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Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus
  1. Sarah A Jones1,
  2. Andrew E J Toh1,
  3. Dragana Odobasic1,
  4. Marie-Anne Virginie Oudin1,
  5. Qiang Cheng1,
  6. Jacinta P W Lee1,
  7. Stefan J White2,
  8. Brendan E Russ3,
  9. Simona Infantino4,5,
  10. Amanda Light4,5,
  11. David M Tarlinton4,5,
  12. James Harris1,
  13. Eric F Morand1
  1. 1Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia
  2. 2Department of Human Genetics, Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands
  3. 3Department of Microbiology and Immunology, The Doherty Institute at The University of Melbourne, Parkville, Victoria, Australia
  4. 4Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  5. 5Department of Experimental Medicine, University of Melbourne, Parkville, Victoria, Australia
  1. Correspondence to Dr Sarah A Jones, Centre for Inflammatory Disease, School of Clinical Sciences at Monash Health, Monash University, 246 Clayton Rd, Clayton, Melbourne 3168, Australia; sarah.a.jones{at}monash.edu

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.

  • Autoimmunity
  • Autoantibodies
  • B cells
  • Inflammation
  • Systemic Lupus Erythematosus

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