We have established that autoantibodies and autoantigens must co-exist even in non-autoimmune individuals. Thus, there must be an active mechanism for maintaining self-tolerance. Our studies using anti-DNA and Rheumatoid Factor transgenics revealed several mechanisms by which autoantibodies were regulated, namely, deletion, anergy and receptor editing. Now we will study the regulation of autoantibody transgenes in autoimmune mice. The transgenes code for autoantibodies typical of the autoimmune diseases, lupus and rheumatoid arthritis, and were derived from autoimmune MRL/lpr mice. The transgenes are constructed by homologous recombination between complete VH and Vk genes and their respective J loci. This places the V regions into their normal context where they retain all of the upstream and downstream regulatory sequences. Apart from the established advantage of enriching the repertoire for a specificity, these transgenes are subject to editing, isotype switch, and meaningful somatic mutation. These transgenes have and will be crossed to MRL/lpr mice and to mice congenic for different SLE susceptibility loci. We will determine which mechanism(s) of tolerance are broken in disease and the influence of clonal expansion, mutation and isotype switch on the development and pathogenesis of autoantibodies. The etiology of autoantibodies in humans parallels that of the MRL/lpr. Thus the results of this proposal are of direct applicability to human disease.
