Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To assess the role of B7, CTLA4, and CD28 in the pathogenesis of chronic synovitis we analyzed the expression and function of these cell surface molecules in patients with rheumatoid arthritis, osteoarthritis, and psoriatic arthritis, and in normal controls. Immunoperoxidase staining of rheumatoid synovial membranes showed reactivity of 30% of T cells with anti-B7 mAb, in contrast to osteoarthritic and normal synovial membranes, in which no such staining was seen. In addition, rheumatoid synovial fluid T cells were positive by flow cytometric analysis for B7 (mean 20%, range 0 to 96%), as measured by staining with anti-B7 mAb or the CTLA4 Ig fusion protein, whereas no B7 expression was detected on peripheral blood T cells (mean 1%). To analyze the functional importance of B7 expressed on synovial fluid T cells, we used these cells as stimulator cells in primary allogeneic MLC. Purified synovial fluid T cells were far stronger stimulator cells compared with paired peripheral blood T cells and resulted in a fivefold greater increase in allogeneic T cell proliferation. Furthermore, the proliferation induced by purified synovial T cells was markedly inhibited by addition of the CTLA4 Ig fusion protein (77%). Moreover, anti-B7 mAb (37%), anti-CTLA4 mAb (33%), and Fab fragments of anti-CD28 mAb (52%) partially inhibited the primary MLC. The expression of functional B7, together with the increased expression of MHC class II molecules, indicates that synovial T cells may serve as functional APCs and may be capable of autocrine stimulation via the CD28 activation pathway.
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PMID:Expression of functional B7 and CTLA4 on rheumatoid synovial T cells. 751 75

Dendritic cells (DC) are the major APC in human peripheral blood (PB) and rheumatoid synovium. We previously identified in PB a population of CD33dim-CD14dim DC precursors, as well as a smaller population of CD33bright CD14dim mature DC. Neither PB DC population expressed the CD28/CTLA4 ligands, suggesting that additional signals are required for full functional DC differentiation. Because rheumatoid synovium is characterized by an ongoing immune response, the expression and function of CD80, CD86, and other markers of DC differentiation by rheumatoid arthritis synovial APC were examined. The phenotype of a large subset of freshly isolated rheumatoid arthritis synovial fluid (SF) DC resembled that of the mature PB DC. These DC expressed CD45R0, CD11c, CMRF-44, and high levels of CD33. Whereas CD80 expression by rheumatoid SF DC and monocytes was minimal, CD86 was expressed by a subset of SF monocytes and by CMRF-44+SF DC. Furthermore, sorted CD86- SF DC spontaneously up-regulated CD86 in vitro. CD80 was expressed diffusely and at low levels by rheumatoid synovial tissue cells, whereas CD86 was expressed by perivascular HLA-DR+HLA-DQ+CD80+CMRF-44+ DC, and by some CD14+ monocytes. Anti-CD86 mAb and CTLA4 Ig, but not anti-CD80 mAb, inhibited the MLR stimulated by SF DC. Both CMRF-44+ and CMRF-44- SF DC were efficient stimulators of the allogeneic MLR, which was in each case blocked by CTLA4 Ig. The data indicate that rheumatoid synovial DC can undergo full functional differentiation, associated with CD86 expression, in vitro and in situ. Synovial DC expressing high levels of MHC molecules and CD86 are strategically located to present arthritogenic Ag to T cells after transendothelial migration.
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PMID:Functional differentiation of dendritic cells in rheumatoid arthritis: role of CD86 in the synovium. 860 31

The genetic susceptibility to rheumatoid arthritis is conferred by genes in the human leukocyte antigen (HLA) region on chromosome 6, but additional genes may be involved to determine disease susceptibility. We have studied the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in rheumatoid arthritis. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, SSCP and RFLP in 258 Caucasian rheumatoid arthritis patients and 456 controls. Rheumatoid arthritis patients were characterized by a decreased frequency of homozygotes for the Thr-17 substitution (32% versus 39%) and an overrepresentation of patients heterozygous for the Thr/Ala substitution (54% versus 46%). Gene frequencies for the Ala/Thr substitution differed only marginally from controls. In contrast, analyses of the CTLA4 exon 1 polymorphism with respect to HLA-DRB1*04 revealed significantly more patients with Ala in the homozygous (19% versus 15% controls) or heterozygous state (54% versus 39% controls) and less homozygous for Thr (27% versus 46% controls), with a particular increase of Ala/Ala genotypes among rheumatoid arthritis patients carrying the HLA-DRB1*0401 subtype. Among HLA-DRB1*04 negative rheumatoid arthritis patients, we observed no difference between the allele frequencies of the Ala-17 or Thr-17 substitution.
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PMID:CTLA4 codon 17 dimorphism in patients with rheumatoid arthritis. 945 4

CTLA-4 is considered to be one of the attractive candidates for the susceptibility genes to rheumatic diseases. In the present study, the association of CTLA-4 polymorphism with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) was examined in the Japanese population using the case-control association analysis. Polymerase chain reaction-preferential homoduplex formation assay (PCR-PHFA) was applied for the screening of genetic variations and for the genotyping of a large number of samples. A greater proportion of Japanese patients with RA (44%) and SLE (44%) compared with healthy individuals (37%) had exon 1 49 G/G genotype, but the difference did not reach statistical significance. However, when the patients with RA and healthy individuals were stratified according to HLA-DRB1 alleles, a weakly significant increase of the positivity of CTLA-4 49G allele was observed in HLA-DRB1*0405-positive patients (87%) compared with DRB1*0405-positive healthy individuals (71%) (P = 0.014, odds ratio = 2.77). These results indicate that CTLA-4 exon 1 polymorphism does not contribute greatly to the susceptibility to RA and SLE, at least in Japanese, although the presence of CTLA4 49G allele could be a minor predisposing factor for RA in HLA-DRB1*0405-positive individuals. In addition, PCR-PHFA was shown to be useful for a mass screening of gene variations.
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PMID:Lack of a strong association of CTLA-4 exon 1 polymorphism with the susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese: an association study using a novel variation screening method. 1067 72

The effect of the gene region on chromosome 2q33 containing the CD28 and the cytotoxic T-lymphocyte associated (CTLA4) genes has been investigated in several diseases with chronic inflammatory nature. In addition to celiac disease (CD), type I diabetes, Grave's disease, rheumatoid arthritis and multiple sclerosis have all demonstrated associations to the A/G single nucleotide polymorphism (SNP) in exon 1, position +49 of the CTLA4 gene. The purpose of this study was to investigate this gene region in a genetically homogeneous population consisting of 107 Swedish and Norwegian families with CD using genetic association and linkage methods. We found a significant association with preferential transmission of the A-allele of the exon 1 +49 polymorphism by using the transmission disequilibrium test (TDT). Suggestive linkage of this region to CD was moreover demonstrated by non-parametric linkage (NPL) analysis giving a NPL-score of 2.1. These data strongly indicates that the CTLA4 region is a susceptibility region in CD. Interestingly, of the several chronic inflammatory diseases that exhibit associations to the CTLA4 +49 A/G dimorphism, CD appears to be the only disease associated to the A allele. This suggests that the +49 alleles of the CTLA4 gene are in linkage disequilibrium with two distinct disease predisposing alleles with separate effects. The peculiar association found in the gut disorder CD may possibly relate to the fact that the gastrointestinal immune system, in contrast to the rest of the immune system, aims to establish tolerance to foreign proteins.
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PMID:The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders. 1109 35

Systemic lupus erythematosus (SLE) is characterized by B cell hyperactivity and the production of autoantibodies, some of which (antibodies to dsDNA) are thought to be pathogenic. T helper cells drive the production of autoantibodies and the aim of this study is to characterize phenotypically a subpopulation of T cells (the CD3+ CD4- CD8-, double negative (DN) T cells) previously identified as helping to enhance anti-DNA antibodies in patients with SLE. Data were obtained using FACS staining of DN T cells that had been purified from PBMCs by magnetic bead separation. The percentage of TCR alphabeta+ DN T cells was found to be significantly higher in patients with SLE as compared with controls (P = 0.02), although there was no significant increase in total percentage of DN T cells, which includes TCR gammadelta+ cells. Activation markers HLA-DR and CD69, the costimulatory molecule CD28 and CTLA-4 were all expressed on the surface of a higher percentage of DN T cells in patients with SLE than in patients with rheumatoid arthritis (RA) or healthy controls (HC). More DN T cells from patients with SLE were of CD45RA phenotype than was found in controls, while CD45RO-expressing cells were reduced. In addition, DN T cells from patients with SLE expressed significantly higher levels of HLA-DR (P = 0.006), CD28 (P = 0.05), CTLA4 (P = 0.03) and CD45RA (P = 0.05) on the cell surface than those from the CD4/8 population. Correlation of expression of the markers measured with various parameters of disease activity and severity showed that high levels of HLA-DR expression correlated with high circulating serum C3 (> 0.9 IU/ml), indicating that an activated phenotype is consistent with severe disease.
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PMID:Characterization of CD3+ CD4- CD8- (double negative) T cells in patients with systemic lupus erythematosus: activation markers. 1222 Jan 3

Collagen Induced Arthritis (CIA) is a widely studied animal model to develop and test novel therapeutic approaches for treating Rheumatoid Arthritis (RA) in humans. Soluble Cytotoxic T-Lymphocyte Antigen 4 (CTLA4-Ig), which binds B7 molecule on antigen presenting cells and blocks CD28 mediated T-lymphocyte activation, has been shown to ameliorate experimental autoimmune diseases such as lupus, diabetes and CIA. Objective of our research was to investigate in vivo the effectiveness of blocking the B7/CD28 T-lymphocyte co-stimulatory pathway, utilizing a gene transfer technology, as a therapeutic strategy against CIA. Replication-deficient adenoviruses encoding a chimeric CTLA4-Ig fusion protein, or beta-galactosidase as control, have been injected intravenously once at arthritis onset. Disease activity has been monitored by the assessment of clinical score, paw thickness and type II collagen (CII) specific cellular and humoral immune responses for 21 days. The adenovirally delivered CTLA4-Ig fusion protein at a dose of 2x10^8 pfu suppressed established CIA, whereas the control beta-galactosidase did not significantly affect the disease course. CII-specific lymphocyte proliferation, IFNgamma production and anti-CII antibodies were significantly reduced by CTLA4-Ig treatment. Our results demonstrate that blockade of the B7/CD28 co-stimulatory pathway by adenovirus-mediated CTLA4-Ig gene transfer is effective in treating established CIA suggesting its potential in treating RA.
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PMID:[Recombinant adenovirus-mediated gene transfer suppresses experimental arthritis] 1246 78

High-quality monoclonal antibodies (mAbs) with specificity for relevant disease molecules can now be produced in abundance. Anti-tumour necrosis factor-alpha therapies have set a new standard for symptom control in rheumatoid arthritis, and blockade of tumour necrosis factor has the potential to protect joints from structural damage. Other targets for therapeutic antibodies include the cytokines interleukin (IL)-1, IL-6, IL-8, IL-15, IL-17 and IL-18. In addition, there is preliminary evidence for the clinical efficacy of both keliximab, a mAb targeting the T cell antigen CD4, and rituximab, a chimeric mAb against the B cell antigen CD20 and CTLA4-Ig, which blocks the CD28/B7 interaction. Phase III studies have yet to be undertaken for these novel biological agents, and it is unclear whether any of these agents will have true disease-modifying capabilities.
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PMID:Antibody therapy for rheumatoid arthritis. 1281 Feb

As rheumatoid arthritis (RA) is a chronic inflammatory disabling disease and a cure is not available, optimisation of therapeutic strategies is mandatory. Within recent years many new details of the inflammatory cascade(s) have been elaborated, leading to new therapeutic options such as neutralisation of tumour necrosis factor-alpha (TNFalpha). T-cell inhibition is another new approach to the treatment of RA. However, it is important to note two points: first, the role of T lymphocytes in the initiation and/or perpetuation of RA is still debated controversially. Second, there are few truly T-cell-specific agents that have proven to be effective and are established in the treatment of inflammatory disorders. Leflunomide may be considered one such agent; another in development is the fusion protein CTLA4-Ig. From a clinical perspective, studies demonstrating efficacy of these agents might represent the strongest support for a role of T cells in RA. In addition to leflunomide and CTLA4-Ig, therapeutic agents with activity against T cells, including anti-CD4 antibodies, cyclosporin, tacrolimus and T-cell receptor (TCR)-Vbeta-chain vaccination strategies, have been studied in patients with RA. Combination therapies including any of these T-cell-activation inhibitors with non-T-cell-specific agents such as methotrexate, antimalarials or anti-TNFalpha biologicals may prove the most effective strategies in controlling this complex disease.
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PMID:T-cell-activation inhibitors in rheumatoid arthritis. 1289 43

After approval of TNF and interleukin-1 inhibiting agents for treatment of refractory rheumathoid arthritis, new agents inhibiting interleukin-6 and costimulatory pathways are entering clinical phase I and II trials. Blockade of costimulation by using a CTLA4 immunoglobulin fusion protein (CTLA4Ig), which inhibits the interaction between CD 28 and CD80/86, has been studied in humans and was demonstrated to be well tolerated and efficacious. A monoclonal antibody to the IL-6 receptor (MRA) blocks bioactivity of IL-6 and also showed favorable effects in first clinical trials. Drug safety data on both substances revealed no severe toxicity or increased incidence of severe infections. For the first time combinations of biological substances like CTLA4Ig and etanercept were demonstrated to be effective and showed no evidence for an increased rate of severe infectious complications. Encouraged by data on these two agents there is substancial hope for a broadened therapeutic armentarium of biological agents in refractory rheumatoid arthritis.
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PMID:[New biological therapeutic options for the treatment of RE: inhibition of costimulatory molecules and blockade of Interleukin-6-interaction]. 1457 30


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