miRNA在脓毒症中调控TLRs信号通路的研究进展

脓毒症(sepsis)是指由感染引起的全身炎症反应综合征.在ICU中脓毒症是危重患者的主要死亡原因之一,并且其发病率和病死率在全球范围内逐年递增.据统计,在中国,脓毒症在ICU中的发病率为8.68％,病死率可高达44.7％.因此,脓毒症成为重症医学领域亟待攻克的难题之一.目前,脓毒症发病机制尚不清楚,主要与过度炎症反应和免疫功能紊乱有关.微小RNAs (miRNAs)作为重要的免疫调控因子,可通过TLRs/NF-κB信号通路参与固有免疫调控,在脓毒症发病过程中发挥重要作用.本文就脓毒症中miRNAs参与TLRs信号通路的研究进展作一综述.     

树突状细胞对脓毒症免疫调理作用的研究进展

近年来研究提示,脓毒症的发生发展与严重创伤、烧伤后机体免疫功能紊乱密切相关[1].恢复机体免疫内稳态和内环境平衡,对脓毒症的治疗并改善其预后具有重要价值[2].而树突状细胞( dendritic cells,DCs)是功能最强的抗原呈递细胞(antigen presenting cell,APC),可激活天然免疫系统,启动更持久的适应性免疫[3].被认为是免疫反应的启动者,是免疫反应的主要调节器.本文拟对树突状细胞在脓毒症中的免疫凋节作用研究进展进行综述.     

microRNAs与心肌梗死

microRNAs（miRNAs）是一类内源性的非编码单链小分子RNA,约22个核苷酸。miRNAs通过调控其靶基因的表达,参与细胞发育、增殖、分化、凋亡等一系列重要的生理学途径。近些年的研究发现,miRNAs在心肌梗死的发生、发展过程中起着关键的作用。现就miRNAs在心肌梗死发生、发展过程中的作用机制进行阐述。     

microRNAs在肿瘤病理学研究中的进展

microRNAs （miRNAs）是一类长度约为20～23 nt的内源性小分子单链非编码RNA,其位于基因组内非编码区,进化上高度保守,可在转录后水平对基因表达进行调节.miRNAs通过调控基因表达、在细胞增殖、凋亡、分化及个体发育等过程中发挥着非常重要的作用.近十多年的研究[4,5]已证实,miRNAs与肿瘤的发生及发展关系密切,通过调控其靶基因的表达从而影响肿瘤的发生发展,发挥着类似癌基因或抑癌基因的作用.这些与肿瘤相关的miRNAs对肿瘤的诊断、治疗及判断预后都具有重要的意义及应用前景.     

MODS大鼠胸腺树突状细胞病理改变及作用的研究

目的：探讨胸腺树突状细胞在多脏器功能障碍综合征（MODS）发病机制中的作用,为严重创伤后脓毒症和MODS的基础研究与临床防治提供新的思路。方法：运用光镜、电镜观察与免疫组织化学（CD1a与S－100）及原位末端标记法（TUNEL）研究MODS大鼠胸腺中树突状细胞的变化及其与细胞凋亡的关系。结果：复制小鼠酵母多糖MODS模型,伤后12小时（MODS早期）观察到胸腺树突状细胞增生和过高反应,伴有淋巴细胞大量凋亡;伤后2－3日（MODS进展期）,树突状细胞数量显著减少、形态萎缩,淋巴细胞凋亡减轻。结论：树突状细胞的病理改变不仅可能是MODS的早发病变和启动因素之一,且可能是影响全身炎症反应综合征（SIRS）或代偿性抗炎反应综合征（CARS）形成和转归,使病程走向MODS的一种重要细胞病变。     

调节性树突状细胞与脓毒症关系的研究进展

<正>脓毒症是感染诱发的全身性炎症反应综合征,是内外科及烧伤危重症患者常见的并发症,进一步发展可导致脓毒症休克、多器官功能障碍综合征,系临床危重症患者最主要的死因之一。脓毒症中免疫功能紊乱贯穿于病理过程的始终,宿主的免疫功能状态在很大程度上决定着炎症反应的预后。树突状细胞(dendritic cell,DC)作为免疫系统的关键调节细胞,是机体免疫系统的重要调节细胞之一。而调节性树突状细胞(regulatory     

MicroRNA调控肿瘤干细胞凋亡的研究进展

摘要： 微小核糖核酸（microRNAs,miRNAs)是一类内源性非蛋白质编码小RNAs,主要在转录后水平负性调控基因表达。miRNAs表达水平的改变与许多人类疾病尤其是癌症密切相关。肿瘤干细胞(CSCs)亦称为肿瘤起源细胞,是存在于肿瘤细胞中的一小群具有干细胞特性的亚群细胞,具有高度致瘤性及耐药性。近年来,miRNAs在CSCs凋亡调控中的作用逐渐成为研究热点。靶向miRNAs的分子疗法有望成为校正CSCs调节异常的有力工具。了解CSCs凋亡信号系统的分子机制对开发新型癌症疗法尤为重要。本文就miRNAs与CSCs凋亡相关研究作一综述。     

microRNAs与肿瘤侵袭转移

microRNAs(miRNAs)是一类进化上保守、长度为20～25 nt的非编码RNA,在个体发育、器官形成、细胞增殖、分化和细胞凋亡等生物学过程中发挥着重要的调节作用。miRNAs可能成为新的致癌基因或抑癌基因,其在转录后水平通过抑制靶mRNA翻译或诱导靶mRNA降解来调控基因表达,具有癌基因或抑癌基因的功能,从而广泛参与肿瘤的发生、发展及侵袭转移过程。本文综述了miRNAs的生物合成过程及其功能,重点介绍了miRNAs与肿瘤侵袭转移之间关系的最新研究进展。     

MicroRNA与乳腺癌关系的研究进展

MicroRNAs（miRNAs）是一类广泛存在于真核细胞中的长约21-22 nt的单链、非编码小RNA,具有转录后基因调控的功能,参与调控胚胎发育、细胞生长和凋亡、细胞分化、细胞能量代谢等多种生理过程以及糖尿病、心血管疾病、神经系统疾病、肿瘤等多种病理过程。近些年来研究发现,miRNAs与乳腺癌之间的关系十分密切。本文综述与乳腺癌发生、发展密切相关的miRNAs。     

树突状细胞体外成熟及免疫功能的18F-FDG评价

背景：既往研究表明,不同剂量的电离辐射对树突状细胞的成熟、免疫功能等也可能有一定的影响。目的：分析不同浓度的18 F-FDG对体外培养的人外周血单个核细胞源性树突状细胞的成熟及免疫功能的影响。方法：人外周血单个核细胞源性树突状细胞诱导成熟后,分为5组,分别加入含PBS及92.5×104,185×104,370×104,740×104 Bq/mL浓度的18 F-FDG培养基,作用24 h后收集细胞,检测树突状细胞的凋亡率、细胞表型(CD1α、CD80、CD83、CD86、HLA-DR)表达、同种混合淋巴细胞反应及细胞培养上清液中的巨噬细胞炎性蛋白1α和单核细胞趋化因子1表达。结果与结论：740×104 Bq/mL浓度的18F-FDG可以引起树突状细胞的凋亡、CD86的表达下调,同种T细胞抗原提呈能力下降,单核细胞趋化因子1的分泌下降;其余浓度的18F-FDG对树突状细胞的成熟及免疫功能无明显影响。结果表明较低浓度的18F-FDG对树突状细胞的凋亡、成熟、抗原提呈、迁移能力等影响较小,可以在选择合适浓度的前提下作为一种树突状细胞细胞的体外标记物。     

microRNA调控树突状细胞研究的新进展

microRNA（miRNA）是一类长度为22个核苷酸左右的非编码单链RNA,通过与靶基因mRNA3’UTR区域结合,引起靶基因mRNA剪切、降解及其翻译抑制,通过这种转录后的调控,进而调节细胞增殖、分化、凋亡、发育以及肿瘤的发生。树突状细胞（DC）是一类重要的免疫细胞,通过呈递抗原,启动下游的免疫应答,参与一系列生理和病理活动。最近的研究发现,多种miRNA能够调控DC的发育、分化及功能。对这方面的研究进展予以归纳总结有利于深入了解miRNA层面的DC调控机制,为建立免疫系统相关疾病的全新诊疗策略提供线索。为此,本文就近年来miRNA调控DC的相关研究做一综述。     

Measles Virus Infects Human Dendritic Cells and Blocks Their Allostimulatory Properties for CD4+ T Cells

Measles causes a profound immune suppression which is responsible for the high morbidity and mortality induced by secondary infections. Dendritic cells (DC) are professional antigen-presenting cells required for initiation of primary immune responses. To determine whether infection of DC by measles virus (MV) may play a role in virus-induced suppression of cell-mediated immunity, we examined the ability of CD1a⁺ DC derived from cord blood CD34⁺ progenitors and Langerhans cells isolated from human epidermis to support MV replication. Here we show that both cultured CD1a⁺ DC and epidermal Langerhans cells can be infected in vitro by both vaccine and wild type strains of MV. DC infection with MV resulted within 24–48 h in cell–cell fusion, cell surface expression of hemagglutinin, and virus budding associated with production of infectious virus. MV infection of DC completely abrogated the ability of the cells to stimulate the proliferation of naive allogeneic CD4⁺ T cell as early as day 2 of mixed leukocyte reaction (MLR) (i.e., on day 4 of DC infection). Mannose receptor–mediated endocytosis and viability studies indicated that the loss of DC stimulatory function could not be attributed to the death or apoptosis of DC. This total loss of DC stimulatory function required viral replication in the DC since ultraviolet (UV)-inactivated MV or UV-treated supernatant from MV-infected DC did not alter the allostimulatory capacity of DC. As few as 10 MV- infected DC could block the stimulatory function of 10⁴ uninfected DC. More importantly, MV-infected DC, in which production of infectious virus was blocked by UV treatment or paraformaldehyde fixation, actively suppressed allogeneic MLR upon transfer to uninfected DC–T-cultures. Thus, the mechanisms which contribute to the loss of the allostimulatory function of DC include both virus release and active suppression mediated by MV-infected DC, independent of virus production. These data suggest that carriage of MV by DC may facilitate virus spreading to secondary lymphoid organs and that MV replication in DC may play a central role in the general immune suppression observed during measles.     

Immune dysfunction in the elderly and its reversal by antihistamines.

The decline in immunity seen in the elderly is a significant contributor to disease burden. This decline has largely been attributed to alterations in T cell immunity and contributes to an overall increased risk and severity of infection in the elderly. A key component of T cell immunity involves antigen presentation, an event where an antigen is processed and presented to specific immune cells for destruction. This event has been found to be crucial to immune function. Recent research has focused on a key antigen presenting cell (APC), the dendritic cell (DC), and changes within its function associated with aging. DCs are considered to be the most professional APCs, and are responsible for the initiation and outcome of effector T cells and their resultant immune response. DCs capture antigens and undergo a maturation process and polarize into either type 1 dendritic cells (DC1) or type 2 dendritic cells (DC2), based upon their ability to favor a T helper1 (Th1) or T helper 2 (Th2) T cell response, respectively. Evidence suggests that in normal healthy adults, a Th1 type response predominates, and in frail elders, a Th2 response predominates. It has been proposed that this change from a predominately Th1 type to a predominate Th2 type response is a possible mechanism for age-associated immune dysfunction. In addition, recent research has focused on how histamine, an inflammatory mediator, promotes a Th2 response. Histamine has also been shown to polarize human DCs into Th2 cell-promoting effector DCs or DC2s. This has been shown to occur via interaction with the H2 receptor. Therefore, we theorize that use of an H2 selective antihistamine will reverse this polarization back to a Th1 type response and therefore improve immune function of the frail elderly.     

白血病细胞系来源的树突状细胞诱导及其抗肿瘤免疫功能研究

树突状细胞（DC）在抗肿瘤免疫反应中起关键作用，但大多数白血病病病人有DC功能缺陷，在外体扩增DC并增强其抗肿瘤免疫功能及以DC为基础的肿瘤疫苗是对白血病有效的免疫治疗方法，为了探讨由不同的髓性白血病细胞诱生DC的条件及其抗白血病反应，选用HL－60，K562和THP－1细胞与不同的细胞因子组合诱生DC，以光学和电子显微镜术观察形态特征，用流式细胞术和单克隆抗体检测细胞表型，以同种混合淋巴细胞反应观察刺激淋巴细胞增殖，用^51Cr释放法检测诱生细胞的细胞术和单克隆抗体检测细胞表型，以同种混合淋巴细胞反应观察刺激淋巴细胞增殖，用^51Cr释放法检测诱生细胞的细胞毒作用，用ELISA法测定DC培养及DC＋血单个核细胞培养的血清中IL－12及INF－γ的量，结果表明，由K562，HL－60和THP－1细胞诱生的DC具有村突状细胞的形太学特征，细胞表达DC的表面分化抗原，其中GM－CSF＋IL－4＋TNF-γ刺激HL－60－DC和THP－DC和GMCSF＋IL－4＋IL－12刺激的K562－DC中有抗原表达。3种细胞诱生的DC对混合淋巴细胞反应CTL反应有强刺激细胞因子能诱导髓性白细胞产生DC，不同细胞需要不同的细胞因子和培养条件，这些DC表达抗原呈递细胞的表型具有刺激T淋巴细胞增殖和诱导CTL反应以及分泌IL－2和促进T细胞分泌INF－γ的作用。     

Immune regulation by dendritic cells and T cells--basic science, diagnostic, and clinical application

Dendritic cells (DC) are professional antigen-presenting cells defined by their ability to transport incoming infectious signals from the periphery to T cell areas in lymphoid organs and by their unique properties to induce primary T cell activation. As sentinels of immunity DC play a critical role in the initiation of immune responses. Thus, they are key targets in antigen-specific immunotherapeutic strategies for cancer. However, beside this essential immunostimulatory function in the immune system, DC also play an important role in the maintenance of peripheral tolerance. Dependent on subtype and mode of activation, tissue resident immature DC differentiate into immunostimulatory or immunosuppressive antigen-presenting cells with a strong capacity to activate or to inhibit T cell responses, respectively. This review summarizes our current knowledge about the complex interaction between DC and T cells considering both--immunity and tolerance--as well as the possibilities to use this knowledge for development of novel diagnostic and immunotherapeutic strategies to treat immune-imbalanced human diseases such as cancer, allergy, and autoimmunity.     

Tolerogenic function of Blimp-1 in dendritic cells

Blimp-1 has been identified as a key regulator of plasma cell differentiation in B cells and effector/memory function in T cells. We demonstrate that Blimp-1 in dendritic cells (DCs) is required to maintain immune tolerance in female but not male mice. Female mice lacking Blimp-1 expression in DCs (DCBlimp-1(ko)) or haploid for Blimp-1 expression exhibit normal DC development but an altered DC function and develop lupus-like autoantibodies. Although DCs have been implicated in the pathogenesis of lupus, a defect in DC function has not previously been shown to initiate the disease process. Blimp-1(ko) DCs display increased production of IL-6 and preferentially induce differentiation of follicular T helper cells (T(FH) cells) in vitro. In vivo, the expansion of T(FH) cells is associated with an enhanced germinal center (GC) response and the development of autoreactivity. These studies demonstrate a critical role for Blimp-1 in the tolerogenic function of DCs and show that a diminished expression of Blimp-1 in DCs can result in aberrant activation of the adaptive immune system with the development of a lupus-like serology in a gender-specific manner. This study is of particular interest because a polymorphism of Blimp-1 associates with SLE.     

Mechanisms of action of extracorporeal photochemotherapy.

Extracorporeal photochemotherapy (ECP) has been shown to be effective in variety of pathologic diseases such as Sezary syndrome, autoimmune diseases, organ graft rejection and graft versus host disease. However, its mechanism of action has remained elusive. Understanding of its mechanisms may be useful to identify the best indications, treatment regimes and to optimize the ECP technique. The first step of the ECP procedure is collection of peripheral mononuclear cells. In this step, several cell environment changes occur. These conditions have been suggested to increase monocyte activation and possibly drive dendritic cell differentiation. The second step of ECP is the cell radiation by UVA in presence of 8-MOP which is presumed to induce cell membrane damage, DNA crosslinking and binding to a variety of cytosolic proteins leading to apoptosis, modification of membrane antigenicity and antigen presenting cell activation. The third step of ECP is the reinfusion of the treated cells to the patient. While it is unclear what exactly occurs in vivo, it is thought that DCs play a critical role by inducing an immunological response against pathogenic cells. The immature DC, activated by ECP, phagocytizes and internalizes the apoptotic cells; processes the antigens and increases the synthesis of class I and II Major Histocompatibility Complex (MHC) molecules. The peptides associated with class II MHC are presented to the CD4+ T helper cells. The final maturation of DC is completed in vivo with the help of these activated T helper cells using a variety of mechanisms including CD40 ligation. Finally, the mature DCs fully loaded with pathogenic T cell peptides migrate to secondary lymphoid organs stimulate the naive CD8+ T cells and induce a cytotoxic response (Th1 immune response) directed against pathogenic clones (tumoral cells of Sezary syndrome). Clinical and haematological improvement after ECP in Sezary syndrome is associated with a shift in Th1/Th2 balance and the increase of Th1 cytokines and IL12. ECP can also down regulate the allo or autoimmune response and induces tolerance by regulatory T cells. The clinical response to ECP in patients with chronic GvHD is associated with increase in NK cells and a shift from DC1 to DC2 and a shift from predominantly Th1 to Th2 immune response. Recruitment and involvement of other immune cells in the mechanism of ECP have been suggested and merit more studies. This immunostimulatory capacity of ECP is the most probable hypothesis of its mechanism but further investigations are necessary to determine the precise players important for this activity.     

Retinoids regulate survival and antigen presentation by immature dendritic cells

Maturation of dendritic cells (DCs) is a critical step for the induction of an immune response. We have examined the role of retinoid nuclear receptor pathways in this process. Retinoids induce DC apoptosis, in the absence of inflammatory signals, through retinoic acid receptor (RAR)alpha/retinoic X receptor (RXR) heterodimers. In contrast, via a cross talk with inflammatory cytokines, retinoids increase DNA binding activity of nuclear factor kappaB in DCs, trigger membrane major histocompatibility complex class II and costimulatory molecule expression, induce the differentiation of immature DCs into mature DCs, and enhance antigen-specific T cell response. This maturation of DCs is mediated via a RXR-dependent/RAR-independent pathway and via an RARalpha/RXR pathway distinct from the one responsible for apoptosis. Apoptosis and activation, mediated through distinct nuclear retinoid receptor pathways, can be dissociated from each other with selective synthetic retinoids. We identify a novel cellular function for retinoids and suggest that selective retinoids might be of interest for controlling antigen presentation.     

In vivo modulation of CD1 and MHC class II expression by sheep afferent lymph dendritic cells. Comparison of primary and secondary immune responses

The experiments described in this article characterize the phenotypic and functional changes in afferent lymph cell populations that occur as a result of in vivo immune stimulation. During the primary immune response (in antigen-naive sheep) there are very transient increases in level of CD1 expression by subpopulations of dendritic cells (DC) but no alterations in cell kinetics or MHC class II expression. In contrast, secondary antigenic challenge (in primed sheep) into the drainage area of an afferent lymphatic causes profound changes in the cell output, characterized by a greater than threefold drop in total cell output on days 1-3 followed by an approximate fivefold rise on day 5. There is also a substantial increase in both the proportion of MHC class II-positive T lymphocytes (from 28 to 54%) and in the quantitative expression of class II by both DC and lymphocytes. Class II expression by DC increases five- to sixfold by day 5, while the level of expression of class II on lymphocytes approximately doubles. The increase in CD1 expression during the secondary response is more prolonged than during the primary response, being detectable between days 2 and 6 after challenge. The rise in class II affects the whole DC population, in contrast to CD1 where the increase affects only a subpopulation of cells. In terms of functional properties, afferent lymph DC isolated during a primary response show no alteration of their activity, whereas DC taken 4-5 d after secondary challenge are up to fivefold more active in their ability to present soluble antigen to primed autologous T cells and to antigen-specific cell lines as well as to stimulate in the MLR. The relative expression of class II correlates temporally with an increased capacity of DC to present antigen. Monoclonal anti-class II antibodies totally inhibit the in vitro assays but anti-CD1 antibodies have no effect. The previous paper has demonstrated that afferent DC can associate with antigen in vivo and can present that antigen to antigen-specific T cells. This article extends our knowledge of DC biology and demonstrates that DC, activated during secondary in vivo immune responses, have an enhanced ability to present an antigen, unrelated to that used for challenge, to specific T cell lines. This enhancement correlates directly with quantitative variation of expressed class II and not CD1 and suggests that this variation in class II expression plays a physiological role in in vivo immune regulation.