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摘要： BACKGROUND:Acute lymphoblastic leukaemia (ALL) is characterized by the clonal proliferation of immature lymphoid precursors in the bone marrow or peripheral blood. This study investigates whether genetic polymorphisms in IL-17RC are associated with an increased risk of ALL in the Saudi population. METHODS:This case-control study included 95 patients with ALL and 95 matched controls. Genetic polymorphisms and their associations with ALL risk were identified using logistic regression analysis. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the level of IL-17RC mRNA. RESULTS:The results revealed that carriers of the GA and AA genotypes of rs76999397 had a significantly increased risk of ALL (GA: odds ratios [OR] = 63.78, 95% confidence interval [CI] = 25.51-159.43, p < 0.0001; AA: OR = 18.22, 95% CI = 1.50-221.37, p < 0.0001). Additionally, we identified that an increased risk of ALL was associated with two haplotypes in IL-17RC, C-A and T-A (in the order of rs708567 and rs76999397) (OR = 46.73, 95% CI = 17.30-126.28; OR = 49.42, 95% CI = 6.95-351.45, respectively). CONCLUSIONS:The results suggested that the GA and AA genotypes of rs76999397 were significantly associated with an increased risk of ALL, whereas rs708567 did not show a significant association. Furthermore, the CA and TA haplotypes (rs708567/rs76999397) were found to be associated with increased susceptibility to ALL.

关键词： 鼠疫耶尔森菌   外膜囊泡   抗原递送   鼠疫疫苗  

摘要： 目的比较不同载体蛋白和信号肽在大肠埃希菌外膜囊泡(outer membrane vesicles，OMVs)上递送抗原的效率和特点。方法将鼠疫耶尔森菌主要保护性抗原F1和LcrV的融合蛋白F1V与载体蛋白细菌溶血素A(cytolysin A，ClyA)、外膜蛋白A(outer membrane protein A，OmpA)或β-内酰胺酶(β-lactamases，Bla)信号肽融合表达，并对F1V蛋白在OMVs上的表达、定位和含量进行比较分析。结果3种递送方式均可将F1V蛋白递送到OMVs中，且定位于OMVs的表面，其中以OmpA为载体蛋白时F1V融合蛋白在OMVs总蛋白质中的占比最高，可达30%；以Bla信号肽为载体的OMVs产量最高，可达4.2 mg/L。结论不同载体蛋白在大肠埃希菌OMVs上递送F1V抗原的效率差别显著，以OMVs产量和抗原在OMVs总蛋白质中的占比为评价指标，Bla信号肽作为载体向OMVs中递送F1V的效率最高，可用于鼠疫耶尔森菌OMVs疫苗的研究。

关键词： B细胞   NSD2基因   滤泡辅助性T细胞   调节性T细胞   MHC  

摘要： 免疫缺陷是含核SET结构域的蛋白2(nuclear SET domain-containing protein 2, NSD2)基因胚系单倍剂量不足变异相关疾病的主要临床表型之一，NSD2基因在免疫系统中具有重要的调节功能，然而其潜在的分子机制尚未完全阐明。近年来，关于NSD2基因在免疫系统中的功能和机制研究取得了极大进展，包括参与B细胞分化发育、促进生发中心B细胞活化和抗体产生、诱导调节性T细胞在母胎界面定位促进母胎界面免疫耐受及上调肿瘤细胞MHCⅠ表达增强肿瘤免疫等。本文主要就NSD2基因在以上免疫过程中的调节功能研究进展进行综述。

关键词： diagnostic algorithm   immune checkpoint inhibitor therapy   melanoma   sarcoidal reactions   soluble IL‐2‐receptor  

摘要： BACKGROUND AND OBJECTIVES:Drug-induced sarcoidosis-like reaction (DISR) is an adverse event with emerging importance during immune checkpoint inhibitor (ICI) treatment in melanoma patients. Its reported frequency varies widely, making accurate diagnosis crucial. Distinguishing DISR from tumor progression is challenging, and misdiagnosis may lead to detrimental treatment changes. Thus, reliable diagnostic markers complementing histopathology as well as a diagnostic algorithm are needed. PATIENTS AND METHODS:This single-center retrospective study, conducted at the University Medical Center in Leipzig, Germany, from 09/2019 to 06/2021, assessed DISR prevalence in melanoma patients treated with ICI for metastatic melanoma. We examined clinical characteristics, radiology, histopathology, and serum parameters. RESULTS:From a total of 177 patients 19 patients were suspicious for DISR. Of those, DISR was diagnosed in seven patients. In a further nine patients DISR was highly probable based on radiological findings and noticeably increased soluble interleukin-2-receptor (sIL2R) levels, resulting in DISR prevalence of 9%. No patient required permanent discontinuation of ICI due to DISR. CONCLUSIONS:In melanoma patients receiving ICI, DISR is common. Histological confirmation through mediastinoscopy or pulmonary wedge resection offers the highest diagnostic accuracy. When histology is not available, sIL2R levels can aid diagnosis. We propose an algorithm to distinguish DISR from tumor progression.

关键词： Autoimmune   Human leukocyte antigen - HLA   Immunotherapy   Infection   Major histocompatibility complex - MHC  

摘要： The human leukocyte antigen (HLA)-presented peptide repertoire, termed immunopeptidome, plays a crucial role for T-cell mediated immune reactions. Previously, the human immunopeptidome of non-malignant tissues has been mapped in a large-scale study, the HLA Ligand Atlas, via high-resolution data-dependent acquisition (DDA) mass spectrometry. This publicly available and user-friendly web interface (https://***) is frequently used as a benign tissue reference in antigen discovery, especially for immunotherapy of cancer. Here, we extend the HLA Ligand Atlas resource with paired data-independent acquisition (DIA) runs for all tissue-subject combinations. This novel dataset comprises 946 DIA HLA class I and II immunopeptidomic runs from 242 non-malignant human samples across 18 subjects and 29 distinct tissues. Together with the published DDA runs, this extends the range and depth of analyses performed on the HLA Ligand Atlas dataset. In a concise analysis, we showcase advantages of DIA over DDA concerning spectral sampling and sensitivity. These findings are attributed to the increased dynamic range in DIA, enabling the identification of peptide transitions with low signal intensities. Moreover, we demonstrate the superior sensitivity by applying an HLA-A*02:01 allotype-specific spectral library search to identify and quantify HLA-presented peptides. We encourage reanalysis of the provided DDA and DIA data in combination as a reference for future research concerning human immunology.

关键词： 艰难梭菌   谷氨酸脱氢酶   抗原表位   驼源   单域抗体  

摘要： 目的研制和筛选识别艰难梭菌(Clostridium difficile)谷氨酸脱氢酶(glutamate dehydrogenase, CD-GDH)线性B细胞抗原表位的驼源单域抗体，并将其应用于Western blot和ELISA等检测方法。方法以重组表达并纯化的CD-GDH作为诱饵，从噬菌体展示驼源天然纳米抗体库中筛选阳性噬菌体克隆。经Western blot验证后测定抗体基因序列，然后密码子优化合成抗体基因序列并克隆至pET28a载体中构建表达载体。经诱导表达和纯化后应用于Western blot和ELISA检测CD-GDH蛋白。结果共获得6个驼源单域抗体阳性克隆，其中克隆GA4被选择在大肠埃希菌中重组表达并纯化。GA4与CD-GDH结合的亲和力良好，Kd值为3 nmol/L，应用于Western blot和ELISA都能特异性地识别重组表达和内源性的CD-GDH蛋白。结论成功制备并获得了1株识别CD-GDH蛋白中线性B细胞抗原表位的驼源单域抗体，为检测CD-GDH蛋白提供了有效工具。

关键词： and “IL-4 signal   Germinal centre   Virus immunity   mRNA vaccine  

摘要： Vaccines effectively stimulate protective immune responses in healthy individuals, but the precise roles of germinal center (GC) and follicular helper T (TFH) cells in SARS-CoV-2 vaccine responses are not fully understood. This study used a conditional loss-of-function mouse model to investigate antibody responses to the Wuhan spike protein, specifically eliminating newly developed TFH cells during either the primary or memory phase. Our findings demonstrated that TFH-mediated GC responses are essential for primary vaccination. However, after booster immunization, memory B cell responses were effectively regulated through extrafollicular mechanisms, independent of TFH cells. Ablating IL-4 receptor signaling in B cells attenuated antibody production in both the primary and memory phases, highlighting the critical role of IL-4 for optimal humoral immunity. We identified a unique population of IL-4-expressing memory T cells (IL-4+Tm), characterized by CD27, GATA3, and IRF4 expression, that is strongly associated with these extrafollicular memory B cell responses, capable of neutralizing SARS-CoV-2 variants. Furthermore, Omicron-based booster immunization recovered the immunity against emerging variants under TFH deficient conditions. These results suggest that IL-4+Tm cells are an alternative pathway to sustain memory responses when GC function is impaired, particularly in immunocompromised states. Our study advances the understanding of memory T cell-mediated humoral responses to SARS-CoV-2, offering insights for future vaccine strategies.

关键词： Hypertensive nephropathy   Rehmannioside A   Inflammation   Fibrosis  

摘要： Background: This study aimed to observe the influences and potential mechanism of rehmannioside A (ReA) in hypertensive nephropathy (HN). Methods: HN model in mice and rat tubular epithelial cells were constructed by angiotensin II (Ang II). The biomarkers of renal function, including uric acid (UA), creatinine (Cre), blood urea nitrogen (BUN), and urine albumin, were assessed. Results: Ang II induced severe kidney injury, while the injury was ameliorated by ReA. In Ang II-induced hypertensive mice model, ReA decreased the levels of UA, Cre, BUN, urine albumin, transforming growth factor (TGF)-beta, Fibronectin, Collagen I, interleukin (IL)-6, IL-1 beta, and tumour necrosis factor (TNF)-alpha. In Ang II-treated cells, ReA reduced the levels of TGF-beta, Fibronectin, Col1agen I, IL-6, IL-1 beta, and TNF-alpha. In vivo and in vitro, ReA promoted angiotensin converting enzyme 2 (ACE2) expression and inhibited the expression of angiotensin II type 1 receptor (AT1R), ACE, IL-17, mitogen activated protein kinase 14 (MAPK14), phosphorylated (p)-MAPK14, p-NF-kappa B P65, and matrix metallopeptidase 9 (MMP-9) in HN model. Moreover, there was a docking for ReA and MAPK14 protein, and ReA inhibited MAPK14 protein expression by promoting MAPK14 ubiquitination. Under Ang II treatment, MAPK14 overexpression reversed the promotive effect of ReA on cell viability and the inhibitory effects of ReA on fibrosis and inflammation in NRK-52E cells. Conclusions: ReA alleviated renal dysfunction and reduced fibrosis and inflammation, which was related to the inhibition of AT1R/MAPK14/IL-17 pathway. For HN treatment, ReA may be a promising pharmacological strategy.

关键词： DHA   Anti-PD-1   Angiogenesis   Tumor immune   Breast cancer   TNF-alpha  

摘要： Tumor vascular abnormality promotes the formation of immunosuppressive microenvironment, thus limiting the efficacy of tumor immunotherapy and promoting tumor development. Dihydroartemisinin (DHA) has shown potential as an anti-tumor agent. The potential role of its anti-angiogenic effect has not yet been discovered. This research investigates whether DHA inhibits tumor-induced angiogenesis, promotes immunotherapy and explored the underlying mechanism. The promoting effect of 4T-1 cell-conditioned media (CM) on SVEC4-10 activity and tube formation can be reversed by DHA-treated with CM. Consistently, following DHA administration in a breast cancer mouse model, the number of transplanted tumor vessels was markedly reduced and perivascular cells increased. Subsequently, in vivo administration of DHA evidently promoted inhibitory effect of anti-PD-1 in tumor and reversed the infiltration of T cells and the phenotypes of macrophages. Network pharmacology and RNA-seq analysis revealed that DHA inhibit tumor growth by angiogenesis through the TNF-alpha pathway. Besides, TNF-alpha cytokine replenishment experiment and the expression of key molecules involved signaling pathway confirmed the above mechanism. In conclusion, DHA alleviates tumor cell-induced abnormal blood vessels through TNF-alpha pathway, which contributes to the anti-PD-1 efficacy of tumors.

关键词： depression   glucocorticoids   polyarthralgia   polychondritis   rheumatoid arthritis