The U1 small nuclear ribonucleoprotein (snRNP), which carries Sm as well as nRNP antigenic determinants, is a major target of autoantibodies in human and murine systemic lupus erythematosus (SLE). These antibodies also are produced by non-autoimmune strains of mice with a lupus-like syndrome induced by pristane. Although anti-Sm and nRNP autoantibodies often are produced tandemly and constitute a """"""""linked set"""""""", mixed connective tissue disease (MCTD) patients with nRNP antibodies fail to develop anti-Sm. Also, it is unclear why anti-Sm antibodies are a highly specific for SLE, whereas anti-nRNP antibodies are produced in SLE as well MCTD and other forms of systemic autoimmunity. Our preliminary studies show that anti-U1- C antibodies and a novel class of autoantibodies that stabilize interactions between U1-C and the SM core particle are present in nearly 100% of human anti-nRNP/Sm sera and some sera from pristane-treated mice, but are absent in MRL mice. The strong association of anti-U1-C with stabilizing antibodies may suggest that the latter play a role in spreading of autoimmunity, possibly by altering antigen processing. These effects also may be consistent with previous studies showing that MRL mice injected with certain anti-Sm antibodies develop additional anti-nRNP/SM specificities. In the proposed studies, the spreading of autoimmunity from one component of the U1 snRNP to another will be investigated, and the role of autoantibodies themselves in the process will be explored. We hypothesize that the fine specificities of the earliest autoantibodies produced may play a critical role in shaping the autoantibody repertoire that eventually develops. Using assays for autoantibodies to the native constituents of U1 snRNPs (U1-A, U1-C, and the Sm core particle) as well as stabilizing antibodies, the spontaneous development of autoimmunity in MRL mice will be compared with autoimmunity in mice with pristane-induced lupus.
Four specific aims are proposed.
In Aim 1, the fine specificities of anti-U1 snRNP autoantibodies will be defined to determine how development of the immune response to this antigen differs between spontaneous and induced forms of lupus.
In Aim 2, the question of why MRL mice do not develop autoantibodies to U1-C or stabilizing antibodies will be investigated by treating young MRL/pr mice with pristane to see if anti-U1-C antibodies are induced and by examining the role of MHC in determining autoantibody fine specificities.
In Aim 3, the order of appearance of various autoantibody specificities will be determined to see if differences in which antibody appears first influence the pattern of autoantibodies that develops subsequently.
In Aim 4, monoclonal antibodies will be administered to mice to see if they alter developing immune responses to U1 snRNPs. These studies may provide insight into the mechanisms of autoantibody spreading as well as information relevant to the pathogenesis of SLE and MCTD.
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