The immunogenetics of rheumatoid arthritis

The clarification of the precise locus within HLA responsible for at least the majority of the MHC-encoded susceptibility has allowed insights into the pathogenesis of RA which could have therapeutic implications. The HLA-DR molecules associated with RA (DR4Dw4, DR4Dw14, DR4Dw15, DR1 and DRw10) have shared epitopes which are likely to influence their ability to bind and present particular antigenic peptides to T lymphocytes. It appears likely, therefore, that a disease-related antigen which can be bound and presented preferentially by these susceptibility molecules is responsible for triggering the disease in the great majority of cases. However, it is clear that environmental or chance events are of fundamental importance to the development of RA and that other genes contribute significantly to both susceptibility and progression of the disease. Based on what we now know of the HLA-related susceptibility, we can develop therapeutic strategies based on blocking the immune response at the HLA/peptide/TCR level. By designing high affinity-binding peptides or other molecules which bind preferentially to those HLA-DR molecules associated with RA, particularly DR4Dw4 and DR4Dw14, competitive blocking of the antigen-binding site may be achieved and the abnormal immune response abolished. This approach has recently been outlines in the mouse EAE model [92]. Alternatively, if it can be shown that a limited TCR repertoire is involved in recognising the diseasecausing peptide/HLA configuration, it may be possible to achieve the same effect with monoclonal antibodies against the variable regions on the TCR. The former approach would have effect on immune recognition mediated by DRβ but this could be limited by local application within the synovial joints. In contrast, blocking specific T cell clones offers the exciting possibility of highly specific immunosuppressants for RA. Finally, if other genes involved in susceptibility and progression of RA can be identified, this may allow further insights into the pathophysiology of the disease. This may directly lead to further novel therapeutic possibilities and the eventual eradication of this common disease.