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)

Felty's syndrome (FS) is a rare complication of rheumatoid arthritis (RA) previously shown to be strongly associated with HLA-DR4 and less significantly with HLA-DQw7. To map more precisely the HLA locus responsible for susceptibility to FS, we have examined HLA-DR4 and DQ beta-chain polymorphisms in FS patients and controls using restriction fragment length polymorphism analysis and polymerase chain reaction amplification in conjunction with oligonucleotide probing. The increased frequency of DR4 in FS (93% vs. 32% controls) was due almost entirely to enrichment for the Dw4 subtype (88% vs. 20% controls) with a secondary increase of the Dw14 subtype. Dw10 and Dw13 subtypes of DR4 were absent from the patient group. Increase in DQw7 frequency among DR4 FS patients could be accounted for by linkage disequilibrium between Dw4 and DQw7 alleles. Whereas susceptibility to RA is strongly associated with a conserved HLA-DR beta epitope associated with several DRB1 alleles, it is primarily the Dw4 allele which is associated with progression to Felty's syndrome. The finding that amino acid sequence variation at the DR4B1 locus rather than DQB1 is associated with development of FS will have important implications for the development of novel immunotherapies which are major histocompatibility complex allele-dependent.
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PMID:Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA-DQw7 association with Felty's syndrome. 168 90

Susceptibility to rheumatoid arthritis (RA) may be due to the presence of shared functional epitopes common to the HLA-DR beta chains of several RA-associated haplotypes. We have obtained direct evidence for this hypothesis by using the polymerase chain reaction and sequencing the DRB1 and DQB1 genes from RA patients. A highly conserved epitope present on DR beta chains of DR4 and DR1 haplotypes was found in 83% of 149 patients with classical or definite RA but was found in only 46% of 100 control individuals (P less than 0.0001). Two Dw subtypes of DR4 (Dw4 and Dw14) were associated with disease susceptibility but two other subtypes (Dw10 and Dw13) were not. Sequence differences between these subtypes implicate those residues around the putative antigen binding site of the DR beta molecule in the pathogenesis of RA. These data provide a basis for understanding host susceptibility to RA at a molecular level.
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PMID:HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. 248 9

We examined the association of individual HLA genes with rheumatoid arthritis (RA), using oligonucleotide probes that identified both DR4-associated and non-DR4-associated genes. Two distinct HLA-DR beta alleles (Dw4 and Dw14) were found in DR4+ RA patients compared with controls (Dw4 50% versus 17%; Dw14 35% versus 5%; total DR4 73% versus 30%), indicating that these 2 alleles are independent susceptibility genes. Remarkably, the majority of the DR4- RA patients also demonstrated a linear DNA sequence, apparently "shuffled" between different susceptibility alleles, identified with an oligonucleotide probe to a key portion of the Dw14 gene.
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PMID:HLA genes associated with rheumatoid arthritis. Identification of susceptibility alleles using specific oligonucleotide probes. 249 97

Because DNA polymorphisms of immunoglobulin kappa confer risk for rheumatoid arthritis (RA) and not all persons with RA have the HLA-DR4 marker, genomic polymorphisms of immunoglobulin kappa and HLA-DR beta were determined in white patients with RA. Compared with control subjects matched for DR beta genotype, the homozygous genotype of the constant segment of immunoglobulin kappa (C kappa) was more frequent in the subgroups of RA patients without the DR beta genotype corresponding to HLA-DR4 (relative risk 6.2, P less than 0.01) and patients without DR4 or DR1 (relative risk 6.7, P = 0.013), but not in the DR4+ RA subgroup. Therefore, RA may be a genetically heterogeneous disease, with HLA-DR4 marking one genetic subset and the homozygous C kappa genotype marking another.
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PMID:Immunoglobulin kappa genotype confers risk of rheumatoid arthritis among HLA-DR4 negative individuals. 251 Jul 39

Two-dimensional gel analysis (NEPHGE) of the molecules precipitated by the HLA-DR monomorphic antibody L243 showed a single and identical alpha chain spot from two consanguineous cell lines, BM14 and MCF. The latter was derived from a rheumatoid arthritis patient. No apparent structural polymorphism of the HLA-DR beta chains was detected. The data suggests that the HLA-DR4 haplotype expresses one alpha chain and up to four beta chains. The electrophoretic pattern of the HLA-DQ molecules precipitated with the monomorphic antibody TU22 revealed clear differences between BM14 and MCF. These differences were mainly in the beta chain profiles. Four acidic beta chains were found with the MCF cell line wheras only three beta chains at different isoelectric points were found with the BM14 cell line. The data obtained in this study argue for a considerable heterogeneity of the HLA-DQ antigens detected at the molecular level.
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PMID:HLA-DQ molecular heterogeneity in HLA-DR4-Dw4 consanguineous cell lines. 350 60

In years to come, new therapeutic modalities for the treatment of chronic arthritis will be launched for general clinical use. These therapies, until today only used in clinical studies, are based on knowledge obtained from animal models of chronic arthritis. This knowledge not only ushers therapeutic use in humans: in many settings, the animal studies have proven to be irreplacable tools to get insights into the pathogenesis of chronic arthritis. Rheumatoid arthritis (RA) shows a strong linkage of susceptibility to a certain epitope common to some HLA-DR beta chains; this immunogenetic linkage is the strongest evidence for specific, T-cell dependent immunity in the pathogenesis of the disease. Despite intense efforts, no unequivocal proofs of T-cell specificity or oligoclonality have been found in RA. Therapeutic efforts directed against T-cells or T-cell functions have also at the best showed partial effects. As compared to the local production of T-cell cytokines in the joint, monokine production is abundant. Therapies aimed at neutralizing the effects of the cartilage-devastating monokine TNF-a have showed remarkable results in small clinical trials. The possibility of increasing the presence of the regulatory cytokines IL-4, IL-10 and TGF-beta has also been explored, but only in animal studies. Immunology has also shed light on the mode of action of the commonly used 'disease modifying' drugs, and combinations of such drugs have shown increased potentials in recent clinical studies. The possibility of combining traditional anti-arthritic drugs with recent immunological tools seem promising for the future. This review discusses recent advances in the understanding of pathogenesis and delineate new therapeutic approaches for chronic arthritis from the point of view of the immunologically oriented clinician.
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PMID:Immunopathogenesis and immunotherapy in rheumatoid arthritis: an area in transition. 767 48

HLA-DR beta 1*04 subtypes associated with rheumatoid arthritis (RA) were studied by polymerase chain reaction with sequence specific primers and the 86th amino acid of the DR beta 1 chain was analysed in RA patients vs healthy controls. The frequency of HLA-DR beta 1*0401 and 0404/0407 alleles was significantly increased in RA patients vs the controls, HLA-DR beta 1*0401 and 0404 being the dominant variants in RA. In most RA patients hydrophilic glycine proved to be the 86th amino acid of the peptide binding region thus it could have an effect on the development of RA.
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PMID:A possible association of HLA-DR beta 1*04 subtypes and rheumatoid arthritis of peptide binding region amino acids. 880 45

Infection with B. burgdorferi can cause a large joint inflammatory arthritis in patients who have not been treated for early Lyme disease; the knee is the most common joint affected. The diagnosis depends on a history of known exposure to the spirochete, characteristic clinical features, and serologic studies (ELISA and Western blot) confirming exposure to the spirochete. In most patients, antibiotic therapy is curative, but in a smaller percentage of patients, the presence of the HLA-DR beta 1*0401 haplotype can trigger treatment-resistant arthritis, in which antibiotic therapy is ineffective; in these instances, remittive agents, such as hydroxychloroquine and methotrexate, are indicated. Arthroscopic synovectomy may be considered when antibiotic therapy is not curative. Fibromyalgia can follow infection with B. burgdorferi but is unresponsive to antibiotic therapy; it is treated with tricyclic antidepressants and an exercise program. Lyme arthritis is the only chronic inflammatory arthritis in which the specific cause is known and can be cured. As such, it serves as an excellent model with which to study the pathogenesis of more common inflammatory arthritides, such as rheumatoid arthritis.
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PMID:Lyme arthritis. 1198 3

The association of rheumatoid arthritis (RA) with the HLA complex has been well established since 1978. But what does that mean? After reminding the reader of some existing immunological interpretations, a more recent variant is introduced. Antigens and molecular chaperones of the HSP70 family form complexes, which interact with HLA-DR beta-chains, especially of the DRB1*0401 genotype, which is the most common among patients with RA in our region. This mechanism might bring *0401(+) persons an advantage in defence against microorganisms, but a disadvantage concerning autoimmunity. Chaperone machines are upregulated in synovial tissue of RA patients. As their number and variety is huge in humans, there exist many possibilities for function, reaching from antigen presentation to immune regulation. In addition to the HLA complex, the "genetic background" plays an important role for the development of an autoimmune disease. This is demonstrated in families of patients with RA or scleroderma, where a high percentage of first degree relatives suffer from a "related" disease.
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PMID:[Immunogenetics--HLA-association, molecular chaperones and "related" diseases]. 1618 48

The genetic association of HLA-DRB1 with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is well documented, but association with other HLA-DR beta genes (HLA-DRB3, HLA-DRB4 and HLA-DRB5) has not been thoroughly studied, despite their similar functions and chromosomal positions. We examined variants in all functional HLA-DR beta genes in RA and SLE patients and controls, down to the amino-acid level, to better understand disease association with the HLA-DR locus. To this end, we improved an existing HLA reference panel to impute variants in all protein-coding HLA-DR beta genes. Using the reference panel, HLA variants were inferred from high-density SNP data of 9,271 RA-control subjects and 5,342 SLE-control subjects. Disease association tests were performed by logistic regression and log-likelihood ratio tests. After imputation using the newly constructed HLA reference panel and statistical analysis, we observed that HLA-DRB1 variants better accounted for the association between MHC and susceptibility to RA and SLE than did the other three HLA-DRB variants. Moreover, there were no secondary effects in HLA-DRB3, HLA-DRB4, or HLA-DRB5 in RA or SLE. Of all the HLA-DR beta chain paralogs, those encoded by HLA-DRB1 solely or dominantly influence susceptibility to RA and SLE.
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PMID:Imputing Variants in HLA-DR Beta Genes Reveals That HLA-DRB1 Is Solely Associated with Rheumatoid Arthritis and Systemic Lupus Erythematosus. 2691 67


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