UMLS:C0003873 - FACTA Search

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Query: UMLS:C0003873 (rheumatoid arthritis)
53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor (TGF)-beta1 is an immunosuppressive cytokine that modulates the expression of class II histocompatibility antigens on human cells. Aberrant HLA class II expression on synovial lining cells of rheumatoid arthritis synovial membrane has been described, and the extent and intensity of class II expression on the cells was claimed to be linked with the severity of the disease. In this study, the effects of TGF-beta1 on HLA class II antigen expression in fibroblast-like synoviocytes (SFC) from rheumatoid synovectomy tissues were determined by flow cytometric analysis and quantitative RT-PCR. We found that pre-incubation of cells with TGF-beta1 was able to down-regulate IFN-gamma-induced DR protein expression in SFC. TGF-beta1, additionally, down-regulated IFN-gamma-stimulated class II transactivator (CIITA) and DRB mRNA expression. The constitutive expression of CIITA mRNA was completely abolished and the constitutive expression of DRB mRNA was decreased after treatment of SFC with TGF-beta1 for 24 h. Addition of the TGF-beta inhibitor decorin to SFC for 24 h before TGF-beta1/IFN-gamma treatment was able to reduce the down-regulatory effect of TGF-beta1 on DR antigen expression induced by IFN-gamma. Using competitive RT-PCR, we found that SFC constitutively expressed decorin mRNA and that treatment of cells with TGF-beta1 for 24 h reduced the constitutive expression of decorin mRNA by 65%. Our results show that TGF-beta1 is able to reduce the expression of HLA class II mRNA and protein, and suggest a tight regulation between TGF-beta1 and decorin in SFC of the rheumatoid synovium.
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PMID:Regulation by transforming growth factor-beta1 of class II mRNA and protein expression in fibroblast-like synoviocytes from patients with rheumatoid arthritis. 964 8

Cytokine production in human whole blood exhibits diurnal rhythmicity. Peak production of the pro-inflammatory cytokines IFN-gamma, TNF-alpha, IL-1 and IL-12 occurs during the night and early morning at a time when plasma cortisol is lowest. The existence of a causal relationship between plasma cortisol and production is suggested by the finding that elevation of plasma cortisol within the physiological range by the administration of cortisone acetate results in a corresponding fall in pro-inflammatory cytokine production. Cortisol may not be the only neuroendocrine hormone that entrains cytokine rhythms; other candidates include 17-hydroxy progesterone, melatonin and dihydroepiandrostene dione (DHEAS). The finding of diurnal cytokine rhythms may be relevant to understanding why immuno-inflammatory disorders such as rheumatoid arthritis or asthma exhibit night-time or early morning exacerbations and to the optimisation of treatment for these disorders. Diurnal rhythmicity of cytokine production also has implications for the timing of blood samples drawn for diagnostic T-cell assays. Finally, diurnal rhythmicity of immune function suggests that the nature of an immune response, for example in response to vaccination, may be modified by the time of day of antigen administration and raises the possibility that immune responses could be therapeutically manipulated by co-administration of immuno-regulatory hormones such as glucocorticoids.
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PMID:The chronobiology of human cytokine production. 964 80

Heat shock proteins (hsp) have been repeatedly implicated to participate in the pathogenesis of rheumatoid arthritis (RA). Herein, we investigated the regulation of synovial hsp70 expression by analyzing the DNA-binding activity of heat shock transcription factor 1 (HSF1) as well as inducible hsp70 expression. Experiments were performed both on synovial tissue and on synovial fibroblast-like cells (SFC). Gel mobility shift analysis revealed increased HSF1 activation, and Western blotting and immunohistochemistry revealed increased hsp70 expression in RA synovial tissue, but not in synovial tissue derived from patients with osteoarthritis. Proinflammatory cytokines (TNF-alpha, IL-1alpha, IL-6), but not IFN-gamma or TGF-beta, induced activation of HSF1-DNA binding and hsp70 expression in cultivated SFC. Activation of HSF1 in SFC was accompanied by hyperphosphorylation and nuclear translocation of HSF1. Furthermore, shear stress also induced a complete heat shock response in cultivated synovial cells. In contrast, nonsteroidal antiinflammatory drugs triggered only an incomplete heat shock response, with HSF1 activation but not hsp70 induction, whereas steroids and immunosuppressive drugs did not affect the heat shock response at all. In summary, these data suggest that induction of hsp70 expression in rheumatoid synovial tissue is based on transcriptional activation of HSF1 due to the presence of proinflammatory cytokines (and possibly also shear stress).
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PMID:Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue. Differential regulation of hsp70 expression and hsf1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs. 966 71

The synovial membrane in osteoarthritis (OA) often exhibits inflammatory infiltrates, but the role of T cells in these infiltrates is not known. T-cell activation antigens were analyzed by immunohistochemistry, and T-cell cytokine transcripts were measured by competitive PCR in synovial membranes from patients with OA and rheumatoid arthritis (RA). Lymphoid cell aggregates, containing primarily CD3+ T lymphocytes, were found in 65% of patients with OA. Mononuclear cells expressing the activation antigens CD69, CD25, CD38, CD43, CD45RO, and HLA class II were present in both patient groups, although in higher numbers in patients with RA. Interleukin 2 (IL-2) transcripts were found in 10 of 18 patients with OA versus 12 of 13 patients with RA (P = 0.03). Gamma interferon (IFN-gamma) transcripts were detected in 9 of 18 patients with OA versus 10 of 13 patients with RA (not significant), whereas IL-10 transcripts were found in nearly all patients. IL-4 and IL-5 were not detected in any patients. The levels of IFN-gamma and IL-2 transcripts, normalized for T-cell number equivalents, were not statistically different between OA and RA, but the levels of IFN-gamma, normalized for total cell number equivalents, were lower in OA than in RA (P = 0.01). Synovial membranes that expressed IL-2 and IFN-gamma transcripts were more likely to have heavier infiltrations of T cells and cells bearing activation markers than synovial membranes that did not express these cytokines. The presence of activated T cells and TH1 cytokine transcripts in chronic joint lesions of patients with OA suggests that T cells contribute to chronic inflammation in a large proportion of these patients.
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PMID:T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis. 966 43

Collagen-induced arthritis (CIA) is an autoimmune animal model for some types of human rheumatoid arthritis (RA). We have evaluated the effectiveness of intranasal administration of antigen in inhibiting CIA in DBA/1 mice. The intranasal administration of heat-denatured or trypsin-digested bovine type II collagen (CII) before immunization with CII strongly delayed the onset of CIA, whereas administration of native CII did not do so. The mice administered denatured or digested CII possessed much lower titers of anti-CII IgG2a than the control mice, whereas titers of anti-CII IgG1 and IgG2b were unchanged or slightly decreased. Responding to CII and peptides containing immunodominant T cell determinants, lymph node cells from mice administered denatured CII produced less IFN-gamma. These results suggest that intranasal administration of antigen downregulated preferentially Th1-type responses, whereas an enhanced Th2-type response was not observed. We demonstrate that the methods shown here are a possible treatment for rheumatoid arthritis.
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PMID:Intranasal administration of denatured type II collagen and its fragments can delay the onset of collagen-induced arthritis. 968 52

In the present study, we examined the therapeutic effects of T-614 (3-formylamino-7-methylsulfonylaminoxy-4H-1-benzopyran-4-one), a new anti-rheumatic drug, on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). T-614 dose-dependently suppressed the development of active EAE induced in Lewis rats by immunization with myelin basic protein (MBP) when administered for 2 weeks starting on the day of immunization (day 0 to 14). Amelioration of clinical signs was also obtained by the treatment at the effector phase (day 7 to 14) of the disease. Furthermore, T-614 treatment of recipient rats that had received MBP-sensitized lymphoid cells resulted in suppression of the clinical severity of EAE. Immunohistological examination revealed that the number of TCR alpha beta-expressing T cells and the extent of MHC class II expression in the spinal cord of rats treated with T-614 was markedly reduced. In vitro study using MBP-specific T cells showed that the addition of T-614 inhibited the proliferative responses of T cells and the production of pro-inflammatory cytokines such as IFN-gamma, IL-6 and TNF produced by T and accessory cells. Taken together, these findings imply that T-614 suppresses the development of EAE by inhibiting the proliferation of autoreactive T cells and pro-inflammatory cytokine production not only by T cells but also by macrophages/microglia. This may be attributable to the result that T-614 is more effective at the effector phase rather than the induction phase. Thus, this drug has a potential value for the treatment of various T cell-mediated autoimmune diseases including multiple sclerosis (MS) as well as rheumatoid arthritis.
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PMID:A new anti-rheumatic drug, T-614, effectively suppresses the development of autoimmune encephalomyelitis. 972 23

Adhesion molecules and cytokines are important in chronic inflammatory conditions such as rheumatoid arthritis (RA) by virtue of their role in cell activation and emigration. Using immunohistochemical techniques we studied the expression of adhesion molecules and cytokines in cryopreserved sections of murine knee joint in the course of antigen-induced arthritis, an animal model of human RA. Various adhesion molecules and cytokines are expressed in the arthritic joint tissue. LFA-1, Mac-1, CD44, ICAM-1 and P-selectin were strongly expressed in the acute phase and to a lesser degree in the chronic phase of arthritis. VLA-4 and VCAM-1 appeared to be moderately expressed on day 1, L-selectin between days 1 and 3. LFA-1, Mac-1, CD44, alpha 4-integrin, ICAM-1 and the selectins were found expressed on cells of the synovial infiltrate, LFA-1, Mac-1 and ICAM-1 on the synovial lining layer, and VCAM-1 and P-selectin on endothelial cells. Expression of E-selectin could be demonstrated throughout the experiment at a low level in cells of the acute cell infiltrate. Cytokines, especially IL-2, IL-4, IL-6, TNF, and IFN-gamma, were heavily expressed during the acute phase of arthritis in cellular infiltrate. Taken together these data demonstrate that cytokines and their activation of adhesion molecules contribute to cell infiltration and activation during the initial phase of arthritis and to the induction and progression of tissue destruction in arthritic joints. These molecules might be potential targets for novel therapeutic strategies in inflammatory and arthritic disorders.
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PMID:Expression of cell adhesion molecules and cytokines in murine antigen-induced arthritis. 975 22

Rheumatoid arthritis (RA) is now recognized as a multigene disorder with a number of genetic polymorphisms contributing to disease pathogenesis. Here, we propose that the diagnostic category of RA includes multiple subtypes of disease and that the different phenotypes of RA correlate to different genotypes. Support for this concept has come from a reappraisal of the clinical heterogeneity of RA and the observation that HLA-DRB1 polymorphisms are useful in describing genetic heterogeneity of RA phenotypes. A series of HLA-DRB1 genes has been identified as RA associated, and in recent years emphasis has been put on the sequence similarities of these alleles. An alternative view focuses on the amino acid variations found in RA-associated HLA-DRB1 alleles with different alleles being enriched in distinct subtypes of RA. Rheumatoid factor-positive destructive joint disease is predominantly associated with the HLA-DRB1*0401 allele, while HLA-DRB1*0404 and B1*0101 predispose for milder and often seronegative disease. Expression of disease-associated alleles on both haplotypes carries a high risk for extra-articular manifestations. In particular, patients homozygous for HLA-DRB1*0401 frequently develop rheumatoid vasculities on follow-up. Besides HLA gene polymorphisms, abnormalities in the generation and function of CD4 T cells and in inflammatory pathways established in synovial lesions can be used to dissect patient subsets with different variants of RA. Emergence of CD28-deficient CD4 T cells identifies RA patients with extra-articular manifestations. These cells undergo clonal expansion in vivo, produce high amounts of IFN-gamma, and exhibit autoreactivity. Concordance of monozygotic twins for the expression of CD4+ CD28- T cells suggests a role for genetic factors in the generation of these unusual T cells. Evidence for heterogeneity of the synovial component of RA comes from studies describing three distinct patterns of lymphoid organization in the synovium. Based upon the topography of tissue-infiltrating mononuclear cells, diffuse, follicular, and granulomatous variants of rheumatoid synovitis can be distinguished. Each pattern of lymphoid organization correlates with a unique profile of tissue cytokines, demonstrating that several pathways of immune deviation modulate disease expression in RA. A dissection of RA variants would have major implications on how the disease is studied, treated, and managed. Identifying combinations of RA risk genes that correlate with disease variants could, therefore, become an important diagnostic tool.
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PMID:Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes. 983 66

In rheumatoid arthritis, T lymphocytes have been proposed to play a pivotal role in the disease process, but they have also been considered to simply represent an epiphenomenon in a primarily synoviocyte/macrophage-driven disease. To directly examine the contribution of CD4 T cells in synovitis, T cells were either depleted from or adoptively transferred into NOD-SCID mice engrafted with rheumatoid synovial tissue. Injection of anti-CD2 antibody resulted in the elimination of 80-90% of tissue-infiltrating T cells in the synovial grafts and was followed by a marked decline in the production of IL-1beta (loss of 70%), TNF-alpha (loss of 86%), and IL-15 (loss of 84%) mRNA. Also, transcription of MMP-1 and MMP-2 was reduced by 72% in anti-CD2-treated chimeras. Immunohistochemistry demonstrated that the cytokines and proteases derived mostly from CD68(+) synovial cells, which disappeared from the tissue upon T cell depletion. Adoptive transfer of autologous tissue-derived T cell lines and T cell clones into synovium-SCID mouse chimeras augmented the production of IFN-gamma as well as TNF-alpha in the synovial infiltrates. Administration of IFN-gamma in small doses to anti-CD2-treated chimeras restored the survival and the functional activity of CD68(+) synovial cells. In vitro studies confirmed the critical role of synovial T cells and IFN-gamma in the survival of synovial CD68(+) cells. These data demonstrate that the production of proinflammatory cytokines and of tissue-degrading enzymes in rheumatoid synovitis is T cell dependent and that CD4 T cells are primary regulatory cells in this disease.
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PMID:Production of cytokines and metalloproteinases in rheumatoid synovitis is T cell dependent. 988 54

IL-17 is defined as a proinflammatory cytokine and produced by activated CD4+ T cells. In rheumatoid arthritis synovial tissue, high levels of IL-17 contribute to IL-6 production by synoviocytes. The present study was performed to see whether Th cells that produce IL-17 are associated with the Th1, Th2, or Th0 subset. Thirty-three CD4+, alphabeta+ T cell clones were developed from synovial membranes and synovial fluid of rheumatoid arthritis patients. Thirteen clones were defined as Th1 since they produced IFN-gamma but not IL-4, and four clones were defined as Th0 type that produced both IL-4 and IFN-gamma. Sixteen clones were defined as Th2 since they produced high levels of IL-4 and/or IL-10 but not IFN-gamma. IL-17 was measured in a bioassay, where IL-6 production from synoviocytes was a measurement for IL-17 activity in the presence and absence of blocking anti-IL-17 mAb. Three Th1 clones and two Th0 clones produced IL-17. In contrast, none of the sixteen Th2 clones analyzed produced IL-17. In addition, six Th2 clones were further cultured in conditions that induced a switch to Th1 type. Induction of this Th1 phenotype also led to production of IL-17 in two of these clones. The results demonstrate that some cells of the Th1/Th0 phenotype produce IL-17 but not cells of the Th2 phenotype. Thus, IL-17 may define a new subset of T cells, and IL-17 production appears to be a mechanism for Th1/Th0 cells, the most frequent Th subtype present in the rheumatoid synovium, to contribute to the local inflammatory reactions.
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PMID:IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. 997 76

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