GILZ regulates type I interferon release and sequesters STAT1.

Glucocorticoids remain a mainstay of modern medicine due to their ability to broadly suppress immune activation. However, they cause severe adverse effects that warrant urgent development of a safer alternative. The glucocorticoid-induced leucine zipper (GILZ) gene, TSC22D3, is one of the most highly upregulated genes in response to glucocorticoid treatment, and reduced GILZ mRNA and protein levels are associated with increased severity of inflammation in systemic lupus erythematosus (SLE), Ulcerative Colitis, Psoriasis, and other autoimmune/autoinflammatory diseases. Here, we demonstrate that low GILZ permits expression of a type I interferon (IFN) signature, which is exacerbated in response to TLR7 and TLR9 stimulation. Conversely, overexpression of GILZ prevents IFN-stimulated gene (ISG) up-regulation in response to IFNα. Moreover, GILZ directly binds STAT1 and prevents its nuclear translocation, thereby negatively regulating IFN-induced gene expression and the auto-amplification loop of the IFN response. Thus, GILZ powerfully regulates both the expression and action of type I IFN, suggesting restoration of GILZ as an attractive therapeutic strategy for reducing reliance on glucocorticoids.

Ubiquitination of MHC Class II Is Required for Development of Regulatory but Not Conventional CD4+ T Cells.

MHC class II (MHC II) displays peptides at the cell surface, a process critical for CD4+ T cell development and priming. Ubiquitination is a mechanism that dictates surface MHC II with the attachment of a polyubiquitin chain to peptide-loaded MHC II, promoting its traffic away from the plasma membrane. In this study, we have examined how MHC II ubiquitination impacts the composition and function of both conventional CD4+ T cell and regulatory T cell (Treg) compartments. Responses were examined in two models of altered MHC II ubiquitination: MHCIIKRKI /KI mice that express a mutant MHC II unable to be ubiquitinated or mice that lack membrane-associated RING-CH 8 (MARCH8), the E3 ubiquitin ligase responsible for MHC II ubiquitination specifically in thymic epithelial cells. Conventional CD4+ T cell populations in thymus, blood, and spleen of MHCIIKRKI/KI and March8 -/- mice were largely unaltered. In MLRs, March8 -/-, but not MHCIIKRKI/KI, CD4+ T cells had reduced reactivity to both self- and allogeneic MHC II. Thymic Treg were significantly reduced in MHCIIKRKI/KI mice, but not March8 -/- mice, whereas splenic Treg were unaffected. Neither scenario provoked autoimmunity, with no evidence of immunohistopathology and normal levels of autoantibody. In summary, MHC II ubiquitination in specific APC types does not have a major impact on the conventional CD4+ T cell compartment but is important for Treg development.

Large-vessel vasculitis in graft-versus-host disease: a case report.

BACKGROUND: Graft-versus-host disease is a common complication seen with allogenic stem cell transplant, which is used to treat a variety of hematological malignancies. Graft-versus-host disease is an allogenic syndrome and can present in a variety of ways, including symptoms mimicking various autoimmune diseases; however, it is quite rare to see graft-versus-host disease affecting the vascular system and causing vasculitis. CASE PRESENTATION: We describe a case of a 59-year-old Caucasian man with follicular lymphoma and diffuse large B-cell transformation who developed graft-versus-host disease post allogenic hematopoietic stem cell transplantation and later progressed to neurological complication foot drop and large-vessel vasculitis. CONCLUSION: The life-threatening vascular complications associated with large-vessel vasculitis include arterial aneurysms and dissections, and ischemic or hemorrhagic stroke. Thus, this rare immunological association needs to be recognized and treated in a timely manner to prevent the long-term complications.

Glucocorticoid gene signatures in systemic lupus erythematosus and the effects of type I interferon: a cross-sectional and in-vitro study.

BACKGROUND: Glucocorticoids, used as a therapy in systemic lupus erythematosus (SLE), interact with the cytoplasmic glucocorticoid receptor to modulate gene transcription. Minimising the use of glucocorticoids is a goal in SLE; however, pharmacological measures to support clinical guidelines are scarce. We evaluated glucocorticoid-regulated genes for their potential use as biomarkers of glucocorticoid exposure in SLE. We examined interactions between changes in gene expression that are induced by glucocorticoids and type I interferon. METHODS: Genes regulated by glucocorticoids and type I interferon were analysed in relation to glucocorticoid exposure in adult patients meeting the American College of Rheumatology criteria for SLE from three cross-sectional cohorts: a local cohort from a tertiary hospital in Melbourne, VIC, Australia, and two public datasets (GSE49454, Hospital de la Conception, Marseille, France, and GSE88884, patients enrolled in a large, multicentre clinical trial). RNA sequencing was done using RNA from healthy donor leucocytes treated with the glucocorticoid dexamethasone, or type I interferon, or both. FINDINGS: Glucocorticoid-regulated genes were analysed in a local SLE cohort (n=18) and public dataset GSE49454 (n=62). Five genes correlated with glucocorticoid dose in both cohorts and were combined to make a glucocorticoid gene signature. Validity of the glucocorticoid gene signature was tested in the public dataset GSE88884 (n=1756). A dose-dependent association was observed with glucocorticoid dose (p<0·0001), and the glucocorticoid gene signature had moderate ability to identify patients taking high-dose glucocorticoid (area under the curve [AUC]=0·77) although was less discriminatory when including all doses (AUC=0·69). We saw no effect of glucocorticoid dose on type I interferon -regulated gene expression. Patients with a high type I interferon gene signature had reduced glucocorticoid gene signature expression compared with patients with a low type I interferon gene signature matched for glucocorticoid dose, suggesting type I interferon inhibits glucocorticoid-stimulated gene expression. In RNA sequencing experiments, type I interferon impaired the expression of glucocorticoid-induced genes, whereas dexamethasone had minimal effect on the expression of type I interferon-stimulated genes. We identified genes regulated by dexamethasone but not affected by type I interferon; combined signatures using these genes also showed moderate ability to distinguish patients taking glucocorticoids. INTERPRETATION: A gene signature for glucocorticoid exposure was identified, but the substantial effect of type I interferon on glucocorticoid-induced genes might limit its application in SLE. These data confirm the insensitivity of type I interferon-regulated genes to glucocorticoids, and together support the concept that type I interferon has a role in glucocorticoid resistance in SLE. FUNDING: Lupus Research Alliance and Australian National Health and Medical Research Council.

GILZ Regulates the Expression of Pro-Inflammatory Cytokines and Protects Against End-Organ Damage in a Model of Lupus.

Glucocorticoid-induced leucine zipper (GILZ) mimics many of the anti-inflammatory effects of glucocorticoids, suggesting it as a point of therapeutic intervention that could bypass GC adverse effects. We previously reported that GILZ down-regulation is a feature of human SLE, and loss of GILZ permits the development of autoantibodies and lupus-like autoimmunity in mice. To further query the contribution of GILZ to protection against autoimmune inflammation, we studied the development of the lupus phenotype in Lyn-deficient (Lyn-/-) mice in which GILZ expression was genetically ablated. In Lyn-/- mice, splenomegaly, glomerulonephritis, anti-dsDNA antibody titres and cytokine expression were exacerbated by GILZ deficiency, while other autoantibody titres and glomerular immune complex deposition were unaffected. Likewise, in patients with SLE, GILZ was inversely correlated with IL23A, and in SLE patients not taking glucocorticoids, GILZ was also inversely correlated with BAFF and IL18. This suggests that at the onset of autoimmunity, GILZ protects against tissue injury by modulating pro-inflammatory pathways, downstream of antibodies, to regulate the cycle of inflammation in SLE.

Atypical Cutaneous Manifestations in Adult Onset Still's Disease.

Adult Onset Still's Disease (AOSD), an adult variant of systemic onset juvenile idiopathic arthritis, is a rare systemic inflammatory disorder of unknown aetiology. The rarity of this disease is associated with low index of suspicion and delayed diagnosis in patients suffering from it and in the presence of atypical features the diagnosis can be further challenging. This is a case report on a 24-year-old woman, who was a diagnostic dilemma for 2 years due to the nonspecific symptoms of recurrent fever, generalized maculopapular persistent pruritic and tender rash, and polyarthralgia. She was initially diagnosed as leukocytoclastic vasculitis on a skin biopsy and was managed by a dermatologist with various medications including NSAIDs, hydroxychloroquine, dapsone, colchicine, cyclosporine, and high doses of oral steroids with minimal response. Subsequently, she has had multiple admissions with similar symptoms with raised inflammatory markers and negative septic workup. On one occasion, her iron study revealed hyperferritinaemia which led to the suspicion of AOSD. Once the rheumatic fever and infectious, malignant, autoimmune, and lymphoproliferative disorders were excluded, she was diagnosed as probable AOSD and managed successfully with IL-1 (interleukin-1) receptor antagonist, Anakinra, with remarkable and lasting response both clinically and biochemically.