Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is complicated by lupus nephritis (LN) in approximately 50 percent of cases. Among African-Americans with LN, standard therapy prevents renal failure in only 50 percent of patients over five years, compared to 85 percent among Caucasians. Adjunctive therapies that are targeted towards mediators of this aggressive LN phenotype are needed to resolve this disparity. LN is characterized by autoantibody production, glomerular immune complex deposition, and, in the case of proliferative disease, complement activation and subsequent innate immune response. An essential arm of the innate immune response is the production of reactive oxygen and nitrogen intermediates (ROI and RNI or RONI). We have described increased production of RNI in human SLE, most noticeably among African-Americans and those with proliferative lupus nephritis (LN). These observations were made using a marker of RNI production that is influenced by diet, making it a potentially less useful clinical biomarker of disease. Pharmacologic inhibition of inducible nitric oxide synthase (NOS) prevents murine LN without affecting autoantibody production or complement activation, suggesting that the effect of NOS on glomerular inflammation is distal to complement activation. However ablation of the inducible NOS gene in a murine lupus model does not prevent renal disease, suggesting that iNOS is not the only enzyme affected by NOS inhibitors that is required for disease. The identity and tissue expression of other RONI-producing enzymes and the mechanisms through which their activity leads to increased glomerular inflammation have not been well characterized. Our overarching hypothesis is that reactive intermediate production is pathogenic in the progression of lupus nephritis. To address the above noted gaps in knowledge, reactive intermediates responsible for pathology must be identified, the location and identity of enzymes producing pathogenic RONI must be determined, and methods for targeting pathogenic RONI must be tested. We propose the following specific aims: 1) Determine the association between a novel set of biomarkers of reactive intermediate production and disease type and response to therapy in human lupus nephritis, 2) Determine the effect of targeted genetic and pharmacologic manipulation of reactive intermediate production on LN in MRL/lpr mice, and 3) Determine the effect of RONI production on MRL/lpr innate immune response and spleen T cell activation. The ultimate goal of the application is to define RONI useful as disease biomarkers and targets for therapy.
The specific aims will further characterize both enzyme and RI targets for such an approach.
. Systemic lupus erythematosus is a serious autoimmune disease that occurs in up to 1/200 young black women. We have shown previously that reactive intermediates like nitric oxide are overproduced in lupus. The proposed research targeting these intermediates will potentially identify new biomarkers of disease and identify potential new targets for disease.
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