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

Author(s): 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;
Details: Publication Year 2015-11-26,Volume 75,Issue #4,Page 739-47
Journal Title: Annals of the Rheumatic Diseases
Publication Type: Journal Article
Abstract: 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.
Publisher: BMJ
Research Division(s): Immunology
PubMed ID: 26612340
Publisher's Version: https://doi.org/10.1136/annrheumdis-2015-207744
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2015-12-10 11:27:47

Last Modified: 2016-08-10 04:18:13