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关键词： platelet immunomodulation   rheumatoid arthritis   T lymphocyte activation   CD40L   cytokine production  

摘要： Background: Platelets (PLTs) from healthy donors (HD) modulate T lymphocyte responses but PLTs from rheumatoid arthritis (RA) patients contribute to persistent systemic inflammation. This suggests that PLTs from RA patients and HD have different immunomodulatory effects. Methods: Using cell culture, flow cytometry, proteomics, and ELISA, we compared PLTs from HD and RA patients and their effects on T lymphocyte activation and cytokine production. Results: HD PLTs suppressed T lymphocyte proliferation and IFN gamma and TNF production, while RA PLTs exhibited reduced suppressive capacity. In the presence of RA PLTs, IFN gamma levels correlated with T lymphocyte proliferation, greater disease activity, and anti-citrullinated protein antibodies (ACPA). Proteomic analysis revealed that RA PLTs show upregulation of proteins linked to acute-phase response and complement activation. RA PLTs secreted higher levels of soluble CD40L (sCD40L) and PDGF-BB that correlated with enhanced IFN gamma production. Seropositive RA patients had higher levels of sCD40L, and these levels were predictive of disease remission in RA patients treated with anti-IL6R. sCD40L was found to enhance T lymphocyte activation and to contribute to increased pro-inflammatory cytokine production. Conclusions: This study highlights the diminished ability of RA PLTs to suppress T lymphocyte activation and that sCD40L can be a potential biomarker and therapeutic target in RA.

关键词： 阶梯型   抗人胸腺细胞免疫球蛋白   IST治疗   中药   重型再生障碍性贫血  

摘要： 目的应用创新性的阶梯型兔抗人胸腺细胞免疫球蛋白治疗SAA并评价疗效；方法回顾性分析2023年11月—2024年5月中国中医科学院西苑医院血液科病房明确诊断为获得性SAA患者45例。实验组15例患者为减剂量阶梯方案r-ATG治疗，同时予以环孢素联合海曲波帕口服；30例患者因低风险治疗意愿非随机进入到对照组，选择接受环孢素联合TPO-RA类药物治疗方案，两组患者均予以大菟丝子饮加减补肾生血。结果实验组治疗3个月时客观缓解率（ORR）66.67%；6个月时客观缓解率（ORR）80.00%。对比治疗3个月、6个月与治疗前血细胞计数均值变化，白细胞、中性粒细胞、血红蛋白、血小板、网织红细胞均较治疗前升高，其中治疗3个月血红蛋白、血小板、网织红细胞计数对比治疗前有统计学意义（*P<0.05)；治疗6个月白细胞计数、中性粒细胞计数、血红蛋白、血小板、网织红细胞计数对比治疗前均有统计学意义(*P<0.05)。治疗6个月白细胞计数、中性粒细胞计数对比治疗3个月均有统计学意义(*P<0.05)。与对照组相比，治疗6个月后中性粒细胞计数、血红蛋白、血小板高于对照组，差异具有统计学意义(*P<0.05)。结论新的阶梯型ATG方案在SAA治疗既能够确保疗效，促进骨髓造血功能的恢复，同时有助于降低ATG的副作用，给SAA患者带来低风险IST治疗机遇。

关键词： bladder cancer   interferon gamma response   AGO2   immunotherapy   antitumor immunity   tumor immune microenvironment   STAT1   CD8 T cell   micro-RNA  

摘要： Interferon-gamma (IFN-y), a cytokine essential for activating cellular immune responses, plays a crucial role in cancer immunosurveillance and the clinical success of immune checkpoint blockade therapy. In this study, we show that Argonaute 2 (AGO2), a key mediator in small RNA-guided gene regulation, inversely correlates with tumor responsiveness to IFN-y and the efficacy of immunotherapy. Mechanistically, IFN-y upregulates miR1246 expression in tumor cells, enhancing its interaction with AGO2. This miR-1246-AGO2 complex disrupts IFN-y-mediated signal transducer and activator of transcription 1 (STAT1) phosphorylation by stabilizing protein tyrosine phosphatase non-receptor 6 (PTPN6) mRNA, thereby suppressing the expression of downstream C-X-C motif chemokine ligands (CXCLs), IFN-stimulated genes (ISGs), and human leukocyte antigen (HLA) molecules, which collectively contribute to tumor immune evasion. In preclinical cancer models, inhibiting AGO2 with BCI-137 or targeting miR-1246 with its antagomir re-sensitizes tumor cells to IFN-y, leading to the enhanced recruitment, activation, and cytotoxicity of CD8+ T cells and ultimately improving immunotherapy efficacy.

关键词： BCG   trained immunity   LDLR   type I interferon pathway   antiviral infection   PCSK9 inhibitor   cholesterol   NFE2L1   IRAK1   RIG-I  

摘要： Trained immunity refers to memory-like responses of innate immune cells when they re-encounter pathogenic stimuli. Bacillus Calmette-Guerin (BCG) vaccination implies enhanced antiviral immunity, whereas the underlying mechanisms remain unclear. Herein, we have uncovered elevated expression of low-density lipoprotein receptor (LDLR) on BCG-trained macrophages with robust type I interferon (IFNI) production and antiviral effects both in vivo and in vitro. Consequently, cholesterol is accumulated in BCG-trained macrophages, leading to the augmentation of NFE2L1 expression and the formation of NFE2L1/IRAK1/TRIM25 complex where TRIM25 mediates IRAK1 K63 polyubiquitination to exaggerate IFNI responses in an RIG-I-dependent manner. We have also observed LDLR+ macrophages displaying heightened IFNI responses in BCG-treated human macrophages. To antagonize LDLR degradation by PCSK9 inhibitors increases IFNI responses in the macrophages and accelerated viral clearance. Our study thus couples LDLR upregulation to antiviral activity in BCG-trained macrophages, making commercial PCSK9 inhibitors potential antiviral indications in clinic.

关键词： ginsenoside Rh2   interferon gamma   combination treatment   cancer   Rh2+IFN gamma signature genes (RISG)  

摘要： Interferon gamma (IFN gamma) can amplify immune cell-mediated anti-tumor immunity, as well as directly kill cancer cells. Ginsenoside Rh2 (Rh2), a bioactive compound in traditional Chinese medicine, exhibits anti-cancer effects such as inhibiting proliferation and metastasis. Our earlier research found that Rh2 combined with IFN gamma enhanced CXCL10 secretion in cancer cells. Here, we explored whether Rh2 and IFN gamma exerted more potent anti-cancer activity in vitro and in vivo, along with its mechanisms and clinical value. Our data showed that Rh2 in combination with IFN gamma resulted in a remarkably increased cytotoxicity in colorectal cancer cells including HT29, LoVo and T84 cell lines. Consistently, intratumoral injection with Rh2 plus IFN gamma further restricted the HT29 tumor growth in vivo, and importantly, it was demonstrated to be safe for mice. Meanwhile, the combo treatment activated the stimulator of interferon genes (STING) pathway in cancer cells, promoting the transcription of downstream type I interferon. RNA sequencing revealed a dramatically transcriptional alteration in cancer cells with combo treatment and indicated that Rh2 further augmented the activation of interferon signaling pathway, compared with the IFN gamma alone. Inhibition of janus kinase (JAK) by ruxolitinib could significantly rescue the cell death-triggered by the combo treatment. Then, a gene set named Rh2+IFN gamma signature genes (RISG) was defined, which contained top 20 significantly upregulated genes from the combo treatment. Patients who exhibited a favorable response to the immunotherapy had a higher expression of RISG in tumor compared with those who did not respond. And the high expression of RISG was correlated with better clinical outcome in patients with colorectal cancer (CRC) and skin cutaneous melanoma (SKCM). Herein, the combination of Rh2 with IFN gamma served as a promising strategy for cancer treatment, and its-derived RISG gene set also exhibited potentia

关键词： C. difficile   innate immunity   innate lymphoid cells   interleukin-22   colitis   immunology   infection   mucosal repair   intestinal stem cells  

摘要： Clostridioides difficile causes debilitating colitis via secreted toxins that disrupt the intestinal barrier, and toxemia is associated with severe disease. Thus, therapies that fortify the intestinal barrier will reduce the severity of infection. Innate lymphoid cells (ILCs) are critical in the defense against acute C. difficile infection and represent a promising therapeutic target to limit disease. Here, we report that oral administration of the Toll-like receptor (TLR) 7 agonist R848 limits intestinal damage and protects mice from lethal C. difficile infection without impacting pathogen burden or altering the intestinal microbiome. R848 induced interleukin (IL)- 22 secretion by ILCs, leading to STAT3 phosphorylation in the intestinal epithelium and increased stem cell proliferation. Genetic ablation of ILCs, IL-22, or epithelial-specific STAT3 abrogated R848-mediated protection. R848 reduced intestinal permeability following infection and limited systemic toxin dissemination. Combined, these data identify an immunostimulatory molecule that activates IL-22 production in ILCs to enhance host tissue defenses following C. difficile infection.

关键词： ICOSL   MHC-I   DLBCL   microRNA   lymphoma  

摘要： Elevated miR-155 levels in B cell malignancies, such as CLL and DLBCL, correlate with increased aggressiveness of the disease. We recently reported that, in two different mouse models of miR-155-driven B cell malignancy, miR-155 targets and down-regulates transcripts encoding ICOSL, the ligand for the Inducible T cell costimulator (ICOS), thereby impairing the capacity of T lymphocytes to recognize and eliminate malignant cells. In report, we extend our previous findings to Human by showing that miR-155 levels negatively correlate with those of both ICOSL and MHC-I in samples from DLBCL patients. We present evidence of miR-155 reducing the levels of ICOSL transcripts in ABC, not in GCB primary tumors (PTs) and cell lines (CLs). In contrast, there was no evidence of miR-155 targeting MHC-I transcript levels in both types of DLBCLs. Nevertheless, miR-155 and MHC-I levels inversely correlated in DLBCLs samples, suggesting the existence of indirect regulatory effects of miR-155. There was also evidence of dose-dependent effects at low miR-155 levels. Altogether, our findings indicate that the deficiency of both ICOSL and MHC-I activity, driven by high levels of miR-155, may be causative in failure of the host immune system to recognize and eliminate malignant B cells.

摘要： Il feocromocitoma e il paraganglioma sono tumori rari in età pediatrica, derivanti dalle cellule cromaffini del sistema nervoso simpatico. Il feocromocitoma si localizza nella midollare del surrene, mentre il paraganglioma può svilupparsi in sedi extra-surrenaliche. Circa il 30–40% dei casi pediatrici ha una base genetica, spesso associata a sindromi ereditarie come MEN2, NF1, VHL e mutazioni SDH. I sintomi principali derivano dall’eccessiva secrezione di catecolamine e includono ipertensione, cefalea, sudorazione, palpitazioni e crisi ipertensive. La diagnosi si basa sul dosaggio delle metanefrine plasmatiche e urinarie, test genetici e imaging con TC, RM, scintigrafia MIBG o PET. Il trattamento principale è chirurgico, preceduto da una preparazione farmacologica per prevenire crisi intraoperatorie. Nei casi avanzati o metastatici si ricorre a radioterapia metabolica con MIBG o terapie mirate. La prognosi dipende dalla precocità della diagnosi e dall’eventuale predisposizione genetica, rendendo fondamentale un follow-up a lungo termine.

关键词： 补肾壮骨方   Wnt/β-catenin信号通路   骨关节炎   软骨细胞  

摘要： 目的：探究补肾壮骨方对大鼠软骨细胞退变的保护作用及其作用机制。方法：分离大鼠原代软骨细胞并给予不同浓度IL-1β（白介素-1β）刺激，探索IL-1β诱导OA（骨关节炎）细胞模型的最佳浓度，同时制备高中低浓度梯度的补肾壮骨方含药血清或盐酸氨基葡萄糖胶囊血清，作为细胞干预手段。检测软骨退化相关蛋白以及Wnt/β-catenin信号通路相关蛋白的mRNA及蛋白质表达，并使用透射电镜评价细胞超微结构变化。结果：经过IL-1β刺激后，软骨细胞的软骨退化相关蛋白以及Wnt/β-catenin通路相关蛋白表达明显异常，超微结构也可观察到细胞严重损伤。而补肾壮骨方通过抑制Wnt/β-catenin信号通路的激活，改善降低了IL-1β诱导的炎症因子和MMP（基质金属蛋白酶）的表达，并促进了Collagen II和Aggrecan的表达，从而保护软骨细胞。结论：补肾壮骨方含药血清能够通过抑制Wnt/β-catenin通路减少退变相关蛋白的异常表达，从而发挥保护作用。

关键词： Antigen presentation   MHCII   Microglia   Parkinson's disease   T cells   Alpha-synuclein   HLA  

摘要： Major histocompatibility complex class II (MHCII) molecules are antigen presentation proteins and increased in post-mortem Parkinson's disease (PD) brain. Attempts to decrease MHCII expression have led to neuroprotection in PD mouse models. Our group reported that a single nucleotide polymorphism (SNP) at rs3129882 in the MHCII gene Human Leukocyte Antigen (HLA) DRA is associated with increased MHCII transcripts and surface protein and increased risk for late-onset idiopathic PD. We therefore hypothesized that decreased MHCII may mitigate dopaminergic degeneration. During an ongoing alpha-synuclein lesion, mice with MHCII reduction in systemic and brain innate immune cells (LysMCre + I-Abfl/fl or CRE+) displayed brain T cell repertoire shifts and greater preservation of the dopaminergic phenotype in nigrostriatal terminals. Next, we investigated a human cohort to characterize the immunophenotype of subjects with and without the high-risk GG genotype at the rs3129882 SNP. We confirmed that the high-risk GG genotype is associated with peripheral changes in MHCII inducibility, frequency of CD4 + T cells, and differentially accessible chromatin regions within the MHCII locus. Although our mouse studies indicate that myeloid MHCII reduction coinciding with an intact adaptive immune system is insufficient to fully protect dopamine neurons from alpha-synuclein-induced degeneration, our data are consistent with the overwhelming evidence implicating antigen presentation in PD pathophysiology.