Immunological characteristics of systemic lupus erythematosus (SLE) include polyclonal B-cell activation and production of specific autoantibodies. However, the autoimmune response is highly restricted to only a few antigens, indicating that there are mechanisms to specifically select target antigens. Autoantibodies to small nuclear ribonucleoproteins (snRNPs: Sm and nRNP) are frequently produced in SLE, MRL mice, and pristane-treated normal mice. In pristane-treated mice, the U1-70K, which has an unusually high arginine content (21%), appears central to the autoimmune process. Arginine is consumed by activated macrophages and arginases in inflammatory sites. In addition, L-canavanine, a non-protein amino acid homologue of L-arginine present in higher plants, may be efficiently incorporated into proteins, producing aberrant proteins that could create cryptic epitopes capable of triggering autoimmunity. In this study, we will investigate why U1 snRNPs are selectively targeted in pristane-induced lupus. We hypothesize that the arginine-rich U1-70K is aberrant in arginine-deficient pristane granulomas, generating cryptic epitopes that initiate autoimmunity.
In aim 1, whether arginine is deficient in pristane-treated mice will be examined by amino acids analysis. Arginine metabolism (uptake, consumption, and reconversion) also will be evaluated.
In Aim 2, U1-70K synthesized in arginine-deficient conditions and in the presence of L-canavanine in vitro will be evaluated for modifications by immunoprecipitation, amino acid analysis, and mass spectrometry. U1-70K from cells in pristane-treated mice also will be examined.
In Aim 3, whether aberrant UlsnRNPs (arginine-deficient, L-canavanine containing) can trigger a specific autoimmune response will be investigated by immunizing mice with purified UlsnRNPs or apoptotic cells derived from these conditions.
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