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The Role of Gut Microbiota in Gastrointestinal Tract Cancers 肠道微生物群在胃肠道癌症中的作用
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2022-02-03 DOI: 10.1007/s00005-021-00641-6
Marta Grochowska, Karol Perlejewski, Tomasz Laskus, Marek Radkowski

Disturbances in gastrointestinal (GI) microbiota could play a significant role in the development of GI cancers, but the underlying mechanisms remain largely unclear. While some bacteria seem to facilitate carcinogenesis, others appear to be protective. So far only one bacterium (Helicobacter pylori) has been classified by the International Agency for Cancer Research as carcinogenic in humans but many other are the subject of intense research. Most studies on the role of microbiota in GI tract oncogenesis focus on pancreatic and colorectal cancers with the following three species: Helicobacter pylori, Escherichia coli, and Porphyromonas gingivalis as likely causative factors. This review summarizes the role of bacteria in GI tract oncogenesis.

胃肠道(GI)微生物群紊乱可能在胃肠道癌症的发展中发挥重要作用,但其潜在机制仍不清楚。虽然有些细菌似乎有助于致癌,但其他细菌似乎具有保护作用。到目前为止,只有一种细菌(幽门螺杆菌)被国际癌症研究机构列为人类致癌物,但其他许多细菌正在进行深入研究。大多数关于微生物群在胃肠道肿瘤发生中的作用的研究集中在胰腺癌和结直肠癌上,其中以下三种细菌:幽门螺杆菌、大肠杆菌和牙龈卟啉单胞菌是可能的致病因素。本文就细菌在胃肠道肿瘤发生中的作用作一综述。
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引用次数: 6
Effects of Local Nasal Immunotherapy with FIP-fve Peptide and Denatured Tyrophagus putrescentiae for Storage Mite-Induced Airway Inflammation fip - 5肽与变性腐噬菌鼻腔局部免疫治疗贮藏螨性气道炎症的疗效观察
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2022-01-31 DOI: 10.1007/s00005-022-00645-w
Chung-Yang Yen, Ching-Hsiang Yu, Jaw-Ji Tsai, Hsiang-Kuang Tseng, En-Chih Liao

Allergic diseases are affecting public health and have increased over the last decade. Sensitization to mite allergens is a considerable trigger for allergy development. Storage mite-Tyrophagus putrescentiae shows great significance of allergenic potential and clinical relevance. The fungal immunomodulatory peptide FIP-fve has been reported to possess immunomodulatory activity. We aimed to determine whether T. putrescentiae-induced sensitization and airway inflammation in mice could be downregulated by FIP-fve in conjunction with denatured T. putrescentiae (FIP-fve and DN-Tp). Immune responses and physiologic variations in immunoglobulins, leukocyte subpopulations, cytokine productions, pulmonary function, lung pathology, cytokines in CD4+ and Treg cells were evaluated after local nasal immunotherapy (LNIT). After the LNIT with FIP-fve and DN-Tp, levels of specific IgE, IgG1, and IgG2a in the sera and IgA in the bronchoalveolar lavage fluid (BALF) were significantly reduced. Infiltrations of inflammatory leukocytes (eosinophils, neutrophils, and lymphocytes) in the airway decreased significantly. Production of proinflammatory cytokines (IL-5, IL-13, IL-17F and IL-23) and chemokine (IL-8) were significantly reduced, and Th1-cytokine (IL-12) increased in the airway BALF after LNIT. Pulmonary functions of Penh values were significantly decreased after the methacholine challenge, which resulted in a reduction of airway hypersensitivity after LNIT. Bronchus pathology showed a reduction of inflammatory cell infiltration and epithelium damage after LNIT. The IL-4+/CD4+ T cells could be downregulated and the IFN-γ+/CD4+ T cells upregulated. The Treg-related immunity of IL-10 and Foxp3 expressions in CD4+CD25+ cells were both upregulated after LNIT. In conclusion, LNIT with FIP-fve and DN-Tp had an anti-inflammatory effect on mite-induced airway inflammations and possesses potential as an immunomodulatory therapy agent for allergic airway diseases.

过敏性疾病正在影响公众健康,并且在过去十年中有所增加。对螨虫过敏原的致敏是过敏发展的一个重要诱因。储藏螨腐败噬菌具有重要的致敏潜力和临床意义。真菌免疫调节肽FIP-fve已被报道具有免疫调节活性。我们的目的是确定FIP-fve和变性的腐败T.Fe(FIP-fve和DN-Tp)是否可以下调腐败T.fve诱导的小鼠致敏和气道炎症。在局部鼻免疫治疗(LNIT)后,评估免疫球蛋白、白细胞亚群、细胞因子产生、肺功能、肺病理、CD4+和Treg细胞中的细胞因子的免疫反应和生理变化。FIP-fve和DN-Tp LNIT后,血清中特异性IgE、IgG1和IgG2a以及支气管肺泡灌洗液(BALF)中的IgA水平显著降低。气道中炎性白细胞(嗜酸性粒细胞、中性粒细胞和淋巴细胞)的浸润显著减少。LNIT后,气道BALF中促炎细胞因子(IL-5、IL-13、IL-17F和IL-23)和趋化因子(IL-8)的产生显著减少,Th1细胞因子(IL-12)增加。乙酰甲胆碱激发后,Penh值的肺功能显著下降,这导致LNIT后气道超敏反应的减少。支气管病理显示LNIT后炎性细胞浸润和上皮损伤减少。IL-4+/CD4+T细胞可下调,IFN-γ+/CD4+T细胞可上调。LNIT后CD4+CD25+细胞中IL-10和Foxp3表达的Treg相关免疫均上调。总之,含有FIP-fve和DN-Tp的LNIT对螨诱导的气道炎症具有抗炎作用,并具有作为过敏性气道疾病免疫调节剂的潜力。
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引用次数: 4
The Role of Immunoproteasomes in Tumor-Immune Cell Interactions in Melanoma and Colon Cancer 免疫蛋白酶体在黑色素瘤和结肠癌中肿瘤-免疫细胞相互作用中的作用
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2022-01-22 DOI: 10.1007/s00005-022-00644-x
Hanna Leister, Felix F. Krause, Rouzbeh Mahdavi, Ulrich Steinhoff, Alexander Visekruna

The participation of proteasomes in vital cellular and metabolic processes that are involved in tumor growth has made this protease complex an attractive target for cancer treatment. In contrast to ubiquitously available constitutive proteasome, the increased enzymatic activity of immunoproteasome is associated with tumor-infiltrating immune cells, such as antigen-presenting cells and T lymphocytes. In various tumors, an effective anti-tumor immunity is provided through generation of tumor-associated antigens by proteasomes, contributing crucially to cancer eradication by T lymphocytes. The knowledge regarding the role of immunoproteasomes in the communication between tumor cells and infiltrating immune cells is limited. Novel data suggest that the involvement of immunoproteasomes in tumorigenesis is more complex than previously thought. In the intestine, in which diverse signals from commensal bacteria and food can contribute to the onset of chronic inflammation and inflammation-driven cancer, immunoproteasomes exert tumorigenic properties by modulating the expression of pro-inflammatory factors. In contrast, in melanoma and non-small cell lung cancer, the immunoproteasome acts against cancer development by promoting an effective anti-tumor immunity. In this review, we highlight the potential of immunoproteasomes to either contribute to inflammatory signaling and tumor development, or to support anti-cancer immunity. Further, we discuss novel therapeutic options for cancer treatments that are associated with modulating the activity of immunoproteasomes in the tumor microenvironment.

蛋白酶体参与参与参与肿瘤生长的重要细胞和代谢过程,使这种蛋白酶复合体成为癌症治疗的有吸引力的靶点。与普遍可用的组成型蛋白酶体相比,免疫蛋白酶体的酶活性增加与肿瘤浸润免疫细胞有关,如抗原呈递细胞和T淋巴细胞。在各种肿瘤中,通过蛋白酶体产生肿瘤相关抗原来提供有效的抗肿瘤免疫,这对T淋巴细胞根除癌症至关重要。关于免疫蛋白酶体在肿瘤细胞和浸润性免疫细胞之间通讯中的作用的知识是有限的。新的数据表明,免疫蛋白酶体在肿瘤发生中的参与比以前认为的更复杂。在肠道中,来自共生细菌和食物的不同信号可能导致慢性炎症和炎症驱动的癌症的发作,免疫蛋白酶体通过调节促炎因子的表达发挥致瘤特性。相反,在黑色素瘤和非小细胞肺癌癌症中,免疫蛋白酶体通过促进有效的抗肿瘤免疫来对抗癌症的发展。在这篇综述中,我们强调了免疫蛋白酶体有助于炎症信号传导和肿瘤发展,或支持抗癌免疫的潜力。此外,我们还讨论了与调节肿瘤微环境中免疫蛋白酶体活性相关的癌症治疗的新治疗方案。
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引用次数: 2
Rho Kinases in Embryonic Development and Stem Cell Research Rho激酶在胚胎发育和干细胞研究中的作用
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2022-01-19 DOI: 10.1007/s00005-022-00642-z
Jianjian Shi, Lei Wei

The Rho-associated coiled-coil containing kinases (ROCKs or Rho kinases) belong to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and are major downstream effectors of small GTPase RhoA, a key regulator of actin-cytoskeleton reorganization. The ROCK family contains two members, ROCK1 and ROCK2, which share 65% overall identity and 92% identity in kinase domain. ROCK1 and ROCK2 were assumed to be functionally redundant, based largely on their major common activators, their high degree kinase domain homology, and study results from overexpression with kinase constructs or chemical inhibitors. ROCK signaling research has expanded to all areas of biology and medicine since its discovery in 1996. The rapid advance is befitting ROCK’s versatile functions in modulating various cell behavior, such as contraction, adhesion, migration, proliferation, polarity, cytokinesis, and differentiation. The rapid advance is noticeably driven by an extensive linking with clinical medicine, including cardiovascular abnormalities, aberrant immune responsive, and cancer development and metastasis. The rapid advance during the past decade is further powered by novel biotechnologies including CRISPR-Cas and single cell omics. Current consensus, derived mainly from gene targeting and RNA interference approaches, is that the two ROCK isoforms have overlapping and distinct cellular, physiological and pathophysiology roles. In this review, we present an overview of the milestone discoveries in ROCK research. We then focus on the current understanding of ROCK signaling in embryonic development, current research status using knockout and knockin mouse models, and stem cell research.

Rho相关的含Rho激酶(ROCKs或Rho激酶)属于AGC (PKA/PKG/PKC)丝氨酸/苏氨酸激酶家族,是小GTPase RhoA的主要下游效应物,是肌动蛋白-细胞骨架重组的关键调节因子。ROCK家族包含两个成员ROCK1和ROCK2,它们在激酶结构域上具有65%的同源性和92%的同源性。ROCK1和ROCK2被认为在功能上是冗余的,这主要基于它们的主要共同激活因子、高度激酶结构域同源性以及与激酶构建物或化学抑制剂过表达的研究结果。ROCK信号研究自1996年被发现以来,已经扩展到生物学和医学的各个领域。这种快速的进展与ROCK在调节各种细胞行为(如收缩、粘附、迁移、增殖、极性、细胞质分裂和分化)方面的多功能功能相适应。与临床医学的广泛联系,包括心血管异常、异常免疫反应和癌症的发展和转移,显著推动了这一快速进展。在过去的十年中,包括CRISPR-Cas和单细胞组学在内的新型生物技术进一步推动了这一快速发展。目前主要来自基因靶向和RNA干扰方法的共识是,这两种ROCK亚型具有重叠和不同的细胞、生理和病理生理作用。在这篇综述中,我们介绍了岩石研究的里程碑式发现的概述。然后,我们将重点关注胚胎发育中ROCK信号的当前理解,使用敲除和敲入小鼠模型的当前研究现状,以及干细胞研究。
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引用次数: 7
Peroxiredoxins as Markers of Oxidative Stress in IgA Nephropathy, Membranous Nephropathy and Lupus Nephritis 过氧化物还毒素作为IgA肾病、膜性肾病和狼疮性肾炎中氧化应激的标志物
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2021-12-16 DOI: 10.1007/s00005-021-00638-1
Natalia Krata, Bartosz Foroncewicz, Radosław Zagożdżon, Barbara Moszczuk, Magdalena Zielenkiewicz, Leszek Pączek, Krzysztof Mucha

IgA nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN) represent important causes of chronic kidney disease. They belong to the immune-mediated glomerulonephritis (GNs), and have distinct pathogenesis, distinct clinical courses, and variable responses to treatment. Therefore, specific diagnostic procedures are necessary for more effective patient management. Recently, a role for oxidative stress has been proposed in various renal disorders. Thus, molecules related to oxidative stress, such as 2-Cys-peroxiredoxins (PRDXs), may represent plausible candidates for biomarkers in renal pathologies. The aim of this study was to assess whether there are differences between individual GNs and healthy controls in the context of PRDXs serum concentration. We enrolled 108 patients with biopsy-proven IgAN (47), MN (26), LN (35) and 30 healthy age- and sex-matched controls. The serum concentrations of PRDX 1–5 were measured with ELISA assays and correlated with demographic and clinical data. The PRDXs’ concentration varied depending on the GN type. We also observed an association of PRDXs with lower estimated glomerular filtration rates, complement, hemoglobin, and body mass index. Our study indicates that individual PRDX can play roles in pathophysiology of selected GNs and that their serum concentrations may become useful as a new supplementary diagnostic markers in IgAN, MN as well as LN. The results of this study open a new avenue for prospective research on PRDXs in renal diseases.

IgA肾病(IgAN)、膜性肾病(MN)和狼疮性肾炎(LN)是慢性肾脏疾病的重要病因。它们属于免疫介导的肾小球肾炎(GNs),具有不同的发病机制、不同的临床病程和不同的治疗反应。因此,特定的诊断程序对于更有效的患者管理是必要的。最近,氧化应激在各种肾脏疾病中的作用已被提出。因此,与氧化应激相关的分子,如2-Cys-peroxiredoxins(PRDXs),可能代表肾脏病理学中生物标志物的可能候选者。本研究的目的是评估个体GNs和健康对照组在PRDXs血清浓度方面是否存在差异。我们招募了108名经活检证实的IgAN(47)、MN(26)、LN(35)患者和30名年龄和性别匹配的健康对照。PRDX 1-5的血清浓度通过ELISA测定进行测量,并与人口统计学和临床数据相关。PRDXs的浓度因GN类型而异。我们还观察到PRDXs与较低的肾小球滤过率、补体、血红蛋白和体重指数有关。我们的研究表明,个体PRDX可以在选定GNs的病理生理学中发挥作用,其血清浓度可能成为IgAN、MN和LN的新的补充诊断标志物。本研究的结果为肾脏疾病中PRDXs的前瞻性研究开辟了一条新的途径。
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引用次数: 14
Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies 诱导多能干细胞衍生car靶向免疫疗法的发展前景
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2021-12-12 DOI: 10.1007/s00005-021-00640-7
Roberta Mazza, John Maher

Technologies required to generate induced pluripotent stem cells (iPSC) were first described 15 years ago, providing a strong impetus to the field of regenerative medicine. In parallel, immunotherapy has finally emerged as a clinically meaningful modality of cancer therapy. In particular, impressive efficacy has been achieved in patients with selected haematological malignancies using ex vivo expanded autologous T cells engineered to express chimeric antigen receptors (CARs). While solid tumours account for over 90% of human cancer, they currently are largely refractory to this therapeutic approach. Nonetheless, given the considerable innovation taking place worldwide in the CAR field, it is likely that effective solutions for common solid tumours will emerge in the near future. Such a development will create significant new challenges in the scalable delivery of these complex, costly and individualised therapies. CAR-engineered immune cell products that originate from iPSCs offer the potential to generate unlimited numbers of homogeneous, standardised cell products in which multiple defined gene modification events have been introduced to ensure safety, potency and reproducibility. Here, we review some of the emerging strategies in use to engineer CAR-expressing iPSC-derived drug products.

产生诱导多能干细胞(iPSC)所需的技术在15年前首次被描述,为再生医学领域提供了强大的推动力。与此同时,免疫疗法终于成为一种临床有意义的癌症治疗方式。特别是,使用体外扩增的自体T细胞来表达嵌合抗原受体(CARs),在某些血液系统恶性肿瘤患者中取得了令人印象深刻的疗效。虽然实体肿瘤占人类癌症的90%以上,但目前这种治疗方法在很大程度上是难治性的。尽管如此,鉴于CAR领域在世界范围内发生的重大创新,很可能在不久的将来出现针对普通实体肿瘤的有效解决方案。这种发展将为这些复杂、昂贵和个性化的治疗方法的可扩展提供带来重大的新挑战。源自多能干细胞的car工程免疫细胞产品有可能产生无限数量的同质、标准化细胞产品,其中引入了多个已定义的基因修饰事件,以确保安全性、效力和可重复性。在这里,我们回顾了一些用于设计car表达ipsc衍生药物产品的新兴策略。
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引用次数: 11
AITE Celebrates Its 70th Year of Publication (1953–2022) AITE庆祝出版70周年(1953-2022)
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2021-12-09 DOI: 10.1007/s00005-021-00639-0
Hubert Krotkiewski, Michał Zimecki, Andrzej Górski
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引用次数: 0
A Novel Human Recombinant Lactoferrin Inhibits Lung Adenocarcinoma Cell Growth and Migration with No Cytotoxic Effect on Normal Human Epithelial Cells 一种新的重组人乳铁蛋白抑制肺腺癌细胞的生长和迁移,对正常人上皮细胞无细胞毒性作用
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2021-11-08 DOI: 10.1007/s00005-021-00637-2
Paulina Olszewska, Barbara Pazdrak, Marian L. Kruzel

Lung cancer remains the leading cause of cancer death worldwide. Despite the recent advances in cancer treatment, only a subset of patients responds to targeted and immune therapies, and many patients developing resistance after an initial response. Lactoferrin (Lf) is a natural glycoprotein with immunomodulatory and anticancer activities. We produced a novel recombinant human Lf (rhLf) that exhibits glycosylation profile compatible with the natural hLf for potential parenteral therapeutic applications. The aim of this study was to evaluate the anticancer effects of this novel rhLf in human lung adenocarcinoma cells and its mechanisms of action. The results showed a concentration-dependent inhibition of A549 cancer cell growth in response to rhLf. Treatment with 1 mg/ml of rhLf for 24 h and 72 h resulted in a significant inhibition of cancer cell growth by 32% and 25%, respectively. Moreover, rhLf increased fourfold the percentage of early and late apoptotic cells compared to the control. This effect was accompanied by increased levels of caspase-3 activity and cell cycle arrest at the S phase in rhLf-treated cancer cells. Furthermore, rhLf significantly attenuated A549 cell migration. Importantly, treatment of normal human bronchial epithelial (NHBE) cells with rhLf showed the cell viability and morphology comparable to the control. In contrast, chemotherapeutic etoposide induced cytotoxicity in NHBE cells and reduced the cell viability by 40%. These results demonstrate the selective anticancer effects of rhLf against lung adenocarcinoma cells without cytotoxicity on normal human cells. This study highlights a potential for clinical utility of this novel rhLf in patients with lung cancer.

癌症仍然是全球癌症死亡的主要原因。尽管癌症治疗最近取得了进展,但只有一小部分患者对靶向和免疫疗法有反应,许多患者在最初反应后出现耐药性。乳铁蛋白是一种具有免疫调节和抗癌活性的天然糖蛋白。我们生产了一种新的重组人Lf(rhLf),其表现出与天然hLf兼容的糖基化特性,用于潜在的胃肠外治疗应用。本研究的目的是评估这种新型rhLf在人肺腺癌细胞中的抗癌作用及其作用机制。结果表明,rhLf对A549癌症细胞生长具有浓度依赖性抑制作用。用1mg/ml的rhLf处理24小时和72小时分别导致癌症细胞生长的显著抑制32%和25%。此外,与对照组相比,rhLf使早期和晚期凋亡细胞的百分比增加了四倍。在rhLf处理的癌症细胞中,这种效应伴随着胱天蛋白酶-3活性水平的增加和S期细胞周期阻滞。此外,rhLf显著减弱A549细胞的迁移。重要的是,用rhLf处理正常人支气管上皮(NHBE)细胞显示出与对照相当的细胞活力和形态。相反,化疗依托泊苷诱导了NHBE细胞的细胞毒性,并使细胞活力降低了40%。这些结果证明了rhLf对肺腺癌细胞的选择性抗癌作用,而对正常人细胞没有细胞毒性。这项研究强调了这种新型rhLf在癌症患者中的临床应用潜力。
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引用次数: 9
Immunology and Donor-Specific Antibodies in Corneal Transplantation 角膜移植中的免疫学和供体特异性抗体
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2021-11-06 DOI: 10.1007/s00005-021-00636-3
Joanna Major, Bartosz Foroncewicz, Jacek Paweł Szaflik, Krzysztof Mucha

The first human corneal transplantation was performed in 1905 by Eduard Zirm in the Olomouc Eye Clinic, now Czech Republic. However, despite great advancements in microsurgical eye procedures, penetrating keratoplasty in high-risk patients (e.g., vascularized or inflamed corneal tissue, consecutive transplants) remains a challenge. The difficulty is mainly due to the risk of irreversible allograft rejection, as an ocular immune privilege in these patients is abolished and graft rejection is the main cause of corneal graft failure. Therefore, tailored immunosuppressive treatment based on immunological monitoring [e.g., donor-specific antibodies (DSA)] is considered one of the best strategies to prevent rejection in transplant recipients. Although there is indirect evidence on the mechanisms underlying antibody-mediated rejection, the impact of DSA on cornea transplantation remains unknown. Determining the role of pre-existing and/or de novo DSA could advance our understanding of corneal graft rejection mechanisms. This may help stratify the immunological risk of rejection, ultimately leading to personalized treatment for this group of transplant recipients.

第一例人类角膜移植是1905年由爱德华·齐姆在奥洛穆茨眼科诊所(现捷克共和国)进行的。然而,尽管眼科显微外科手术取得了巨大的进步,但对于高风险患者(如血管化或发炎的角膜组织,连续移植)的穿透性角膜移植术仍然是一个挑战。困难的主要原因是由于不可逆的异体移植排斥反应的风险,因为这些患者的眼部免疫特权被取消,移植排斥反应是角膜移植失败的主要原因。因此,基于免疫监测的量身定制的免疫抑制治疗[例如,供体特异性抗体(DSA)]被认为是预防移植受者排斥反应的最佳策略之一。虽然有间接证据表明抗体介导的排斥反应机制,但DSA对角膜移植的影响尚不清楚。确定已有和/或新生DSA的作用可以促进我们对角膜移植排斥机制的理解。这可能有助于对排斥的免疫风险进行分层,最终导致对这组移植受者的个性化治疗。
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引用次数: 8
Molecular Genetics Diversity of Primary Hemophagocytic Lymphohistiocytosis among Polish Pediatric Patients 波兰儿科患者原发性噬血细胞淋巴组织细胞病的分子遗传学多样性
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2021-10-22 DOI: 10.1007/s00005-021-00635-4
Katarzyna Bąbol-Pokora, Magdalena Wołowiec, Katarzyna Popko, Aleksandra Jaworowska, Yenan T. Bryceson, Bianca Tesi, Jan-Inge Henter, Wojciech Młynarski, Wanda Badowska, Walentyna Balwierz, Katarzyna Drabko, Krzysztof Kałwak, Lucyna Maciejka-Kembłowska, Anna Pieczonka, Grażyna Sobol-Milejska, Sylwia Kołtan, Iwona Malinowska, for the Polish Pediatric Hematology, Oncology Society

Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of life-threatening inflammation caused by an excessive, prolonged and ineffective immune response. An increasing number of HLH cases is recognized in Poland, but the genetic causes of familial HLH (FHL) have not been reported. We investigated the molecular genetics and associated outcomes of pediatric patients who met HLH criteria. We studied 54 patients with HLH, 36 of whom received genetic studies. Twenty-five patients were subjected to direct sequencing of the PRF1, UNC13D, STX11, XIAP and SH2D1A genes. Additionally, 11 patients were subjected to targeted next-generation sequencing. In our study group, 17 patients (31%) were diagnosed with primary HLH, with bi-allelic FHL variants identified in 13 (36%) patients whereas hemizygous changes were identified in 4 patients with X-linked lymphoproliferative diseases. In addition, one patient was diagnosed with X-linked immunodeficiency with magnesium defect, Epstein–Barr virus infection and neoplasia due to a hemizygous MAGT1 variant; another newborn was diagnosed with auto-inflammatory syndrome caused by MVK variants. The majority (65%) of FHL patients carried UNC13D pathogenic variants, whereas PRF1 variants occurred in two patients. Novel variants in UNC13D, PRF1 and XIAP were detected. Epstein–Barr virus was the most common trigger noted in 23 (65%) of the patients with secondary HLH. In three patients with secondary HLH, heterozygous variants of FHL genes were found. Overall survival for the entire study group was 74% with a median of 3.6 years of follow-up. Our results highlight the diversity of molecular causes of primary HLH in Poland.

吞噬血淋巴组织细胞增多症(HLH)是一种由过度、长期和无效的免疫反应引起的危及生命的炎症的临床综合征。在波兰,HLH病例的数量越来越多,但家族性HLH(FHL)的遗传原因尚未报道。我们调查了符合HLH标准的儿科患者的分子遗传学和相关结果。我们研究了54名HLH患者,其中36人接受了基因研究。对25名患者进行了PRF1、UNC13D、STX11、XIAP和SH2D1A基因的直接测序。此外,11名患者接受了靶向下一代测序。在我们的研究组中,17名患者(31%)被诊断为原发性HLH,在13名患者(36%)中发现了双等位基因FHL变体,而在4名患有X连锁淋巴增生性疾病的患者中发现了半合子改变。此外,一名患者被诊断为X连锁免疫缺陷,伴有镁缺陷、EB病毒感染和半合子MAGT1变体引起的肿瘤形成;另一名新生儿被诊断为MVK变异引起的自身炎症综合征。大多数(65%)FHL患者携带UNC13D致病性变体,而PRF1变体发生在两名患者中。在UNC13D、PRF1和XIAP中检测到新的变体。爱泼斯坦-巴尔病毒是23例(65%)继发性HLH患者中最常见的诱因。在3例继发性HLH患者中,发现FHL基因的杂合变异。整个研究组的总生存率为74%,中位随访时间为3.6年。我们的研究结果突出了波兰原发性HLH分子病因的多样性。
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引用次数: 3
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Archivum Immunologiae et Therapiae Experimentalis
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