Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus
- Jones, SA; Toh, AE; Odobasic, D; Oudin, MV; Cheng, Q; Lee, JP; White, SJ; Russ, BE; Infantino, S; Light, A; Tarlinton, DM; Harris, J; MORAND, EF;
Publication Year 2015-11-26, Volume 75, Issue #4, Page 739-47
- Journal Title
- Annals of the Rheumatic Diseases
- Publication Type
- Journal Article
- OBJECTIVES: Systemic lupus erythematosus (SLE) is a serious multisystem autoimmune disease, mediated by disrupted B cell quiescence and typically treated with glucocorticoids. We studied whether B cells in SLE are regulated by the glucocorticoid-induced leucine zipper (GILZ) protein, an endogenous mediator of anti-inflammatory effects of glucocorticoids. METHODS: We conducted a study of GILZ expression in blood mononuclear cells of patients with SLE, performed in vitro analyses of GILZ function in mouse and human B cells, assessed the contributions of GILZ to autoimmunity in mice, and used the nitrophenol coupled to keyhole limpet haemocyanin model of immunisation in mice. RESULTS: Reduced B cell GILZ was observed in patients with SLE and lupus-prone mice, and impaired induction of GILZ in patients with SLE receiving glucocorticoids was associated with increased disease activity. GILZ was downregulated in naive B cells upon stimulation in vitro and in germinal centre B cells, which contained less enrichment of H3K4me3 at the GILZ promoter compared with naive and memory B cells. Mice lacking GILZ spontaneously developed lupus-like autoimmunity, and GILZ deficiency resulted in excessive B cell responses to T-dependent stimulation. Accordingly, loss of GILZ in naive B cells allowed upregulation of multiple genes that promote the germinal centre B cell phenotype, including lupus susceptibility genes and genes involved in cell survival and proliferation. Finally, treatment of human B cells with a cell-permeable GILZ fusion protein potently suppressed their responsiveness to T-dependent stimuli. CONCLUSIONS: Our findings demonstrated that GILZ is a non-redundant regulator of B cell activity, with important potential clinical implications in SLE.
- WEHI Research Division(s)
- PubMed ID
- Publisher's Version
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Creation Date: 2015-12-10 11:27:47Last Modified: 2016-08-10 04:18:13