Differential effects of sympathetic nervous system and hypothalamic–pituitary–adrenal axis on systemic immune cells after severe experimental stroke

Infectious complications are the leading cause of death in the post-acute phase of stroke. Post-stroke immunodeficiency is believed to result from neurohormonal dysregulation of the sympathetic nervous system (SNS) and hypothalamic–pituitary–adrenal (HPA) axis. However, the differential effects of these neuroendocrine systems on the peripheral immune cells are only partially understood. Here, we determined the impact of the hormones of the SNS and HPA on distinct immune cell populations and characterized their interactions after stroke.At various time points after cortical or extensive hemispheric cerebral ischemia, plasma cortisone, corticosterone, metanephrine and adrenocorticotropic hormone (ACTH) levels were measured in mice. Leukocyte subpopulations were flow cytometrically analyzed in spleen and blood. To investigate their differential sensitivity to stress hormones, splenocytes were incubated in vitro with prednisolone, epinephrine and their respective receptor blockers. Glucocorticoid receptor (GCR) and beta2-adrenergic receptor (β2-AR) on leukocyte subpopulations were quantified by flow cytometry. In vivo effects of GCR and selective β2-AR blockade, respectively, were defined on serum hormone concentrations, lymphopenia and interferon-γ production after severe ischemia.We found elevated cortisone, corticosterone and metanephrine levels and associated lymphocytopenia only after extensive brain infarction. Prednisolone resulted in a 5 times higher cell death rate of splenocytes than epinephrine in vitro. Prednisolone and epinephrine-induced leukocyte cell death was prevented by GCR and β2-AR blockade, respectively. In vivo, only GCR blockade prevented post ischemic lymphopenia whereas β2-AR preserved interferon-γ secretion by lymphocytes. GCR blockade increased metanephrine levels in vivo and prednisolone, in turn, decreased β2-AR expression on lymphocytes.In conclusion, mediators of the SNS and the HPA axis differentially affect the systemic immune system after stroke. Moreover, our findings suggest a negative-feedback of corticosteroids on the sympathetic axis which may control the post-stroke stress-reaction. This complex interplay between the HPA and the SNS after stroke has to be considered when targeting the neurohormonal systems in the post acute phase of severe stroke.     

The immune checkpoints CTLA-4 and PD-L1 in carcinomas of the uterine cervix

BackgroundEvasion of immune control is a major feature of malignant tumors. This tumor aspect is poorly studied in cervical lesions.Aim of the studyTo investigate the expression of PD-L1 and CTLA-4 in lesions of the uterine cervix.Material and methodsSixty-three cervical lesions from 52 patients were immunohistochemically studied. The 63 lesions included 27 invasive adenocarcinomas, 19 squamous cell carcinomas (SCCs), 7 adenocarcinomas in situ, and 10 high-grade squamous intraepithelial lesions (CIN3).ResultsCTLA-4 and PD-L1 tumor cell expression was found in 61.5 % and 26.9 % of the invasive cases, respectively. CTLA-4 tumor cell expression and PD-L1 tumor and immune cell expression were more often found in SCCs than in adenocarcinomas. CTLA-4 tumor cell expression was more often found in advanced FIGO tumors. PD-L1 and CTLA-4 immune cell expression was associated with lymph node metastasis. CTLA-4 expression did not affect survival. The prognosis was worse for PD-L1-expressing tumors.ConclusionCTLA-4 and PD-L1 are potential therapeutic targets in cervical cancer.     

A hyper-ferritinemia syndrome evolving in recurrent macrophage activation syndrome,as an onset of amyopathic juvenile dermatomyositis: A challenging clinical case in light of the current diagnostic criteria

Juvenile dermatomyositis is an immune-mediated inflammatory multi-system disease involving mainly striated muscles and skin. Typical dermatological features are fundamental to establish the diagnosis, especially whenever the myopathy is very mild or absent, as it occurs in the form called as amyopathic juvenile dermatomyositis. Sometimes, systemic rheumatic diseases can develop a hyperferritinemia syndrome characterized by hemophagocytosis, namely macrophage activation syndrome, which represents a severe and life-threatening complication. Here, we describe a complex clinical history characterized by a hyper-ferritinemia syndrome after infectious mononucleosis, leading to recurrent episodes of macrophage activation syndrome. Finally, the late onset of several skin changes brought to a diagnosis of amyopathic juvenile dermatomyositis.     

Mucosal Vaccination Shapes the Expression of Salivary Antibodies and Establishment of CD8+ T‐Cells

Background: Mucosal vaccination for preventing periodontitis shows promising results. However, various administration routes and adjuvants may have a substantial role in the efficacy of the vaccination. The aim of the study is to compare different modes of mucosal vaccination with whole‐cell Porphyromonas gingivalis and to test the role of various adjuvants as potential modifiers of this process. Methods: Mucosal vaccine was administered through oral or nasal routes to BALB/C mice. The tested adjuvants included Escherichia coli cholera toxin, E. coli labile toxin (LT), and unmethylated CpG dinucleotide (CpG). Control mice were vaccinated subcutaneously. Saliva and serum were collected; anti–P. gingivalis salivary immunoglobulin A (IgA) and serum IgG were quantified. A quantitative enzyme‐linked immunosorbent assay to measure anti–P. gingivalis IgA levels was established. In addition, cells were extracted from head and neck lymph nodes, and the relative CD8⁺ cells were quantified using flow cytometry. Results: All mucosal vaccination modes induced anti–P. gingivalis salivary IgA but not anti–P. gingivalis serum IgG. Subcutaneous vaccination induced both salivary IgA and serum IgG against P. gingivalis. Mucosal vaccination also induced greater establishment of CD8⁺ cells compared to the subcutaneous vaccination. Oral mucosal vaccinations with LT or CpG were the most efficient for salivary IgA expression and CD8 cell establishment in lymph nodes. Conclusions: Oral and nasal mucosal vaccination induced a local host response with little systemic effect. The use of CpG or LT as adjuvants with the oral mucosal vaccination was the most efficient vaccination mode in the present mouse model.     

淋巴瘤主要组织相容性复合物Ⅰ类分子表达情况的实验研究

目的了解淋巴瘤组织和血液淋巴细胞主要组织相容性复合物Ⅰ(MHCⅠ)类分子的表达情况。方法采用实时荧光定量PCR检测淋巴瘤组织mRNA表达,Westernblot检测淋巴瘤组织蛋白表达,流式细胞仪检测血液淋巴细胞MHCⅠ类分子荧光强度。结果淋巴瘤组织mRNA表达由正常对照组的8.52±0.58下降为1.16±0.16(P<0.01);蛋白表达由正常对照组的16.36±1.06下降为2.35±0.24(P<0.01);血液淋巴细胞MHCⅠ类分子平均荧光强度由正常对照组的426±48下降为268±27(P<0.01),均有统计学差异。结论淋巴瘤组织MHCⅠ类分子mRNA和蛋白表达下降,同时血液淋巴细胞MHCⅠ类分子表达也下降。有可能通过检测血液淋巴细胞MHCⅠ类分子表达下降来辅助早期诊断淋巴瘤。     

维生素D与慢性荨麻疹的研究进展

慢性荨麻疹患者的平均维生素D与对照组相比明显偏低,且与病情严重程度及病程存在负相关.尽管尚不明确其中的因果关系,两者间的潜在联系可能与维生素D所起的免疫调节作用有关.有研究表明,维生素D可通过结合维生素D受体影响下游信号通路及核内转录水平,从而对肥大细胞、淋巴细胞以及嗜酸性粒细胞等多种免疫细胞的功能产生调节效应.维生素D可抑制肥大细胞释放活性介质,还可影响T淋巴细胞亚群动态平衡和迁移,引起干扰素γ水平下降和白细胞介素10水平升高等变化,可能是维生素D影响荨麻疹发病的重要机制.同时,临床药物试验显示,补充维生素D对慢性荨麻疹的治疗具有潜在的辅助作用.因此,若能继续明确维生素D与慢性荨麻疹发病的因果关系,从细胞及基因层面研究维生素D对肥大细胞等主要效应细胞的具体影响,将有助于为慢性荨麻疹的诊断和治疗找到新的理论依据.     

氯丙嗪和氯氮平对小鼠生殖细胞和人淋巴细胞的诱变效应

为探讨氯丙嗪和氯氮平在使用临床治疗剂量时的遗传毒理效应，研究了两药对小鼠生殖细胞和小鼠子代体细胞的影响，以及对人体淋巴细胞姊妹染色单体互换（ＳＣＥ）频率及微核率的影响。结果显示：（１）连续给药５天后第１周两药高、中、低三个剂量组均能引起小鼠精子头部畸形率明显增高，但停药４周后对精子的致畸作用基本消失；（２）两药对小鼠睾丸细胞及子代体细胞的染色体结构畸变率均无明显影响；（３）两药在治疗剂量时对人淋巴细胞的ＳＣＥ频率及微核率无明显影响，治疗前后的自身对照研究亦未见两频率有明显改变；（４）两药的血药浓度与ＳＣＥ频率及微核率之间无量效关系。研究结果提示，两药在临床治疗剂量时对小鼠生殖细胞染色体结构以及对人体遗传物质均无明显损伤作用。     

中性粒细胞/淋巴细胞比值与急性缺血性卒中患者脑微出血的相关性

目的 探讨急性缺血性卒中患者中性粒细胞/淋巴细胞比值(neutrophil to lymphocyte ratio, NLR)与脑微出血(cerebral microbleeds, CMBs)的相关性.方法 连续纳入住院的急性缺血性卒中患者.采用梯度回波T2*加权成像评估CMBs及其数量.采用单变量分析比较CMBs组与非CMBs组的基线资料,利用多变量logistic回归分析确定NLR与CMBs的独立相关性.结果 共纳入218例急性缺血性卒中患者,其中66例(30.3%)伴有CMBs.非CMBs组年龄[(64.7 ± 6.6)岁对(66.9 ± 8.6)岁;t=2.052,P=0.041]、高敏C反应蛋白水平[7.0(2.3~13.9)mg/L对8.9(4.0~28.1)mg/L;Z=2.008,P=0.045]和NLR[1.9(1.4~2.9)对2.3(1.7~3.6);Z=2.071,P=0.038]显著低于CMBs组.多变量logistic回归分析显示,NLR(优势比1.276,95%可信区间1.008~1.670;P=0.045)和年龄(优势比1.044,95%可信区间1.002~1.087;P=0.040)是CMBs的独立危险因素.Spearman相关分析显示,NLR与CMBs严重程度呈显著正相关(r=0.210,P=0.007).结论 在急性缺血性卒中患者中,NLR与CMBs及其严重程度相关,提示炎性反应可能参与了CMBs的发生.     

淋巴细胞转移干扰素抗病毒活性的机理研究

本文研究了人淋巴细胞与羊膜FL细胞之间干扰素介导的抗病毒活性转移的机理。受者FL细胞表达的抗病毒转移活性具有下述特征:1.用放线菌素D抑制FL细胞的RNA合成,能抑制抗病毒活性的表达;2.共同培养中存在的抗2-5_P_3A_3抗体不干扰细胞间抗病毒活性的转移;3.FL细胞膜上干扰素受体用植物血凝素封闭后,不影响抗病毒活性转移的表达。因此,我们认为,淋巴细胞膜上干扰素活化的第二信使分子可能是在细胞之间传递干扰素信息的重要效应物质。