LAUSR

Background Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease of unknown etiology. Lyn-deficient mice develop lupus-like autoimmunity due to hyperactive B cells resulting in excess IL-6 production, and cyclical exacerbation of inflammation by further activation of B and T cells. Tsantikos et al., 2010 C57BL/6 mice deficient in glucocorticoid-induced leucine zipper (GILZ), an intracellular protein involved in glucocorticoid effects on immunity, develop lupus-like autoimmunity and excess B cell activation. Jones et al., 2016. However, the effect of GILZ in lupus-prone mice is unknown. Objectives We aim to test the hypothesis that GILZ modulates autoimmunity in the lyn deficient murine model of lupus. Methods We generated GILZ-deficient mice on a lyn-deficient background (GILZ-lyn double knock out (DKO)) and compared them to WT and lynKO mice. The effects of GILZ deficiency on spleen weight, nephritis, Type I interferon-induced genes (ISG) and autoantibodies were examined. Results We observed heightened lupus-like autoimmunity in GILZ-lyn DKO mice, compared to LynKO, that include increased spleen weights (p=0.041) and more severe glomerulonephritis, especially segmental necrosis. A panel of ISG (ifi44, usp18, oas3, cxcl10, isg15, mx1, irf7, stat1 and ifit3) and an overall ISG score was significantly increased (p=0.0023) in GILZ-lyn DKO mice compared to LynKO. In contrast, serum autoantibodies (dsDNA, Sm, histone, Jo-1, Scl-70, SSA, SSB, U1RNP, Ro52,) were not increased in GILZ-lyn DKO mice compared to LynKO mice. Conclusions In LynKO lupus-prone mice, spleen weight, glomerulonephritis, and ISG profiles were significantly exacerbated by GILZ deficiency, while autoantibody titres were unaffected. This suggests that endogenous GILZ exerts an inhibitory effect on IFN pathways, in this lupus model. Therefore, GILZ potentially regulates the cycle of inflammation in SLE by inhibiting IFN responses downstream of autoantibodies. A GILZ-based treatment could be a potential therapeutic strategy in SLE. References [1] Jones SA, Toh AE, Odobasic D, Oudin MA, Cheng Q, Lee JP, … Morand EF. Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus. Ann Rheum Dis, 2016;75(4):739–747. doi:10.1136/annrheumdis-2015-207744 [2] Tsantikos E, Oracki SA, Quilici C, Anderson GP, Tarlinton DM, Hibbs ML. Autoimmune disease in Lyn-deficient mice is dependent on an inflammatory environment established by IL-6. J Immunol2010;184(3):1348–1360. doi:10.4049/jimmunol.0901878 Acknowledgements NHMRC Disclosure of Interest None declared