Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus. Issue 4 (26th November 2015)

• Record Type: Journal Article
• Authors: Jones, Sarah A; Toh, Andrew E J; Odobasic, Dragana; Oudin, Marie-Anne Virginie; Cheng, Qiang; Lee, Jacinta P W; White, Stefan J; Russ, Brendan E; Infantino, Simona; Light, Amanda; Tarlinton, David M; Harris, James; Morand, Eric F
• Is Part Of: Annals of the rheumatic diseases. Volume 75:Issue 4(2016)
• Page Start: 739
• Page End: 747
• Publication Date: 2015-11-26
• Subjects: Autoimmunity -- Autoantibodies -- B cells -- Inflammation -- Systemic Lupus Erythematosus; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2015-207744
• Languages: English
• ISSNs: 0003-4967

Abstract

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 naïve B cells upon stimulation in vitro and in germinal centre B cells, which contained less enrichment of H3K4me3 at the GILZ promoter compared with naïve 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 naïve 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.