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type I Interferon and autoimmune diseases

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...
November 21, 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
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
Sarah-Kim Friedrich, Philipp A Lang, Justa Friebus-Kardash, Vikas Duhan, Judith Bezgovsek, Karl S Lang
Viral infections can be fatal because of the direct cytopathic effects of the virus or the induction of a strong, uncontrolled inflammatory response. Virus and host intrinsic characteristics strongly modulate the outcome of viral infection. Recently we determined the circumstances under which enhanced replication of virus within the lymphoid tissue is beneficial for the outcome of a disease. This enforced viral replication promotes antiviral immune activation and, counterintuitively, accelerates virus control...
November 16, 2018: Clinical and Experimental Immunology
Catherine M Sawai, Lee Serpas, Antonio Galvao Neto, Geunhyo Jang, Ali Rashidfarrokhi, Roland Kolbeck, Miguel A Sanjuan, Boris Reizis, Vanja Sisirak
Inflammatory bowel disease (IBD) is a chronic inflammatory condition caused by an aberrant immune response to microbial components of the gastrointestinal tract. Plasmacytoid dendritic cells (pDCs) are innate immune cells specialized in the production of type I interferons and were recently implicated in the pathogenesis of autoimmune disorders such as lupus and scleroderma. While pDCs were shown to infiltrate intestinal mucosa of IBD patients and proposed to participate in intestinal inflammation, their net contribution to the disease remains unclear...
2018: Frontiers in Immunology
Megumi Tatematsu, Kenji Funami, Tsukasa Seya, Misako Matsumoto
RNA works as a genome and messenger in RNA viruses, and it sends messages in most of the creatures of the Earth, including viruses, bacteria, fungi, plants, and animals. The human innate immune system has evolved to detect single- and double-stranded RNA molecules from microbes by pattern recognition receptors and induce defense reactions against infections such as the production of type I interferons and inflammatory cytokines. To avoid cytokine toxicity causing chronic inflammation or autoimmunity by sensing self-RNA, the activation of RNA sensors is strictly regulated...
November 7, 2018: Journal of Innate Immunity
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
A Berglund, L Cleemann, B E Oftedal, K Holm, E S Husebye, C H Gravholt
Turner syndrome (TS) is associated with an increased frequency of autoimmunity. Frequently observed autoimmune diseases in TS are also seen in the autoimmune polyendocrine syndrome type I (APS I), of which Addison disease is a key component. An overlapping antibody profile between TS and APS I could be considered. The aim of this work was to study women with TS regarding 21-hydroxylase (21-OH) antibodies and interferon omega (IFN-ω) antibodies, a highly specific marker for APS I, to determine if there are immunological overlaps between TS and APS I...
October 29, 2018: Clinical and Experimental Immunology
Yuliia I Komisarenko, Maryna I Bobryk
Introduction: Combined endocrine pathology is a serious healthcare problem in Ukraine. This prospective study assessed the blood levels of 25-hydroxyvitamin D [25(OH)D] and markers of immune function in response to vitamin D intervention in patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively) and autoimmune thyroiditis (AIT). Objective: This study evaluated the relationship between the metabolic and immune status of DM + AIT patients with respect to their vitamin D status and changes after vitamin D3 supplementation...
2018: Frontiers in Endocrinology
Yury Chaly, Jennifer Y Barr, David A Sullivan, Helen E Thomas, Thomas C Brodnicki, Scott M Lieberman
Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland autoimmunity spontaneously occurs only in males with testosterone playing a role in promoting lacrimal gland inflammation, while female lacrimal glands are protected by regulatory T cells (Tregs). The mechanisms of this male-specific lacrimal gland autoimmunity are not known...
October 20, 2018: International Journal of Molecular Sciences
Mary K Crow, Mikhail Olferiev, Kyriakos A Kirou
Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease...
October 17, 2018: Annual Review of Pathology
Yan-Zhe Wang, Ding-Yu Zhu, Xin-Miao Xie, Miao Ding, Yong-Lan Wang, Lin-Lin Sun, Nan Zhang, E Shen, Xiao-Xia Wang
This study aimed to investigate the molecular mechanisms of diabetic kidney disease (DKD) and to explore new potential therapeutic strategies and biomarkers for DKD. First we analyzed the differentially expressed changes between patients with DKD and the control group using the chip data in Gene Expression Omnibus (GEO) database. Then the gene chip was subjected to be annotated again, so as to screen long noncoding RNAs (lncRNAs) and study expression differences of these lncRNAs in DKD and controlled samples...
October 14, 2018: Journal of Cellular Physiology
Teresa Rodriguez-Calvo
Enteroviruses have been historically associated to type 1 diabetes. Definitive proof for their implication in disease development is lacking but growing evidence suggests that they could be involved in beta cell destruction either directly by killing beta cells or indirectly, by creating an exacerbated inflammatory response in the islets, capable of attracting autoreactive T cells to the "scene of crime". Epidemiological and serological studies have been associated with the appearance of islet autoimmunity and EV RNA has been detected in prospective studies...
October 11, 2018: Clinical and Experimental Immunology
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...
October 6, 2018: 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
Loredana Frasca, Raffaella Palazzo, Maria S Chimenti, Stefano Alivernini, Barbara Tolusso, Laura Bui, Elisabetta Botti, Alessandro Giunta, Luca Bianchi, Luca Petricca, Simone E Auteri, Francesca Spadaro, Giulia L Fonti, Mario Falchi, Antonella Evangelista, Barbara Marinari, Immacolata Pietraforte, Francesca R Spinelli, Tania Colasanti, Cristiano Alessandri, Fabrizio Conti, Elisa Gremese, Antonio Costanzo, Guido Valesini, Roberto Perricone, Roberto Lande
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. A third of psoriatic patients develop PsA via unknown mechanisms. No reliable diagnostic markers are available for PsA, or prognostic biomarkers for PsA development in psoriasis. We previously uncovered a pro-inflammatory role for cathelicidin LL37 in lesional psoriasis skin. LL37 binds nucleic acids and stimulates plasmacytoid/myeloid dendritic cells (pDC, mDCs) to secrete type I interferon (IFN-I) and pro-inflammatory factors...
2018: Frontiers in Immunology
Xiang Chen, Xingguang Liu, Yunkai Zhang, Wanwan Huai, Qingqing Zhou, Sheng Xu, Xi Chen, Nan Li, Xuetao Cao
Epigenetic modification, including histone modification, precisely controls target gene expression. The posttranscriptional regulation of the innate signaling-triggered production of inflammatory cytokines and type I interferons has been fully elucidated, whereas the roles of histone modification alteration and epigenetic modifiers in regulating inflammatory responses need to be further explored. Di/tri-methylation modifications of histone 3 lysine 79 (H3K79me2/3) have been shown to be associated with gene transcriptional activation...
October 1, 2018: Cellular & Molecular Immunology
Maikel L Colli, Jessica L E Hill, Laura Marroquí, Jessica Chaffey, Reinaldo S Dos Santos, Pia Leete, Alexandra Coomans de Brachène, Flavia M M Paula, Anne Op de Beeck, Angela Castela, Lorella Marselli, Lars Krogvold, Knut Dahl-Jorgensen, Piero Marchetti, Noel G Morgan, Sarah J Richardson, Décio L Eizirik
BACKGROUND: Antibodies targeting PD-1 and its ligand PDL1 are used in cancer immunotherapy but may lead to autoimmune diseases, including type 1 diabetes (T1D). It remains unclear whether PDL1 is expressed in pancreatic islets of people with T1D and how is it regulated. METHODS: The expression of PDL1, IRF1, insulin and glucagon was evaluated in samples of T1D donors by immunofluorescence. Cytokine-induced PDL1 expression in the human beta cell line, EndoC-βH1, and in primary human pancreatic islets was determined by real-time RT-PCR, flow cytometry and Western blot...
October 2018: EBioMedicine
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