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)

We have examined the T cell receptor (TcR) expression of clones specific for epitopes of mycobacterial 65-kDa heat-shock protein (hsp65) in the context of two different HLA molecules, and used this system as a model to assess the selection of T cells responsive to this antigen in vivo. DR3-restricted clones were raised from both the synovial fluid (SF) and peripheral blood (PB) of a patient with reactive arthritis in three separate cloning events. Five of five SF-derived clones tested expressed either V beta 5.2 or a closely related beta chain, V beta 5.6. The alpha chains expressed by V beta 5.2+ and V beta 5.6+ clones were from different families, V alpha 2.4 and V alpha 23.2, respectively. Nine of ten clones derived from two cloning procedures on PB taken 3 years later also expressed either V beta 5.2 or V beta 5.6. This suggests that the TcR repertoire for recognizing this major histocompatibility complex/peptide complex is relatively restricted and favors the use of V beta 5. Conservation of the beta chain third complementarity-determining region (CDR3) sequence was not evident, however. Sequencing alpha and beta chains of representative V beta 5.2+ and V beta 5.6+ PB-derived clones revealed TcR which were identical to those utilized by the SF-derived clones, showing that the repertoire for recognition of this antigen is stable over time. Similar studies of TcR expression were carried out on hsp65-specific, DP4-restricted clones derived from the SF of a patient with rheumatoid arthritis by two independent cloning procedures. There was conservation of alpha chain usage, since all clones expressed a member of the V alpha 1 family, but again CDR3 sequence conservation was not apparent. beta chain usage was not restricted since different clones expressed V beta 6.7, V beta 22.3 and V beta 12. Subtle differences in epitope specificity were detected for two clones with differing TcR. Once more, T cell clones with identical alpha and beta TcR chains were obtained from the separate cloning procedures, suggesting oligoclonalty of T cells with this defined specificity in the patient's SF.
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PMID:Restricted T cell receptor expression by human T cell clones specific for mycobacterial 65-kDa heat-shock protein: selective in vivo expansion of T cells bearing defined receptors. 768 83

In normal, healthy joints, synovial fibroblasts do not express major histocompatibility complex (MHC) class II molecules. However, in inflamed joints of rheumatoid arthritis (RA) patients, synovial fibroblasts show an abundant expression of MHC class II. Does this increase in expression have functional consequences for antigen presentation to T cells? To date, the precise role of synovial fibroblasts in antigen presentation has not been documented. Here, we show by three different examples that cultured synovial fibroblasts with interferon-gamma (IFN-gamma)-induced MHC class II expression are capable of processing soluble protein for presentation to CD4+ T cells. First, the antigen-presenting cell (APC) function of synovial fibroblasts was studied in an autologous model. From synovial tissue of a RA patient both a fibroblast cell line and a tetanus toxoid (TT)-specific CD4+ T-cell line were generated. A dose-dependent TT response was observed only when TT was presented by IFN-gamma-pretreated synovial fibroblasts. As more direct evidence for MHC class II-restricted antigen presentation, the response of a Mycobacterium tuberculosis-specific CD4+ T-cell clone isolated from rheumatoid synovial fluid was demonstrated in the presence of synovial fibroblasts. The response was DR4Dw4-restricted and could be inhibited by monoclonal antibody (mAb) to HLA-DR. In addition, the lymphokine secretion pattern of the synovial T-cell clone did not differ qualitatively upon antigen-specific stimulation using peripheral blood mononuclear cells (PBMC) or synovial fibroblasts as APC. In order to provide evidence for intracellular antigen processing we next examined the response of a M. leprae-specific T-cell clone with known epitope specificity. Our data suggest that synovial fibroblasts are not passive bystanders, but can become active participants in the development and maintenance of chronic inflammation.
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PMID:Antigen-presenting capacity of rheumatoid synovial fibroblasts. 792 99

Collagen-induced arthritis (CIA) is an animal model of autoimmune inflammatory polyarthritis that has features similar to rheumatoid arthritis (RA). Much like RA, susceptibility to mouse CIA is influenced by the major histocompatibility complex (MHC), H-2, and restricted to the H-2q and H-2r haplotypes. Whereas the role of the H-2A molecule in susceptibility to CIA is well established, little is known about the role of H-2E molecule in the disease. In this study, we analyzed the effect of a transgenic E beta d molecule on CIA susceptibility in a recombinant mouse B10.RQB3, which expresses the CIA susceptible Aq genes and an Eak gene, but does not produce an E molecule since Ebq is nonfunctional. In the presence of an Ebd transgene, a viable E molecule is generated. Whereas B10.RQB3 were susceptible to CIA, B10.RQB3-E beta d+ showed a dramatic reduction in the incidence of arthritis as well as a decrease in the level of anti-mouse and anti-bovine CII antibodies in their serum. No clear cut differences in the expression of T cell receptor (TCR) V beta was observed between E beta d+ and E beta d- transgenic mice. Mechanisms underlying the protective effect of E beta d transgenic molecule on CIA may shed light on how HLA-DR molecules influence human RA.
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PMID:Protective role of major histocompatibility complex class II Ebd transgene on collagen-induced arthritis. 793 Oct 88

The major histocompatibility complex (MHC) class II region is assumed to influence autoimmune diseases such as rheumatoid arthritis. In the mouse, the H-2q haplotype is associated with susceptibility to collagen-induced arthritis, while the H-2p haplotype is not. The class II A molecules of these haplotypes differ by only four amino acids in the first domain of the beta chain. To test if this difference accounts for the MHC influence on susceptibility to collagen-induced arthritis, H-2p mice were made transgenic with an Abp gene altered to resemble the Abq gene. The transgenic A beta chain hybridized with the A alpha p chain and was shown to be physiologically expressed by testing antigen-presentation capacity to Aq-restricted T cell hybridomas and with FACS analyses. These transgenic mice developed an autoimmune response to type II collagen and also collagen-induced arthritis. The data unequivocally suggest the Ab gene as a major genetic susceptibility locus for autoimmune collagen-induced arthritis.
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PMID:Expression of a transgenic class II Ab gene confers susceptibility to collagen-induced arthritis. 802 30

Rheumatoid arthritis is a common autoimmune disorder for which current treatments are unsatisfactory since they usually fail to control joint destruction. Pathophysiological mechanisms are incompletely understood but T-lymphocytes and antigen-presenting cells play a key role. Novel therapeutic approaches are directed to these cell types via the trimolecular T-cell receptor-major histocompatibility complex molecules-peptide (TCR-MHC-peptide) complex and other molecules involved in lymphocyte activation. The goal is to restore tolerance through highly selective immunosuppression to minimize adverse effects. Monoclonal antibodies (Ab) directed against a number of targets are potent tools. Antibodies to CD5, CD7, CD54 and CDw52 act on the overall T-cell population. Antibodies against CD4, CD25 or HLA-DR produce more limited immunomodulatory effects. Most human studies to date are encouraging but not controlled study has yet been published. The most satisfactory therapeutic approach involves restoration of tolerance through inhibition of auto-immune T-cell clones. The existence of these clones has been demonstrated in animal models of autoimmune diseases. Successfully developed, highly specific immunological tools include anti-clonotypic monoclonal antibodies, peptide analogs, and anti-T-cell vaccines. The extrapolation to human disease of insights acquired in animal models and the feasibility of these novel therapeutic approaches in rheumatoid arthritis patients are discussed.
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PMID:[New treatments of rheumatoid arthritis for future use]. 816 8

The human major histocompatibility complex (MHC) contains two closely related genes (TAP) that encode a family of transporter proteins. It is known that the TAP genes, like other MHC (class I and class II) genes, are polymorphic. In this study we investigated the polymorphisms in the ATP-binding domain of the TAP2 gene and examined the relationship of these polymorphisms to susceptibility to rheumatoid arthritis (RA). On the basis of the distribution of polymorphisms in these genes, three TAP2 alleles could be identified in homozygous typing cell lines, RA patients and normal subjects: TAP2*0101-1693.G, TAP2*0101-1693.A and TAP2*0201-1693.G. The prevalence of the variant (nucleotide A at position 1693), and thus also of the TAP2*0101-1693.A allele, was significantly (p < 0.006, RR = 4.25) higher in RA patients (35.3%) than in normal controls (11.4%). In addition, the TAP2*0101-1693.A allele showed significant (r = 0.45, p < 0.0003) association with HLA-DR4 only in RA patients and the prevalence of both TAP2*0101-1693.A and DR4 genes gave the highest relative risk (RR = 19.21, p < 0.0002) for RA. These data suggest that the MHC region containing both class II and TAP genes confers the strongest susceptibility to RA, with the highest RR value reported so far. It is likely that the genetic variability in the putative peptide transporter could also be implicated in immunological disorders associated with MHC.
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PMID:Polymorphisms in the TAP2 gene and their association with rheumatoid arthritis. 816 39

The HLA (human leukocyte antigens) system, or human major histocompatibility complex, is the most polymorphic functional genetic entity known at present. It consists of HLA class I genes and molecules (A, B and C) which control CD8+ cell-mediated antiviral responses, and class II genes and molecules (DR, DQ and DP) which control CD4+ cell responses (anti-bacterial and anti-toxin). HLA molecules function by presenting antigenic peptides to CD8+ cells (class I) and CD4+ cells (class II). Antigen presentation depends on the intracellular location of the antigen. Antigens present in the exocytosis pathway are presented by class I molecules, while class II molecules present antigens associated with the endocytosis pathway. More than 200 alleles have been detected by means of serological testing (microlymphocytotoxicity) and biochemical methods (IEF) in the HLA class I system, and now by means of molecular biology techniques for class II molecules (PCR-SSO and PCR-RFLP). This molecular typing has revealed the amino acids in HLA molecules that confer genetic susceptibility or resistance to numerous HLA-associated diseases. This is the case for example of ankylosing spondylitis (region 45-46 of HLA-B27 molecules), juvenile diabetes (aa 57 of D beta Q) and rheumatoid arthritis (aa 65-71 of DR beta). Thus, the HLA system is a genetic tool for diagnostic and therapeutic decision-making.
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PMID:[Human major histocompatibility complex: the HLA system]. 817 53

Soluble factors produced by Mycoplasma arthritidis play an important role in the pathology of arthritis in rodents, which closely resembles human rheumatoid arthritis. At least one of the products of these microorganisms, M. arthritidis-T cell mitogen (MAM), has biological activities in common with superantigens. These superantigens activate T cells in a V beta-restricted fashion, and this response is strictly dependent on the presence of major histocompatibility complex (MHC) class II-positive cells. In the present study, we have examined the ability of MAM to induce proinflammatory monokine (interleukin 1 beta [IL-1 beta] and tumor necrosis factor alpha [TNF-alpha]) gene expression in the THP-1 monocytic cell line. Treatment of these cells (which express a very low level of HLA-DR molecules) with gamma interferon (INF-gamma) induced HLA-DR, -DQ, and -DP molecules and enabled them to respond to MAM in a dose-dependent manner, resulting in an increase in the level of steady-state mRNA for IL-1 beta and TNF-alpha. Stimulation of the U937 monocytic cell line (MHC class II-negative even after INF-gamma treatment) with MAM did not induce either IL-1 beta or TNF-alpha transcription. Moreover, MAM adsorption on Raji (MHC class II-positive) cells resulted in the loss of its cytokine-inducing activity to induce monokine gene expression. These findings demonstrate clearly that MAM induces monokine gene expression following interaction with MHC class II molecules. Pretreatment of INF-gamma-treated THP-1 cells with the transcription inhibitor actinomycin D prevented the induction of monokine mRNA, whereas cycloheximide superinduced mRNA after stimulation with MAM. Finally, our results, obtained with protein tyrosine kinase inhibitors and antiphosphotyrosine Western blotting (immunoblotting), indicate that protein tyrosine kinase is involved in MAM-induced IL-1 beta and TNF-alpha gene expression in the THP-1 monocytic cell line. The capacity of MAM to induce proinflammatory cytokine transcription in monocytes via MHC class II molecules can be one pathway of MAM contribution to autoimmune diseases.
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PMID:Mycoplasma arthritidis-derived superantigen induces proinflammatory monokine gene expression in the THP-1 human monocytic cell line. 818 66

A severe flare-up of chronic hepatitis B infection with liver cell insufficiency has been observed in two patients after discontinuation of chloroquine administered either as malaria prophylaxis or as treatment of presumed rheumatoid arthritis. Chloroquine is known to inhibit the association of the major histocompatibility complex type II with hepatitis B virus antigens, thereby inhibiting T-cell mediated lysis of infected cells. Furthermore, it inhibits uptake of duck hepatitis B virus by duck liver cells. These in vitro studies and our clinical observations suggest that chloroquine inhibits the lysis of hepatitis B virus infected hepatocytes. Withdrawal of chloroquine in patients with chronic hepatitis B virus infection can lead to a rebound immune response manifesting as a reactivation of hepatitis B, similar to that observed after steroid withdrawal.
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PMID:[Reactivation of hepatitis B following withdrawal of chloroquine]. 820 73

The determination of peptide stability in human serum (HS) or plasma constitutes a powerful screening assay for eliminating unstable peptides from further development. Herein we report on the stability in HS of several major histocompatibility complex (MHC)-binding peptides. Some of these peptides are in development for the novel treatment of selected autoimmune disorders such as rheumatoid arthritis and insulin-dependent diabetes. For most of the l-amino acid peptides studied, the predominant degradation mechanism is exopeptidase-catalyzed cleavage. Peptides that were protected by d-amino acids at both termini were found to be more stable than predicted, based on additivity of single substitutions. In addition, N-acetylglucosamine glycopeptides were significantly stabilized, even when the glycosylation site was several amino acids from the predominant site(s) of cleavage. This indicates that long-range stabilization is possible, and likely due to altered peptide conformation. Finally, the effect of single amino acid substitutions on peptide stability in HS was determined using a model set of poly-Ala peptides which were protected from exopeptidase cleavage, allowing the study of endopeptidase cleavage pathways.
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PMID:Peptide stability in drug development. II. Effect of single amino acid substitution and glycosylation on peptide reactivity in human serum. 823 61


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