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)

HLA DQ alpha and DQ beta cDNA probes were used to study TaqI generated restriction fragment length polymorphisms (RFLPs) in DR4-positive patients with Felty's syndrome (FS), seropositive rheumatoid arthritis (RA), and in HLA-DR4 positive controls. The results of this analysis revealed two DQ beta RFLP patterns (DQ beta 3a and DQ beta 3b) associated with DR4, of which DQ beta 3b was found at significantly higher frequency in patients with FS (73%) or with RA (52%) than in DR4 controls (29%). Hind III generated RFLPs provide evidence that DQ beta 3b is in strong linkage disequilibrium with the gene encoding the serologically recognized epitope TA10. Results obtained using a DQ alpha chain probe revealed polymorphic differences between DQ alpha chain genes associated with different DR types, thereby providing a possible explanation for the lack of association between RA and other DR haplotypes in linkage disequilibrium with TA10. We conclude that both DQ alpha and DQ beta genes may be important in determining HLA-linked susceptibility to severe forms of RA.
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PMID:HLA DQ alpha and DQ beta restriction fragment length polymorphisms associated with Felty's syndrome and DR4-positive rheumatoid arthritis. 244 15

Although the polymorphic human Ia epitope recognized by monoclonal antibody 109d6 typically is expressed by DRw53 beta 2 chains, the epitope was shown to be encoded by distinctive DR beta 1 chains of a DRw10 haplotype in three unrelated DR4-negative individuals with rheumatoid arthritis. No evidence of a DR beta 2 (DR beta 4) chain molecule was found to be encoded by this haplotype. Using two-dimensional gel analysis and partial radioactive N-terminal microsequencing, the DR and DQ products were characterized in the heterozygous members of a family in which the segregation of both varieties of DR beta chains specifying the 109d6 epitope was demonstrated. The expression of the epitope on the DR beta 2 chain, but not on the DR beta 1 chain, was abolished by preventing N-linked glycosylation, although in both molecules the epitope was not altered by neuraminidase digestion. The potential structural bases of the serologic cross reactions of DRw10 are discussed, as are the possible implications of the findings for the definition of susceptibility to rheumatoid arthritis.
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PMID:Identification of the DRw10 DR beta 1-chain allele as encoding a polymorphic class II major histocompatibility complex epitope otherwise restricted to DR beta 2 molecules of the DRw53 type. 244 81

The nucleotide and inferred amino acid sequence of a DRw10 beta chain was obtained from cDNA clones isolated from a DR1, DRw10 heterozygous cell line. The sequence of this beta chain gene was distinctive, differing from those of all other defined DR types. The DRw10 beta chain gene was shown by transfection experiments to encode a polymorphic epitope recognized by mAb 109d6 that is also encoded by the DRw53 beta 2 chain gene. Comparison of the nucleotide sequence of both genes revealed that their third D regions (amino acids 67 to 73) were identical. This suggested first that the 109d6 epitope could be encoded by residues of this region, and second, that a putative gene conversion event transferred this sequence along with the information encoding the 109d6 epitope from a donor gene such as DRw53 beta 2. The sequence of the DRw10 beta chain gene was observed to be identical to that of clone pII beta 4 derived from the non-DR3 haplotype in the Raji cell line, which was also demonstrated to express the determinant recognized by antibody 109d6, suggesting that the typing of this cell line is HLA-DR3/DRw10. No evidence was found for the existence of a DR beta 2 chain gene product encoded by the DRw10 haplotype. The DRw10 haplotype was of particular interest because it was present along with a DR1 haplotype in the propositus who had rheumatoid arthritis, and was shared by the DR4-positive son of the propositus, who also had rheumatoid arthritis. This raised the possibility that the DRw10 haplotype, and most probably one or more specific conformations encoded by the DR beta chain, are involved in the definition of the disease susceptibility phenotype.
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PMID:Nucleotide sequence of a DRw10 beta chain cDNA clone. Identity of the third D region with that of the DRw53 allele of the beta 2 locus and as the probable site encoding a polymorphic MHC class II epitope. 245 Sep 24

We evaluated the association of a new HLA-D encoded determinant, MC1, with adult rheumatoid arthritis (RA). This determinant associates with DR1 and DR4 and can be defined by serological typing. We found MC1 in 83% of 80 patients with RA vs 43% of controls. Although the frequencies of DR1 and DR4 were both significantly increased in patients with RA compared with controls, MC1 had the highest relative risk (6.2) of any HLA-DR antigen tested. MC1 negative and positive populations were not significantly different in any of a variety of clinical and laboratory variables including age, sex, disease duration, age at onset, hours of morning stiffness, functional class, joint count, presence of subcutaneous nodules or bony erosions, frequency of side effects to gold or D-penicillamine, sedimentation rate, and antinuclear antibody.
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PMID:Adult rheumatoid arthritis is associated with MC1, a new HLA-D encoded determinant. 245 15

We have studied HLA-A, B, C, and DR antigens in 37 unrelated Caucasian families with multiple cases of definite or classic rheumatoid arthritis (RA). HLA-DR4 was observed in 26 of 36 probands tested (73 per cent); and six of the 10 DR4 negative probands possessed DR1. HLA haplotype sharing among affected siblings was more often observed than would be expected if RA and HLA haplotype were segregating independently (p = 0.041). In families with a DR4-heterozygous parent, the affected parent's HLA haplotype co-segregates significantly with RA among the offspring (p less than 0.005); and in families where both parents are unaffected, occurrence of RA among the offspring co-segregates significantly with DR4 haplotype (p = 0.004). Our data strongly indicate that at least one genetic determinant for susceptibility to RA resides in the HLA region, closely linked to the DR locus, or that the susceptibility determinant may be an epitope or structure that is commonly found on DR4 molecules but occasionally on other DR molecules.
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PMID:Analysis of genetic susceptibility to familial rheumatoid arthritis. 245 75

Analysis of individual human leukocyte antigen (HLA) genes associated with rheumatoid arthritis was performed using oligonucleotide probes to identify putative susceptibility genes highly associated with disease. Among DR4-positive rheumatoid arthritis patients, two distinct DR-beta genes, Dw4 and Dw14, appear to be individual susceptibility alleles. Linked HLA genes at the DQ locus do not appear to contribute to this genetic risk. Among non-DR4 rheumatoid arthritis patients, a specific DNA sequence was identified that is shared by the Dw14 susceptibility gene and a majority of the non-DR4 rheumatoid arthritis patients. This sequence defines a specific small genetic element encoding a "Dw14 epitope" that appears to be a rheumatoid arthritis-associated risk factor indicative of a common genetic pathway in both DR4 and non-DR4-associated disease.
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PMID:Structural and genetic features of human leukocytic antigen class II elements associated with rheumatoid arthritis. 246 45

The striking correlation observed between T cell recognition and the sharing of the DR-beta-1 gene sequences (position 67-74) among patients with rheumatoid arthritis studied suggests that the third hypervariable region might be an important contribution to one restriction site for the putative causative agent(s) in rheumatoid arthritis. The fact that this sequence was found in DR1, DR4,Dw14, and DR4,Dw15 beta-1 genes lends support to the hypothesis that, in some cases, human leukocyte antigen and disease association may involve the association of discrete disease-related epitopes rather than entire human leukocyte antigen genes and that these epitopes are immunologically relevant in terms of T cell recognition. The association of these polymorphisms with susceptibility to rheumatoid arthritis would then support the hypothesis that binding and presentation of "arthritogenic peptides" by major histocompatibility complex class II molecules is one of the pathogenic events in developing rheumatoid arthritis.
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PMID:A new look at the shared epitope hypothesis. 246 47

An interpretive summary of recent immunologic and molecular biologic data concerning the molecular basis of susceptibility of rheumatoid arthritis will be presented. The central point of view is taken that the MHC class II molecules encoding disease susceptibility function in a specific immune recognition event. This could involve an antigen "X" that currently eludes characterization or be directed to polymorphic determinants on the MHC molecule itself. The problem of understanding the meaning of the association of susceptibility to rheumatoid arthritis with diverse MHC alleles such as DR4 (Dw4 and Dw14) and DR1 is approached by detailed biochemical analysis that led to the identification of common stretches of amino acid sequence, presumably encoding conformationally equivalent structures. The sequence shared by the otherwise unrelated DR1 and DR4 haplotypes from residue 67 in the DR a chain that appears to confer susceptibility is Leu-X-X-Gln-Arg/Lys. Non-classic MHC polymorphisms related to disease susceptibility but not associated with particular alleles such as identified by Ab109d6 prove especially valuable in suggesting new directions for attempting to understand the significance of these associations. Consideration is given to the possibility that a family of either slightly different or identical conformations encoded in either cis or trans cumulatively confer the liability to develop rheumatoid arthritis. This implies a highly non-classic mode of inheritance. It seems reasonable to consider the pathogenesis of rheumatoid arthritis as evolving from a typical immune response based on a simple immune recognition event directed to a single antigen.
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PMID:Hypotheses on the molecular basis of susceptibility to rheumatoid arthritis. 247 3

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

Several lines of research have indicated a possible association of the Epstein-Barr virus and rheumatoid arthritis (RA). The earliest evidence suggested that RA patients develop a stronger humoral immune response to EBV nuclear antigens (EBNA) which may in part account for the increased titers of antibody to the RA nuclear antigen (RANA). It was then pointed out that mononuclear cells from RA patients may be impaired in their capacity to control EBV infection. This may be related to a decrease in the production of IFN gamma and a consequence of monocyte-derived inhibitory activities. These cellular defects, however, are not specific for RA and may rather be the result of chronic inflammatory responses. These findings and the lack of increased virus presence in RA tissues did not provide a strong basis for a possible association of EBV and RA. A new concept for this association is now being tested on the basis of the sequence homology between the genetic RA susceptibility determinant HLA DR4 and the EBV glycoprotein 110.
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PMID:Epstein-Barr virus and rheumatoid arthritis: cellular and molecular aspects. 248 74


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