Nat Commun:寄生虫激活免疫或可抑制类风湿性关节炎

正来自德国的科学家们在国际学术期刊Nature Communication上发表了一项最新研究进展,他们发现寄生虫感染激活的特定免疫反应可以帮助治疗小鼠的类风湿性关节炎。这项研究对于人类类风湿性关节炎的治疗也有一定提示意义。类风湿性关节炎是一种影响关节的自身免疫性疾病。与类风湿性关节炎相关的Th1和Th17这两种免疫反应本身具有对抗细菌和病毒的作用,但是在类风湿性关节炎患者中它们会攻击病人的软骨,造成组织损伤,炎症和疼痛。如何阻断类风湿性关节炎疾病中免疫细胞对自身的攻击     

科研快讯

《科学》:新蛋白可助治疗类风湿性关节炎来自纽约大学医学院,山东大学医学院,耶鲁大学医学院等处的研究人员研发了一种能用于治疗类风湿性关节炎的蛋白,从而为治疗这种自身免性疾病提供新的治疗靶标。这一研究成果公布在《科学》杂志上。     

用于治疗类风湿性关节炎的JAK 抑制剂

类风湿性关节炎是一种临床常见的慢性自身免疫性疾病,发病过程中滑膜组织及细胞分泌的大量细胞因子通过不同途径激活JAK/STAT 信号通路,并导致病变。因此,选择JAK 抑制剂针对性地阻断JAK/STAT 通路,可达到改善类风湿性关节炎病理过程的目的。概述JAK/STAT 信号通路的组成与结构、功能与机制以及在类风湿性关节炎发病过程中的作用,并着重介绍若干具代表性的已上市和尚处于临床及临床前研究阶段的JAK 抑制剂在类风湿性关节炎治疗中的应用研究。     

B细胞活化因子与类风湿性关节炎

B细胞活化因子具有刺激B细胞增殖和成熟的作用,过表达的B细胞活化因子与类风湿性关节炎等自身免疫疾病有着密切的关系,因此研究以B细胞活化因子为靶点治疗类风湿性关节炎具有一定的前景。本文对B细胞活化因子的表达、受体及其功能、BAFF在类风湿性关节炎发病机制中的作用、以B细胞活化因子为靶点治疗类风湿性关节炎等方面的研究现状及前景作综述。     

PNAS：彻底治愈类风湿性关节炎的新型疗法

类风湿性关节炎是一种引发机体许多关节疼痛炎症的一种疾病,其会引发关节囊肿胀。这种疾病往往会破坏机体的软骨组织和骨质;在世界范围内类风湿性关节炎影响着0．5％至1％的人群的健康,到目前为止医生们已经可以使用多种药物来缓解或者阻断该疾病的发展。近日,刊登在国际杂志PNAS上的一篇研究论文中,来自苏黎世联邦理工学院的研究人员通过研究开发了一种新型疗法。其在治疗患类风湿性关节炎小鼠的功效上可以达到一个新的水平,即小鼠在接受这种新型疗法治疗后会完全被治愈。     

PNAS:彻底治愈类风湿性关节炎的新型疗法

<正>类风湿性关节炎是一种引发机体许多关节疼痛炎症的一种疾病,其会引发关节囊肿胀,这种疾病往往会破坏机体的软骨组织和骨质;在世界范围内类风湿性关节炎影响着0.5%至1%的人群的健康,到目前为止医生们已经可以使用多种药物来缓解或者阻断该疾病的发展。近日,刊登在国际杂志PNAS上的一篇研究论文中,来自苏黎世联邦理工学院的研究人员通过研究开发了一种新型疗法,其在治疗患类风湿性关节炎小鼠的功效上可以达到一个新的水平,即小鼠在接受这种新型疗法治疗后会完全被治愈。     

类风湿性关节炎治疗药物进展

类风湿性关节炎是常见的自身免疫性疾病,可引起关节肿痛、畸形以及不同程度的残疾,影响了患者的生活质量。随着对发病机制的深入研究,出现了越来越多的治疗类风湿性关节炎的药物,依据发展的时间及原理,共分为五代:第一代是非甾体类抗炎药物;第二代是糖皮质激素;第三代是改变病情药(慢作用抗风湿药);第四代是以α肿瘤坏死因子(TNF-α)抑制剂为主的早期生物制剂;第五代为直接针对T细胞发生作用的新型生物制剂。其中第四代和第五代的生物制剂是近年来治疗类风湿性关节炎的新型药物,与传统药物相比体现了明显的优势,具有广泛的应用前景。本文对类风湿性关节炎的发病机制进行简要阐述,重点对类风湿性关节炎治疗药物的新进展进行综述。     

治疗类风湿关节炎的研究进展

生物制剂在类风湿性关节炎治疗中的应用虽然不到二十年的时间,却取得了较大的效果,并且逐渐成为一种常规的疗法.根据类风湿关节炎发病机制中的不同作用环节,人们开发出了分别针对细胞因子和淋巴细胞的各种各样的生物制剂.本文介绍生物制剂主要作用的对象有肿瘤坏死因子、白细胞介素、淋巴细胞等,他们是类风湿性关节炎各个发病环节中的重要部分.这些生物制剂对于顽固性RA患者有很好的治疗作用,且有较好的安全性.     

类风湿性关节炎啮齿动物模型的研究进展

类风湿性关节炎是一种常见的致残性疾病之一,病因未明。研究此类疾病的有效方法是建立、研究并应用动物模型。通过对目前国内外类风湿性关节炎模型复制方法、机制和应用的研究,分析各自的特点及不足之处,提出复制更加符合类风湿性关节炎临床特点的动物模型的展望与设想。     

人体菌群与类风湿性关节炎相关性的研究进展

类风湿性关节炎(rheumatoid arthritis,RA)是一种慢性炎症性自身免疫性疾病,严重影响患者生理以及心理健康。尽管过去20多年RA的治疗进展迅速,但我们对RA的病因学仍知之甚少。研究表明,RA的发病与遗传、环境以及免疫这三大因素息息相关。众所周知,人体菌群与这三大因素亦有着密切的联系。越来越多的临床试验及动物实验指出,人体菌群失调在RA病程的发生发展中起着至关重要的作用。本综述整理近年来人体菌群与类风湿性关节炎相关性的研究进展,通过循证人体菌群,为类风湿性关节炎的诊断、预防和治疗提供新思路。     

Long non‐coding RNAs in rheumatoid arthritis

Rheumatoid arthritis, a disabling autoimmune disease, is associated with altered gene expression in circulating immune cells and synovial tissues. Accumulating evidence has suggested that long non‐coding RNAs (lncRNAs), which modulate gene expression through multiple mechanisms, are important molecules involved in immune and inflammatory pathways. Importantly, many studies have reported that lncRNAs can be utilized as biomarkers for disease diagnosis and prognostication. Recently, dysregulation of lncRNAs in rheumatoid arthritis and other autoimmune diseases has been revealed. Experimental studies also confirmed their crosstalk with matrix metalloproteinases, nuclear factor‐κB signalling and T‐cell response pertinent to autoimmunity and inflammation. Circulating lncRNAs, such as HOTAIR, differentiated patients with rheumatoid arthritis from healthy subjects. Taken together, lncRNAs are good candidates as biomarkers and therapeutic targets in rheumatoid arthritis. Further investigation on in vivo delivery of these regulatory molecules and large‐cohort validation of their clinical applicability may be useful.     

Phytochemicals targeting matrix metalloproteinases regulating tissue degradation in inflammation and rheumatoid arthritis

PurposeMatrix metalloproteinases, zinc dependent proteolytic enzymes, have significant implications in extracellular matrix degradation associated with tissue damage in inflammation and Rheumatoid arthritis. Numerous orchestrated pathways affects instigation and blockade of metalloproteinases as well as various factors that increase the expression of MMPs including inflammatory cytokines, hormones and growth factors. Direct inhibition of these proteolytic enzymes or modulation of these pathways can provide protection against tissue destruction in inflammation and rheumatoid arthritis. Inclination towards use of plant derived phytochemicals to prevent tissue damage has been increasing day by day. Diversity of phytochemicals have been known to directly inhibit metalloproteinases. Hence, thorough knowledge of phytochemicals is very important in novel drug discovery.MethodsPresent communication evaluates various classes of phytochemicals, in effort to unveil the lead molecules as potential therapeutic agents, for prevention of MMPs mediated tissue damage in inflammation and rheumatoid arthritis. Data have been analyzed through different search engines.ResultsNumerous phytochemicals have been studied for their role as MMPs inhibitors which can be processed further to develop into useful drugs for the treatment of inflammation and rheumatoid arthritis.ConclusionIn search of new drugs, phytochemicals like flavonoids, glycosides, alkaloids, lignans & terpenes offer a wide canvas to develop into valuable forthcoming medicaments.     

Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood

Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine that controls the initiation and progression of inflammatory diseases such as rheumatoid arthritis. Tpl2 is a MAPKKK in the MAPK (i.e. ERK) pathway, and the Tpl2-MEK-ERK signaling pathway is activated by the pro-inflammatory mediators TNFalpha, interleukin (IL)-1beta, and bacterial endotoxin (lipopolysaccharide (LPS)). Moreover, Tpl2 is required for TNFalpha expression. Thus, pharmacologic inhibition of Tpl2 should be a valid approach to therapeutic intervention in the pathogenesis of rheumatoid arthritis and other inflammatory diseases in humans. We have developed a series of highly selective and potent Tpl2 inhibitors, and in the present study we have used these inhibitors to demonstrate that the catalytic activity of Tpl2 is required for the LPS-induced activation of MEK and ERK in primary human monocytes. These inhibitors selectively target Tpl2 in these cells, and they block LPS- and IL-1beta-induced TNFalpha production in both primary human monocytes and human blood. In rheumatoid arthritis fibroblast-like synoviocytes these inhibitors block ERK activation, cyclooxygenase-2 expression, and the production of IL-6, IL-8, and prostaglandin E(2), and the matrix metalloproteinases MMP-1 and MMP-3. Taken together, our results show that inhibition of Tpl2 in primary human cell types can decrease the production of TNFalpha and other pro-inflammatory mediators during inflammatory events, and they further support the notion that Tpl2 is an appropriate therapeutic target for rheumatoid arthritis and other human inflammatory diseases.     

Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators

Introduction  

The role of adiponectin in the pathogenesis of arthritis is still controversial. This study was performed to examine whether adiponectin is involved in joint inflammation and destruction in rheumatoid arthritis (RA) in relation to the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs).     

The role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis

Matrix metalloproteinases (MMPs) are a large group of enzymes responsible for matrix degradation. Among them, the family of gelatinases (MMP-2/gelatinase A and MMP-9/gelatinase B) is overproduced in the joints of patients with rheumatoid arthritis. Because of their degradative effects on the extracellular matrix, gelatinases have been believed to play an important role in progression and cartilage degradation in this disease, although their precise roles are yet to be defined. To clarify these roles, we investigated the development of Ab-induced arthritis, one of the murine models of rheumatoid arthritis, in MMP-2 or MMP-9 knockout (KO) mice. Surprisingly, the MMP-2 KO mice exhibited severe clinical and histologic arthritis than wild-type mice. The MMP-9 KO mice displayed milder arthritis. Recovery from exacerbated arthritis in the MMP-2 KO mice was possible by injection of wild-type fibroblasts. These results indicated a suppressive role of MMP-2 and a pivotal role of MMP-9 in the development of inflammatory joint disease.     

Pathogenesis of rheumatoid arthritis and c-Fos/AP-1

c-Fos/AP-1 controls the expression of inflammatory cytokines and matrix-degrading matrix metalloproteinases (MMPs) important in arthritis via promoter AP-1 binding motif. Among inflammatory cytokines, IL-1β is the most important inducer of a variety of MMPs, and mainly responsible for cartilage breakdown and osteoclastogenesis. IL-1β and c-Fos/AP-1 influence each other’s gene expression and activity, resulting in an orchestrated cross-talk that is crucial to arthritic joint destruction, where TNFα can act synergistically with them. While how to stop the degradation of bone and cartilage, i.e., to control MMP, has long been the central issue in the research of rheumatoid arthritis (RA), selective inhibition of c-Fos/AP-1 does resolve arthritic joint destruction. Thus, the blockade of IL-1β and/or c-Fos/AP-1 can be promising as an effective therapy for rheumatoid joint destruction in addition to the currently available TNFα blocking agents that act mainly on arthritis.     

Matrix metalloproteinases as targets for the immune system during experimental arthritis

Novel therapies for rheumatoid arthritis aiming at intervention in the inflammatory process by manipulation of autoreactive T and B lymphocytes receive major interest. However, the development of such therapies is largely hampered by the lack of knowledge of self-Ags recognized during the disease process. Recently, we predicted putative T cell self-epitopes based on a computer search profile. In the present study, the predicted self-epitopes were tested for T cell recognition in two experimental arthritis models, and their arthritogenic capacity was analyzed. Fourteen of n = 51 predicted self-epitopes were recognized during experimental arthritis of which six were able to actively induce arthritis. Interestingly, three of these six peptides were derived from matrix metalloproteinases (MMP), and only T cells responsive to MMP-derived epitopes were able to passively transfer arthritis to naive rats. Moreover, we demonstrate the presence of Abs to MMP-3 during the course of adjuvant arthritis. Together these data indicate that MMPs play a pivotal role as target for T and B cells during the development of inflammatory arthritis. This finding sheds new light on the pathophysiological role of MMPs during arthritis and opens novel possibilities for Ag-specific immunotherapy.     

Gene transfer of tissue inhibitor of metalloproteinases-3 reverses the inhibitory effects of TNF-alpha on Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts

Apart from counteracting matrix metalloproteinases, tissue inhibitor of metalloproteinases-3 (TIMP-3) has proapoptotic properties. These features have been attributed to the inhibition of metalloproteinases involved in the shedding of cell surface receptors such as the TNFR. However, little is known about effects of TIMP-3 in cells that are not susceptible to apoptosis by TNF-alpha. In this study, we report that gene transfer of TIMP-3 into human rheumatoid arthritis synovial fibroblasts and MRC-5 human fetal lung fibroblasts facilitates apoptosis and completely reverses the apoptosis-inhibiting effects of TNF-alpha. Although TNF-alpha inhibits Fas/CD95-induced apoptosis in untransfected and mock-transfected cells, fibroblasts ectopically expressing TIMP-3 are sensitized most strongly to Fas/CD95-mediated cell death by TNF-alpha. Neither synthetic MMP inhibitors nor glycosylated bioactive TIMP-3 are able to achieve these effects. Gene transfer of TIMP-3 inhibits the TNF-alpha-induced activation of NF-kappaB in rheumatoid arthritis synovial fibroblasts and reduces the up-regulation of soluble Fas/CD95 by TNF-alpha, but has no effects on the cell surface expression of Fas. Collectively, our data demonstrate that intracellularly produced TIMP-3 not only induces apoptosis, but also modulates the apoptosis-inhibiting effects of TNF-alpha in human rheumatoid arthritis synovial fibroblast-like cells. Thus, our findings may stimulate further studies on the therapeutic potential of gene transfer strategies with TIMP-3.     

Therapeutic antibodies elicited by immunization against TNF-alpha.

Tumor necrosis factor-alpha (TNF-alpha) is critically involved in the pathogenesis of several chronic inflammatory diseases. Monoclonal antibodies against TNF-alpha are currently used for the treatment of rheumatoid arthritis and Crohn's disease. This report describes a simple and effective method for active immunization against self TNF-alpha. This vaccination approach leads to a T-cell-dependent polyclonal and sustainable anti-TNF-alpha autoantibody response that declines upon discontinuation of booster injections. The autoantibodies are elicited by injecting modified recombinant TNF-alpha molecules containing foreign immunodominant T-helper epitopes. In mice immunized with such molecules, the symptoms of experimental cachexia and type II collagen-induced arthritis are ameliorated. These results suggest that vaccination against TNF-alpha may be a useful approach for the treatment of rheumatoid arthritis and other chronic inflammatory diseases.     

Interleukin-17: the missing link between T-cell accumulation and effector cell actions in rheumatoid arthritis?

The prominence of T cells and monocyte/macrophages in rheumatoid synovium suggests T cells may localize and amplify the effector functions of monocyte/macrophages in rheumatoid disease. However, while T cells are abundant in rheumatoid joints, classic T-cell derived cytokines are scarce, especially when compared to the levels of monokines IL-1 beta and TNF-alpha. For this reason, it has been speculated that monocyte/macrophages may act independently of T cells in rheumatoid disease and that the role of T cells may be more or less irrelevant to core disease mechanisms. The question of T-cell influence requires re-evaluation in light of the characterization of IL-17, a T-cell derived cytokine that is abundant in rheumatoid synovium and synovial fluid. IL-17 has a number of pro-inflammatory effects, both directly and through amplification of the effects of IL-1 beta and TNF-alpha. IL-17 is able to induce expression of pro-inflammatory cytokines and stimulate release of eicosanoids by monocytes and synoviocytes. Furthermore, IL-17 has been implicated in the pathogenesis of inflammatory bone and joint damage through induction of matrix metalloproteinases and osteoclasts, as well as inhibition of proteoglycan synthesis. In animal models of arthritis, intra-articular injection of IL-17 results in joint inflammation and damage. The recognition of IL-17 as a pro-inflammatory T cell derived cytokine, and its abundance within rheumatoid joints, provides the strongest candidate mechanism to date through which T cells can capture and localize macrophage effector functions in rheumatoid arthritis. As such, IL-17 warrants consideration for its potential as a therapeutic target in rheumatoid arthritis.