Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that primarily affects joints. In rheumatoid joints there is extensive synovial proliferation with diseased synovium becoming highly aggressive, attaching to the articular cartilage and bone to form what is termed a pannus. The formation of active pannus is central to erosive disease and resulting joint destruction. In this study, we examined the ability to eliminate the hyperplastic synovium by adenoviral-mediated gene transfer of human TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family that is able to induce apoptosis through interaction with receptors containing death domains, DR4 and DR5. Infection of synovial cells derived from RA patients with Ad.TRAIL resulted in significant apoptosis in three out of five lines. Moreover, primary rabbit synovial fibroblasts were also sensitive to Ad.TRAIL-mediated gene transfer. In a rabbit model of arthritis, intra-articular gene transfer of TRAIL induced apoptosis in cells within the synovial lining, reduced leukocytic infiltration and stimulated new matrix synthesis by cartilage. These results demonstrate that TRAIL can affect the viability of the cells populating the activated synovium in arthritic joints and suggest that the delivery of TRAIL to arthritic joints may represent a non-invasive mechanism for inducing pannus regression.
 ...
PMID:Intra-articular adenoviral-mediated gene transfer of trail induces apoptosis of arthritic rabbit synovium. 1277 64

Collagen-induced arthritis (CIA) is an animal model of autoimmunity that has been studied extensively because of its similarities to rheumatoid arthritis (RA). CIA is induced in genetically susceptible strains of mice by immunization with type II collagen (CII), and both T cell and B cell immunity to CII are required for disease manifestation. Like RA, CIA is primarily an autoimmune disease of articular joints and susceptibility to CIA is linked to specific class II molecules of the major histocompatibility complex (H-2(r) and H-2(q)). Recently, it was demonstrated that transgenic expression of HLA-DR1 (*0101) or DR4 (*0401) molecules associated with susceptibility to RA also conferred susceptibility to CIA in the mouse model. The T cell response to CII has been extensively characterized in both the DR transgenic and naturally susceptible mouse strains, including the antigenic determinants recognized, the role of post transcriptional modifications of these determinants in the pathogenic T cell response, and the cytokines produced. Like most class II-mediated autoimmune diseases, the cytokine production of CII-specific T cells reflects a Th1 phenotype of the autoimmune response. While the direct role of T cells in the pathogenesis of CIA is unclear, the B cell response in terms of anti-CII immunoglobulin is critical to the development of the disease. This response, predominated by the IgG2 isotype, requires the activation of the complement cascade for the development of CIA. In recent years, the pathogenesis of this model has been studied extensively and the CIA model is proving to be a valuable asset for the design of new immunotherapeutics for the potential treatment of RA and other autoimmune diseases.
 ...
PMID:Immunopathogenesis of collagen arthritis. 1290 88

Articular lesions in 157 patients infected with ixodes tick-borne borreliosis (ITB) in a central Russia's region set on, on the average, in 4 months after tick attack; they were associated with systemic signs of an early disseminated infection and set on less seldom in a late period. The most often encountered systemic signs were as follows: secondary erythema (32% of patients), neurological syndrome (13%), cardio-vascular lesions (22%), ocular lesions (13%) and hepatic lesions (8%). The articular syndrome manifested itself through arthralgia (53 patients) and arthritis (104 patients), which set on quite often in the tick-attack area. There was a peculiarity typical of articular lesions, which made it possible to distinguish them from other rheumatic disease. A dynamic follow-up revealed different clinical variations of Lyme's arthritis and peculiarities of the genetic profile, i.e. a higher prevalence of HLA A2, HLA-B15 and HLA-DR4 as well as of haplo-types HLA A2-B15 and HLAB15-DR4. The articular lesions were associated with an intensive specific humoral immune response. The instrumental examination methods, i.e. ultrasonography of joints as well as scintigraphy of bones and joints, did not reveal any qualitative differences between arthralgia and arthritis, which is indicative of a common nature different-intensity manifestations of arthropathy in thick-borne borreliosis.
 ...
PMID:[Articular lesions in Ixodes tick-borne borreliosis (Lyme disease)]. 1293 71

We studied how tumor necrosis-factor (TNF)-family proteins interact with osteoblasts to resolve several controversial points. We measured expression of TNFs, TNF-receptors, and nonsignaling (decoy) TNF receptors in human osteoblasts derived from mesenchymal stem cells and in MG63 human osteosarcoma cells using unamplified mRNA screening, with secondary Western or PCR analysis where indicated, and studied the effects of TNFs on osteoblasts in cell culture. Expression of TNFs and receptors was similar in MG63 cells and osteoblasts. TNF-R1 (p55), TRAIL receptor 1 and 2 (DR4 and 5), and Fas were expressed; RANK was undetectable. TNF-family ligands RANKL, TRAIL, and TNFalpha were expressed, but mRNAs were typically at low levels relative to receptors, suggesting that osteoblastic TNF signals, including RANKL, require specific stimuli. Flow cytometry of MG63 cells confirmed TNFalpha receptors and identified subpopulations with high surface-bound TNFalpha. Decoy receptors expressed included a novel soluble form of TNFRSF25 (formerly DR3 or Apo3), implicated in rheumatoid-arthritis linkage studies, as well as osteoprotegerin, a well-characterized osteoblast protein that binds TRAIL and RANKL, and DcR2, which binds TRAIL. Osteoblast apoptosis was studied using terminal deoxynucleotidyl transferase labeling and annexin V binding. MG63 cells were resistant to apoptosis by exogenous TNFalpha except when grown in media promoting osteoblast-like growth or matrix nodules. However, in media supporting osteoblast-like phenotype, apoptosis was induced by anti-Fas or TNF, in contrast to other studies with human osteoblasts. TRAIL caused cell retraction, supporting functional TRAIL response in cell differentiation, but did not cause apoptosis. We conclude that human osteoblasts have functional receptors for FasL, TNFalpha, TRAIL, but not RANKL, and that osteoblasts are protected by multiple nonsignaling TNF receptors against destruction by TNF-family proteins under conditions favoring cell growth.
 ...
PMID:Expression and function of TNF-family proteins and receptors in human osteoblasts. 1462 51

Although associations between the expression of particular HLA genes and susceptibility to specific autoimmune diseases has been known for some time, the role HLA molecules play in the autoimmune response is unclear. Through the establishment of chimeric HLA-DR/I-E transgenes, the authors examined the function of the rheumatoid arthritis (RA) susceptibility alleles HLA-DR1 (DRB1*0101) and DR4 (DRB1*0401) in presenting antigenic peptides derived from the model antigen, type II collagen (CII), and in mediating an autoimmune response. As a transgene, these chimeric DR molecules confer susceptibility to an autoimmune arthritis induced by immunization with human CII. Both the DR1 and DR4-restricted T cell responses to CII are focused on an immunodominant determinant CII(263-270). Peptide binding studies revealed that the majority of the CII-peptide binding affinity for DR1 and DR4 is controlled by the Phe at 263 and, unexpectedly, the adjacent Lys. Only these 2 CII amino acids were found to provide binding anchors. Amino acid substitutions at the remaining positions had either no effect or significantly increased the affinity of the hCII peptide. These data indicate that DR1 and DR4 bind this CII peptide in a nearly identical manner and that the primary structure of CII may dictate a different binding motif for DR1 and DR4 than has been described for other peptides. In all, these studies demonstrate that DR1 and DR4 are capable of binding peptides derived from human type II collagen (hCII) and support the hypothesis that autoimmune responses to hCII play a role in the pathogenesis of RA.
 ...
PMID:Collagen-induced arthritis mediated by HLA-DR1 (*0101) and HLA-DR4 (*0401). 1508 12

The genetic background of rheumatoid arthritis (RA) is only partly understood, and several genes seem to be involved. The matrix metalloproteinases MMP1 (interstitial collagenase) and MMP3 (stromelysin 1) are thought to be important in destructive joint changes seen in RA. In the present study, functional relevant promoter polymorphisms of MMP1 and MMP3 were genotyped in 308 patients and in 110 controls, to test whether the polymorphisms contribute to the severity of the disease measured by radiographic progression of joint destruction. For comparison, the shared epitope of HLA DR4 and DR1 (SE) was determined by polymerase chain reaction. There was no association of MMP polymorphisms with susceptibility to RA. However, a strong linkage disequilibrium was observed between the 1G/2G (MMP1) and the 5A/6A (MMP3) polymorphisms (P << 10(-6); linkage disequilibrium index D' = 0.46). In factorial regression, the degree of radiographic joint destruction correlated significantly with the 1G-5A haplotype (P = 0.0001) and the interaction term 'estimated number of 1G-5A haplotypes x duration of disease' (P = 0.0007). This association was phasic, indicating that possession of the 1G-5A haplotype has a protective effect over a period of about 15 years of RA, but might be associated with a more pronounced radiographic progression later on. Similar results were also found with the 1G allele of MMP1 alone (P = 0.015) and with the interaction term 'estimated number of 1G alleles x duration of disease' (P = 0.014). The correlation of SE with the Ratingen score was comparable (0.044). The regression model of MMP haplotypes explained 35% of the variance of the radiographic score, whereas the SE explained 29%. The 1G-5A haplotype across the closely linked MMP1 and MMP3 gene loci is a newly described genetic factor strongly associated with the progression of joint damage in RA. Our findings suggest that there are haplotypes in a MMP cluster region that modify the joint destruction in RA in a phasic manner.
Arthritis Res Ther 2004
PMID:Association of a specific haplotype across the genes MMP1 and MMP3 with radiographic joint destruction in rheumatoid arthritis. 1514 65

Rheumatoid arthritis is a chronic inflammatory disease associated with certain HLA-DR4 subtypes. The target autoantigen(s) is unknown, but type II collagen (CII) is a candidate, with a single immunodominant DR4-restricted 261-273 T cell epitope (CII(261-273)). In the present study, we have prepared HLA-DR4:CII(261-273) tetramers and analyzed peripheral blood, lymph node, and synovial fluid cells from DR4-transgenic mice with early and late collagen-induced arthritis to draw a fuller picture of the role of CII-reactive Th cells in disease development. Their frequencies increased approximately 20-fold in blood 1-2 wk postimmunization, and even more in acutely arthritic joints. Our data strongly suggest that CII-specific Th cells are necessary, but not sufficient for collagen-induced arthritis. The CII-specific Th cells displayed an activated proinflammatory Th1 phenotype, and their expansion correlated with onset and severity of arthritis and also with anti-CII Ab levels. Surprisingly, shortly after the first clinical signs of arthritis, activated HLA-DR4:CII tetramer(+) cells became undetectable in the synovial fluid and rare in the blood, but persisted in lymph nodes. Consequently, future human studies should focus on patients with early arthritis, and on their synovial cells, to re-evaluate the occurrence and pathogenic importance of CII-specific or other Th cells in rheumatoid arthritis.
 ...
PMID:Tracking of proinflammatory collagen-specific T cells in early and late collagen-induced arthritis in humanized mice. 1555 1

An association has previously been shown between antibiotic-refractory Lyme arthritis, the human histocompatibility leukocyte antigen (HLA)-DR4 molecule, and T cell recognition of an epitope of Borrelia burgdorferi outer-surface protein A (OspA163-175). We studied the frequencies of HLA-DRB1-DQA1-DQB1 haplotypes in 121 patients with antibiotic-refractory or antibiotic-responsive Lyme arthritis and correlated these frequencies with in vitro binding of the OspA163-175 peptide to 14 DRB molecules. Among the 121 patients, the frequencies of HLA-DRB1-DQA1-DQB1 haplotypes were similar to those in control subjects. However, when stratified by antibiotic response, the frequencies of DRB1 alleles in the 71 patients with antibiotic-refractory arthritis differed significantly from those in the 50 antibiotic-responsive patients (log likelihood test, P = 0.006; exact test, P = 0.008; effect size, Wn = 0.38). 7 of the 14 DRB molecules (DRB1*0401, 0101, 0404, 0405, DRB5*0101, DRB1*0402, and 0102) showed strong to weak binding of OspA163-175, whereas the other seven showed negligible or no binding of the peptide. Altogether, 79% of the antibiotic-refractory patients had at least one of the seven known OspA peptide-binding DR molecules compared with 46% of the antibiotic-responsive patients (odds ratio = 4.4; P < 0.001). We conclude that binding of a single spirochetal peptide to certain DRB molecules is a marker for antibiotic-refractory Lyme arthritis and might play a role in the pathogenesis of the disease.
 ...
PMID:Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide. 1658 67

Rheumatoid arthritis (RA) is an autoimmune disease associated with the recognition of self proteins secluded in diarthrodial joints. We have previously established that mice transgenic for the human DR genes associated with RA are susceptible to collagen-induced arthritis (CIA) and we have identified a determinant of type II collagen (CII(263-270)) that triggers T-cell immune responses in these mice. We have also determined that an analog of CII(263-270) would suppress disease in DR1 transgenic mice. Because the immunodominant determinant is the same for both DR1 transgenic and DR4 transgenic mice, we attempted to determine whether the analog peptide that was suppressive in DR1 transgenic mice would also be effective in suppressing CIA in DR4 transgenic mice. We treated DR4 transgenic mice with two analog peptides of CII that contained substitutions in the core of the immunodominant determinant: CII(256-276) (F263N, E266D) and CII(256-270) (F263N, E266A). Mice were observed for CIA, and T-cell proliferative responses were determined. Either peptide administered at the time of immunization with CII significantly downregulated arthritis. Binding studies demonstrated that replacement of the phenylalanine residue in position 263 of the CII peptide with asparagine significantly decreased the affinity of the peptide for the DR4 molecule. In contrast, replacement of the glutamic acid residue in position 266 with aspartic acid or with alanine had differing results. Aspartic acid reduced the affinity (35-fold) whereas alanine did not. Both peptides were capable of suppressing CIA. With the use of either peptide, CII(256-276) (F263N, E266D) or CII(256-270) (F263N, E266A), the modulation of CIA was associated with an increase in T-cell secretion of IL-4 together with a decrease in IFN-gamma. We have identified two analog peptides that are potent suppressors of CIA in DR4 transgenic mice. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of HLA-DR4 that can suppress autoimmune arthritis.
Arthritis Res Ther 2006
PMID:Analog peptides of type II collagen can suppress arthritis in HLA-DR4 (DRB1*0401) transgenic mice. 1698 3

The objective of this study was to evaluate the degree of immunosenescence in patients with autoimmune disease. T cell receptor excision circles (TREC) and the percentage of CD4+CD28null T cells were studied as markers of immunosenescence in 175 patients with chronic autoimmune arthritis, other connective tissue autoimmune diseases, multiple sclerosis and 60 healthy controls. In both the rheumatoid arthritis (RA) and multiple sclerosis patient group, TREC numbers were age-inappropriately declined which points to an accelerated thymic output. Furthermore, enhanced percentages of CD4+CD28null T cells could be detected in a significant proportion of patients included in this study. These immunosenescent phenomena seemed to be present already early in the disease process. High percentages of CD4+CD28null T cells were associated with the presence of RA linked HLA DR4 alleles and with plasma reactivity to cytomegalovirus. Further analysis of CD4+CD28null T cells provided indications for a restricted T cell receptor (TCR) BV gene expression and cytoplasmic stores of various cytotoxic molecules. This study indicates that the immune system of patients with autoimmune diseases shows signs of an accelerated aging. Both genetic factors, such as HLA DR4, and environmental factors, like CMV infection, might speed up this immunosenescence and contribute in this way to disease pathogenesis.
 ...
PMID:Analyses of immunosenescent markers in patients with autoimmune disease. 1731 20


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>