The association of the HLA-DRB1 gene with rheumatoid arthritis

The association between rheumatoid arthritis (RA) and the HLA-DR4 is known since 1978. However, the significance of the HLA-DR4 for the pathogenesis of RA has not been uniformly accepted. Further studies revealed that also other HLA-DR alleles were associated with RA. With the application of molecular biology techniques, it could be demonstrated that the serologically typed HLA-DR4 allele consists of different alleles. Only some of them predispose for RA. These predisposing alleles share a conserved aminoacid sequence of the 3(rd) hypervariable region of the HLA-DRB1 gene at positions 70-74 and 86. This RA-associated sequence is called ''Shaped Epitope'' (SE). This SE is conserved not only between associated HLA-DR4 alleles, but between all HLA-DR-alleles which predispose for RA. Patients homozygous for the SE appear to have a more severe disease course than heterozygous patients. These data are based mainly on the results of cross-sectional studies. The value of HLA-DR alleles as prognostic markers for RA has to be investigated further in prospective studies.