analyses utilizing peripheral blood mononuclear cells from 57 SLE patients and 31 healthy adult volunteers. We show that the increase in CD26(-) T cell population reflects the abnormal expansion of CD26(-)CD28(-) cytotoxic subsets of both CD8 T cells and CD4 T cells in SLE patients. Single cell RNA sequencing analysis of the CD26(-)CD28(-) CD4 and CD8 T cell populations reveals unique characteristics with similarities to natural killer T cells. In addition, the level of CD26(-)CD28(-) T cells is increased in some active stage SLE patients with renal manifestation. Meanwhile, effect of prednisolone treatment on these populations varies from patient to patient, with levels of these cytotoxic effector populations still being elevated in some inactive stage SLE patients. Taken together, our data suggest that analysis of these populations in SLE may be a useful tool to classify this markedly heterogeneous condition.
CD26 是一种人类 T 细胞共振分子,也是一种 T 细胞亚群标志物,在多种自身免疫性疾病中都有 CD26+ T 细胞在炎症组织和外周血中增加的报道。相比之下,我们的研究小组以前曾发现,系统性红斑狼疮(SLE)患者的循环 CD26+ T 细胞水平降低,但 CD26 T 细胞表面表达减少在系统性红斑狼疮病理学中的作用仍有待阐明。在本研究中,我们利用 57 名系统性红斑狼疮患者和 31 名健康成年志愿者的外周血单核细胞进行了基于 CD26 的 T 细胞亚群分析。我们发现,CD26(-)T 细胞群的增加反映了系统性红斑狼疮患者 CD8 T 细胞和 CD4 T 细胞中 CD26(-)CD28(-)细胞毒性亚群的异常扩张。对CD26(-)CD28(-) CD4和CD8 T细胞群的单细胞RNA测序分析表明,它们具有与自然杀伤T细胞相似的独特特征。此外,在一些有肾脏表现的活动期系统性红斑狼疮患者中,CD26(-)CD28(-)T细胞的水平会升高。同时,泼尼松龙治疗对这些细胞群的影响因人而异,在一些非活动期系统性红斑狼疮患者中,这些细胞毒性效应细胞群的水平仍然升高。总之,我们的数据表明,对系统性红斑狼疮患者的这些细胞毒效应群进行分析,可能是对这一明显异质性疾病进行分类的有用工具。
{"title":"An abnormal increase in CD26(-)CD28(-) cytotoxic effector CD4 and CD8 T cell populations in patients with systemic lupus erythematosus.","authors":"Ryo Hatano, Hayato Nakamura, Ayako Yamamoto, Haruna Otsuka, Takumi Itoh, Nao Hosokawa, Jinghui Yu, Sedigheh Ranjbar, Yuta Hasegawa, Tsutomu Sato, Nam H Dang, Kei Ohnuma, Shinji Morimoto, Iwao Sekigawa, Tomonori Ishii, Chikao Morimoto","doi":"10.1093/intimm/dxae062","DOIUrl":"https://doi.org/10.1093/intimm/dxae062","url":null,"abstract":"<p><p>CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and increase of CD26+ T cells in inflamed tissues and peripheral blood has been reported in diverse autoimmune diseases. In contrast, our group has previously shown that levels of circulating CD26+ T cells are decreased in patients with systemic lupus erythematosus (SLE), although the role of reduced CD26 T cell surface expression in SLE pathology remains to be elucidated. In the present study, we conducted CD26-based T cell subset analyses utilizing peripheral blood mononuclear cells from 57 SLE patients and 31 healthy adult volunteers. We show that the increase in CD26(-) T cell population reflects the abnormal expansion of CD26(-)CD28(-) cytotoxic subsets of both CD8 T cells and CD4 T cells in SLE patients. Single cell RNA sequencing analysis of the CD26(-)CD28(-) CD4 and CD8 T cell populations reveals unique characteristics with similarities to natural killer T cells. In addition, the level of CD26(-)CD28(-) T cells is increased in some active stage SLE patients with renal manifestation. Meanwhile, effect of prednisolone treatment on these populations varies from patient to patient, with levels of these cytotoxic effector populations still being elevated in some inactive stage SLE patients. Taken together, our data suggest that analysis of these populations in SLE may be a useful tool to classify this markedly heterogeneous condition.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammation often with autoimmunity, which may underlie the development of diverse disorders with age. Immunosenescent phenotypes are associated with the emergence of unique lymphocyte subpopulations of both T and B lineages. We report that a CD153+ PD-1+ CD4+ T-cell subpopulation with severely attenuated T-cell receptor (TCR)-responsiveness, termed senescence-associated T (SAT) cells, co-evolve with potentially autoreactive CD30+ B cells, such as spontaneous germinal center B cells and age-associated B cells, in aging mice. SAT cells and CD30+ B cells are reciprocally activated with the aid of the interaction of CD153 with CD30 in trans and with the TCR complex in cis, resulting in the restoration of TCR-mediated proliferation and secretion of abundant proinflammatory cytokines in SAT cells and the activation and production of autoantibodies by CD30+ B cells. Besides normal aging, the development of SAT cells coupled with counterpart B cells may be robustly accelerated and accumulated in the relevant tissues of lymphoid or extra-lymphoid organs under chronic inflammatory conditions including autoimmunity and may contribute to the pathogenesis and aggravation of the disorders. This review summarizes and discusses recent advances in the understanding of SAT cells in the contexts of immunosenescent phenotypes, autoimmune and chronic inflammatory diseases and provides a novel therapeutic clue.
免疫系统中与年龄有关的变化被称为免疫衰老,这种变化似乎具有相当矛盾的表现,即适应性免疫能力减弱,慢性炎症倾向增加,往往伴有自身免疫,这可能是随着年龄增长出现各种疾病的原因。免疫增强表型与 T 系和 B 系独特淋巴细胞亚群的出现有关。我们报告说,在衰老的小鼠中,一个对 T 细胞受体(TCR)反应性严重减弱的 CD153+ PD-1+ CD4+ T 细胞亚群(称为衰老相关 T 细胞(SAT))与潜在的自反应性 CD30+ B 细胞(如自发生殖中心 B 细胞和年龄相关 B 细胞)共同进化。SAT 细胞和 CD30+ B 细胞借助 CD153 与 CD30 的反式相互作用和与 TCR 复合物的顺式相互作用相互激活,导致 TCR 介导的增殖恢复,SAT 细胞分泌大量促炎细胞因子,CD30+ B 细胞激活并产生自身抗体。除正常衰老外,在慢性炎症(包括自身免疫)条件下,SAT 细胞和对应的 B 细胞可能会在淋巴或淋巴外器官的相关组织中加速发育和积累,并可能导致疾病的发病机制和恶化。这篇综述总结并讨论了在免疫增强表型、自身免疫和慢性炎症疾病背景下了解 SAT 细胞的最新进展,并提供了一条新的治疗线索。
{"title":"Senescence-Associated T cells in Immunosenescence and Diseases.","authors":"Yuji Fukushima, Ryuji Ueno, Nagahiro Minato, Masakazu Hattori","doi":"10.1093/intimm/dxae056","DOIUrl":"https://doi.org/10.1093/intimm/dxae056","url":null,"abstract":"<p><p>Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammation often with autoimmunity, which may underlie the development of diverse disorders with age. Immunosenescent phenotypes are associated with the emergence of unique lymphocyte subpopulations of both T and B lineages. We report that a CD153+ PD-1+ CD4+ T-cell subpopulation with severely attenuated T-cell receptor (TCR)-responsiveness, termed senescence-associated T (SAT) cells, co-evolve with potentially autoreactive CD30+ B cells, such as spontaneous germinal center B cells and age-associated B cells, in aging mice. SAT cells and CD30+ B cells are reciprocally activated with the aid of the interaction of CD153 with CD30 in trans and with the TCR complex in cis, resulting in the restoration of TCR-mediated proliferation and secretion of abundant proinflammatory cytokines in SAT cells and the activation and production of autoantibodies by CD30+ B cells. Besides normal aging, the development of SAT cells coupled with counterpart B cells may be robustly accelerated and accumulated in the relevant tissues of lymphoid or extra-lymphoid organs under chronic inflammatory conditions including autoimmunity and may contribute to the pathogenesis and aggravation of the disorders. This review summarizes and discusses recent advances in the understanding of SAT cells in the contexts of immunosenescent phenotypes, autoimmune and chronic inflammatory diseases and provides a novel therapeutic clue.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}