Systems-investigation of aberrant signaling in immune cells of SLE mouse model

Abstract

Autoimmune diseases occur when the immune cells react against self-antigens and subsequently lead to inflammation in the tissues. The interactions between genetics and environmental triggers regulate the phenotypes and outcome of the diseases. Type I interferon has been shown as one of the most crucial cytokines involving in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). SLE is a chronic systemic autoimmune disease which can result in autoantibody production and fatal glomerulonephritis. Activation via nucleic acid sensors can induce the production of type I interferon from dendritic cells and promote SLE severity. Stimulator of interferon genes (Sting) is a cytoplasmic DNA sensor that signals downstream to enhance type I interferon production after its activation. Recently, it was shown that a gain mutation in the STING gene resulting in over-activity of the IFN pathway can cause familial inflammatory syndrome with lupus-like manifestations in humans. However, the functional studies of Sting in different autoimmune mouse models suggest the conflicting roles of Sting in the pathogenesis ofautoimmune diseases. In order to determine if Sting participates in lupus pathogenesis, the Fcgr2b-deficienct mice (lupus mouse model) were bred with Sting-deficient mice to create the double-deficient mice. In the absence of Sting, the Fcgr2b-deficient mice do not develop fatal glomerulonephritis and autoantibodies. The original knowledge from this study is a proof of concept for targeting Sting as a future promising treatment in autoimmune diseases.