Antinuclear antibodies are a central feature of SLE and related rheumatic diseases, and are thought to be directly involved in the pathogenesis of these disorders. The antigens recognized by these autoantibodies are generally components of large DNA-protein or RNA-protein particles. It has been shown that Th clones inducing the production of pathogenic anti-DNA antibodies are responsive to DNA-histone complexes, but not to either DNA or histones alone. We have found that autoantibody production and the activation of autoreactive T cells specific for a chromatin protein can be triggered by alterations in its quaternary structure induced by the binding of a viral protein. Thus, the quaternary structure of an autoantigen may be critical for the presentation of epitopes recognized by autoreactive T cells. In view of the importance of quaternary structure in generating autoreactive T cells, it seems worthwhile to characterize the interactions of autoantigenic chromatin proteins with other self and nonself antigens. This competitive renewal application will extend our previous work on the Ku (p70/p80) heterodimer, a nonhistone chromatin antigen recognized by autoantibodies found in the sera of certain patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and overlap syndromes. The basis for autoimmunity to this autoantigen in human disease will also be examined. We hypothesize that the binding of either foreign antigens or autoantibodies to certain functional domains of Ku or other antigens may trigger autoimmunity by enhancing the presentation of cryptic T cell epitopes of self to which tolerance is incomplete.
In Specific Aim 1, the domains of Ku mediating p70-p80 dimerization and binding to a 350 kDa protein (p350) with DNA-dependent protein kinase activity will be determined using prokaryotic and eukaryotic expression systems and specific monoclonal antibodies generated previously in our laboratory. Parallel studies will address the question of whether the same domains are involved in interactions with foreign (viral) antigens that might potentially trigger autoimmunity.
In Specific Aim 2, the importance of these functional domains as targets of autoantibodies in SLE, SSc and overlap syndrome will be determined. The HLA associations of autoantibodies to individual epitopes of Ku will be determined, and the basis for the association of anti-Ku, anti-Su, and anti-RNA polymerase II autoantibodies in many sera will be explored. Finally, the possibility that autoantibodies of particular specificities can spread autoimmunity from one antigen to another by altering antigen processing will be investigated. Although the latter studies are exploratory in nature, they may provide direct evidence that the binding of certain autoantibodies, like some foreign proteins, can trigger autoimmunity by altering the quaternary structure of an autoantigen.
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