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Poliosis Is Associated with Response to Checkpoint-Inhibitor Therapy: A Case Report of Two Patients with Multifocal Metastatic Melanoma 脊髓灰质炎与检查点抑制剂治疗反应相关:两例多灶性转移性黑色素瘤患者的病例报告
Pub Date : 2022-03-31 DOI: 10.3390/immuno2020020
M. Haist, H. Stege, Verena Maikranz, Maria Halley Blanco, S. Grabbe, C. Loquai
The advent of immune-checkpoint inhibitors (ICIs) led to significant improvements in the treatment of patients with advanced melanoma and resulted in durable tumor responses in a considerable number of advanced melanoma patients. Next to the immune-mediated anti-neoplastic effects, ICIs may cause various immune-related adverse events (irAEs), often requiring early discontinuation of therapy. By contrast, cutaneous irAE rarely enforce treatment discontinuation but may represent simple and robust predictive markers for treatment response. The relevance of irAEs as clinical markers for an improved response to immunotherapy is still debated. We report here on two patients with multifocal metastatic melanoma who developed the rare event of generalized poliosis during combined immunotherapy with ipilimumab plus nivolumab, followed by a near-complete and durable response. Our observations suggest that poliosis may be a useful and simple clinical indicator of anti-tumor immunity, clinical response and favorable survival outcome in advanced melanoma patients treated with ICI.
免疫检查点抑制剂(ici)的出现显著改善了晚期黑色素瘤患者的治疗,并在相当数量的晚期黑色素瘤患者中产生了持久的肿瘤反应。除了免疫介导的抗肿瘤作用外,ICIs还可能引起各种免疫相关不良事件(irAEs),通常需要早期停止治疗。相比之下,皮肤irAE很少强制停止治疗,但可能是治疗反应的简单而可靠的预测指标。irae作为改善免疫治疗反应的临床标志物的相关性仍存在争议。我们在此报告了两例多灶性转移性黑色素瘤患者,他们在ipilimumab和nivolumab联合免疫治疗期间发生了罕见的广泛性脊髓灰质炎事件,随后出现了近乎完全和持久的反应。我们的观察结果表明,脊髓灰质炎可能是ICI治疗晚期黑色素瘤患者抗肿瘤免疫、临床反应和良好生存结果的一个有用和简单的临床指标。
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引用次数: 2
Effect of Wild Blueberry Metabolites on Biomarkers of Gastrointestinal and Immune Health In Vitro 野生蓝莓代谢物对体外胃肠道和免疫健康生物标志物的影响
Pub Date : 2022-03-25 DOI: 10.3390/immuno2020019
Thirumurugan Rathinasabapathy, Jade Lomax, Kavin Srikanth, D. Esposito, C. Kay, S. Komarnytsky
Wild blueberries (Vaccinium angustifolium Aiton.) are a rich source of dietary fiber and (poly)phenols with gastrointestinal and immune health-promoting properties, however, their mechanisms of action on the intestinal epithelial cells and transient tissue macrophages remain to be elucidated. In this study, we evaluated the individual effects of anthocyanins, short-chain fatty acids (metabolites derived from fiber), and a series of hydroxycinnamic and hydroxybenzoic acid metabolites common to anthocyanins and other polyphenols on epithelial gut homeostasis in human colon epithelial CCD-18 cells and murine RAW 264.7 macrophages. Gastrointestinal cell migration was enhanced in response to anthocyanin glucosides with the maximum effect observed for malvidin-3-glucoside, and a structural subset of hydroxybenzoic acids, especially 2-hydroxybenzoic acid. Enhanced staining for ZO-1 protein in the junctional complexes was observed in CCD-18 cells treated with malvidin and butyrate, as well as several phenolic metabolites, including hydroxybenzoic and hydroxycinnamic acids. Nitric oxide production and pro-inflammatory gene expression profiles in the LPS-stimulated macrophages were mostly affected by treatments with 3-caffeoylquinic (chlorogenic) and 3,4-dihydroxycinnamic (caffeic) acids, as well as 2-hydroxybenzoic acid. This study lays the foundation for future investigations evaluating the effects of dietary interventions on managing gastrointestinal and inflammatory pathophysiological outcomes.
野生蓝莓(Vaccinium angustifolium Aiton.)富含膳食纤维和(多)酚,具有促进胃肠道和免疫健康的特性,但其对肠上皮细胞和瞬态组织巨噬细胞的作用机制尚不清楚。在这项研究中,我们评估了花青素、短链脂肪酸(来自纤维的代谢物)以及花青素和其他多酚共同的一系列羟基肉桂酸和羟基苯甲酸代谢物对人结肠上皮CCD-18细胞和小鼠RAW 264.7巨噬细胞上皮肠道稳态的个体影响。胃肠道细胞迁移响应于花青素糖苷,其中最大的影响观察到malvidin-3-葡萄糖苷和羟基苯甲酸的结构亚群,特别是2-羟基苯甲酸。在malvidin和丁酸以及几种酚类代谢物(包括羟基苯甲酸和羟基肉桂酸)处理的CCD-18细胞中,观察到连接复合物中ZO-1蛋白的染色增强。在lps刺激的巨噬细胞中,一氧化氮的产生和促炎基因表达谱主要受到3-咖啡酰奎宁酸(绿原)和3,4-二羟基肉桂酸(咖啡酸)以及2-羟基苯甲酸的影响。本研究为未来研究评估饮食干预对胃肠道和炎症病理生理结果的影响奠定了基础。
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引用次数: 3
Proteogenomics Analysis Reveals Novel Micropeptides in Primary Human Immune Cells 蛋白质基因组学分析揭示了人类原代免疫细胞中新的微肽
Pub Date : 2022-03-23 DOI: 10.3390/immuno2020018
Yashwanth Subbannayya, Ankit Bhatta, S. Pinto, K. Fitzgerald, R. K. Kandasamy
Short open reading frames (sORFs) encoding functional peptides have emerged as important mediators of biological processes. Recent studies indicate that sORFs of long non-coding RNAs (lncRNAs) can encode functional micropeptides regulating immunity and inflammation. However, large-scale identification of potential micropeptide-encoding sequences is a significant challenge. We present a data analysis pipeline that uses immune cell-derived mass spectrometry-based proteomic data reanalyzed using a rigorous proteogenomics-based workflow. Our analysis resulted in the identification of 2815 putative lncRNA-encoded micropeptides across three human immune cell types. Stringent score cut-off and manual verification confidently identified 185 high-confidence putative micropeptide-coding events, of which a majority have not been reported previously. Functional validation revealed the expression and localization of lnc-MKKS in both nucleus and cytoplasmic compartments. Our pilot analysis serves as a resource for future studies focusing on the role of micropeptides in immune cell response.
编码功能肽的短开放阅读框(sorf)已成为生物过程的重要介质。最近的研究表明,长链非编码rna (lncRNAs)的sorf可以编码调节免疫和炎症的功能性微肽。然而,大规模鉴定潜在的微肽编码序列是一个重大挑战。我们提出了一个数据分析管道,使用免疫细胞衍生的基于质谱的蛋白质组学数据,使用严格的基于蛋白质基因组学的工作流程重新分析。我们的分析结果在三种人类免疫细胞类型中鉴定了2815种假定的lncrna编码微肽。严格的分值截止和人工验证自信地确定了185个高置信度的假定的微肽编码事件,其中大多数以前没有报道过。功能验证显示lnc-MKKS在细胞核和细胞质区室中均有表达和定位。我们的初步分析为未来研究微肽在免疫细胞反应中的作用提供了资源。
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引用次数: 1
The New Anatomy of Neuroimmunology 神经免疫学新解剖学
Pub Date : 2022-03-16 DOI: 10.3390/immuno2010016
C. Solaro, D. Barratt, M. Vaccarezza
In the past few years, a renowned interest in the interplay between the immune system and central nervous systems (CNS) has sparked a wealth of new experimental studies. Two recent publications in Science shed new light on the “resident” immune cell populations in the CNS and their functions in homeostasis and pathological status, with potential implications in understanding CNS disease mechanisms and in designing new “intelligent” therapies.
在过去的几年里,免疫系统和中枢神经系统(CNS)之间的相互作用引起了广泛的兴趣,引发了大量新的实验研究。最近发表在《科学》杂志上的两篇文章揭示了中枢神经系统中“常驻”免疫细胞群及其在稳态和病理状态中的功能,这对理解中枢神经系统疾病机制和设计新的“智能”疗法具有潜在的意义。
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引用次数: 0
Host–Pathogen Interaction in Leishmaniasis: Immune Response and Vaccination Strategies 利什曼病的宿主-病原体相互作用:免疫反应和疫苗接种策略
Pub Date : 2022-03-09 DOI: 10.3390/immuno2010015
H. Yasmin, Anureeta Adhikary, M. Al-Ahdal, Syamal Roy, U. Kishore
Leishmaniasis is a zoonotic and vector-borne infectious disease that is caused by the genus Leishmania belonging to the trypanosomatid family. The protozoan parasite has a digenetic life cycle involving a mammalian host and an insect vector. Leishmaniasisis is a worldwide public health problem falling under the neglected tropical disease category, with over 90 endemic countries, and approximately 1 million new cases and 20,000 deaths annually. Leishmania infection can progress toward the development of species–specific pathologic disorders, ranging in severity from self-healing cutaneous lesions to disseminating muco-cutaneous and fatal visceral manifestations. The severity and the outcome of leishmaniasis is determined by the parasite’s antigenic epitope characteristics, the vector physiology, and most importantly, the immune response and immune status of the host. This review examines the nature of host–pathogen interaction in leishmaniasis, innate and adaptive immune responses, and various strategies that have been employed for vaccine development.
利什曼病是一种人畜共患和媒介传播的传染病,由属于锥虫病科的利什曼属引起。原生动物寄生虫具有包括哺乳动物宿主和昆虫载体的遗传生命周期。利什曼病是一个被忽视的热带病范畴的全球性公共卫生问题,有90多个流行国家,每年约有100万新病例和20 000人死亡。利什曼原虫感染可发展为物种特异性病理疾病,其严重程度从自愈性皮肤病变到弥漫性皮肤粘膜和致命的内脏表现不等。利什曼病的严重程度和结果取决于寄生虫的抗原表位特征、媒介生理学,最重要的是,宿主的免疫反应和免疫状态。本文综述了利什曼病中宿主-病原体相互作用的性质,先天和适应性免疫反应,以及用于疫苗开发的各种策略。
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引用次数: 16
Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma 铁下垂在肝癌免疫治疗中的意义
Pub Date : 2022-02-15 DOI: 10.3390/immuno2010014
Johanna Kusnick, Alix Bruneau, F. Tacke, L. Hammerich
Ferroptosis is a recently recognized iron-dependent form of non-apoptotic regulated cell death (RCD) characterized by lipid peroxide accumulation to lethal levels. Cancer cells, which show an increased iron dependency to enable rapid growth, seem vulnerable to ferroptosis. There is also increasing evidence that ferroptosis might be immunogenic and therefore could synergize with immunotherapies. Hepatocellular carcinoma (HCC) is the most common primary liver tumor with a low survival rate due to frequent recurrence and limited efficacy of conventional chemotherapies, illustrating the urgent need for novel drug approaches or combinatorial strategies. Immunotherapy is a new treatment approach for advanced HCC patients. In this setting, ferroptosis inducers may have substantial clinical potential. However, there are still many questions to answer before the mystery of ferroptosis is fully unveiled. This review discusses the existing studies and our current understanding regarding the molecular mechanisms of ferroptosis with the goal of enhancing response to immunotherapy of liver cancer. In addition, challenges and opportunities in clinical applications of potential candidates for ferroptosis-driven therapeutic strategies will be summarized. Unraveling the role of ferroptosis in the immune response could benefit the development of promising anti-cancer therapies that overcome drug resistance and prevent tumor metastasis.
铁凋亡是最近发现的一种铁依赖形式的非凋亡调节细胞死亡(RCD),其特征是脂质过氧化积累到致死水平。癌细胞表现出对铁的依赖性,使其能够快速生长,似乎易受铁下垂的影响。也有越来越多的证据表明,铁下垂可能是免疫原性的,因此可以与免疫疗法协同作用。肝细胞癌(HCC)是最常见的原发性肝脏肿瘤,由于其复发频繁和常规化疗疗效有限,生存率较低,迫切需要新的药物途径或联合治疗策略。免疫治疗是晚期肝癌患者的一种新的治疗方法。在这种情况下,铁下垂诱导剂可能具有巨大的临床潜力。然而,在铁下垂之谜完全揭开之前,仍有许多问题需要回答。本文就铁下垂的分子机制进行综述,以期提高肝癌免疫治疗的应答。此外,本文还将总结在临床应用中潜在候选铁中毒驱动的治疗策略的挑战和机遇。揭示铁下垂在免疫反应中的作用可能有助于开发有前途的抗癌疗法,克服耐药性并防止肿瘤转移。
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引用次数: 3
Orchestration of Immune Cells Contributes to Fibrosis in IgG4-Related Disease 免疫细胞协调促进igg4相关疾病的纤维化
Pub Date : 2022-02-10 DOI: 10.3390/immuno2010013
N. Kaneko, M. Moriyama, T. Maehara, Hu Chen, Yuka Miyahara, Seiji Nakamura
This review summarizes recent progress in understanding the pathogenesis of IgG4-related disease (IgG4-RD), with a focus on fibrosis. Several studies reported that CD4+ T cells with cytotoxic activity promoted by the secretion of granzyme and perforin, cytotoxic CD4+ T cells (CD4+CTLs), and disease-specific activated B cells, infiltrated inflamed tissues and cooperated to induce tissue fibrosis in autoimmune fibrotic diseases such as IgG4-RD, systemic sclerosis, and fibrosing mediastinitis. An accumulation of cells undergoing apoptotic cell death induced by CD4+CTLs and CD8+CTLs followed by macrophage-mediated clearing and finally tissue remodeling driven by cytokines released by CD4+CTLs, activated B cells, and M2 macrophages may contribute to the activation of fibroblasts and collagen production. In IgG4-RD, this process likely involves the apoptosis of non-immune, non-endothelial cells of mesenchymal origin and subsequent tissue remodeling. In summary, CD4+CTLs infiltrate affected tissues where they may cooperate with activated B cells, CD8+CTLs, and M2 macrophages, to induce apoptosis by secreting cytotoxic cytokines. These immune cells also drive fibrosis by secreting pro-fibrotic molecules in IgG4-RD.
本文综述了igg4相关疾病(IgG4-RD)发病机制的最新进展,重点是纤维化。有研究报道,在IgG4-RD、系统性硬化症、纤维化性纵隔炎等自身免疫性纤维化疾病中,由颗粒酶和穿孔素分泌促进具有细胞毒活性的CD4+ T细胞、细胞毒CD4+ T细胞(CD4+ ctl)和疾病特异性活化的B细胞浸润炎症组织,共同诱导组织纤维化。CD4+ ctl和CD8+ ctl诱导的细胞凋亡,随后是巨噬细胞介导的清除,最后是由CD4+ ctl释放的细胞因子、活化的B细胞和M2巨噬细胞驱动的组织重塑,这些细胞的积累可能有助于成纤维细胞的激活和胶原蛋白的产生。在IgG4-RD中,这一过程可能涉及间充质来源的非免疫、非内皮细胞的凋亡和随后的组织重塑。综上所述,CD4+ ctl浸润病变组织,与活化的B细胞、CD8+ ctl和M2巨噬细胞合作,通过分泌细胞毒性细胞因子诱导细胞凋亡。这些免疫细胞也通过在IgG4-RD中分泌促纤维化分子来驱动纤维化。
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引用次数: 2
Acknowledgment to Reviewers of Immuno in 2021 向2021年Immuno审稿人致谢
Pub Date : 2022-01-27 DOI: 10.3390/immuno2010011
Rigorous peer-reviews are the basis of high-quality academic publishing [...]
严格的同行评议是高质量学术出版的基础[…]
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引用次数: 0
Anti-Inflammatory, Antimicrobial, and Vasoconstriction Activities of an Anti-Hemorrhoidal Mixture of Alchemilla vulgaris, Conyza bonariensis, and Nigella sativa: In Vitro and Clinical Evaluations 金缕草、黑草和黑草的抗痔疮混合物的抗炎、抗菌和血管收缩活性:体外和临床评价
Pub Date : 2022-01-26 DOI: 10.3390/immuno2010010
O. Said, I. Khamaysi, Abdalsalam Kmail, O. Sadiq, Besan Saied, S. Fulder, Basheer Abofarekh, Mahmud Masalha, R. Amin, B. Saad
Nigella sativa, Conyza bonariensis, and Alchemilla vulgaris are highly recommended in Greco-Arab traditional medicine as anti-hemorrhoid medicinal plants. The efficacy and safety of a topical cream (HPC) consisting of water–ethanol extracts of these three plants were evaluated here in vitro and in a randomized, double-blind, placebo-controlled study (RDBPC). HPC showed no significant cytotoxic effects in fibroblast cell line 3T3 (LDH-release and MTT assay); it inhibited the nitric oxide production by cultured monocyte cell line THP-1 in a dose-dependent manner (reaching the control levels of untreated cells at a concentration of 100 μg/mL). HPC showed a dose-dependent antibacterial activity against Escherichia coli (60% inhibition compared to Ampicillin at 5 mg/disc) and a significant vasoconstriction effect on intestinal vein rings (40% increase compared to phenylephrine). In a RDBPC with 77 hemorrhoidal disease (patients ages 19–61 years with a median grade of hemorrhoids of 2.0), we determined the anti-hemorrhoid efficacy and safety of HPC. The patients were randomly assigned to the HPC group (54 patients) or the placebo group (23 patients). They were asked to apply 2–3 mL of HPC or placebo twice daily for 6 days. The degree of hemorrhoidal disease severity, hemorrhage severity, pain, and itching served as an evaluation of the HPC efficacy. Compared to the placebo group, the obtained results showed that 6 days of treatment with HPC reduced the indexes of hemorrhage severity, severity of pain, and severity of itching to 0–1, 1, and 1 after 6 days, respectively. In conclusion, patients treated with HPC had a significant clinical improvement in all disease severity parameters compared to placebo. In vitro evaluations proved HPC to have significant antimicrobial, anti-inflammatory, and vasoconstriction effects. Therefore, HPC represents an interesting alternative treatment for hemorrhoidal disease.
黑皮草、黑参、金缕草是希腊-阿拉伯传统医学中非常推荐的抗痔疮药用植物。我们在体外和随机、双盲、安慰剂对照研究(RDBPC)中评估了由这三种植物的水乙醇提取物组成的外用乳膏(HPC)的疗效和安全性。HPC对成纤维细胞系3T3无明显的细胞毒作用(ldh释放和MTT测定);抑制THP-1单核细胞产生一氧化氮呈剂量依赖性(浓度为100 μg/mL时达到对照水平)。HPC对大肠杆菌的抑菌活性呈剂量依赖性(与5 mg/盘的氨苄青霉素相比,抑制率为60%),对肠静脉环的血管收缩作用显著(与苯肾上腺素相比,抑制率提高了40%)。在77例RDBPC合并痔疮疾病(患者年龄19-61岁,痔疮中位分级2.0)的病例中,我们确定了HPC的抗痔疮疗效和安全性。患者被随机分配到HPC组(54例)或安慰剂组(23例)。他们被要求使用2-3毫升的HPC或安慰剂,每天两次,持续6天。痔疮疾病严重程度、出血严重程度、疼痛和瘙痒程度作为HPC疗效的评价指标。结果显示,与安慰剂组相比,HPC治疗6天后出血严重程度、疼痛严重程度和瘙痒严重程度指标分别降低至0-1、1和1。总之,与安慰剂相比,接受HPC治疗的患者在所有疾病严重程度参数方面均有显著的临床改善。体外评价证明HPC具有显著的抗菌、抗炎和血管收缩作用。因此,HPC代表了一个有趣的替代治疗痔疮疾病。
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引用次数: 2
CIDP: Current Treatments and Identification of Targets for Future Specific Therapeutic Intervention CIDP:目前的治疗方法和未来特异性治疗干预目标的确定
Pub Date : 2022-01-21 DOI: 10.3390/immuno2010009
S. Brun, J. de Seze, S. Muller
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder of the peripheral nervous system. This clinically heterogeneous neurological disorder is closely related to Guillain–Barré syndrome and is considered the chronic counterpart of that acute disease. Currently available treatments are mostly empirical; they include corticosteroids, intravenous immunoglobulins, plasma exchange and chronic immunosuppressive agents, either alone or in combination. Recent advances in the understanding of the underlying pathogenic mechanisms in CIDP have brought a number of novel ways of possible intervention for use in CIDP. This review summarizes selected pre-clinical and clinical findings, highlights the importance of using adapted animal models to evaluate the efficacy of novel treatments, and proposes the outlines of future directions to ameliorate the conditions of patients with CIDP.
慢性炎症性脱髓鞘性多神经病变(CIDP)是一种获得性免疫介导的周围神经系统炎症性疾病。这种临床异质性神经系统疾病与格林-巴-罗综合征密切相关,被认为是该急性疾病的慢性对应物。目前可用的治疗方法大多是经验性的;它们包括皮质类固醇、静脉注射免疫球蛋白、血浆交换和慢性免疫抑制剂,单独或联合使用。最近对CIDP潜在致病机制的理解取得了进展,为CIDP的治疗带来了许多新的可能干预方法。本文总结了临床前和临床研究结果,强调了使用适应性动物模型评估新疗法疗效的重要性,并提出了改善CIDP患者病情的未来方向。
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引用次数: 2
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