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).
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.
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.
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.