TACI deficiency delays the onset of systemic lupus erythematosus symptoms and improves the survival of MRL/Lpr mouse

Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies and immune-complex deposition in organs such as skin and kidney. Ablation of BAFF with anti-BAFF antibodies alleviates SLE symptoms but the receptor responsible for the generation of pathogenic antibodies has been controversial. Since TACI is critical in the development of antibody secreting plasma cells, we evaluated the contribution of TACI in the formation of autoantibodies and the development of SLE in TACI deficient “lupus mouse”, generated by backcrossing the lupus prone Mrl/Lpr mouse with TACI−/− mouse. We found that TACI deficiency (Lpr-TACI−/−) increased the survival of lupus mouse as compared to the littermates, LPR-TACI +/+ and LPR-TACI +/− mice. The survival of Lpr-TACI−/− mice correlated with a delay in the development of anti-dsDNA and anti-SAM/RNP antibody titers. The prolonged survival of LPR-TACI −/− mice is likely a result of protection from kidney damage since proteinuria levels and IgG accumulation in the renal glomeruli were significantly less in LPR-TACI −/− mice as compared to the age-matched control mice with disease. Coinciding with the preserved kidney function, four month old LPR-TACI −/− mice kidney macrophages manifested M2-skewed phenotype, while macrophages harvested from kidneys of the age-matched control littermates were M1-skewed. Further supporting the protective role of M2-skewed macrophages, adoptively transferred LPR-TACI−/− macrophages improved the proteinuria and glomerulonephritis in control animals with kidney pathology. Collectively, LPR-TACI −/− mice experiments suggest that blocking TACI function may be a novel approach for the treatment of SLE disease.