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.

Public Health Relevance

. 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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Wang, Yan Z
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical University of South Carolina
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Buie, Joy Jones; Renaud, Ludivine L; Muise-Helmericks, Robin et al. (2017) IFN-? Negatively Regulates the Expression of Endothelial Nitric Oxide Synthase and Nitric Oxide Production: Implications for Systemic Lupus Erythematosus. J Immunol 199:1979-1988
Wolf, Bethany J; Spainhour, John C; Arthur, John M et al. (2016) Development of Biomarker Models to Predict Outcomes in Lupus Nephritis. Arthritis Rheumatol 68:1955-63
Oates, Jim C (2015) Endothelial dysfunction in injury and inflammation. Am J Med Sci 349:2
Mashmoushi, Ahmad K; Oates, Jim C (2015) Lipopolysaccharide induces inducible nitric oxide synthase-dependent podocyte dysfunction via a hypoxia-inducible factor 1? and cell division control protein 42 and Ras-related C3 botulinum toxin substrate 1 pathway. Free Radic Biol Med 84:185-195
Nowling, Tamara K; Mather, Andrew R; Thiyagarajan, Thirumagal et al. (2015) Renal glycosphingolipid metabolism is dysfunctional in lupus nephritis. J Am Soc Nephrol 26:1402-13
Jones Buie, Joy N; Oates, Jim C (2014) Role of interferon alpha in endothelial dysfunction: insights into endothelial nitric oxide synthase-related mechanisms. Am J Med Sci 348:168-75
Oates, J C; Mashmoushi, A K; Shaftman, S R et al. (2013) NADPH oxidase and nitric oxide synthase-dependent superoxide production is increased in proliferative lupus nephritis. Lupus 22:1361-70
Gilkeson, Gary S; Mashmoushi, Ahmad K; Ruiz, Phillip et al. (2013) Endothelial nitric oxide synthase reduces crescentic and necrotic glomerular lesions, reactive oxygen production, and MCP1 production in murine lupus nephritis. PLoS One 8:e64650
Ramos, Paula S; Oates, James C; Kamen, Diane L et al. (2013) Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry. J Rheumatol 40:842-9
Al Gadban, Mohammed M; German, Jashalynn; Truman, Jean-Philip et al. (2012) Lack of nitric oxide synthases increases lipoprotein immune complex deposition in the aorta and elevates plasma sphingolipid levels in lupus. Cell Immunol 276:42-51

Showing the most recent 10 out of 26 publications