Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG

Rheumatoid arthritis (RA) is a widely prevalent (1-3%) chronic systemic disease thought to have an autoimmune component; both humoral and cellular mechanisms have been implicated. Primary osteoarthritis (OA) is considered to be distinct from rheumatoid arthritis, and here damage is thought to be secondary to cartilage degeneration. In rheumatoid arthritis, immune complexes are present that consist exclusively of immunoglobulin, implying that this is both the 'antibody' (rheumatoid factor [RF]) and the 'antigen' (most commonly IgG). Autoantigenic reactivity has been localized to the constant-region (C gamma 2) domains of IgG. There is no evidence for a polypeptide determinant but carbohydrate changes have been reported. We have therefore conducted a study, simultaneously in Oxford and Tokyo, to compare in detail the N-glycosylation pattern of serum IgG (Fig. 1) isolated from normal individuals and from patients with either primary osteoarthritis or rheumatoid arthritis. The results, which required an evaluation of the primary sequences of approximately 1,400 oligosaccharides from 46 IgG samples, indicate that: (1) IgG isolated from normal individuals, patients with RA and patients with OA contains different distributions of asparagine-linked bi-antennary complex-type oligosaccharide structures, (2) in neither disease is the IgG associated with novel oligosaccharide structures, but the observed differences are due to changes in the relative extent of galactosylation compared with normal individuals. This change results in a 'shift' in the population of IgG molecules towards those carrying complex oligosaccharides, one or both of whose arms terminate in N-acetylglucosamine. These two arthritides may therefore be glycosylation diseases, reflecting changes in the intracellular processing, or post-secretory degradation of N-linked oligosaccharides.     

基于网络药理学和分子对接探究威灵仙治疗类风湿性关节炎的作用机制

运用网络药理学和分子对接方法探究威灵仙治疗类风湿性关节炎的作用机制。中药系统药理学数据库与分析平台、PubChem、SwissTargetPrediction数据库筛选威灵仙的活性成分及其作用靶点;OMIM、GeneCards数据库预测类风湿性关节炎的靶点;Venn图获取威灵仙-类风湿性关节炎的交集靶点;STRING数据库构建蛋白质-蛋白质相互作用网络后导入Cytoscape3.7.1获取核心靶点;DAVID数据库进行基因本体和京都基因与基因组百科全书富集分析; AutoDock Vina1.5.6对关键活性成分和核心靶点进行分子对接验证。威灵仙中的关键活性成分齐墩果酸、β-谷甾醇、豆甾醇、3-表齐墩果酸作用于MAPK3、PTGS2、CYP19A1等核心靶点,通过调控花生四烯酸代谢通路、卵巢类固醇生成等发挥治疗类风湿性关节炎的作用,分子对接结果显示关键活性成分与核心靶点具有较好的结合活性。该研究初步探讨了威灵仙治疗类风湿性关节炎的关键活性成分、核心作用靶点及其相关通路,为威灵仙的临床应用提供参考。     

基于网络药理学和分子对接探究麻黄加术汤治疗类风湿关节炎的潜在作用机制

利用网络药理学和分子对接方法探究麻黄加术汤治疗类风湿关节炎的潜在作用机制。通过数据库检索、筛选得到麻黄加术汤主要活性成分及其作用靶点,通过GeneCards、OMIM和Drugbank数据库筛选得到类风湿关节炎疾病靶点,使用STRING数据库和Cytoscape软件构建PPI(protein-protein interaction)网络;使用Metascape数据库对麻黄加术汤治疗类风湿关节炎的作用靶点进行GO(gene ontology)和KEGG(Kyoto encyclopedia of genes and genomes)富集分析;Cytoscape软件构建药物成分-靶点-通路网络;使用AutoDock软件对关键成分和靶点进行分子对接。结果筛选得到麻黄加术汤的潜在活性成分共131个,治疗类风湿关节炎的关键靶点133个,主要成分包括槲皮素、木犀草素、山奈酚等,关键靶点包括IL-6、TNF、TP53、STAT3等。GO和KEGG分析显示生物过程2 250条,细胞成分89条,分子功能152条,富集通路主要涉及AGE-RAGE信号通路、IL-17信号通路和TNF信号通路等。分子对接结果显示Phaseol和甘草酚与AKT1、PTGS2、MAPK1、MAPK8等关键靶点具有较好的结合活性。研究发现麻黄加术汤是通过多成分、多靶点、多通路的作用方式发挥治疗类风湿关节炎的作用,为类风湿关节炎的治疗提供了重要的科学信息。     

The role of clonal selection and somatic mutation in autoimmunity

Polyclonal activation has been proposed as the reason that autoantibodies are produced during autoimmune disease. This model denies a role for specific antigen selection of B cells and predicts instead a multiclonal population of unmutated or randomly mutated autoantibodies. We have found that the genetic features and clonal composition of spontaneously derived immunoglobulin G (IgG) antiself-IgG (rheumatoid factor (RF] autoantibodies derived from the autoimmune MRL/lpr mouse strain are inconsistent with both the predictions of this model and the actual outcome of experimental polyclonal activation. Instead we have found that MRL/lpr RFs are oligoclonal or even monoclonal in origin. They harbour numerous somatic mutations which are distributed in a way that suggests immunoglobulin-receptor-dependent selection of these mutations. In this sense, the MRL/lpr RFs resemble antibodies elicited by exogenous antigens after secondary immunization. The parallels suggest that, like secondary immune responses, antigen stimulation is important in the generation of MRL/lpr RFs.     

基于网络药理学和分子对接研究三七抗类风湿关节炎的分子机制

通过中药系统药理学数据库与分析平台获取三七的主要活性成分及其相关靶点;通过GeneCards数据库预测类风湿关节炎相关靶点,并运用Uniprot数据库标准化蛋白名称,取三七-类风湿关节炎的交集靶点;通过STRING平台进行蛋白质-蛋白质相互作用分析;采用Metascape平台进行GO(gene ontology)功能分析和KEGG(Kyoto encyclopedia of genes and genomes)信号通路富集分析;采用Cytoscape3.7.2构建活性成分-靶点-信号通路相互作用网络;利用AutoDock Vina 1.1.2软件对关键靶点和成分进行分子对接。结果表明:通过筛选获得三七核心活性成分7种,三七-类风湿关节炎共同作用靶点100个,其中核心靶点包括AKT1、IL6、VEGFA、TNF、TP53、JUN、CASP3、PTGS2等;GO分析获得1 064条信号通路,KEGG分析得到102条信号通路,其中与类风湿关节炎相关的信号通路包括AGE-RAGE、MAPK、TNF、IL-17以及HIF-1等;分子对接结果显示关键靶点与成分具有较好的结合活性。研究认为三七抗类风湿关节炎可能是通过对物质代谢、信号转导、炎症反应等多靶点及多通路的调节从而发挥作用。     

CD305分子在类风湿关节炎滑膜成纤维细胞中的表达

目的：研究CD305分子在类风湿关节炎滑膜中的表达。方法：通过免疫组织化学染色方法分别检测CD305分子在类风湿关节炎（Rheumatoid arthritis,RA）、骨性关节炎（Osteoarthritis,OA）和正常创伤患者滑膜中的分布规律。结果：在RA组,CD305分子在所有患者滑膜组织中均有表达。在OA组,CD305分子在部分患者滑膜组织中表达。而在正常患者中,CD305分子在大部分滑膜组织中不表达,仅在部分样本边缘处有少量表达。结论：CD305分子在RA患者滑膜组织中表达高于正常创伤患者,且主要在里衬层（lining layer）滑膜成纤维细胞(fibroblast-like synoviocytes, FLS) 上高表达。     

桂枝芍药知母汤加减治疗类风湿性关节炎60例

目的 :探讨桂枝芍药知母汤加减治疗类风湿关节炎的临床效果。方法 :运用桂枝芍药知母汤加减辨证分型治疗类风湿性关节炎患者60例 ,并进行临床观察和疗效分析。结果 :服药1疗程显效48例 ,好转9例 ,无效3例。结论 :类风湿关节炎为虚实寒热夹杂之证 ,解决好清热与温阳的矛盾 ,治疗上以通为要 ,则能达到理想的治疗效果     

Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages

A large amount of chromosomal DNA is degraded during programmed cell death and definitive erythropoiesis. DNase II is an enzyme that digests the chromosomal DNA of apoptotic cells and nuclei expelled from erythroid precursor cells after macrophages have engulfed them. Here we show that DNase II-/-IFN-IR-/- mice and mice with an induced deletion of the DNase II gene develop a chronic polyarthritis resembling human rheumatoid arthritis. A set of cytokine genes was strongly activated in the affected joints of these mice, and their serum contained high levels of anti-cyclic citrullinated peptide antibody, rheumatoid factor and matrix metalloproteinase-3. Early in the pathogenesis, expression of the gene encoding tumour necrosis factor (TNF)-alpha was upregulated in the bone marrow, and administration of anti-TNF-alpha antibody prevented the development of arthritis. These results indicate that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNF-alpha, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.     

胸腺素的临床应用

本文阐述胸腺素的生物学功能和临床应用动态.已知诸如类风湿性关节炎和强直性脊柱炎等风湿性疾病的发病机制与机体免疫功能异常密切相关,而胸腺素对免疫功能有调节平衡的作用;结合作者用胸腺素治疗风湿性疾病的临床体会,胸腺素可能是对强直性脊柱炎和类风湿性关节炎等一些风湿性疾病有致缓解作用的一种药物.有必要对其临床应用价直和机制作更深入的研究.     

Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors

Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent. When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences. B cells expressing an antigen receptor specific for self-immunoglobulin-gamma (IgG) make a class of autoantibodies known as rheumatoid factor (RF). Here we show that effective activation of RF+ B cells is mediated by IgG2a-chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family. Inhibitor studies implicate TLR9. These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid-protein particles. The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells.     

利用血管回声跟踪技术研究老年人类风湿关节炎与动脉弹性的相关性

为了给早期预防和治疗心血管疾病提供参考,利用血管回声跟踪技术研究老年人类风湿关节炎与动脉弹性的相关性。研究对象选择年龄在60～79岁之间的老年人类风湿关节炎患者40例和健康老年人40例,依次作为实验组与对照组。采用ALOKA Prosoundα10.型彩色超声诊断仪对颈动脉和肱动脉内中膜厚度以及弹性相关参数进行检测。结果发现:检测结果中有35例类风湿关节炎患者颈动脉IMT值超过1 mm,有31例健康研究对象颈动脉IMT值超过1 mm;实验组颈动脉IMT和对照组相比差异无统计学意义(p 0. 05),β、Ep、PWVβ和AI与对照组相比差异有统计学意义(p 0. 05,p 0. 01);实验组与对照组的肱动脉IMT值间无显著差异(p 0. 05),β、PWVβ与AI间有显著性差异(p 0. 05); ROC曲线分析结果中,两组研究对象动脉弹性参数差异有统计学意义(p 0. 05)。可见类风湿关节炎与老年人颈动脉和肱动脉弹性存在显著相关性,但受年龄的影响,动脉IMT值改变无法体现RA和动脉粥样硬化在统计学上的相关性,根据实验结果可知,可将ET技术当成一种早期发现RA患者动脉弹性功能下降的诊断方法预防心血管疾病。     

藏药翁布提取物对SD大鼠FCA诱导性关节炎的试验研究

目的：研究单味藏药翁布（Myricaria germanica（L.）Desv.）对SD大鼠佐剂性关节炎（AA）的作用.方法：以SD大鼠为实验动物,采用Freund’s佐剂作为致炎因子,复制急性关节炎症并伴随继发性风湿性关节模型,用不同提取物灌胃24d,测定体重、关节炎指数、足趾肿胀度.结果：藏药翁布各提取物显著抑制SD大鼠关节炎指数、足趾肿胀度.结论：藏药翁布提取物对Freund’s佐剂诱导性关节炎有显著的抗炎作用.     

Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage

During inflammatory reactions, activated leukocytes are thought to produce a variety of small proteins (cytokines) that influence the behaviour of other cells (including other leukocytes). Of these substances, which include the interleukins, interferons and tumour necrosis factors (TNFs), interleukin-1 (IL-1) has been considered potentially a most important inflammatory mediator because of its wide range of effects. In vivo it is pyrogenic and promotes the acute phase response; in vitro it activates lymphocytes and stimulates resorption of cartilage and bone. Cartilage resorption is a major feature of inflammatory diseases such as rheumatoid arthritis, and IL-1 is the only cytokine hitherto known to promote it. TNFs are characterized by their effects on tumours and cytotoxicity to transformed cells, but share some actions with IL-1. I report here that recombinant human TNF alpha stimulates resorption and inhibits synthesis of proteoglycan in explants of cartilage. Its action is similar to and additive with IL-1, and it is a second macrophage-derived cytokine whose production in rheumatoid arthritis, or inflammation generally, could contribute to tissue destruction.     

HCV感染与多种自身抗体高检出率的关系

为探讨丙型肝炎病毒（ＨＣＶ）感染后体内出现的自身抗体的病理意义及其引起的自身免疫的发生机制。方法：对１６１例ＨＣＶ感染者进行了八种自身抗体（抗核抗体、类风湿因子、抗甲状腺球蛋白抗体、抗甲状腺微粒体抗体、抗双链ＤＮＡ抗体、抗ＲＮＰ抗体、抗Ｓｍ抗体、抗精子抗体）的检测。结果：有５２例检出６９项次自身抗体,自身抗体检出率为３２．３％,显著高于健康人对照组（Ｐ＜０．００５）（未计抗精子抗体）。结论：ＨＣＶ感染可能是诱发自身免疫反应的一个重要因素     

八角枫对佐剂性关节炎大鼠的治疗作用及毒性

文章通过考察八角枫醇提物、八角枫总碱对佐剂性关节炎(AA)大鼠的治疗作用及毒性,研究八角枫治疗关节炎的有效部位;分别采用足容积法和5级评分法测定大鼠足肿胀度及关节炎指数(AI),采用HE染色法观察大鼠关节和肝脏组织的形态学变化,并作血清常规检测。结果表明,八角枫醇提物、八角枫总碱可明显减轻AA大鼠的足肿胀度,降低其关节炎指数,改善关节的病理学变化。实验证明了八角枫醇提物对AA大鼠的治疗作用较好,且对肝脏无明显毒性。     

雷公藤治疗老年性类风湿性关节炎临床实验研究

试验用雷公藤治疗老年性类风湿性关节炎。治疗效果表明,55例近期总有效率达98．18％,且尚可作为皮质激素的良好替代药物;雷公藤副作用轻微,与同期中青年组比较,无显著性差异（P＞0．05）,表明短期使用雷公藤治疗老年性类风湿关节炎是安全有效的。     

柳氮磺胺吡啶的合成、药理及配合物的研究进展

柳氮磺胺吡啶具有消炎和抗菌的性质，主要用于治疗溃疡性结肠炎和类风湿关节炎，对柳氨磺胺吡啶的合成，药理和金属配合物研究进展进行了评述。     

类风湿关节炎并发心血管系统损害43例临床分析

对43例类风湿关节炎急性活动期进行系统检查，发现并发心血病变较为常见，并可引起严重后果。心包积液、二尖瓣狭窄各占35.3%、心律失常55.8%。心脏传导阻滞20.9%、冠状动脉炎9.3%、左心室血栓5.9%。揭示在诊治类风湿关节炎同时应重视心血管系统病变的时期诊断和治疗，对改善预后具有重要意义。     

鱼油长碳链多不饱和脂肪酸的生理效应及其开发和利用

较系统地介绍了鱼油长碳链多不饱和脂肪酸，并重点阐述了二十碳五烯酸，抗心血管病和抗风湿性关节炎的原理以及二十二碳六烯酸促进幼儿的智力、视力和生殖系统发育的原理，并且对其历史作了一些叙述。本文明确指出开发和利用鱼油中长碳链多不饱和脂肪酸的关键问题是提高其产品的氧化稳定性，并对其提取工艺提出了改进意见。     

TRPC channel activation by extracellular thioredoxin

Mammalian homologues of Drosophila melanogaster transient receptor potential (TRP) are a large family of multimeric cation channels that act, or putatively act, as sensors of one or more chemical factor. Major research objectives are the identification of endogenous activators and the determination of cellular and tissue functions of these channels. Here we show the activation of TRPC5 (canonical TRP 5) homomultimeric and TRPC5-TRPC1 heteromultimeric channels by extracellular reduced thioredoxin, which acts by breaking a disulphide bridge in the predicted extracellular loop adjacent to the ion-selectivity filter of TRPC5. Thioredoxin is an endogenous redox protein with established intracellular functions, but it is also secreted and its extracellular targets are largely unknown. Particularly high extracellular concentrations of thioredoxin are apparent in rheumatoid arthritis, an inflammatory joint disease that disables millions of people worldwide. We show that TRPC5 and TRPC1 are expressed in secretory fibroblast-like synoviocytes from patients with rheumatoid arthritis, that endogenous TRPC5-TRPC1 channels of the cells are activated by reduced thioredoxin, and that blockade of the channels enhances secretory activity and prevents the suppression of secretion by thioredoxin. The data indicate the presence of a previously unrecognized ion-channel activation mechanism that couples extracellular thioredoxin to cell function.