免疫负调控因子TIPE2在自身免疫性疾病发病过程中的作用及机制研究进展

自身免疫性疾病是由于机体免疫系统对自身组织和器官发生了免疫应答并造成组织损伤和功能障碍的一类疾病,约占全世界人口的5％～10％.多种器官特异性自身免疫性疾病主要是由T细胞介导的,此外,其它的免疫细胞,如B细胞、T调节细胞、树突状细胞和巨噬细胞等在自身免疫性疾病的发生过程中也起着非常重要的作用.肿瘤坏死因子α诱导蛋白8-2(TNFAIP8L2或TIPE2)是2008年发现的免疫负调控因子,主要在免疫细胞中表达,通过对固有免疫和适应性免疫进行负性调控,从而维持体内环境稳定,实现免疫耐受.最近的研究发现,TIPE2在自身免疫性疾病的发病过程中起着非常重要的作用.     

外泌体在类风湿关节炎发病机制和诊疗中的作用

类风湿关节炎(rheumatoid arthritis,RA)作为一种自身免疫性疾病,其引起的慢性炎症可对人体滑膜关节产生不可逆损伤,其发病机制复杂且预后不理想,目前没有彻底治愈的疗法.外泌体是细胞外囊泡中的一个亚群,其携带的相关物质可以多方面对靶细胞的生理状态进行调节.近年来多项研究提示,外泌体可能在RA发病中起到了...     

抗-CCP抗体和RF在类风湿关节炎诊断中的临床应用

类风湿关节炎(rheumatoid arthritis,RA)是一种常见的自身免疫性疾病.全世界大约有0.5%的人罹患此病[1].目前该病的诊断主要依赖于临床表现,X线检查以及类风湿因子(RF)检查.     

表达Foxp3的调节性T细胞在类风湿关节炎发病中的意义

目的：研究表达Foxp3的调节性T细胞在类风湿关节炎（RA）发病中的意义及其与类风湿关节炎临床特征的相关性。方法：提取外周血总RNA，并逆转录为cDNA。应用实时荧光定量PCR法对RA治疗组（n=25）、RA未治疗组（n=25）及健康对照组（n=30）外周血Foxp3 mRNA含量进行检测，并研究其与RA患者病情活动程度、抗环瓜氨酸（CCP）抗体、C反应蛋白（CRP）、血沉（ESR）及类风湿因子（RF）的关系。结果：RA患者的Foxp3 mRNA含量明显低于正常对照组（P〈0．01）；RA未治疗组Foxp3表达水平明显低于RA治疗组（P〈0．01）。RA患者Foxp3表达水平与DAS28评分、抗CCP抗体及ESR水平呈明显负相关（P〈0．05），而与CRP及RF无明显相关性。结论：RA患者存在表达Foxp3的调节性T细胞数量减少和／或功能降低，这种调节性T细胞亚群的异常可能参与了RA的发病和病变进展。     

MEKK2在类风湿关节炎患者中的表达及临床意义

研究丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路中有丝分裂原活化蛋白激酶激酶激酶2(mitogen-activated protein kinase kinase kinase 2,MEKK2)分子在类风湿关节炎(rheumatoid arthritis,RA)患者中的表达及临床意义。Western blotting和Real-time PCR分别检测20例RA患者经艾拉莫德治疗前后,外周血单个核细胞(peripheral blood mononuclear cell,PBMC)中MEKK2蛋白和基因的表达水平变化,并与健康对照者比较其表达情况。结果显示:与健康对照者相比,RA患者PBMC中MEKK2的蛋白及基因水平降低,经艾拉莫德治疗后临床症状明显改善,且MEKK2的表达水平有所升高。该研究提示MEKK2的表达对RA发病过程起到重要作用,缓解病情抗风湿药物艾拉莫德有可能影响到MEKK2通路而发挥其临床疗效。     

Ⅱ型胶原诱导的小鼠关节炎模型IL-25表达水平的变化及意义

目的以Ⅱ型胶原诱导的DBA/1小鼠关节炎模型为研究对象,动态观察其IL-25的表达水平,探讨IL-25与关节炎发生发展的关系及其可能的机制,为寻找新的类风湿性关节炎免疫干预新途径积累实验数据。方法采用RT-PCR法扩增目的基因,构建mIL-25标准质粒,QRT-PCR检测模型鼠脾脏及其关节病变局部IL-25的表达水平;应用ELISA技术检测模型鼠血清和脾细胞培养上清IL-25蛋白的含量。结果在Ⅱ型胶原诱导的小鼠关节炎的发病过程中,模型鼠脾细胞和关节滑膜组织IL-25的mRNA表达水平、均呈持续上升趋势,与对照小鼠相比差异显著(P<0.05)。这种IL-25蛋白和转录水平的表达,随着关节炎症程度的增加而升高。此外,模型鼠脾细胞对ConA的刺激表现出强IL-25表达性应答。结论 IL-25的表达水平与Ⅱ型胶原诱导的关节炎的发生发展密切相关。     

类风湿关节炎四种自身抗体的检测及意义

为评估类风湿因子(rheumatoid factor,RF)、抗环瓜氨酸肽(cyclic citrullinated pepdide,CCP)抗体、抗Sa抗体和抗角蛋白抗体(anti-keratin antibody,AKA)自身抗体对类风湿关节炎(rheumatoid arthritis,RA)诊断的意义,采用速率散...     

类风湿关节炎患者的观察与护理

类风湿关节炎是一种原因不明的自身免疫性疾病,主要表现为对称性、慢性、进行性多关节炎,最终导致关节畸形和功能丧失。我科自2007年收治190例类风湿关节炎病人,在此谈一下自己的护理体会。     

降植烷诱导小鼠类风湿关节炎的模型北大核心CSCD

目的：利用降植烷构建一种模拟人类风湿性关节炎发病过程的小鼠模型。方法：6-8周雌性BALB/c小鼠30只,随机分为模型组和对照组,每组15只。模型组于0周、9周、18周时经腹腔注射0.5 ml降植烷;对照组注射0.5 ml生理盐水。观察各组小鼠后足足掌厚度变化,并对关节炎的肿胀程度进行评分;H＆E染色评估滑膜增生和炎性细胞浸润程度;流式细胞术方法检测小鼠脾脏中巨噬细胞、树突状细胞、中性粒细胞、T细胞和B细胞的亚群变化。结果：21周时,模型组有11只小鼠出现足爪红肿,足掌平均厚度为（2.90±0.51）mm,与对照组（1.29±0.47）mm比较,差异有统计学意义（P〈0.05）;关节炎评分为9.55±2.80。H＆E染色结果显示模型组胫骨远端骨小梁吸收破坏,累及骨皮质,关节软骨可见坏死脱落、纤维化,呈现出明显的类风湿关节炎病理改变。流式细胞术分析结果显示,造模21周时,脾脏细胞中CD11b、CD11c和GR1表达明显增加,提示巨噬细胞、树突状细胞和中性粒细胞亚群数量增加;同时,CD4、CD8、CD154的分子表达也明显上调,与对照组比较,差异有统计学意义（P〈0.05）。结论：经腹腔注射降植烷能够成功诱导小鼠关节炎,并产生与RA患者类似的组织病理和免疫学改变。降植烷诱导的小鼠关节炎模型,能够较为准确地模拟临床类风湿关节炎的发病过程。     

树突状细胞在类风湿关节炎中的研究进展

类风湿关节炎(RA)是以关节滑膜炎为主要特征的全身性、炎性反应自身免疫病。目前认为RA的发生是由抗原提呈细胞(APC)对自身抗原的异常提呈所引起的。树突状细胞(DC)是已知功能最强的APC,它能处理并提呈抗原,引发免疫应答;同时它还具有诱导免疫耐受的功能,这一特点使其可能成为临床治疗RA的新途径。     

高迁移率族蛋白1在类风湿性关节炎发生中的作用

高迁移率族蛋白1（HMGB1）是一种非组蛋白核蛋白,是一个具有双重功能的警报素,其免疫活性取决于细胞定位。在细胞内,HMGB1结合DNA调节转录;在细胞外,HMGB1具有和TNF相似的细胞因子活性。HMGB1参与许多免疫介导疾病的发病过程包括类风湿性关节炎（RA）。因而,研究炎症性关节炎新的发病机制可以提供新的治疗靶点。     

Neutrophil extracellular traps exacerbate Th1‐mediated autoimmune responses in rheumatoid arthritis by promoting DC maturation

Aberrant formation of neutrophil extracellular traps (NETs) is a key feature in rheumatoid arthritis (RA) and plays a pivotal role in disease pathogenesis. However, the mechanism through which NETs shape the autoimmune response in RA remains elusive. In this study, we demonstrate that inhibition of peptidylarginine deiminases activity in collagen‐induced arthritis (CIA) mouse model significantly reduces NET formation, attenuates clinical disease activity, and prevents joint destruction. Importantly, peptidylarginine deiminase 4 blocking markedly reduces the frequency of collagen‐specific IFN‐γ‐producing T helper 1 (Th1) cells in the draining lymph nodes of immunized mice. Exposure of dendritic cells (DCs) to CIA‐derived NETs induces DC maturation characterized by significant upregulation of costimulatory molecules, as well as elevated secretion of IL‐6. Moreover, CIA‐NET‐treated DCs promote the induction of antigen‐specific Th1 cells in vitro. Finally, NETs from RA patients show an increased potential to induce the maturation of DCs from healthy individuals, corroborating the findings obtained in CIA mouse model. Collectively, our findings delineate an important role of NETs in the induction and expansion of Th1 pathogenic cells in CIA through maturation of DCs and reveal a novel role of NETs in shaping the RA‐autoimmune response that could be exploited therapeutically.     

滑膜成纤维细胞在类风湿性关节炎发病中的作用

类风湿性关节炎是复杂的多系统疾病,近年来,越来越多的证据表明,滑膜成纤维细胞在类风湿性关节炎中过度增殖,介导炎症反应,造成关节结构破坏。滑膜成纤维细胞在类风湿性关节炎发病过程中具有重要的作用。     

The role of COX-2 in angiogenesis and rheumatoid arthritis

Recent evidence suggests that cyclooxygenase (COX)-2 is a mediator of angiogenesis, and COX-2 activity is known to be upregulated in the rheumatoid arthritis (RA) synovium. We examined whether mediation of angiogenesis by COX-2 was occuring in cells of the RA synovium and in microvascular endothelial cells (ECs) that are similar to those found in the RA synovium. We demonstrate that rofecoxib, a selective COX-2 inhibitor, acts directly on human dermal microvascular ECs (HMVECs) to inhibit their chemotactic and tube forming ability. Likewise, pretreatment of HMVECs with rofecoxib significantly inhibited their ability to form tubes induced by conditioned media (CM) of activated RA synovial fibroblasts. When RA synovial fibroblasts were pretreated with rofecoxib for 16 h and then stimulated with interleukin (IL)-1beta, their CM induced significantly less HMVEC tube formation when compared with CM from vehicle-treated RA synovial fibroblasts. ELISAs performed on activated RA fibroblast CM for known proangiogenic factors demonstrated a significant reduction in bFGF, in addition to the expected decrease in PGE(2). Our studies suggest that COX-2-induced angiogenic activity is an active mechanism within diseased synovium and may provide an additional rationale for the use of COX-2 inhibitors in RA.     

Role of 2-methoxyestradiol as inhibitor of arthritis and osteoporosis in a model of postmenopausal rheumatoid arthritis

In postmenopausal rheumatoid arthritis, both the inflammatory disease and estrogen deficiency contribute to the development of osteoporosis. As hormone replacement therapy is no longer an option, we hypothesized that 2-methoxyestradiol (2me2) could be beneficial, and asked if such therapy was associated with effects on reproductive organs. Mice were ovariectomized and arthritis was induced, whereafter mice were administered 2me2, estradiol, or placebo. Clinical and histological scores of arthritis, together with bone mineral density were evaluated. Uteri weight, reactive oxygen species (ROS) from spleen cells, and characterization of cells from joints and lymph nodes were analyzed. In addition, in vivo activation of estrogen response elements (ERE) by 2me2 was evaluated. Treatment with 2me2 and estradiol decreased the frequency and severity of arthritis and preserved bone. Joint destruction was reduced, neutrophils diminished and ROS production decreased. The uterine weight increased upon long-term 2me2 exposure, however short-term exposure did not activate ERE in vivo.     

巨噬细胞移动抑制因子在类风湿性关节炎中的地位和作用

类风湿性关节炎是一种细胞因子参与介导的自身免疫性疾病;巨噬细胞移动抑制因子是一种具有广泛生物学活性的细胞因子,大量表达在类风湿性关节炎患者血清和滑膜组织中,促进巨噬细胞、滑膜细胞和内皮细胞的活化,促进类风湿性关节炎的炎症反应、滑膜组织增生和关节损伤。巨噬细胞移动抑制因子在类风湿性关节炎中的地位和作用十分重要。     

Altered collagen II peptides inhibited T-cell activation in rheumatoid arthritis

It has been reported that collagen II (CII)-derived peptide induced T-cell activation via its amino acids responsible for T-cell receptor (TCR) recognition. In this study, three altered CII263-272 peptide ligands (APL) containing multiple substitutions of TCR contact residues were synthesized. Their roles in inhibition of T-cell activation were evaluated in peripheral blood lymphocytes (PBL) of rheumatoid arthritis (RA) in vitro. It was shown that 41% (25/61) of RA patients were responsive to the wild-type antigenic CII263-272. In contrast, marginal or silent T-cell responses to the three APLs were found, accompanied by inhibitory effects on secretion of Th1 type cytokines and expression of cell surface markers, CD69 and CD25. In addition, T-cell activation induced by the wild-type antigenic CII263-272 was inhibited by all the three APLs in a dose-dependent manner. It is demonstrated that APLs with substitutions of TCR contact residues are capable of down-regulating T-cell responses in PBLs of RA, suggesting that the CII-derived APLs are potentially therapeutic in RA.