title: Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus.
abstract: OBJECTIVE
  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.
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia.
authors.forename: Sarah A
authors.identifier: http://orcid.org/0000-0001-9571-3289
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia.
authors.forename: Andrew E J
authors.initials: AE
authors.lastname: Toh
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Odobasic
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia.
authors.forename: Marie-Anne Virginie
authors.initials: MA
authors.lastname: Oudin
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia.
authors.forename: Jacinta P W
authors.initials: JP
authors.lastname: Lee
authors.affiliation: Department of Human Genetics, Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: White
authors.affiliation: Department of Microbiology and Immunology, The Doherty Institute at The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Brendan E
authors.initials: BE
authors.lastname: Russ
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Experimental Medicine, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Simona
authors.initials: S
authors.lastname: Infantino
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Experimental Medicine, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Light
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Experimental Medicine, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Harris
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D016175:B-Lymphocyte Subsets; D001402:B-Lymphocytes / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D018858:Germinal Center / Q000166:cytology; D005938:Glucocorticoids / Q000627:therapeutic use; D006433:Hemocyanins / Q000494:pharmacology; D006657:Histones; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009596:Nitrophenols / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D000276:Adjuvants, Immunologic; C498608:Dsip1 protein, mouse; D005938:Glucocorticoids; D006657:Histones; D009596:Nitrophenols; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin
keywords: Autoantibodies; Autoimmunity; B cells; Inflammation; Systemic Lupus Erythematosus