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interferon type I AND SLE

Michelle Remião Ugolini-Lopes, Giovana Tardin Torrezan, Ana Paula Rossi Gândara, Eloisa Helena Ribeiro Olivieri, Iana Souza Nascimento, Erika Okazaki, Eloisa Bonfá, Dirce Maria Carraro, Danieli Castro Oliveira de Andrade
OBJECTIVE: Recently, two studies demonstrated that a relevant percentage of primary antiphospholipid syndrome (PAPS) patients had an upregulation of interferon (IFN) genes. However, 20%-28% of these patients had anti-dsDNA, a highly specific systemic lupus erythematosus (SLE) autoantibody. This study aimed to determine the prevalence of the type I IFN signature in the peripheral blood mononuclear cells of PAPS patients without specific SLE autoantibodies and search for its clinical associations...
February 14, 2019: Autoimmunity Reviews
Shin-Ichiroh Saitoh, Yoshiko Mori Saitoh, Kenji Kontani, Katsuaki Sato, Kensuke Miyake
Toll-like receptor (TLR) 7 and type I interferon (IFN-1) are essential for the development of systemic lupus erythematosus (SLE) models such as BXSB.Yaa and 2,6,10,14-tetramethyl-pentadecane (TMPD)-induced experimental lupus. However, the mechanism underlying the development of SLE remains undefined. We report a requirement for ADP-ribosylation factor-like 8b (Arl8b) for TLR7-dependent IFN-1 production in plasmacytoid dendritic cells (pDCs). We analyzed whether Arl8b plays a role in two SLE models by comparing wild-type and Arl8b-deficient Arl8b GeneTrap (Arl8bGt/Gt) mice...
February 7, 2019: International Immunology
Kornvalee Meesilpavikkai, Willem A Dik, Benjamin Schrijver, Cornelia G van Helden-Meeuwsen, Emilia K Bijlsma, Claudia A L Ruivenkamp, Margreet J Oele, Marjan A Versnel, P Martin van Hagen, Virgil A S H Dalm
Aicardi-Goutières syndrome (AGS) is a rare early-onset auto-inflammatory disease characterized by basal ganglia calcification, chronic cerebrospinal fluid (CSF) lymphocytosis, and elevated type I interferon (IFN) levels in the CSF (1, 2). Typical clinical manifestations include developmental delay, intellectual impairment, chilblain, panniculitis, glaucoma, and autoimmunity overlapping with systemic lupus erythematosus (SLE) This article is protected by copyright. All rights reserved.
January 22, 2019: Arthritis & Rheumatology
Sarfaraz Hasni, Sarthak Gupta, Michael Davis, Elaine Poncio, Yenealem Temesgen-Oyelakin, Elizabeth Joyal, Alice Fike, Zerai Manna, Sungyoung Auh, Yinghui Shi, Diana Chan, Philip Carlucci, Ann Biehl, Barbara Dema, Nicolas Charles, James E Balow, Meryl Waldman, Richard M Siegel, Mariana J Kaplan, Juan Rivera
BACKGROUND: Autoreactive IgE antibodies have been implicated in the pathogenesis systemic lupus erythematosus (SLE). We hypothesized that omalizumab, a monoclonal antibody (mAb) binding IgE, may improve SLE activity by reducing type I IFN production by hampering plasmacytoid dendritic cells and basophil activation. This study assessed the safety, tolerability, and clinical efficacy of omalizumab in mild to moderate SLE. METHODS: Fifteen subjects with SLE and a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) of > 4 and elevated autoreactive IgE antibodies were randomized to receive omalizumab or placebo (2:1) for 16 weeks, followed by 16-week open label treatment and 4-week washout period...
December 29, 2018: Arthritis & Rheumatology
Joan T Merrill, Richard Furie, Victoria P Werth, Munther Khamashta, Jorn Drappa, Liangwei Wang, Gabor Illei, Raj Tummala
Objective: This post hoc analysis compared anifrolumab 300 mg every 4 weeks with placebo on rash and arthritis measures with different stringency in patients with moderate to severe SLE (phase IIb; MUSE; NCT01438489). Subgroups were analysed by type I interferon gene signature (IFNGS test-high or test-low). Methods: Rash was measured with the SLE Disease Activity Index 2000 (SLEDAI-2K), British Isles Lupus Assessment Group (BILAG) Index and modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI)...
2018: Lupus Science & Medicine
Maiko Yoshikawa, Shingo Nakayamada, Satoshi Kubo, Aya Nawata, Yukihiro Kitanaga, Shigeru Iwata, Kei Sakata, Ma Xiaoxue, Sheau Pey Wang, Kazuhisa Nakano, Kazuyoshi Saito, Yoshiya Tanaka
Memory B cells are increased in systemic lupus erythematosus (SLE) cases, but the qualitative abnormalities and induction mechanism of these cells are unclear. Here, we subclassified B cells by their chemokine receptor expression and investigated their induction mechanism. The peripheral blood of patients with SLE showed higher levels of CXCR5- and CXCR3+ B cells. CXCR5- CXCR3+ B cell levels were elevated in patients with active SLE, which decreased with improving disease conditions. Interferon (IFN)-γ stimulation increased CXCR3 expression, whereas IFN-β stimulation reduced CXCR5 expression in B cells...
December 18, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Hiroshi Nishi, Tanya N Mayadas
PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease characterized by IgG-autoantibodies to nuclear antigens that can deposit in the kidney and trigger lupus nephritis. Neutrophils accumulate in the kidneys of patients with proliferative LUPUS NEPHRITIS and neutrophil products and a subset of granulocytes, called low-density granulocytes (LDG) may contribute to lupus nephritis pathogenesis. Here, we will discuss recent studies implicating neutrophils in the pathogenesis of human SLE nephritis and then examine studies that provide mechanistic insights into how these cells are recruited to the glomerulus following immune complex deposition and how their products may promote lupus nephritis...
March 2019: Current Opinion in Rheumatology
Kerry A Casey, Xiang Guo, Michael A Smith, Shiliang Wang, Dominic Sinibaldi, Miguel A Sanjuan, Liangwei Wang, Gabor G Illei, Wendy I White
Objective: Anifrolumab is a fully human immunoglobulin G1 κ monoclonal antibody specific for subunit 1 of the type I interferon (IFN) α receptor. In a phase IIb study of adults with moderate to severe SLE, anifrolumab treatment demonstrated substantial reductions in multiple clinical endpoints. Here, we evaluated serum proteins and immune cells associated with SLE pathogenesis, type I interferon gene signature (IFNGS) test status and disease activity, and how anifrolumab affected these components...
2018: Lupus Science & Medicine
Bo Chen, Katherine A Vousden, Brian Naiman, Sean Turman, Hong Sun, Shu Wang, Lisa M K Vinall, Benjamin P Kemp, Srinath Kasturiangan, D Gareth Rees, Ethan Grant, Mary Jane Hinrichs, Steven Eck, Antonio DiGiandomenico, M Jack Borrok, Martin J Borrok, Neang Ly, Ximing Xiong, Carlos Gonzalez, Christopher Morehouse, Yue Wang, Yebin Zhou, Jennifer Cann, Weiguang Zhao, Holly Koelkebeck, Koshu Okubo, Tanya N Mayadas, David Howe, Janet Griffiths, Roland Kolbeck, Ronald Herbst, Gary P Sims
OBJECTIVE: Immune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim of this study was to generate and characterise a first-in-class anti-FcγRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development. METHODS: VIB9600 was humanised and optimised from the IV.3 Ab. Binding affinity and specificity were determined by Biacore and ELISA. Confocal microscopy, Flow Cytometry-based assays and binding competition assays were used to assess the mode of action of the antibody...
November 20, 2018: Annals of the Rheumatic Diseases
Andrea Fava, Michelle Petri
Systemic lupus erythematosus (SLE) is a worldwide chronic autoimmune disease which may affect every organ and tissue. Genetic predisposition, environmental triggers, and the hormonal milieu, interplay in disease development and activity. Clinical manifestations and the pattern of organ involvement are widely heterogenous, reflecting the complex mosaic of disrupted molecular pathways converging into the SLE clinical phenotype. The SLE complex pathogenesis involves multiple cellular components of the innate and immune systems, presence of autoantibodies and immunocomplexes, engagement of the complement system, dysregulation of several cytokines including type I interferons, and disruption of the clearance of nucleic acids after cell death...
November 15, 2018: Journal of Autoimmunity
Colleen S Curran, Sarthak Gupta, Ignacio Sanz, Elad Sharon
Programmed death (PD)-1 receptors and their ligands have been identified in the pathogenesis and development of systemic lupus erythematosus (SLE). Two key pathways, toll-like receptor and type I interferon, are significant to SLE pathogenesis and modulate the expression of PD-1 and the ligands (PD-L1, PD-L2) through activation of NF-κB and/or STAT1. These cell signals are regulated by tyrosine kinase (Tyro, Axl, Mer) receptors (TAMs) that are aberrantly activated in SLE. STAT1 and NF-κB also exhibit crosstalk with the aryl hydrocarbon receptor (AHR)...
November 2, 2018: Journal of Autoimmunity
Li Zheng, Hao Zhang, Youzhou Tang
Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple organs involved. Kidney damage is common among SLE patients. In lupus nephritis, extracellular DNA accumulation from necrosis cells and activated cells is perceived as initial step of inflammation. The up-regulated type I IFN is one pivotal cytokine causing downstream inflammation enlargement. Currently, intracellular DNA sensor cGAS signaling has been found to be related to lupus nephritis and the aberrant up-regulation of type I IFN...
December 2018: Medical Hypotheses
Stancy Joseph, Nysia I George, Bridgett Green-Knox, Edward L Treadwell, Beverly Word, Sarah Yim, Beverly Lyn-Cook
Systemic lupus erythematosus (SLE or lupus) is a heterogeneous autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. DNA methylation plays an important role in the pathogenesis of lupus. We have performed an epigenome-wide DNA methylation study in lupus and healthy control (non-lupus) subjects to identify epigenetic patterns in lupus characterized ethnicity and SLE disease activity index (SLEDAI). A total of fifty-seven lupus patients (39 African American (AA) and 18 European American (EA)) and 33 healthy controls (17 AA and 16 EA) were studied...
January 2019: Journal of Autoimmunity
Michelle L Ratliff, Joshua Garton, Lori Garman, M David Barron, Constantin Georgescu, Kathryn A White, Eliza Chakravarty, Jonathan D Wren, Courtney G Montgomery, Judith A James, Carol F Webb
Type I interferons (IFN) causes inflammatory responses to pathogens, and can be elevated in autoimmune diseases such as systemic lupus erythematosus (SLE). We previously reported unexpected associations of increased numbers of B lymphocytes expressing the DNA-binding protein ARID3a with both IFN alpha (IFNα) expression and increased disease activity in SLE. Here, we determined that IFNα producing low density neutrophils (LDNs) and plasmacytoid dendritic cells (pDCs) from SLE patients exhibit strong associations between ARID3a protein expression and IFNα production...
October 5, 2018: Journal of Autoimmunity
Allison Sang, Thomas Danhorn, Jacob N Peterson, Andrew L Rankin, Brian P O'Connor, Sonia M Leach, Raul M Torres, Roberta Pelanda
Autoreactive B cells have a major function in autoimmunity. A small subset of B cells expressing two distinct B-cell-antigen-receptors (B2R cells) is elevated in many patients with systematic lupus erythematosus (SLE) and in the MRL(/lpr) mouse model of lupus, and is often autoreactive. Here we show, using RNAseq and in vitro and in vivo analyses, signals that are required for promoting B2R cell numbers and effector function in autoimmune mice. Compared with conventional B cells, B2R cells are more responsive to Toll-like receptor 7/9 and type I/II interferon treatment, display higher levels of MHCII and co-receptors, and depend on IL-21 for their homeostasis; moreover they expand better upon T cell-dependent antigen stimulation, and mount a more robust memory response, which are characteristics essential for enhanced (auto)immune responses...
September 28, 2018: Nature Communications
Kei Sakata, Shingo Nakayamada, Yusuke Miyazaki, Satoshi Kubo, Akina Ishii, Kazuhisa Nakano, Yoshiya Tanaka
Objectives: Aberrant and persistent production of interferon-α (IFN-α) by plasmacytoid dendritic cells (pDCs) is known to play a key role in the pathogenesis of systemic lupus erythematosus (SLE). To assess the precise function of pDCs in SLE patients, we investigated the differential regulation of Toll-like receptor 7 (TLR7) and TLR9 responses during IFN-α production by pDCs. Methods: Peripheral blood mononuclear cells (PBMCs) in SLE patients without hydroxychloroquine treatment, rheumatoid arthritis patients and heathy controls were stimulated with TLR7 and TLR9 agonists...
2018: Frontiers in Immunology
Christina Adamichou, Spyros Georgakis, George Bertsias
Despite advancements in the care of lupus nephritis, a considerable proportion of patients may respond poorly or flare while on conventional immunosuppressive agents. Studies in murine and human lupus have illustrated a pathogenic role for several cytokines by enhancing T- and B-cell activation, autoantibodies production and affecting the function of kidney resident cells, therefore supporting their potential therapeutic targeting. To this end, there is limited post-hoc randomized evidence to suggest beneficial effect of belimumab, administered on top of standard-of-care, during maintenance therapy in lupus nephritis...
September 2, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Maurer Kelly, Shi Lihua, Zhang Zhe, Song Li, Paucar Yoselin, Petri Michelle, E Sullivan Kathleen
Systemic lupus erythematosus (SLE) represents an autoimmune disease in which activation of the type I interferon pathway leads to dysregulation of tolerance and the generation of autoantibodies directed against nuclear constituents. The mechanisms driving the activation of the interferon pathway in SLE have been the subject of intense investigation but are still incompletely understood. Transposable elements represent an enormous source of RNA that could potentially stimulate the cell intrinsic RNA-recognition pathway, leading to upregulation of interferons...
December 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Linyu Geng, Shiying Wang, Xia Li, Dandan Wang, Haifeng Chen, Jinyun Chen, Yue Sun, Weiwei Chen, Genhong Yao, Xiang Gao, Wanjun Chen, Songtao Shi, Xuebing Feng, Lingyun Sun
Patients with systemic lupus erythematosus (SLE) have a tremendously increased risk for cardiovascular disease (CVD), which could not be accounted in entirety by traditional Framingham risk factors. To study whether the accelerated atherosclerosis in SLE patients is mediated by type I interferon (IFN-I) through the regulation of endothelial progenitor cells (EPCs), we created a line of C57BL/6 mice with deficiency in both apolipoprotein E (ApoE-/-) and fas ligand (FasL-/-, gld.). As expected, the resultant gld...
September 2018: Current Research in Translational Medicine
Sang-Cheol Bae, Young Ho Lee
Our purpose was to identify differentially expressed (DE) genes and biological processes associated with gene expression changes in systemic lupus erythematosus (SLE). We performed a meta-analysis using the INMEX program (integrative meta-analysis of expression data) on publicly available microarray Genetic Expression Omnibus (GEO) datasets of peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls. We performed Gene Ontology (GO) enrichment analysis by using hypergeometric tests. In total, five comparisons (2 B cells, 2 CD4 T cells, and 1 myeloid cell) from two GEO datasets containing 51 cases and 46 controls were included in the meta-analysis...
July 30, 2018: Cellular and Molecular Biology
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