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interferon type I autoimmunities

Iris L A Bodewes, Albin Björk, Marjan A Versnel, Marie Wahren-Herlenius
Primary SS (pSS) is a rheumatic disease characterized by an immune-mediated exocrinopathy, resulting in severe dryness of eyes and mouth. Systemic symptoms include fatigue and joint pain and a subset of patients develop more severe disease with multi-organ involvement. Accumulating evidence points to involvement of innate immunity and aberrant activity of the type I IFN system in both the initiation and propagation of this disease. Analysis of the activity of IFN-inducible genes has evidenced that more than half of pSS patients present with a so-called 'type I IFN signature'...
February 15, 2019: Rheumatology
Marita Chakhtoura, Robert W Chain, Priscila Y Sato, Connie C Qiu, Michael H Lee, Joseph J Meissler, Toby K Eisenstein, Walter J Koch, Roberto Caricchio, Stefania Gallucci
Attenuating the innate immunity activation could ameliorate inflammation and disease in settings such as transplant rejection or autoimmunity. Recently, a pivotal role for metabolic re-programming in TLR-induced dendritic cell (DC) activation has emerged. Ethyl pyruvate (EP), a pyruvate derivative, possesses anti-inflammatory properties in vitro and in animal models of disease. However, its effects on DCs remain elusive. We found that EP attenuated LPS-induced activation of murine GM-CSF bone marrow-derived dendritic cells (DCs) in vitro , reducing pro-inflammatory cytokine and IL-10 production, costimulatory molecule and MHC expression, the type I Interferon (IFN-I) response, the LPS-induced cell death, and the ability of DCs to stimulate allogeneic T cells...
2019: Frontiers in Immunology
Valentina Salvi, Veronica Gianello, Laura Tiberio, Silvano Sozzani, Daniela Bosisio
Persistent and excessive cytokine production is a hallmark of autoimmune diseases and may play a role in disease pathogenesis and amplification. Therefore, cytokine neutralization is a useful therapeutic strategy to treat immune-mediated conditions. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression in diverse biological processes. Altered miRNA levels are observed in most autoimmune diseases and are recognized to influence autoimmunity through different mechanisms. Here, we review the impact of altered miRNA levels on the expression of cytokines that play a relevant pathogenic role in autoimmunity, namely primary pro-inflammatory cytokines, the IL-17/IL-23 axis, type I interferons and IL-10...
2019: Frontiers in Immunology
Alice E Denton, Silvia Innocentin, Edward J Carr, Barry M Bradford, Fanny Lafouresse, Neil A Mabbott, Urs Mörbe, Burkhard Ludewig, Joanna R Groom, Kim L Good-Jacobson, Michelle A Linterman
Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection-induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ...
February 5, 2019: Journal of Experimental Medicine
Brian Skaug, Shervin Assassi
Systemic Sclerosis (Scleroderma, SSc) is a multifaceted disease characterized by autoimmunity, vasculopathy, and fibrosis affecting the skin and internal organs. Despite advances in the understanding and treatment of SSc in recent years, SSc continues to cause reduced quality of life and premature mortality. Type I interferons (IFNs), a family of cytokines with essential roles in the immune response to microbial infection, play a pathogenic role in certain autoimmune diseases (reviewed elsewhere in this edition)...
January 23, 2019: Cytokine
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
Boris Reizis
Plasmacytoid dendritic cells (pDCs) are a unique sentinel cell type that can detect pathogen-derived nucleic acids and respond with rapid and massive production of type I interferon. This review summarizes our current understanding of pDC biology, including transcriptional regulation, heterogeneity, role in antiviral immune responses, and involvement in immune pathology, particularly in autoimmune diseases, immunodeficiency, and cancer. We also highlight the remaining gaps in our knowledge and important questions for the field, such as the molecular basis of unique interferon-producing capacity of pDCs...
January 15, 2019: Immunity
Sonal Srikanth, Jin Seok Woo, Beibei Wu, Yasser M El-Sherbiny, Jennifer Leung, Koollawat Chupradit, Laura Rice, Gil Ju Seo, Guillaume Calmettes, Chandran Ramakrishna, Edouard Cantin, Dong Sung An, Ren Sun, Ting-Ting Wu, Jae U Jung, Sinisa Savic, Yousang Gwack
Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency...
January 14, 2019: Nature Immunology
Peter D Burbelo, Sarah Browne, Steve M Holland, Michael J Iadarola, Ilias Alevizos
BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disease characterized by immune attack on the salivary and lacrimal glands. Given the known cytokine activation and type I interferon gene expression signature found in SS, we hypothesized that anticytokine autoantibodies might be detectable by Luciferase immunoprecipitation systems in some SS patients and correlate with clinical symptoms. RESULTS: Luciferase immunoprecipitation systems was used to screen for serum anti-cytokine autoantibodies in 57 primary SS patients and 25 healthy volunteers...
January 3, 2019: Clinical and Translational Medicine
Chao-Wen Cheng, Shun-Fa Yang, Yuan-Hung Wang, Wen-Fang Fang, Ying-Chin Lin, Kam-Tsun Tang, Jiunn-Diann Lin
BACKGROUND: Dysregulation of the type 1 interferon (IFN)-related signaling pathway predisposes one to autoimmune diseases. Possible associations of single-nucleotide polymorphisms (SNPs) of Secreted phosphoprotein 1 (SPP1) and B lymphocyte kinase (BLK) of the type 1 IFN-related signaling pathway with autoimmune thyroid disease (AITD) in an ethnic Chinese (i.e., Taiwanese) population were tested. METHODS: Totally, 83 Hashimoto's thyroiditis (HT) patients, 319 Graves' disease (GD) patients, and 369 controls were enrolled...
December 27, 2018: European Journal of Clinical Investigation
José A Villegas, Alexandra C Bayer, Katia Ider, Jacky Bismuth, Frédérique Truffault, Régine Roussin, Nicola Santelmo, Rozen Le Panse, Sonia Berrih-Aknin, Nadine Dragin
IL-23/Th17 pathway has been identified to sustain inflammatory condition in several autoimmune diseases and therefore being targeted in various therapeutic and effective approaches. Patients affected with autoimmune myasthenia gravis exhibit a disease effector tissue, the thymus, that harbors ectopic germinal centers that sustain production of auto-antibodies, targeting proteins located in the neuromuscular junction, cause of the organ-specific chronic autoimmune disease. The present study aims to investigate the IL-23/Th17 cell pathway in the thymic inflammatory and pathogenic events...
December 18, 2018: Journal of Autoimmunity
Rehana Z Hussain, Petra C Cravens, Richard Doelger, Brianne Dentel, Emily Herndon, Nicolas Loof, Peter Tsai, Darin T Okuda, Michael K Racke, Olaf Stüve
Objective: Natalizumab blocks α 4-integrin-mediated leukocyte migration into the central nervous system (CNS). It diminishes disease activity in multiple sclerosis (MS), but carries a high risk of progressive multifocal encephalopathy (PML), an opportunistic infection with JV virus that may be prompted by diminished CNS immune surveillance. The initial host response to viral infections entails the synthesis of type I interferons (IFN) upon engagement of TLR3 receptors. We hypothesized that TLR3 agonism reestablishes CNS immune competence in the setting of α 4-integrin deficiency...
December 2018: Annals of Clinical and Translational Neurology
Alessio Mylonas, Curdin Conrad
Chronic plaque psoriasis is a common debilitating skin disease. The identification of the pathogenic role of the TNF/IL-23/TH 17 pathway has enabled the development of targeted therapies used in the clinic today. Particularly, TNF inhibitors have become a benchmark for the treatment of numerous chronic inflammatory diseases such as psoriasis. Although being highly effective in psoriasis treatment, anti-TNFs can themselves induce psoriasis-like skin lesions, a side effect called paradoxical psoriasis. In this review, we provide a comprehensive look at the different cellular and molecular players involved in classical plaque psoriasis and contrast its pathogenesis to paradoxical psoriasis, which is clinically similar but immunologically distinct...
2018: Frontiers in Immunology
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
Grace A Hile, Johann E Gudjonsson, J Michelle Kahlenberg
Type I interferons (IFNs) are an immunomodulatory class of cytokines that serve to protect against viral and bacterial infection. In addition, mounting evidence suggests IFNs, particularly type I but also IFNγ, are important to the pathogenesis of autoimmune and inflammatory skin diseases, such as cutaneous lupus erythematosus (CLE). Understanding the role of IFNs is relevant to anti-viral responses in the skin, skin biology, and therapeutics for these IFN-related conditions. Type I IFNs (α and β) are produced by recruited inflammatory cells and by the epidermis itself (IFNκ) and have important roles in autoimmune and inflammatory skin disease...
December 6, 2018: Cytokine
Hui Qiu, Richard Caldwell, Lesley Liu-Bujalski, Andreas Goutopoulos, Reinaldo Jones, Justin Potnick, Brian Sherer, Andrea Bender, Roland Grenningloh, Daigen Xu, Theresa Johnson, Ariele Viacava Follis, Jared Head, Federica Morandi
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of the aforementioned diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the Btk protein by these Btk covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy...
December 6, 2018: ChemMedChem
Cherrie D Thompson, Bharati Matta, Betsy J Barnes
The interferon regulatory factors (IRFs) are a family of master transcription factors that regulate pathogen-induced innate and acquired immune responses. Aberration(s) in IRF signaling pathways due to infection, genetic predisposition and/or mutation, which can lead to increased expression of type I interferon (IFN) genes, IFN-stimulated genes (ISGs), and other pro-inflammatory cytokines/chemokines, has been linked to the development of numerous diseases, including (but not limited to) autoimmune and cancer...
2018: Frontiers in Immunology
Anje Cauwels, Sandra Van Lint, Dominiek Catteeuw, Shengru Pang, Franciane Paul, Elke Rogge, Annick Verhee, Marco Prinz, Niko Kley, Gilles Uzé, Jan Tavernier
Type I Interferon (IFN) is widely used for multiple sclerosis (MS) treatment, but its side effects are limiting and its mechanism of action still unknown. Furthermore, 30-50% of MS patients are unresponsive, and IFN can even induce relapses. Fundamental understanding of the cellular target(s) of IFN will help to optimize treatments by reducing side effects and separating beneficial from detrimental effects. To improve clinical systemic IFN usage, we are developing AcTaferons (Activity-on-Target IFNs = AFNs), optimized IFN-based immunocytokines that allow cell-specific targeting...
November 19, 2018: Journal of Autoimmunity
Rosa M Rubio, Daniel P Depledge, Christopher Bianco, Letitia Thompson, Ian Mohr
Modification of mRNA by N 6 -adenosine methylation (m6 A) on internal bases influences gene expression in eukaryotes. How the dynamic genome-wide landscape of m6 A-modified mRNAs impacts virus infection and host immune responses remains poorly understood. Here, we show that type I interferon (IFN) production triggered by dsDNA or human cytomegalovirus (HCMV) is controlled by the cellular m6 A methyltrasferase subunit METTL14 and ALKBH5 demethylase. While METTL14 depletion reduced virus reproduction and stimulated dsDNA- or HCMV-induced IFNB1 mRNA accumulation, ALKBH5 depletion had the opposite effect...
December 1, 2018: Genes & Development
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
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