Prospective measure of serum 3-nitrotyrosine levels in systemic lupus erythematosus: Correlation with disease activity

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease. Overproduction of nitric oxide (NO) has been implicated in its pathogenesis. Several retrospective studies have indicated a correlation between serum nitrate and nitrite (NOX) and disease activity. This measure of NO production can be falsely elevated by exogenous dietary and medication sources of NOX and Variably reduced by serum thiols. These variables can make NOX a less reliable tool for studying the role of NO in SLE. Peroxynitrite, a by-product of NO and superoxide, nitrates tyrosine moieties. The resulting 3-nitrotyrosine (3NT) serves as a long-term indicator of NO-mediated protein modifications that is not affected by exogenous sources of NOX or serum thiols. We hypothesized that for these reasons serum 3NT levels would correlate with lupus disease activity more significantly than serum NOX. To address this hypothesis, we prospectively evaluated lupus disease activity, serum protein 3NT levels, and NOX levels in a cohort of lupus patients at 3-month intervals, Serum 3NT correlated with disease activity among African-Americans, while NOX correlated with disease activity among Caucasians. Subjects with active lupus nephritis had higher levels of serum 3NT than those without renal disease. Immunohistochemical analysis of renal biopsies from subjects with active proliferative lupus nephritis revealed renal expression of inducible NO synthase. The results of this study suggest that overproduction of NO may play a pathogenic role in SLE and lupus nephritis. Serum 3NT may be a useful, new tool for studying the contributions of NO to the pathogenesis of SLE.