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关键词： T -helper cell 9   Interleukin-9   Autoimmune disease   Rheumatoid arthritis   Multiple sclerosis   Systemic lupus erythematosus  

摘要： Autoimmune diseases (AIDs), such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, are caused by abnormal immune response that targets the body's own tissues. T-helper cell 9 (Th9) is a recently discovered subpopulation of T cells that primarily participates in inflammatory responses and immune regulation by secreting interleukin-9 (IL-9). IL-9 is a multifunctional cytokine that regulates the function of T and B cells, and also affects the activation and response of mast cells, macrophages, and other cells. Studies have shown that Th9 cells significantly affect the development of autoimmune diseases and are closely related to disease activity and pathological processes. Exploring drugs targeting Th9 cells or IL-9 and elucidating the regulatory mechanisms of Th9 and IL-9 in various AIDs will provide important insights for the development of novel therapeutic strategies.

关键词： Microenvironment   Immune response   Cancer  

摘要： The accumulation of CD103 + CD8 tumor-resident memory T (T RM ) cells is predictive of response to cancer immunotherapy. Here, we show that a therapeutic peptide vaccine controls tumor growth in wild-type mice, but not in CD103-knockout mice. CD8 tumor-infiltrating T lymphocytes include two major T RM subpopulations expressing either CD49a or CD103 integrin, with a subset co-expressing CD103 and Tcf-1. Vaccination induces a decrease in the percentage of Tcf-1 + CD103 + T RM -like cells and expansion of CD49a + T RM displaying an effector/exhausted profile. Tcf-1 + CD103 + T RM -cell density increases in tumors from transgenic mice constitutively expressing active TGF-β-type-2-receptor and wild-type mice challenged with neutralizing anti-IL-12 antibodies. The stimulation of CD8 T cells with recombinant (r)TGF-β combined with anti-CD3 antibodies results in an increase in the proportion of Tcf-1 + CD103 + cells, whereas rIL-12 decreases CD103 expression. These results highlight the opposite effects of TGF-β and IL-12 in the regulation of T RM -cell development and suggest that targeting Tcf-1 + CD103 + CD8 T RM may improve immunotherapy efficacy.

关键词： Asthma exacerbation   IL-33   Immune homeostasis   Oxidative stress   Ozone  

摘要： Short-term exposure to ozone is linked to the onset and exacerbation of asthma, yet the underlying mechanisms remain unclear. This study aims to elucidate the molecular pathways and key mediators involved in ozone-induced asthma exacerbation. In a longitudinal epidemiological study, each 10 mu g/m3 increase in ozone is associated with decreases in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF) of 26.24 ml (95 % confidence interval [CI]: 11.16 ml, 41.33 ml), 19.10 ml (95 % CI: 6.96 ml, 31.24 ml), and 41.65 ml/s (95 % CI: 3.87 ml/s, 79.43 ml/s), respectively. In asthmatic mice, ozone exposure induces oxidative stress and worsens pulmonary dysfunction, lung tissue damage, and inflammation, disrupting the balance of type 2 innate lymphoid cells (ILC2s), T helper type 2 (Th2), and T helper type 17 (Th17) cells. These effects are partially mitigated by N-acetylcysteine (NAC). Furthermore, ozone exposure significantly increases the interleukin (IL)-33 level, while treatment with an IL-33 neutralizing antibody markedly improves lung dysfunction, inflammatory cell infiltration, and immune response dysregulation. In conclusion, this study highlights that short-term exposure to ozone has deleterious effects on asthmatic patients and animals by inducing oxidative stress in lungs and disrupting immune function via IL-33.

摘要： BACKGROUND:Aflatoxin remains an under-recognized hepatocellular‑carcinoma (HCC) risk factor in the United States, where the permissible food limit (20 ppb) is five‑fold higher than in Europe. METHODS:We analyzed 350 TCGA-HCC cases with whole‑exome, RNA‑seq, and clinical data. Aflatoxin burden was quantified by single-base-substitution signature 24 (SBS24). HLA diversity was quantified from RNA‑seq reads using the Shannon diversity index. Multivariable Cox models estimated hazard ratios (HRs) for disease specific survival (DSS) with aflatoxin-virus interactions , adjusting for tumor stage, age, sex, race, alcohol use, fatty liver disease, aristolochic‑acid signature, and HLA diversity. Linear regression evaluated the association between HLA diversity and aflatoxin burden. RESULTS:Higher aflatoxin burden was associated with poorer DSS (aHR = 1.16, 95 % CI 1.01-1.33). Among HCV-positive patients, HBV infection was associated with improved DSS at low aflatoxin levels; however, this association was reversed at aflatoxin levels exceeding 30 units. HCV infection was consistently associated with worse DSS across aflatoxin levels. Asian American and Black/African American (AA) patients carried higher aflatoxin burdens than Whites (P = 0.016 and 0.014). Greater HLA diversity was independently associated with lower aflatoxin burden (P < 0.001), suggesting a protective effect. CONCLUSIONS:Somatic aflatoxin exposure, both independently and synergistically with HBV/HCV infection, adversely affects HCC prognosis, whereas greater HLA diversity may mitigate the detrimental effects of aflatoxin. Aflatoxin exposure disproportionately affected Asian-American and Black/AA patients (other minority groups not represented). IMPACT:Tightening U.S. aflatoxin food limits and expanding HBV vaccination coverage in high‑risk communities could reduce HCC disparities and improve patient survival.

关键词： 再生障碍性贫血   异体淋巴细胞   X射线   外周血   生存率   骨髓   免疫  

摘要： 目的 探讨不同剂量X射线联合异体淋巴细胞输注对建立再生障碍性贫血小鼠模型的影响。方法 取BALB/c小鼠40只,随机分为正常对照组（n=12）、3 Gy组（n=9）、4 Gy组（n=9）、5 Gy组（n=10）。3 Gy、4 Gy、5 Gy组指经过相应剂量的X射线辐照并在辐照后4 h内尾静脉输注0.2 mL DBA/2小鼠胸腺、脾脏细胞混合悬液,浓度为1×10～7个/mL。对照组不经过X射线辐照,并输注等体积生理盐水。BALB/c小鼠经眼眶静脉丛采血,用小鼠血常规分析仪检测外周血红细胞（RBC）、白细胞（WBC）、血小板（PLT）。每日观察小鼠一般情况,统计各组生存率。实验终点,取小鼠胫骨做苏木精-伊红染色（HE）,同时取股骨做骨髓涂片进行形态学检测。在实验终点,流式细胞术检测5 Gy组T细胞亚群,酶联免疫吸附测定（ELISA）检测细胞因子。结果 3 Gy组,全血细胞减少,但血小板恢复较快,造模第17天恢复正常水平。观察期内小鼠无死亡。实验终点,骨髓形态学表明骨髓增生活跃,粒细胞系、红细胞系比值正常,各阶段细胞形态未见明显异常。HE结果表明正常组骨髓组织致密,组织中充满血细胞。4 Gy组,全血细胞减少且一直维持到观察终点。观察期内生存率为90%。实验终点,骨髓形态学表明骨髓增生降低。HE结果表明骨髓组织较少脂肪浸润。5 Gy组,全血细胞减少,但红细胞在24 d恢复正常水平。观察期内生存率为50%。实验终点,骨髓形态学表明骨髓小粒空虚,造血细胞减少,多呈非造血细胞。HE结果表明5 Gy组骨髓组织严重脂肪浸润,几乎无幼稚细胞和造血前体细胞。流式检测结果显示CD4+T（%）细胞比例降低、CD8+T（%）细胞比例增加。ELISA结果显示负造血调控因子干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）的分泌升高。结论 不同剂量的射线联合异体淋巴细胞输注均可导致小鼠外周血RBC、WBC、PLT降低。结合骨髓形态学、骨髓HE和免疫学相关指标,5 Gy X射线联合2×10～6个异体淋巴细胞输注可用于建立再生障碍性贫血小鼠模型。

关键词： CRISPR/Cas9   基因编辑   Rag1基因   Il2rg基因   双基因敲除   金黄地鼠   免疫缺陷模型  

摘要： 目的 利用成簇规律间隔短回文重复序列及其相关蛋白9（clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9， CRISPR/Cas9）技术构建Rag1/Il2rg双基因敲除金黄地鼠模型，为免疫功能低下人群中腺病毒感染研究提供参考动物模型。方法 选择金黄地鼠Rag1基因第1外显子和Il2rg基因第4外显子为靶位点，设计sgRNA并进行体外转录。将sgRNA和Cas9蛋白注射至双细胞期胚胎中，并移植至妊娠0.5 d的受体母鼠输卵管，获得F0代鼠。将F0代鼠与野生型（wild type， WT）鼠交配，基因型鉴定后筛选出F1代Rag1和Il2rg基因的单等位基因敲除杂合子（Rag1 +/-、Il2rg+/-），再通过雌雄杂合子交配，经两代繁育获得Rag1/Il2rg双基因敲除纯合子（Rag1/Il2rg-/-）。通过流式细胞术检测脾脏混合细胞中的CD3、CD4、CD8、CD19、CD20阳性群，并采用常规病理技术观察胸腺和脾脏的组织结构变化。结果 基因型鉴定成功获得Rag1/Il2rg双基因敲除纯合子（Rag1/Il2rg-/-）。流式细胞术结果显示，基因敲除鼠的CD3、CD4、CD8、CD19、CD20细胞均未出现阴阳分群。WT鼠仅CD4细胞出现阴阳分群。组织病理观察显示，与WT鼠相比，双基因敲除鼠脾脏皮质和髓质结构无明显差异；胸腺萎缩，皮质和髓质分界不清，纤维性被膜变薄，髓质中可见脂肪组织及流产型腺样结构，未见胸腺小体，细胞稀疏，上皮细胞胞质较少。结论 利用CRISPR/Cas9系统成功构建Rag1/Il2rg双基因敲除金黄地鼠模型，可为免疫功能低下人群中腺病毒感染机制的研究提供有价值的实验动物模型。

关键词： Sophocarpine   microglia   BV-2 cells   AMPK/NF-kappa B pathway   oxidative stress   neuroinflammation  

摘要： BackgroundMicroglia can be continuously activated to produce proinflammatory cytokines and reactive oxygen species, leading to progressive neurodegeneration. Sophocarpine (ScP) has been reported to exhibit neuroprotective and anti-inflammatory activities, but it remains unclear whether microglia are involved in these ***-2 cells were exposed to ScP, AMP-activated protein kinase (AMPK) agonist AICAR, and the AMPK inhibitor Compound C for 30 min before being treated with lipopolysaccharide (LPS) and IFN-gamma for 24 h. The levels of oxidative response and inflammation were detected by kits, immunofluorescence, ELISA, and western blotting. The AMPK/NF-kappa B expression was measured using western blotting. In vivo effects were next verified using LPS-induced neuroinflammatory mouse ***, 1, 2, and 4 mu M ScP had no effects on BV-2 cells. After BV-2 cells were stimulated with LPS and IFN-gamma, the levels of antioxidant enzymes were decreased, whereas the levels of allograft inflammatory factor 1 (Iba-1) and inflammatory mediators were increased. After LPS and IFN-gamma stimulation, the levels of phosphorylated (p)-AMPK protein were decreased, whilst the levels of p-I kappa B alpha and p-p65 protein were increased. ScP then reduced the levels of Iba-1, inflammatory mediators, p-I kappa B alpha, and p-p65 proteins, whilst increasing the levels of antioxidant enzymes and p-AMPK. ScP treatment reduced the extent of neuronal damage in mice, significantly improving inflammation and oxidative stress damage. The antioxidant and anti-inflammatory effects of ScP were found to be enhanced after AICAR *** can inhibit LPS and IFN-gamma-stimulated oxidative response and neuroinflammation in BV-2 cells through the AMPK/NF-kappa B axis.

关键词： Delayed hypersensitivity reactions   Drug reaction with eosinophilia and systemic symptoms   Ex vivo diagnostic tools   In vivo diagnostic tools   Iodinated contrast media   Maculopapular exanthema  

摘要： BACKGROUND:The use of in vivo and ex vivo diagnostic tools for delayed hypersensitivity reactions (DHRs) associated with iodinated contrast media (ICM) is currently ill-defined. OBJECTIVE:To evaluate the role of in vivo and ex vivo diagnostic tools for DHRs occurring >6 h following intravenous low-osmolality ICM. METHODS:We conducted a prospective, multicenter, international cohort study. The patients were recruited from two tertiary care adult allergy clinics, Austin Health, Australia and the McGill University Health Centre, Canada. Eligible participants were adults who reported a DHR after receiving ICM. In vivo testing (skin testing and intravenous challenge) was performed to identify an alternative agent. Ex vivo testing using interferon-γ enzyme-linked ImmunoSpot assay was performed in four Australian patients to explore its diagnostic performance. RESULTS:The culprit ICM was identified by dIDT in 17/20 (85%) while in 3/20 (15%) a challenge was necessary to confirm delayed hypersensitivity. All patients with a positive dIDT to iohexol were positive to iodixanol (15/15; 100%) while 3/4 (75%), 3/4 (75%), 4/6 (67%), and 3/5 (60%) were positive to iopromide, ioversol, iopamidol, and iobitridol, respectively. Overall, 7/20 (35%) patients tolerated a challenge with an alternative ICM. The IFN-γ release assay was negative for the implicated ICM in 4 patients with confirmed DHR through a positive dIDT. CONCLUSION:dIDT allowed confirmation of T cell-mediated allergy to the implicated ICM in 85% of patients with a strong clinical suspicion of DHR and identification of non-cross-reactive ICM in 35% of patients. The IFN-y ELISpot was not useful in the four patients tested.

关键词： 血清信号淋巴细胞激活分子家族成员8   卒中后认知功能障碍   预测   生物学标志物  

摘要： 目的探讨血清信号淋巴细胞激活分子家族成员8(signal lymphocyte activation molecule family member 8，SLAMF8)水平对卒中后认知功能障碍(PSCI)的预测价值。方法在基因表达综合数据库(GEO)中选取GSE122063数据集，通过STRING网络和Cytoscape软件筛选出血管性痴呆的关键基因。前瞻性队列研究，纳入江苏大学附属医院神经内科2023年1—12月收治的123例急性脑梗死(ACI)患者，随访6个月，根据是否发生PSCI，将患者分为PSCI组和卒中后非认知障碍(PSNCI)组，收集两组基线期一般资料、随访6个月时的简易智能状态检查量表(MMSE)和蒙特利尔认知评估量表(MoCA)评分，检测基线期血清SLAMF8、稳定蛋白1(STAB1)水平以及随访6个月时的血清白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)水平。采用Pearson相关分析变量间的相关性。采用logistic回归分析影响PSCI发生的基线因素。绘制受试者工作特征曲线(ROC曲线)分析变量对PSCI发生的预测价值。结果在GSE122063数据集中，通过Cytoscape软件的最大邻域组件密度(DNMC)和离心率(Eccentricity)算法筛选出血管性痴呆的关键基因SLAMF8和STAB1。在队列研究中，与PSNCI组相比，PSCI组患者基线期美国国立卫生研究院卒中量表(NIHSS)评分和血清SLAMF8水平增高(t＝3.033、5.422，P<0.01)，6个月随访时MMSE和MoCA评分降低(t＝16.340、18.634，P<0.001)、血清IL-1β和IL-6水平增高(t＝2.633、2.632，P<0.05)。基线期STAB1水平在两组间无明显差异(t＝1.280，P>0.05)。在PSCI组，基线期血清SLAMF8与入院NIHSS评分相关性没有差异(r＝0.257，P＝0.082)；与6个月随访时MMSE评分(r＝－0.711，P<0.001)和MoCA评分(r＝－0.686，P<0.001)均呈负相关。logistic回归显示基线期血清SLAMF8水平(OR＝1.142，P＝0.001)和NIHSS评分(OR＝1.094，P＝0.007)是ACI患者发生PSCI的危险因素。基线期血清SLAMF8水平预测ACI患者发生PSCI的ROC曲线下面积(AUC)为0.776，SLAMF8联合NIHSS评分预测PSCI发生的AUC为0.796。基线期血清SLAMF8水平与6个月随访时血清IL-1β水平(r＝0.652，P<0.001)和IL-6水平(r＝0.710，P<0.001)均呈正相关。结论ACI患者早期高表达的血清SLAMF8水平可作为预测PSCI发生的潜在生物学标志物。