The molecular basis of susceptibility to rheumatoid arthritis: the conformational equivalence hypothesis

This is an interpretive review of recent immunologic and molecular biologic data concerning the molecular basis of susceptibility to rheumatoid arthritis. The central point of view was taken that the major histocompatibility complex (MHC) class II molecules encoding disease susceptibility function in an immune recognition event involving an antigen "X" that currently eludes characterization. The problem of understanding the meaning of the association of susceptibility with diverse MHC alleles such as DR4 (Dw4 and Dw14), DR1, and DRw10 is approached by detailed biochemical analysis that led to the identification of common stretches of amino acid sequence, presumably encoding conformationally equivalent structures. Non-classic MHC polymorphisms related to disease susceptibility but not associated with particular alleles such as identified by Ab 109d6 proved especially valuable in suggesting new directions for attempting to understand the significance of these associations. Consideration is given to the possibility that a family of either slightly different or identical conformations encoded in either cis or trans cumulatively confer the liability to develop rheumatoid arthritis, and implying a highly non-classic mode of inheritance. The available data do not permit a distinction between the possibilities that an antigen "X" was being presented to T cells or whether the distinctive conformations of the MHC class II molecule serve the same role as antigen "X" but are directly recognized by T cells. However, with additional data, some limited insight should be able to be inferred about the nature of an antigen "X" that specifically binds to the MHC conformation with a complementary interaction. It seems reasonable to consider the pathogenesis of rheumatoid arthritis as a typical immune response resulting from a simple immune recognition event of a single antigenic molecule.