Much work investigating the inheritance of RA has focussed on the associations between HLA class II serological specificities and disease. This has demonstrated association with different DR4 serological subtypes in some populations, lack of association with DR4 in others and association with certain other DR alleles, particularly DR1 in DR4 negative patients. Analysis at DNA sequence level revealed that the DR4 serological subtypes differed only in the DRB1 gene and that these differences were restricted to the codons surrounding position 70 of the N-terminal domain of the molecule, the region corresponding to the third hypervariable region of the DRB1 molecule. The differences in sequence lead to amino acid substitutions with substantial implication in terms of charge and therefore protein binding. The substitutions in the DR4 subtypes associated with RA (Dw4, Dw14, Dw15) and in DR1 are of similarly charged amino acids, whereas those not associated (Dw10) differ markedly. These regions of shared sequence therefore have a similar conformation when expressed as protein, with similar properties in terms of antigen binding, presentation and immune regulation. The protein epitope is thereby shared by serologically distinct HLA haplotypes.