The pathogenesis of rheumatoid arthritis (RA) is a major focus of my research group. We have used molecular and immunologic techniques to attack three main problems: 1) the role of anti-lgG autoantibodies (rheumatoid factors) in normal immune responses to environmental antigens, and in RA, 2) the mechanism by which HLA-DR4 contributes to the pathogenesis of RA, and 3) the role of the synovial microenvironment in RA.
The results of our investigations have shown that genes encoding rheumatoid factor autoantibodies are present in the germ line of most people. Their immunoglobulin products greatly potentiate the presentation of tiny amounts of antigen during secondary immune responses, and also may provide bystander help for T cell activation. The development of high-affinity pathogenic lgG rheumatoid factors is normally prevented by an antigen-specific deletion mechanism. This mechanism fails in RA.
HLA-DR4 molecules contain a short peptide sequence, `the shared epitope,' that is duplicated in the dnaJ class of heat shock proteins in bacteria and in the gp 120 capsid protein of EBV. Patients with early RA, but not normal subjects, have circulating Th1-type T lymphocytes that respond to these exogenous antigens but not to autologous HLA-DR4 molecules.
The synovium has a rich blood supply and macrophage lining. Consequently, exogenous antigens easily become trapped there. Although rheumatoid factors and HLA-DR4 molecules normally protect the host from infection, they may promote the conversion of a low-grade, nonspecific synovitis into the chronic granulation tissue characteristic of RA.