RA patients without QRRAA (P < 0.01 for both). Of the 9 RA patients without QRRAA, none had DR4/Dw4. No significant association was observed between IgG binding activity and rheumatoid factor positivity, rheumatoid factor titer (by Rose-Waaler test), or sex, in the group of RA patients as a whole or in the subgroups with and without QRRAA. No significant difference was observed in the reactivity of serum to an unrelated peptide (H2N-VRSSSRTPSDKPVAHVVANP-COOH) among these 3 groups.
The present study indicates a correlation between positivity of the amino acid sequence QRRAA and the level of antibody to DwlSp in Japanese RA patients and supports the importance of this sequence in the pathogenesis of RA. In our preliminary experiments, high-titer anti-Dwl5p antisera also have been shown to recognize synthetic peptides (H,N-KDLLEQKRAAVDTYCR-COOH and H2N-KDLLERRRAAVDTYCR-COOH, cqrresponding to DR4/ Dw4 and DRwlO, respectively). Up to. now, several environmental antigens have been proposed to have a role in the pathogenesis of RA (8), and there appear to be various agents carrying the particular amino acid sequences. These findings are consistent with the shared epitope hypothesis (9).
It is plausible that exposure to an agent(s) containing this particular amino acid sequence leads to an abnormal autoreactive immune response to the HLA-DRP molecule due to molecular mimicry. Furthermore, autoantibodies against the HLA-B27 molecule (10) or peptides shared by HLA-B27. L and Klebsiella pneumoniae nitrogenase (1 1) have been detected in the sera ofHLA-B27 positive patients with ankylosing spondylitis. In Japanese RA patients, antibodies to DwlSp could make immunologic function or recognition abnormal, because the thud hypervariable region of HLA-DRpl is critical for T cell recognition (9). Otherwise, the possibility remains that these antibodies are merely reactive products of triggering agents. Considering the similarity of the RA-associated amino acid sequences on HLA-DRP chains, some agent(s) could be a common trigger for RA patients who have QRRAA or similar sequences.