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interferon type I autoimmunities

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
Fernanda Guimarães Weiler, Pärt Peterson, Beatriz Tavares Costa-Carvalho, Mayra de Barros Dorna, Joya Emilie de Menezes Correia-Deur, Soraya Lopes Sader, Daniela Espíndola-Antunes, Gil Guerra-Junior, Magnus Régios Dias-da-Silva, Marise Lazaretti-Castro
Autoimmune polyendocrine syndrome type 1 (APS1) is characterized by multiorgan autoimmunity. We aim at characterizing a multi-center Brazilian cohort of APS1 patients by clinical evaluation, searching mutation in the AIRE gene, measuring serum autoantibodies, and investigating correlations between findings. We recruited patients based on the clinical criteria and tested them for AIRE mutations, antibodies against interferon type I and interleukins 17A, 17F and 22. We identified 12 unrelated families (13 patients) with typical signs of APS1 in the proband, and the screening of relatives recognized an asymptomatic child...
October 1, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
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
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
Brianna Burlock, Gabrielle Richardson, Sonia García-Rodríguez, Salvador Guerrero, Mercedes Zubiaur, Jaime Sancho
Previous work from our group has shown that Cd38-/- mice develop a milder pristane-induced lupus disease than WT or Art2-/- counterparts, demonstrating a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via a Transient Receptor Potential Melastatin 2 (TRPM2)-dependent apoptosis-driven mechanism. In this study we asked whether CD38 may play a role in the expression and function of regulatory B cells (IL-10-producing B cells or B10 cells). In pristane-treated mice the frequency of spleen CD19⁺CD1dhi CD5⁺ B cells, which are highly enriched in B10 cells, was significantly increased in Cd38-/- splenocytes compared to WT, while the frequency of peritoneal plasmacytoid dendritic cells (pDCs), which are major type I Interferon (IFN) producers, was greatly diminished...
September 25, 2018: International Journal of Molecular Sciences
Ashish Kabra, Catherine A Benson, Ying Li
Ubiquitination is one of the most prevalent forms of post-translational modifications that are important for regulating many cellular processes in eukaryotes. Deubiquitinases are proteases that hydrolyze the isopeptide or peptide bonds formed between ubiquitin and the target proteins or within a polyubiquitin chain. Deubiquitinase A (DUBA) is a deubiquitinase known to be a negative regulator of innate immune responses in humans by suppressing production of type I interferons (INF-I). Excess INF-I production has been associated with autoimmune diseases...
September 19, 2018: Biomolecular NMR Assignments
Rochelle C Joslyn, Adriana Forero, Richard Green, Stephen E Parker, Ram Savan
Long noncoding RNAs (lncRNAs) exhibit highly lineage-specific expression and act through diverse mechanisms to exert control over a wide range of cellular processes. lncRNAs can function as potent modulators of innate immune responses through control of transcriptional and posttranscriptional regulation of mRNA expression and processing. Recent studies have demonstrated that lncRNAs participate in the regulation of antiviral responses and autoimmune disease. Despite their emerging role as immune mediators, the mechanisms that govern lncRNA expression and function have only begun to be characterized...
September 2018: Journal of Interferon & Cytokine Research
Rosana Gonzalez-Quintial, Anthony Nguyen, Dwight H Kono, Michael B A Oldstone, Argyrios N Theofilopoulos, Roberto Baccala
Viruses have long been implicated in the pathogenesis of autoimmunity, yet their contribution remains circumstantial partly due to the lack of well-documented information on infections prior to autoimmune disease onset. Here, we used the lymphocytic choriomeningitis virus (LCMV) as a model to mechanistically dissect the impact of viral infection on lupus-like autoimmunity. Virus persistence strongly enhanced disease in mice with otherwise weak genetic predisposition but not in highly predisposed or non-autoimmune mice, indicating a synergistic interplay between genetic susceptibility and virus infection...
2018: PloS One
Yanqing Yang, Xueting Lang, Song Sun, Chun Gao, Jianguo Hu, Shuqin Ding, Jing Li, Yuyun Li, Fengchao Wang, Tao Gong
Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular pattern recognition receptors (PRRs) that regulate a variety of inflammatory and host defense responses. Unlike the well-established NLRs, the roles of NLRP2 are controversial and poorly defined. Here, we report that NLRP2 acts as a negative regulator of TANK-binding kinase 1 (TBK1)-mediated type I interferon (IFN) signaling. Mechanistically, NLRP2 interacted directly with TBK1, and this binding disrupted the interaction of TBK1 and interferon regulatory factor 3 (IRF3), which interfered with TBK1-induced IRF3 phosphorylation...
September 5, 2018: European Journal of Immunology
Renato Mastrangeli, Wolf Palinsky, Horst Bierau
All type I interferons share structural homology and bind to a common heterodimeric receptor consisting of the IFNAR1 and IFNAR2 subunits, which are expressed on most cell types. Although binding to the same receptor pair, they evoke a broad range of activities within the cell affecting the expression of numerous genes and resulting in profound cellular changes. Differential activation results from multiple levels of cellular and molecular events including binding affinity, receptor density, cell type-specific variations, and post-translational modification of signaling molecules downstream...
August 31, 2018: Cytokine
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...
August 24, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Roli Mandhana, Lily K Qian, Curt M Horvath
Excessive interferon (IFN) production and signaling can lead to immunological and developmental defects giving rise to autoimmune diseases referred to collectively as "type I interferonopathies." A subset of these diseases is caused by monogenic mutations affecting proteins involved in nucleic acid sensing, homeostasis, and metabolism. Interferonopathic mutations in the cytosolic antiviral sensor MDA5 render it constitutively hyperactive, resulting in chronic IFN production and IFN-stimulated gene expression...
August 2018: Journal of Interferon & Cytokine Research
Angela Lombardi, Effie Tsomos, Sara S Hammerstad, Yaron Tomer
IFNα is a cytokine essential to a vast array of immunologic processes. Its induction early in the innate immune response provides a priming mechanism that orchestrates numerous subsequent pathways in innate and adaptive immunity. Despite its beneficial effects in viral infections IFNα has been reported to be associated with several autoimmune diseases including autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, primary biliary cholangitis, and recently emerged as a major cytokine that triggers Type 1 Diabetes...
August 14, 2018: Journal of Autoimmunity
Andrew Fensome, Catherine M Ambler, Eric Arnold, Mary Ellen Banker, Matthew F Brown, Jill Chrencik, James D Clark, Martin E Dowty, Ivan V Efremov, Andrew Flick, Brian S Gerstenberger, Ariamala Gopalsamy, Matthew M Hayward, Martin Hegen, Brett D Hollingshead, Jason Jussif, John D Knafels, David C Limburg, David Lin, Tsung H Lin, Betsy S Pierce, Eddine Saiah, Raman Sharma, Peter T Symanowicz, Jean-Baptiste Telliez, John I Trujillo, Felix F Vajdos, Fabien Vincent, Zhao-Kui Wan, Li Xing, Xiaojing Yang, Xin Yang, Liying Zhang
Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies, leading to multiple drug approvals...
August 16, 2018: Journal of Medicinal Chemistry
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