Session Type: Poster Session (Sunday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Lyn-deficient mice develop hyperactive B cells, excess IL-6 production, and nephritis. Mice deficient in glucocorticoid-induced leucine zipper (GILZ), an intracellular protein involved in glucocorticoid effects on immunity, also develop spontaneous lupus-like autoimmunity and excess B cell activation (Jones 2016). However, whether GILZ is operative as a suppressor in lupus-prone Lyn-/- mice is unknown.
Methods: We compared WT C57Bl/6 mice to Lyn knockout (KO) mice and LynKO mice crossed to a GILZ-deficient background (GILZ- Lyn double knock out (DKO)) mice. The effects of GILZ deficiency on LynKO phenotype, including spleen weight, autoantibodies, nephritis, and cytokines including Type I interferon-induced genes (ISG) were examined.
Results: Lupus-like autoimmunity was increased in GILZ-Lyn DKO mice, compared to LynKO, including increased spleen weight and more severe glomerulonephritis, especially crescents and segmental necrosis. 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. Serum IL-6, BAFF, IL-17A, IL-18, and TNF were increased in GILZ-Lyn DKO mice. A panel of ISG (ifi44, usp18, oas3, cxcl10, isg15, mx1, irf7, stat1 and ifit3) and an overall ISG score were also significantly increased in GILZ-Lyn DKO mice.
Conclusion: The LynKO lupus-prone model was significantly exacerbated by GILZ deficiency, an effect accompanied by evidence of activation of the Type I IFN program. This suggests that endogenous GILZ exerts an inhibitory effect on IFN pathways in this lupus model, and thus that GILZ regulates inflammation in SLE by inhibiting IFN responses downstream of autoantibodies.
To cite this abstract in AMA style:Nataraja C, Flynn J, Dankers W, Harris J, Jones S, Morand E. Lyn-Deficient Murine Lupus Is Exacerbated by Glucocorticoid-Induced Leucine Zipper (GILZ) Deficiency [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/lyn-deficient-murine-lupus-is-exacerbated-by-glucocorticoid-induced-leucine-zipper-gilz-deficiency/. Accessed December 5, 2020.
« Back to 2019 ACR/ARP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/lyn-deficient-murine-lupus-is-exacerbated-by-glucocorticoid-induced-leucine-zipper-gilz-deficiency/