Y box-binding trans-regulatory nuclear proteins and susceptibility to rheumatoid arthritis.
OBJECTIVE
Inappropriately high levels of expression of HLA-DR molecules or their expression on inappropriate cells, e.g. synovial tissue and T cells, may result in an aberrant tissue-destructive immune response and thus cause susceptibility to rheumatoid arthritis (RA).


METHODS
Patients and controls were typed for HLA-DR antigens by oligonucleotide typing of PCR-amplified DNA. Trans-regulatory nuclear proteins that bind to the Y box in DRB promotors were examined by the gel-mobility shift assay.


RESULTS
We found that the trans-regulatory nuclear protein (NF-Y), which binds to the Y box in DRB promoters and which plays a dominant role on the level of the expression and inducibility of DR genes, was absent in 50% of RA patients but not in healthy individuals (0%). Furthermore, we observed that all patients (100%) either lacked the NF-Y protein and/or carried the disease susceptibility DRB1 gene, which gives the highest relative risk value (RR = 46.6; p < 1.6 x 10(-6)) reported so far for susceptibility to RA.


CONCLUSIONS
The absence of the trans-regulatory nuclear protein that binds to the Y box with an inverted CCAAT motif in DRB promotors and the presence of the DRB1 gene with the amino acid motif QKRAA and QRRAA cause susceptibility to RA.
Singal
D P
DP
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Ye
M
M
Fleisig
H
H
Buchanan
W W
WW
Qiu
X
X
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000378:metabolism; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins; D002460:Cell Line; D004247:DNA / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004198:Disease Susceptibility; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes / Q000737:chemistry; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D004247:DNA