Autophagy and cytokines

Autophagy is a highly conserved homoeostatic mechanism for the lysosomal degradation of cytosolic constituents, including long-lived macromolecules, organelles and intracellular pathogens. Autophagosomes are formed in response to a number of environmental stimuli, including amino acid deprivation, but also by both host- and pathogen-derived molecules, including toll-like receptor ligands and cytokines. In particular, IFN-γ, TNF-α, IL-1, IL-2, IL-6 and TGF-β have been shown to induce autophagy, while IL-4, IL-10 and IL-13 are inhibitory. Moreover, autophagy can itself regulate the production and secretion of cytokines, including IL-1, IL-18, TNF-α, and Type I IFN. This review discusses the potentially pivotal roles of autophagy in the regulation of inflammation and the coordination of innate and adaptive immune responses.     

隐球菌性脑膜炎患者外周血中Th9和Th17细胞水平变化及意义

目的：比较初发隐球菌性脑膜炎患者治疗前后与健康对照人群外周血 CD4＋ T 细胞中 Th9和 Th17细胞的比值,探讨 Th9和 Th17细胞在隐球菌性脑膜炎发病机制中的作用。方法选取初发未经治疗隐球菌性脑膜炎患者及健康对照各12例,抽取隐球菌性脑膜炎患者治疗前和治疗后3周及健康对照的外周血,分离外周血单核细胞,应用流式细胞仪检测技术对3组病例外周血 CD4＋ T 细胞中 Th9和 Th17的比值进行比较。结果与健康对照相比,隐球菌性脑膜炎患者治疗前Th17表达下调,差异有统计学意义;在治疗好转患者中,治疗后 Th17表达显著上调,与治疗前及健康对照相比差异均有统计学意义。Th9在治疗前与健康对照相比无差异,在治疗后隐球菌性脑膜炎患者中表达上调。结论 Th17免疫途径是隐球菌性脑膜炎患者抵御隐球菌感染的重要免疫机制,隐球菌性脑膜炎发病及治疗拮抗可能与 Th17缺乏有关。     

A gradient of glucocorticoid sensitivity among helper T cell cytokines

Helper T (Th) cells secret specific cytokines that promote immune responses whereas glucocorticoids limit the extent of immune responses by inhibiting cytokine secretion and other functions of Th cells. However, glucocorticoid resistance develops in subgroups of patients with Th cell-driven diseases such as asthma and Crohn’s disease. Recent evidence supports that Th1, Th2, and Th17 cells have distinct glucocorticoid sensitivity. Th1 cells are sensitive to glucocorticoid-induced apoptosis and cytokine suppression while Th2 cells are sensitive to the latter but not the former and Th17 cells are resistant to both. This gradient of glucocorticoid sensitivity of Th cells corresponds to the glucocorticoid sensitivity of the diseases they underlie. We identify the mechanisms contributing to distinct glucocorticoid sensitivity of Th cells and their cytokines in the literature, as this information is useful to improve treatment strategies for glucocorticoid resistant immunological disorders.     

骨化三醇对自身免疫性甲状腺炎大鼠T淋巴细胞亚群的影响

目的:研究骨化三醇对自身免疫性甲状腺炎模型大鼠甲状腺功能、甲状腺过氧化物酶抗体(TPOAb)、甲状腺球蛋白抗体(TGAb)及脾脏T淋巴细胞亚群的影响。方法:20只Lewis大鼠采用高碘饮水联合猪甲状腺球蛋白皮下注射的方法建立自身免疫性甲状腺炎动物模型。造模成功后大鼠随机分为模型组和骨化三醇组。经10周灌胃后,检测各组大鼠甲状腺功能三项、甲状腺抗体,流式细胞技术检测大鼠脾脏T淋巴细胞亚群的比例。结果:(1)与正常组相比,模型组及骨化三醇组大鼠促甲状腺激素(TSH)明显降低,血清游离甲状腺素(FT4)及TPOAb、TGAb明显升高,差异均具有统计学意义(P0.01);与模型组大鼠相比,骨化三醇组大鼠TPOAb、TGAb明显降低(P0.01);(2)与正常组相比,模型组大鼠表现为Th1、Th17细胞比例升高(P0.05),Th1/Th2、Th17/Treg比例升高(P0.05),与模型组相比,骨化三醇组大鼠Th1、Th17细胞比例降低(P0.05),Th2、Treg比例升高(P0.05),Th1/Th2、Th17/Treg比例降低(P0.01)。结论:骨化三醇可通过抑制Th1、Th17免疫亢进,改善Th1/Th2、Th17/Treg失调,改善自身免疫性甲状腺炎免疫反应。     

沙门菌- 斑马鱼感染模型用于Th1/Th2 免疫应答的研究

目的:通过构建斑马鱼成鱼感染模型,研究鼠伤寒沙门菌感染对机体Th1/Th2免疫应答的影响。方法:用不同剂量细菌口饲感染8月龄的斑马鱼成鱼,绘制3周生存率曲线。观察各剂量下对成鱼的感染情况,并用实时荧光定量聚合酶链式反应检测肝脏Th1、Th2型细胞相关基因和细胞因子的mRNA转录水平,计算Th2/Th1相对表达量比值。结果:用105 CFU感染2周斑马鱼全部存活,第15天开始出现死亡,且在3周后死亡率达到50%;感染后3周解剖发现,肝脏、脾脏和肠道有明显红肿和糜烂;肝脏Th1、Th2型细胞相关基因和细胞因子mRNA转录水平明显向Th2偏移。结论:用105 CFU鼠伤寒沙门菌口饲感染斑马鱼成鱼构建的模型,能反映机体感染和免疫功能变化,可用于研究体内Th1/Th2免疫应答,为进一步研究鼠伤寒沙门菌感染与免疫机制提供了很好的实验工具。     

轮状病毒致乳鼠肠道外感染Th1/Th2细胞因子变化的研究

目的通过复制轮状病毒（RV）肠道外感染乳鼠的动物模型,检测接种后乳鼠体内Th1/Th2平衡改变,对RV肠道外感染后机体免疫状态进行初步研究。方法48只乳鼠随机均分为3组：肠道外组、肠道内组和正常对照组。肠道外组通过腹腔注射猴RVSA11株,肠道内组灌胃等量RV悬液,对照组无特殊处理。分别在接种后第4天、第8天处死乳鼠,收集标本,观察心、肝、肾、肺等脏器病理变化,用ELISA法检测血清中IL-10和IFN-γ的表达。结果光镜下肠道外组乳鼠肾、肝、肺和脾脏出现病理改变。感染后第4天,肠道内、外组乳鼠血清IFN-γ水平均高于正常组,到第8天明显下降,基本达到基线水平;IL-10在肠道外组第4天增高,到第8天小幅下降,但仍然高于正常组;而肠道内组IL-10无明显改变。结论RV肠道外感染早期呈现Th1-Th2混合反应,而后期则以IL-10的表达为主,T细胞向Th2型免疫应答方向偏离,Th1/Th2细胞因子失衡机制可能是RV肠道外感染的重要因素。     

The attenuation of Th1 and Th17 responses via autophagy protects against methicillin-resistant Staphylococcus aureus-induced sepsis

Whether autophagy affects methicillin-resistant Staphylococcus aureus (MRSA)-induced sepsis and the associated mechanisms are largely unknown. This study investigated the role of autophagy in MRSA-induced sepsis. The levels of microtubule-associated protein light chain 3 (LC3)-II/I, Beclin-1 and p62 after USA300 infection were examined by Western blotting and immunohistochemical staining. Bacterial burden analysis, hematoxylin-eosin staining, and Kaplan–Meier analysis were performed to evaluate the effect of autophagy on MRSA-induced sepsis. IFN-γ and IL-17 were analyzed by ELISA, and CD4⁺ T cell differentiation was assessed by flow cytometry. Our results showed that LC3-II/I and Beclin-1 were increased, while p62 was decreased after infection. Survival rates were decreased in the LC3B^−/− and Beclin-1^+/− groups, accompanied by worsened organ injuries and increased IFN-γ and IL-17 levels, whereas rapamycin alleviated organ damage, decreased IFN-γ and IL-17 levels, and improved the survival rate. However, there was no significant difference in bacterial burden. Flow cytometric analysis showed that rapamycin treatment decreased the frequencies of Th1 and Th17 cells, whereas these cells were upregulated in the LC3B^−/− and Beclin-1^+/− groups. Therefore, autophagy plays a protective role in MRSA-induced sepsis, which may be partly associated with the alleviation of organ injuries via the downregulation of Th1 and Th17 responses. These results provide a nonantibiotic treatment strategy for sepsis.     

Th17及Th1相关细胞因子与支气管哮喘的关系研究

目的:分析外周血Th17、Th1及相关细胞因子表达水平和支气管哮喘(bronchial asthma,BA)发生、发展的相关性研究。方法:回顾选取我院收治的BA病例57份,称作BA组,另选取呼吸系统正常的病例55例为对照组,检测两组入选者的外周血IL-2、TNF-α、Th17、IL-6、Th1指标表达差异,并进行多因素回归分析。结果:BA组Th17(0.62±1.67)%、Th1(1.45±0.48)%及Th1/Th17(2.33±1.28)均显著低于对照组(P均0.05);BA组TNF-α(27.46±8.12)pg/mL、IL-6(11.69±2.14)pg/mL表达量显著高于对照组,IL-2(2.58±3.89)pg/mL、IFN-γ(3.74±6.15)pg/mL含量均显著低于对照组(P均0.05);经Logistic回归分析,TNF-α、IL-6、IFN-γ、Th1/Th17、IL-2均和BA有密切相关性(P均0.05)。结论:IL-2、IFN-γ、Th1/Th17、TNF-α、IL-6表达水平均与BA有密切关联,可能是参与BA发病的主要原因,及早进行Th17、Th1及相关细胞因子检查有助于明确病情。     

Mechanisms of resistance to S. mansoni infection: the rat model

Human schistosomiasis is associated with IgE and eosinophilia, feature of a type 2 response. In experimental investigations, murine model has been widely used in order to dissect the immune responses involved in the expression of protective immunity or disease in Schistosoma mansoni infection. Collectively, observations made in this model and in humans demonstrated a strong contrast since a Th2 response in infected mice is involved in the expression of pathology, however, in infected humans the same type of response is rather beneficial for the host. This review will consider the relevance of extrapolating studies of immune responses from experimentally infected rats a semi-permissive host, to studies on S. mansoni infected humans.     

New insights into CD4+ T cell abnormalities in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune connective tissue disease that is characterized by vasculopathy and excessive deposition of extracellular matrix, which causes fibrosis of the skin and internal organs and eventually leads to multiorgan dysfunction. Studies have shown that CD4⁺ T cell activation is a key factor in the pathogenesis of scleroderma because activated T cells can release various cytokines, resulting in inflammation, microvascular damage and fibrosis. T helper cell 17 (Th17) and regulatory T (Treg) cell activities are a hallmark SSc, as Th17-type cytokines can induce both inflammation and fibrosis. More recently, several studies have reported new T cell subsets, including Th9 and Th22 cells, along with their respective cytokines in the peripheral blood, serum and skin lesions of individuals with SSc. Herein, we review recent data on various CD4⁺ T helper cell subsets in SSc, and discuss potential roles of these cells in promoting inflammation and fibrosis.     

益生菌辅助防治过敏性疾病的研究进展

益生菌是一类在适当的摄入数量时会对宿主机体带来益处的活体微生物,其对于机体的免疫系统具有调节作用.研究表明,益生菌可以通过调节Th1/Th2平衡,增加宿主对相关抗原的口服耐受,从而缓解过敏性症状.本文综述了近十年来研究益生菌抗过敏作用在体外试验、动物实验和临床试验三方面的进展.     

Deviated balance between Th1 and Th17 cells exacerbates acute graft-versus-host disease in mice

BackgroundTh1/Th17 imbalance had been indicated to mediate several kinds of inflammatory diseases. We deduce that Th1/Th17 imbalance might also contribute to the pathogenesis of acute graft-versus-host disease (GVHD). This study is to investigate the relation between Th1/Th17 imbalance and acute GVHD.MethodsWe applied a murine GVHD model of C57BL/6 (H-2^b) donor to BALB/c (H-2^d) recipient by treating the recipients with low dose of halofuginone (HF), which is competent in selectively inhibiting Th17 differentiation and facilitating Th1 differentiation. Recipient mice were monitored for survival rate, body weight change, clinical symptoms and pathological evidence of acute GVHD. We also measured the proportions of Th1 and Th17 cells in circulation and expression levels of IFN-γ and IL-17A in tissues involved in GVHD.ResultsFirstly, we confirm the existence of Th1/Th17 imbalance in acute GVHD and Th1/Th17 imbalance positively correlates with severity of acute GVHD. Secondly, low dose of HF augments Th1/Th17 imbalance by driving the Th1/Th17 balance to a Th1-dominant reaction. Finally, augmented Th1/Th17 imbalance leads to aggravated systemic GVHD. An increased Th1-type reaction results in aggravated hepatic and intestinal GVHD, and inhibiting Th17 differentiation is sufficient to alleviate pulmonic impairment.ConclusionOur study is indicative for a critical role of Th1/Th17 imbalance in the pathogenesis of murine GVHD.     

Th1/Th2平衡调节与疾病发生的研究进展

正常情况下,辅助性T淋巴细胞亚群Th1/Th2细胞处于平衡状态,Th1/Th2平衡失调并向Th1或Th2状态转化的趋势称为Th1/Th2的漂移。习惯上把Th1及其细胞因子占优势的状态称为Th1状态,Th2及其细胞因子占优势的状态称为Th2状态。Th1/Th2平衡影响细胞因子网络的平衡,与许多疾病的发生、发展、治疗、转归有密切的关系。现就Th1/Th2平衡与人类相关疾病间的关系及相关研究作一综述。     

Anti-P- and E-selectin therapy prevents abortion in the CBA/J x DBA/2J combination by blocking the migration of Th1 lymphocytes into the foetal-maternal interface

Leukocyte migration into inflamed tissues comprises dynamic interactions between immune and endothelial cells through events controlled by adhesion molecules, e.g., P- and E-selectins, which mediate Th1 cells recruitment after injury. Since miscarriage is known to be a Th1 event and selectins are expressed at the murine foetal-maternal interface, the purpose of our study was to investigate whether blocking P- and E-selectins before implantation could inhibit Th1 migration into the foetal-maternal interface and thus prevent foetal rejection. DBA/2J-mated CBA/J females were treated with monoclonal antibodies (mAbs) against P-selectin or with both, anti-P- and anti-E-selectins combined on days 2 and 4 of pregnancy. PBS-treated females served as controls. Our data revealed a significant improvement in pregnancy outcome in both treated groups compared to the control, which is due to the effectiveness of the mAb against P-selectin, since the treatment with anti-E-selectin alone could not prevent abortion. We further observed that there was diminished Th1 cytokine production by decidual immune cells in all treated groups in comparison to the controls. Our data first confirm the important role of P-selectin in mediating the extravasation of abortive cells, while opening new therapeutic opportunities.     

T helper cell mediated-tolerance towards fetal allograft in successful pregnancy

Trophoblast HLA-C antigens from paternal origins, which liken the trophoblast to a semiallograft, could be presented by the maternal APCs to the specific maternal CD4+ T helper cells, which could release various cytokines in response to these alloantigens. On the basis of the cytokines produced, these cells can be classified in Th1, Th2 and Th17 cells. Th1 and Th17 cells, known to be responsible for acute allograft rejection, could be involved in miscarriage and Th2 cells together with regulatory CD4+ T cells, known to be involved in allograft tolerance, could be responsible, at least in part, for the success of pregnancy. In this review we focus the role effector CD4+ T cells Th1, Th2 and Th17 cells on the fetal allograft tolerance.     

原发性肝癌患者Th_1/Th_2亚群研究

目的：探讨原发性肝癌患者血清中淋巴细胞亚群中Th1/Th2的变化,为分析肝癌的发生发展状症和临床治疗提供免疫学指标。方法：应用放射免疫分析及酶联免疫分析法（ELISA）,测定46例肝癌患者,及43例正常对照组进行比较。以IL-2、INF-γ和TNF-α水平代表Th1型细胞因子,以IL-4,IL-6、IL-8、IL-10的水平代表Th2型细胞因子。结果：肝癌患者IL-2、TNF-γ、IL-6的水平明显低正常对照组,P〈0.01。IL-4、IL-8、IL-10、TNF-α的水平明显高于正常对照组,P〈0.01。结论：肝癌患者体内存在Th1/Th2细胞因子失衡,其中Th1亚群功能抑制,Th2亚群功能亢进,其与肿瘤在宿主体内生长密切相关。通过纠正这些免疫失调将成为肝癌治疗的重要手段。     

T-helper (Th)1/Th2 imbalance in the peripheral blood of dogs with malignant tumor

T helper type 1 cell (Th1)/Th2 imbalance has been observed in a variety of pathological conditions, including malignant diseases. We evaluated the Th1/Th2 in peripheral blood Th cells by means of intracytoplasmic cytokine analysis in 11 dogs with advanced malignant tumor; four of them showed metastatic tumor. The percentage of Th1 was significantly lower and the percentage of Th2 was significantly higher in diseased dogs compared to healthy dogs. The percentage of Th1 in three patients with metastatic tumor was significantly lower than that in the patients with non-metastatic tumor. We conclude that the Th1/Th2 balance was polarized to Th2 in dogs with cancer.     

原发性肝癌患者Th1/Th2 亚群研究*

目的:探讨原发性肝癌患者血清中淋巴细胞亚群中Th1/Th2的变化,为分析肝癌的发生发展状症和临床治疗提供免疫学指标。方法:应用放射免疫分析及酶联免疫分析法(ELISA),测定46例肝癌患者,及43例正常对照组进行比较。以IL-2、INF-γ和TNF-α水平代表Th1型细胞因子,以IL-4,IL-6、IL-8、IL-10的水平代表Th2型细胞因子。结果:肝癌患者IL-2、TNF-γ、IL-6的水平明显低正常对照组,P<0.01。IL-4、IL-8、IL-10、TNF-α的水平明显高于正常对照组,P<0.01。结论:肝癌患者体内存在Th1/Th2细胞因子失衡,其中Th1亚群功能抑制,Th2亚群功能亢进,其与肿瘤在宿主体内生长密切相关。通过纠正这些免疫失调将成为肝癌治疗的重要手段。