Decoy receptor 3: a pleiotropic immunomodulator and biomarker for inflammatory diseases, autoimmune diseases and cancer

Recently, several decoy molecules belonging to tumor necrosis factor receptor superfamily (TNFRSF) have been identified, including decoy receptor 1 (DcR1), decoy receptor 2 (DcR2), and decoy receptor 3 (DcR3). One of the tumor necrosis factor superfamily (TNFSF) members, TNF-related apoptosis-inducing ligand (TRAIL), binds to DcR1 and DcR2, which are membranous receptors with a truncated cytoplasmic domain, thus unable to transduce TRAIL-mediated signaling. In contrast to DcR1 and DcR2, DcR3 is a soluble receptor capable of neutralizing the biological effects of three other TNFSF members: Fas ligand (FasL/TNFSF6/CD95L), LIGHT (TNFSF14) and TNF-like molecule 1A (TL1A/TNFSF15). Since FasL is a potent apoptosis- and inflammation-inducing factor, LIGHT is involved in apoptosis and inflammation, and TL1A is a T cell costimulator and is involved in gut inflammation, DcR3 can be defined as an immunomodulator on the basis of its neutralizing effects on FasL, LIGHT, and TL1A. Initial studies demonstrated that DcR3 expression is elevated in tumors cells; however, later work showed that DcR3 expression is also upregulated in inflammatory diseases, where serum DcR3 levels correlate with disease progression. In addition to its neutralizing effect, DcR3 also acts as an effector molecule to modulate cell function via ‘non-decoy’ activities. This review focuses on the immunomodulatory effects of DcR3 via ‘decoy’ and ‘non-decoy’ functions, and discusses the potential of DcR3 as a biomarker to predict cancer invasion and inflammation progression. We also discuss the possible utility of recombinant DcR3 as a therapeutic agent to control autoimmune diseases, as well as the potential to attenuate tumor progression by inhibiting DcR3 expression.     

Interleukin-2 as immunotherapeutic in the autoimmune diseases

Interleukins, also called cytokines are secretory proteins that bind to specific receptors and play a critical role in the intercellular communication between cells of the immune system. Cytokines are mainly produced by T lymphocytes, macrophages and eosinophils. Among its functions are the activation and suppression of immune system responses, induction of cell division and regulation of memory cells. Interleukin 2 (IL-2) is a secretory monomeric glycoprotein composed of 149 amino acids containing a signal peptide of 20 amino acids. It is classified as a member of the type I cytokines family. IL-2 binds to its receptor (IL-2R receptor) with high affinity and its signaling function promotes the activation of various subtypes of lymphocytes during the process of cell differentiation to generate an immune or homeostatic response. The specificity of IL-2 depends on its binding to low, medium or high-affinity receptors. Interleukin 2 acts as a regulator of the proliferation of CD4+ and CD8+ T cells. There is a relationship between IL-2 and autoimmune diseases due to its influence in the differentiation of T helper cells, which in turn directly influence immunological response processes. Therefore, IL-2 is a key element in the control and treatment of those diseases. In recent years, many therapeutic agents based on biomolecules and recombinant chimeric proteins have been developed to treat different autoimmune diseases. In this review, we focus on the use of interleukin 2 as a versatile therapeutic agent, alone or associated with other molecules to increase the efficiency of autoimmune disease treatment.     

多种自身抗体联合检测对自身免疫性疾病临床诊断的意义

目的探讨多种自身抗体联合检测在自身免疫病中的临床意义。方法对100例自身免疫性疾病患者的实验室及临床资料进行回顾性分析。结果抗ds-DNA、抗Sm、Po与系统性红斑狼疮(SLE)相关,抗Histones与多种结缔组织病相关,抗U1-RNP与混合性结缔组织病(MCTD)、类风湿性关节炎(RA)、硬皮病、干燥综合征相关,CENP-B与局限型系统性硬化、RA、SLE、原发性干燥综合征相关,抗SS-A、抗SS-B与干燥综合征及SLE相关,Scl-70与系统性硬化相关,Jo与多发性肌炎相关。结论自身抗体的实验室检测对自身免疫疾病的诊断有重要意义。     

IL—2,IL—2R,IL—6mRNA在自身免疫性甲状腺病甲状腺组织中的原位表达

本实验分别用Ｄｉｇ标记的ＩＬ－２、ＩＬ－２Ｒ、ＩＬ－６ｃＲＮＡ探针在３７例自身免疫性甲状腺疾病患者甲状腺石蜡切片上行原位杂交，结果显示患者甲状腺浸润细胞中有ＩＬ－２、ＩＬ－２Ｒ、ＩＬ－６ｍＲＮＡ的异常表达，其分布与病理损伤部位一致，这种异常表达是引起甲状腺内免疫功能紊乱的重要因素之一。     

Molecular pathology of drug-disease interactions in chronic autoimmune inflammatory diseases

The aetiology of autoimmune, chronic inflammatory disease is reviewed, together with the contributing roles of oxygen radicals, the cytochromes P450, the eicosanoids, the interleukins, and the corticosteroids and estrogens. The importance of drug metabolism in the formation of reactive intermediates of drugs and environmental chemicals, and hence in the production of neoantigens, autoantibodies and autoimmune disease is considered, together with the possible involvement of genetic variations in sulphoxidation, sulphotransferase and acetyltransferase activities in predisposing patients to rheumatoid arthritis, lupus and other autoimmune diseases. The toxicity of anti-inflammatory drugs, and the molecular mechanisms involved, are reviewed, including the formation of neoantigens and autoantibodies by the acylation of proteins by ester glucuronide metabolites of non-steroidal anti-inflammatory drugs, by the formation of disulphide protein conjugates of penicillamine, by theN-oxygenation of sulphonamides, and the oxygenation of hydralazine, procainamide and other drugs by leukocyte NADPH-oxidase and myeloperoxidase. The limitations of the existing procedures for the safety evaluation of new drugs, and their inability to identify potential immunotoxicity in man, are considered, and the advantages of the molecular structure procedure of COMPACT (Computer Optimised Molecular Parametric Analysis for Chemical Toxicity), and the enzyme induction procedure of ENACT (Enzyme Induction Analysis for Chemical Toxicity), for identifying potential carcinogenic and immunotoxic chemicals, are briefly discussed.     

血管生成素2在大鼠内毒性急性肺损伤中的作用与机制研究

目的 探讨血管生成素-2(Ang-2)在脂多糖(LPS)致大鼠急性肺损伤(ALI)时的表达及其机制。方法 48只清洁级SD大鼠随机分为正常对照组、1 mg/kg LPS组、5 mg/kg LPS组和10 mg/kg LPS组,每组12只。LPS组尾静脉注射不同剂量LPS复制ALI模型,对照组注射同等体积生理盐水,留取肺组织标本,观察肺湿/干重(W/D)比值、HE染色光镜观察肺组织标本病理改变并进行肺损伤评分,各组ELISA法检测血浆中Ang-2与血管内皮生长因子(VEGF)的表达,Westernblot方法检测肺组织中Ang-2的蛋白表达情况。结果 LPS注射进入大鼠尾静脉6 h后,光镜下可见肺组织内的炎性细胞浸润,肺泡隔增宽,肺间质水肿和肺结构破坏等病理改变;LPS各组的肺损伤评分与W/D比值明显高于对照组(P<0.05);LPS不同剂量组血浆中Ang-2与VEGF的表达水平较对照组明显增高(P<0.05),血浆中Ang-2的表达与VEGF、肺损伤评分呈正相关(r=0.826,P<0.05;r=0.775,P<0.05);LPS不同剂量组与Ang-2蛋白的表达水平呈现剂量效应关系(P<0.05)。结论 Ang-2参与大鼠ALI的发病过程,且Ang-2水平增高与ALI严重程度有关。     

血管生成素-2检测对胃癌的诊断价值

目的 探讨血清血管生成素-2(Ang-2)检测对胃癌的诊断价值.方法 采用酶联免疫吸附法(ELISA)定量检测108例胃癌患者、50例慢性胃炎患者和50名健康体检者血清Ang-2水平.结果 胃癌患者血清Ang-2水平[(1539.0±449.3) ng/L]显著高于胃炎患者[(1044.6±246.1) ng/L,P＜0.01]和健康体检者[(1075.6 ±228.2) ng/L,P＜0.01].胃炎患者与健康体检者血清Ang-2水平差异无统计学意义.有淋巴结转移患者显著高于无转移患者(P＜0.01).血清Ang-2水平诊断胃癌的ROC曲线下面积为0.819.结论 血清Ang-2水平可以作为胃癌诊断的有价值指标之一.     

CXCR6-based immunotherapy in autoimmune,cancer and inflammatory infliction

T cells, including both CD4⁺ and CD8⁺ T cells, play a pivotal role in mediating various inflammation and immune disorders. A long-standing challenge in T cell-based immunotherapy is to precisely inactivate or delete the pathogenic T cells in inflammation and autoimmune diseases, or to selectively expand the immunocompetent T cell in tumor or other immune compromised situations, without inducing global immunosuppression or zealous immune activation respectively. To achieve this, a specific marker is needed to differentiate the pathogenic or immunocompetent T cell among the rests. Indeed, recent progress of immunology strongly suggests that CXC chemokine receptor 6 (CXCR6, CD186) is such a kind of marker. Here, we review the emerging role of CXCR6 as a novel target for immunotherapy and discuss the underlying mechanism. We propose that CXCR6-based immunotherapy will play a significant role in autoimmune, nonalcoholic steatohepatitis (NASH), tumor, coronavirus disease 2019 (COVID-19) and even ageing-related inflammatory infliction.     

Pharmacological insights into autophagy modulation in autoimmune diseases

As a cellular bulk degradation and survival mechanism, autophagy is implicated in diverse biological processes. Genome-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibility of autoimmune diseases including systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD), indicating that autophagy dysregulation may be involved in the development of autoimmune diseases. A series of autophagy modulators have displayed protective effects on autoimmune disease models, highlighting the emerging role of autophagy modulators in treating autoimmune diseases. This review explores the roles of autophagy in the autoimmune diseases, with emphasis on four major autoimmune diseases [SLE, rheumatoid arthritis (RA), IBD, and experimental autoimmune encephalomyelitis (EAE)]. More importantly, the therapeutic potentials of small molecular autophagy modulators (including autophagy inducers and inhibitors) on autoimmune diseases are comprehensively analyzed.     

Ang-1对高糖中培养的RF/6A的影响

目的探讨血管生成素-1（angiopoietin-1,Ang-1）对高浓度葡萄糖中培养的猴脉络膜-视网膜内皮细胞（RF/6A）的保护作用。方法RF/6A分3组培养：对照组（DMEM培养基含25mmol/L葡萄糖）、高糖组（DMEM培养基含40mmol/L葡萄糖）、Ang-高糖组（DMEM培养基含40mmol/L葡萄糖＋0.25mg/LAng-1）。利用台盼兰染色法及MTT比色法检测体外培养的各种RF/6A存活率及细胞活力,利用western-blotting法检测各组suivivin表达。结果1d时各组细胞存活率及活力无差异。3、5、7d时高糖组和Ang-高糖组细胞存活率及细胞活力均较正常组下降（P〈0.05）,高糖组细胞存活率及细胞活力低于Ang-高糖组（P〈0.05）。5d时,Ang-高糖组survivin表达明显较其他两组增多（P〈0.05）。结论高糖能降低RF/6A的存活率和活力,而Ang-1能明显增强高糖环境中RF/6A的存活率和活力,其机制可能与Ang-1上调凋亡抑制基因survivin的表达有关。     

Ginsenoside Rg1 prevent and treat inflammatory diseases: A review

Ginseng has been used as reinforcing drugs or for traditional Chinese medicine in aging, inflammation, stress, diabetes mellitus, hepatic diseases and cancer. The aim of this current review is to provide an integrative overview of the uses, relative human diseases and related mechanisms of ginseng. Nowadays, numerous animal experiments and clinical studies conducted to investigate the efficacy and safety of ginseng components. Inflammation is an immune response that protects human from pathogens, toxins and other dangers, which is initiated by recognizing pathogen- or danger- associated molecular patterns. Inflammasomes are cytosolic protein complexes which form in response to challenges, which also controls the activity of caspase-1, important for maturation and release of cytokines. Ice protease-activating factor, oligomerization domain-like receptor family pyrin domain-containing 1 and absent in melanoma 2 inflammasome recognize peculiar substances, while NLRP3 inflammasome responds towards structurally and chemically diverse triggers. The functional relationship between ginsenosides and inflammasome provides new insight into the understanding of molecular mechanisms of ginsenoside-mediated anti-inflammatory actions. It also has applications regarding the development of anti-inflammatory remedies by ginsenoside-mediated targeting inflammasomes, which could prevent and treat inflammatory diseases.     

自身免疫病的表观遗传学研究进展

自身免疫病是一类严重危害人类健康的慢性复杂性疾病,包括器官特异性自身免疫病和系统性自身免疫病等20余种疾病.表观遗传学是研究DNA序列未改变而基因表达发生变化的一种可遗传改变,其调节机制主要有三种：DNA甲基化、组蛋白修饰以及微RNA调节.此文综述了这三种调节机制对基因表达的影响及在自身免疫病发病中所起的作用.     

Th17细胞在自身免疫性疾病中的研究进展

经典的Th1和Th2模式为人们理解CD4+T细胞的生物学特性以及固有免疫和适应性免疫提供了基本框架.近来,新发现的Th17细胞以优先产生IL-17、IL-17F和IL-22等细胞因子为特征,它不仅参与宿主防御免疫而且在自身免疫方面起重要作用.这种新的效应T细胞的发现改变了传统的对宿主免疫防御、免疫调节和免疫致病的理解.此文就Th17细胞在自身免疫性疾病中的研究进展作一综述.     

CD160/HVEM/BTLA/LIGHT通路在自身免疫病中的研究进展

共信号分子是免疫细胞表面信号传递分子及其配体，对调控T细胞或B细胞的活化有重要作用。近年来，研究显示多种共信号分子对T细胞的激活与免疫平衡有重要调控作用，这些分子的异常表达可以引起T细胞的过度激活并引发自身免疫病。CD160/HVEM/BTLA/LIGHT通路是近年来共信号分子领域的研究热点，该信号通路在免疫调节中起重要的作用，其功能异常或异常表达与自身免疫病的发生密切相关。本文对该通路在自身免疫病中的研究进展做一简要综述。     

The role of inflammatory cytokines in suicidal behavior: A systematic review

There is growing evidence that inflammatory mediators play a critical role in the pathophysiology of both major depression and suicidal behavior. Immunological differences have been reported in both major affective disorders and suicidal behavior. Specifically, increased levels of pro-inflammatory cytokines have been shown to correlate with the severity of depression and various cytokines have been identified as potentially important in understanding the pathophysiology of major affective disorders/suicidality. We aimed to conduct a systematic review of the current literature to investigate the association between inflammatory cytokines and suicidal behavior. Only articles from peer-reviewed journals were selected for inclusion in the present review. Most studies documented the association between suicidality and IL2, IL-6, IL-8, TNF-α and VEGF levels that have been found altered in suicidal behavior. The presence of major depressive disorder (MDD) with suicidal ideation/attempts was associated with differences in inflammatory cytokine profile when compared to that without suicidal ideation/attempts. Most suicide attempters or subjects with suicidal ideation showed an imbalance of the immune system but this does not imply the existence of a causal link. Also, not all studies demonstrated a positive correlation between inflammatory cytokines and suicidal behavior. Further additional studies should elucidate the molecular mechanisms of the immune activation pathways underlying suicidality.     

苏金单抗治疗自身免疫病研究进展

白细胞介素（interleukin,IL）-17A是IL-17家族中功能最强的细胞因子。研究发现,IL-17A参与多种自身免疫炎性疾病的发生和发展,抑制IL-17A可能对这类疾病起治疗作用。随着对IL-17A研究的深入,人们已经开发出针对IL-17A的抗体。苏金单抗作为一种针对IL-17A的生物制剂,在自身免疫病治疗中具有广阔的应用前景。     

Toll样受体在自身免疫性疾病中的作用机制研究现状

Toll样受体（Toll-like receptor,TLR）是近年来发现的一类模式识别受体,通过识别病原相关分子模式（pathogen associated molecular pattem,PAMP）,激活天然免疫。TLR信号还通过上调抗原提呈细胞（antigen presenting cells,APC）表面共刺激分子及APC分泌的炎症细胞因子调节获得性免疫。本文就TLR通过调节T、B淋巴细胞及TLR,MyD88信号通路在介导自身免疫性疾病中的作用机制以及其在皮肤病如系统性红斑狼疮等发病中的作用做一综述。     

类风湿关节炎自身抗体的临床意义

目的分析类风湿因子(RF)、抗环瓜氨酸肽抗体(CCP)、抗角蛋白抗体(AKA)在RA诊断中的意义。方法选取RA患者356例,其他自身免疫性疾病150例,进行相关实验指标的测定,并对结果进行统计学分析。结果 RF、抗CCP抗体、AKA在RA患者中阳性率、灵敏度及特异度均较高,抗CCP抗体阳性组肿胀关节数、压痛关节数、C反应蛋白(CRP)、28个关节疾病活动度评分(DAS28)、RF高于抗CCP抗体阴性组,2组比较P<0.05,差异有统计学意义。结论联合检测RF、抗CCP抗体、AKA有助于RA的诊断和鉴别诊断,且抗CCP抗体和RA疾病活动度有关。     

蛋白酶体抑制剂硼替佐米治疗自身免疫病的研究进展

泛素-蛋白酶体系统是细胞内蛋白降解的主要途径,目前认为这一系统参与多种炎症和自身免疫病的发生,因此,通过阻断泛素调节蛋白降解成为治疗自身免疫病的新方法。此文就蛋白酶体抑制剂硼替佐米治疗自身免疫病的研究进展做一综述。