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1.
Martine Chabaud Erik Lubberts Leo Joosten Wim van den Berg Pierre Miossec 《Arthritis research & therapy》2001,3(3):168-10
The origin and role of IL-17, a T-cell derived cytokine, in cartilage and bone destruction during rheumatoid arthritis (RA) remain to be clarified. In human ex vivo models, addition of IL-17 enhanced IL-6 production and collagen destruction, and inhibited collagen synthesis by RA synovium explants. On mouse cartilage, IL-17 enhanced cartilage proteoglycan loss and inhibited its synthesis. On human RA bone explants, IL-17 also increased bone resorption and decreased formation. Addition of IL-1 in these conditions increased the effect of IL-17. Blocking of bone-derived endogenous IL-17 with specific inhibitors resulted in a protective inhibition of bone destruction. Conversely, intra-articular administration of IL-17 into a normal mouse joint induced cartilage degradation. In conclusion, the contribution of IL-17 derived from synovium and bone marrow T cells to joint destruction suggests the control of IL-17 for the treatment of RA. 相似文献
2.
Xia Li Wei-Guo Lu Yi-qing Zhao Cheng-wan Li Jian-ping Li Rui-Sheng Xu 《Biochemical and biophysical research communications》2010,397(2):131-135
Rheumatoid arthritis (RA) is a chronic, persistent inflammatory joint disease with systemic involvement that affects about 1% of the world’s population, that ultimately leads to the progressive destruction of joint. Effective medical treatment for joint destruction in RA is lacking because the knowledge about molecular mechanisms leading to joint destruction are incompletely understood. It has been confirmed that cytokine-mediated immunity plays a crucial role in the pathogenesis of various autoimmune diseases including RA. Recently, IL-17 was identified, which production by Th17 cells. IL-17 has proinflammatory properties and may promote bone and joint damage through induction of matrix metalloproteinases and osteoclasts. In mice, intra-articular injection of IL-17 into the knee joint results in joint inflammation and damage. In addition, it has been shown that blocking IL-17/IL-17R signaling is effective in the control of rheumatoid arthritis symptoms and in the prevention of joint destruction. In this article, we will briefly discuss the biological features of IL-17/IL-17R and summarize recent advances on the role of IL-17/IL-17R in the pathogenesis and treatment of joint destruction in RA. 相似文献
3.
4.
Suurmond J Dorjée AL Boon MR Knol EF Huizinga TW Toes RE Schuerwegh AJ 《Arthritis research & therapy》2011,13(5):R150
Introduction
Mast cells have been implicated to play a functional role in arthritis, especially in autoantibody-positive disease. Among the cytokines involved in rheumatoid arthritis (RA), IL-17 is an important inflammatory mediator. Recent data suggest that the synovial mast cell is a main producer of IL-17, although T cells have also been implicated as prominent IL-17 producers as well. We aimed to identify IL-17 expression by mast cells and T cells in synovium of arthritis patients. 相似文献5.
The multitude and abundance of macrophage-derived mediators in rheumatoid arthritis and their paracrine/autocrine effects
identify macrophages as local and systemic amplifiers of disease. Although uncovering the etiology of rheumatoid arthritis
remains the ultimate means to silence the pathogenetic process, efforts in understanding how activated macrophages influence
disease have led to optimization strategies to selectively target macrophages by agents tailored to specific features of macrophage
activation. This approach has two advantages: (a) striking the cell population that mediates/amplifies most of the irreversible
tissue destruction and (b) sparing other cells that have no (or only marginal) effects on joint damage. 相似文献
6.
Rheumatoid arthritis (RA) is one of the inflammatory joint diseases in a heterogeneous group of disorders that share features
of destruction of the extracellular matrices of articular cartilage and bone. The underlying disturbance in immune regulation
that is responsible for the localized joint pathology results in the release of inflammatory mediators in the synovial fluid
and synovium that directly and indirectly influence cartilage homeostasis. Analysis of the breakdown products of the matrix
components of joint cartilage in body fluids and quantitative imaging techniques have been used to assess the effects of the
inflammatory joint disease on the local remodeling of joint structures. The role of the chondrocyte itself in cartilage destruction
in the human rheumatoid joint has been difficult to address but has been inferred from studies in vitro and in animal models. This review covers current knowledge about the specific cellular and biochemical mechanisms that account
for the disruption of the integrity of the cartilage matrix in RA. 相似文献
7.
Schett G 《Arthritis research & therapy》2007,9(1):203
Osteoclasts are multinucleated cells of hematopoietic origin and are the primary bone resorbing cells. Numerous osteoclasts
are found within the synovial tissue at sites adjacent to bone, creating resorption pits and local bone destruction. They
are equipped with specific enzymes and a proton pump that enable them to degrade bone matrix and solubilize calcium, respectively.
The synovial tissue of inflamed joints has a particularly high potential to accumulate osteoclasts because it harbors monocytes/macrophages,
which function as osteoclast precursors, as well as cells that provide the specific molecular signals that drive osteoclast
formation. Osteoclasts thus represent a link between joint inflammation and structural damage since they resorb mineralized
tissue adjacent to the joint and destroy the joint architecture. 相似文献
8.
9.
There is significant evidence arising from experimental models that autoantibodies play a key role in the pathogenesis of
inflammatory arthritis. In addition to autoantibody production, B cells efficiently present antigen to T cells, produce soluble
factors, including cytokines and chemokines, and form B cell aggregates in the target organ of rheumatoid arthritis. In this
review we analyze the multifaceted role that B cells play in the pathogenesis of rheumatoid arthritis and discuss how this
information can be used to guide more specific targeting of B cells for the therapy of this disease. 相似文献
10.
Dendritic cells are the major antigen-presenting and antigen-priming cells of the immune system. We review the antigen-presenting
and proinflammatory roles played by dendritic cells in the initiation of rheumatoid arthritis (RA) and atherosclerosis, which
complicates RA. Various signals that promote the activation of NF-κB and the secretion of TNF and IL-1 drive the maturation
of dendritic cells to prime self-specific responses, and drive the perpetuation of synovial inflammation. These signals may
include genetic factors, infection, cigarette smoking, immunostimulatory DNA and oxidized low-density lipoprotein, with major
involvement of autoantibodies. We propose that the pathogenesis of RA and atherosclerosis is intimately linked, with the vascular
disease of RA driven by similar and simultaneous triggers to NF-κB. 相似文献
11.
Recent findings have substantiated the importance of T lymphocytes to the pathogenesis of rheumatoid arthritis (RA). Here,
we review emerging data regarding genetic predisposition, spontaneous animal models of arthritis, and cell-cell interactions
that implicate T cells as driving synovial inflammation and joint destruction. Information regarding the proinflammatory role
of interleukin-17-producing T cells and the functional state of regulatory T cells both in animal models and in patients with
RA is also discussed. In light of the overwhelming evidence that disrupted T-cell homeostasis greatly contributes to joint
pathology in RA, the therapeutic potential of targeting activators of pro-inflammatory T cells or their products is compelling. 相似文献
12.
For some time synovial fibroblasts have been regarded simply as innocent synovial cells, mainly responsible for synovial homeostasis.
During the past decade, however, a body of evidence has accumulated illustrating that rheumatoid arthritis synovial fibroblasts
(RASFs) are active drivers of joint destruction in rheumatoid arthritis. Details regarding the intracellular signalling cascades
that result in long-term activation and synthesis of proinflammatory molecules and matrix-degrading enzymes by RASFs have
been analyzed. Molecular, cellular and animal studies have identified various interactions with other synovial and inflammatory
cells. This expanded knowledge of the distinct role played by RASFs in the pathophysiology of rheumatoid arthritis has moved
these fascinating cells to the fore, and work to identify targeted therapies to inhibit their joint destructive potential
is underway. 相似文献
13.
Introduction
The aim of this study was to quantify the number of T-helper (TH)-17 cells present in rheumatoid arthritis (RA) synovial fluid (SF) and to determine the level of interleukin (IL)-17 cytokine in RA, osteoarthritis (OA) and normal synovial tissue, as well as to examine SF macrophages for the presence of IL-23, IL-27 and interferon (IFN)-γ. 相似文献14.
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16.
Yamanishi Y Boyle DL Green DR Keystone EC Connor A Zollman S Firestein GS 《Arthritis research & therapy》2005,7(1):R12-R18
Abnormalities in the p53 tumor suppressor gene have been detected in rheumatoid arthritis (RA) and could contribute to the pathogenesis of chronic disease. To determine whether synoviocytes from invasive synovium in RA have an increased number of mutations compared with non-erosion synoviocytes, p53 cDNA subclones from fibroblast-like synoviocytes (FLS) derived from erosion and non-erosion sites of the same synovium were examined in patients requiring total joint replacement. Ten erosion FLS lines and nine non-erosion FLS lines were established from nine patients with RA. Exons 5-10 from 209 p53 subclones were sequenced (114 from erosion FLS, 95 from non-erosion FLS). Sixty percent of RA FLS cell lines and 8.6% of the p53 subclones isolated from FLS contained p53 mutations. No significant differences were observed between the erosion and non-erosion FLS with regard to the frequency or type of p53 mutation. The majority of the mutations were missense transition mutations, which are characteristic of oxidative damage. In addition, paired intact RA synovium and cultured FLS from the same joints were evaluated for p53 mutations. Matched synovium and cultured synoviocytes contained p53 mutations, although there was no overlap in the specific mutations identified in the paired samples. Clusters of p53 mutations in subclones were detected in some FLS, including one in codon 249, which is a well-recognized 'hot spot' associated with cancer. Our data are consistent with the hypothesis that p53 mutations are randomly induced by genotoxic exposure in small numbers of RA synoviocytes localized to erosion and non-erosion regions of RA synovium. The determining factor for invasiveness might be proximity to bone or cartilage rather than the presence of a p53 mutation. 相似文献
17.
Matsuo K Xiang Y Nakamura H Masuko K Yudoh K Noyori K Nishioka K Saito T Kato T 《Arthritis research & therapy》2006,8(6):R175-13
Recently, autoantibodies to some citrullinated autoantigens have been reported to be specific for rheumatoid arthritis (RA). However, an entire profile of and autoimmunity of the citrullinated proteins have been poorly understood. To understand the profile, we examined citrullinated autoantigens by a proteomic approach and further investigated the significance of citrullination in antigenicity of one of the autoantigens. Specifically, we detected citrullinated autoantigens in synovial tissue of a patient with RA by two-dimensional electrophoresis and Western blotting by using pooled sera from five patients with RA and anti-citrulline antibodies. After identifying the detected autoantigens by mass spectrometry, we investigated the contribution of citrullination to autoantigenicity by using a recombinant protein with or without citrullination on one of the identified novel citrullinated autoantigens. As a result, we found 51 citrullinated protein spots. Thirty (58.8%) of these spots were autoantigenic. We identified 13 out of the 30 detected citrullinated autoantigenic proteins. They contained three fibrinogen derivatives and several novel citrullinated autoantigens (for example, asporin and F-actin capping protein alpha-1 subunit [CapZalpha-1]). We further analyzed the contribution of citrullination to autoantigenicity in one of the detected citrullinated autoantigens, CapZalpha-1. As a result, frequencies of autoantibodies to non-citrullinated CapZalpha-1 were 36.7% in the RA group tested, 10.7% in the osteoarthritis (OA) group, and 6.5% in healthy donors. On the other hand, those to citrullinated CapZalpha-1 were 53.3% in the RA group, 7.1% in the OA group, and 6.5% in the healthy donors. This shows that autoantigenicity of citrullinated or non-citrullinated CapZalpha-1 is relevant to RA. The antibody titers to the citrullinated CapZalpha-1 were significantly higher than those to the non-citrullinated CapZalpha-1 in 36.7% of patients; however, the other patients showed almost equal antibody titers to both citrullinated and non-citrullinated CapZalpha-1. Therefore, the autoantibodies would target citrulline-related and/or citrulline-unrelated epitope(s) of CapZalpha-1. In conclusion, we report a profile of citrullinated autoantigens for the first time. Even though citrullination is closely related to autoantigenicity, citrullination would not always produce autoantigenicity in RA. Citrullinated and non-citrullinated autoantigens/autoepitopes would have different pathological roles in RA. 相似文献
18.
Kosuke Matsuo Yang Xiang Hiroshi Nakamura Kayo Masuko Kazuo Yudoh Koji Noyori Kusuki Nishioka Tomoyuki Saito Tomohiro Kato 《Arthritis research & therapy》2007,8(6):R175
Recently, autoantibodies to some citrullinated autoantigens have been reported to be specific for rheumatoid arthritis (RA).
However, an entire profile of and autoimmunity of the citrullinated proteins have been poorly understood. To understand the
profile, we examined citrullinated autoantigens by a proteomic approach and further investigated the significance of citrullination
in antigenicity of one of the autoantigens. Specifically, we detected citrullinated autoantigens in synovial tissue of a patient
with RA by two-dimensional electrophoresis and Western blotting by using pooled sera from five patients with RA and anti-citrulline
antibodies. After identifying the detected autoantigens by mass spectrometry, we investigated the contribution of citrullination
to autoantigenicity by using a recombinant protein with or without citrullination on one of the identified novel citrullinated
autoantigens. As a result, we found 51 citrullinated protein spots. Thirty (58.8%) of these spots were autoantigenic. We identified
13 out of the 30 detected citrullinated autoantigenic proteins. They contained three fibrinogen derivatives and several novel
citrullinated autoantigens (for example, asporin and F-actin capping protein α-1 subunit [CapZα-1]). We further analyzed the
contribution of citrullination to autoantigenicity in one of the detected citrullinated autoantigens, CapZα-1. As a result,
frequencies of autoantibodies to non-citrullinated CapZα-1 were 36.7% in the RA group tested, 10.7% in the osteoarthritis
(OA) group, and 6.5% in healthy donors. On the other hand, those to citrullinated CapZα-1 were 53.3% in the RA group, 7.1%
in the OA group, and 6.5% in the healthy donors. This shows that autoantigenicity of citrullinated or non-citrullinated CapZα-1
is relevant to RA. The antibody titers to the citrullinated CapZα-1 were significantly higher than those to the non-citrullinated
CapZα-1 in 36.7% of patients; however, the other patients showed almost equal antibody titers to both citrullinated and non-citrullinated
CapZα-1. Therefore, the autoantibodies would target citrulline-related and/or citrulline-unrelated epitope(s) of CapZα-1.
In conclusion, we report a profile of citrullinated autoantigens for the first time. Even though citrullination is closely
related to autoantigenicity, citrullination would not always produce autoantigenicity in RA. Citrullinated and non-citrullinated
autoantigens/autoepitopes would have different pathological roles in RA. 相似文献
19.
20.
Chao C Joyce-Shaikh B Grein J Moshrefi M Raoufi F Laface DM McClanahan TK Bourne PA Pierce RH Gorman DM Pflanz S 《PloS one》2011,6(7):e22256
C17 was first described about ten years ago as a gene expressed in CD34+ cells. A more recent study has suggested a role for C17 in chondrogenesis and development of cartilage. However, based on sequence analysis, we believe that C17 has homology to IL-2 and hence we present the hypothesis that C17 is a cytokine possessing immune-regulatory properties. We provide evidence that C17 is a secreted protein preferentially expressed in chondrocytes, hence in cartilage-rich tissues. Systemic expression of C17 in vivo reduces disease in a collagen antibody-induced arthritis model in mice (CAIA). Joint protection is evident by delayed disease onset, minimal edema, bone protection and absence of diverse histological features of disease. Expression of genes typically associated with acute joint inflammation and erosion of cartilage or bone is blunted in the presence of C17. Consistent with the observed reduction in bone erosion, we demonstrate reduced levels of RANKL in the paws and sera of mice over-expressing C17. Administration of C17 at the peak of disease, however, had no effect on disease progression, indicating that C17's immune-regulatory activity must be most prominent prior to or at the onset of severe joint inflammation. Based on this data we propose C17 as a cytokine that s contributes to immune homeostasis systemically or in a tissue-specific manner in the joint. 相似文献