The immunogenetic component of susceptibility to rheumatoid arthritis

The precise nature of the HLA element associated with rheumatoid arthritis has been identified as a short sequence of amino acids on the alpha helix of a range of DR beta alleles. Recently the range of alleles known to bear this sequence and to be associated with rheumatoid arthritis has increased considerably. Although these findings lend further weight to the validity of the original hypothesis, they have also made it very difficult to propose a mechanism for the association. It has also become clear that the simple model of dominant susceptibility is unsatisfactory. Patients with early disease show little or no association with any HLA alleles, whereas patients with severe forms of rheumatoid arthritis are frequently homozygous for DR4, showing a disproportionate tendency toward compound heterozygocity--expressing two different molecules sharing the conserved sequence.