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Mannie Man Wai Lam, Jonathan P Mapletoft, Matthew S Miller
Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis are a few examples of debilitating neurological/neurodegenerative diseases for which there are currently no curative treatments. Recent evidence has strongly suggested a role for neuroinflammation in both the onset and progression of these diseases. However, the mechanisms that initiate neuroinflammation are presently unclear. Mounting evidence suggests that environmental factors are likely involved. One proposed mechanism linking both genetic and environmental factors is dysregulation of the antiviral response...
December 2016: Cytokine
Hanna Kim, Gina A Montealegre Sanchez, Raphaela Goldbach-Mansky
Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever and disease-specific patterns of organ inflammation. Recently, the discoveries of monogenic disorders with strong type I interferon (IFN) signatures caused by mutations in proteasome degradation and cytoplasmic RNA and DNA sensing pathways suggest a pathogenic role of IFNs in causing autoinflammatory phenotypes. The IFN response gene signature (IGS) has been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases...
October 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
C Picard, A Belot
Thanks to the tremendous progress of genetics, a new field of inherited inflammatory disorders related to an overproduction of interferon has recently emerged. The so-called type I interferonopathies represent an heterogeneous group of Mendelian diseases presenting with various features starting in childhood, although the diagnosis can also be made later in life. Several clinical and biological characteristics are shared across these patients such as a positive interferon (IFN) signature and neurological and cutaneous involvement, some of which display organ specificity...
September 19, 2016: La Revue de Médecine Interne
John H Livingston, Yanick J Crow
The Aicardi-Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7)...
September 19, 2016: Neuropediatrics
Min Ae Lee-Kirsch, Claudia Günther, Axel Roers
No abstract text is available yet for this article.
October 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Gholamreza Azizi, Mohsen Rastegar Pouyani, Hassan Abolhassani, Laleh Sharifi, Majid Zaki Dizaji, Javad Mohammadi, Abbas Mirshafiey, Asghar Aghamohammadi
Primary immunodeficiencies (PIDs) constitute a large group of rare disorders that affect the function of the immune system. A specific group of PIDs entitled "diseases of immune dysregulation" are developed due to mutation in the genes which have critical roles in the regulation of immune responses and immunological tolerance. This group of PID patients develop autoimmune and inflammatory disorders as a result of their impaired immunity, therefore they could be considered as a model for analyzing the link between immune dysregulation and autoimmunity...
August 27, 2016: Cellular Immunology
Cécile Picard, Guillaume Thouvenin, Caroline Kannengiesser, Jean-Christophe Dubus, Nadia Jeremiah, Frédéric Rieux-Laucat, Bruno Crestani, Alexandre Belot, Françoise Thivolet-Béjui, Véronique Secq, Christelle Ménard, Martine Reynaud-Gaubert, Philippe Reix
We report three cases of pulmonary disease suggesting fibrosis in two familial and one sporadic case. Pulmonary symptoms were associated with various clinical features of systemic inflammation and vasculitis involving the skin, and appeared at different ages. A strong interferon signature was found in all three cases. Disease was not responsive to corticosteroids, and lung transplantation was considered for all three subjects at an early age. One of them underwent double-lung transplantation, but she immediately experienced a primary graft dysfunction and died soon after...
September 2016: Chest
Marie-Louise Frémond, Mathieu Paul Rodero, Nadia Jeremiah, Alexandre Belot, Eric Jeziorski, Darragh Duffy, Didier Bessis, Guilhem Cros, Gillian I Rice, Bruno Charbit, Anne Hulin, Nihel Khoudour, Consuelo Modesto Caballero, Christine Bodemer, Monique Fabre, Laureline Berteloot, Muriel Le Bourgeois, Philippe Reix, Thierry Walzer, Despina Moshous, Stéphane Blanche, Alain Fischer, Brigitte Bader-Meunier, Fréderic Rieux-Laucat, Yanick Joseph Crow, Bénédicte Neven
BACKGROUND: Gain-of-function mutations in TMEM173 encoding STING (Stimulator of Interferon Genes) underlie a novel type I interferonopathy. This disease is seemingly minimally responsive to conventional immunosuppressive therapies - and thus associated with high childhood morbidity and mortality. OBJECTIVE: Our aim was to describe the use of ruxolitinib, an oral Janus kinase (JAK) 1/2 inhibitor, in the treatment of vasculopathy associated with TMEM173-activating mutations...
August 20, 2016: Journal of Allergy and Clinical Immunology
Victoria Marcu-Malina, Sanja Goldberg, Einav Vax, Ninette Amariglio, Itamar Goldstein, Gideon Rechavi
Adenosine deaminase acting on RNA (ADAR) 1 is the master editor of the transcriptome, catalyzing the conversion of adenosine to inosine (A-to-I). RNA transcripts fold into a variety of secondary structures including long intramolecular RNA duplexes that are the major substrate of ADAR1. Most A-to-I editing sites occur within RNA duplexes formed by complementary pairing of inverted retrotransposable elements interspersed within noncoding regions of transcripts. This catalytic activity of ADAR1 most likely prevents the abnormal activation of cytosolic nucleic acid sensors by self-dsRNAs...
August 2, 2016: Oncotarget
Eugen Feist, Gerd-Rüdiger Burmester, Elke Krüger
The ubiquitin proteasome system is closely connected to apoptosis, autophagy, signaling of inflammatory cytokines and generation of ligands for MHC class I antigen presentation. Proteasome function in the innate immune response becomes particularly evident in patients with proteasome-associated autoinflammatory syndromes (PRAAS), where disease causing mutations result in reduced proteasome activity. PRAAS can be classified as a novel type of interferonopathy, however the molecular mechanism and signaling pathways leading from impaired proteasome capacity, the accumulation of damaged proteins, and the induction of type I IFN-genes remain to be determined...
July 27, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Maroof Hasan, Nan Yan
The serine/threonine protein kinase, TBK1, plays a crucial role as the hub for many innate immune signaling pathways that lead to the induction of type I interferon (IFN) and interferon-stimulated genes (ISGs). Due to its key function in maintaining homeostasis of the immune system, cell survival and proliferation, TBK1 activity is tightly regulated. Dysregulation of TBK1 activity is often associated with autoimmune diseases and cancer, implicating the potential therapeutic benefit for targeting TBK1. Tremendous effort from both academic institutions and private sectors during the past few years has led to the development of many potent and selective TBK1 inhibitors, many of which have shown great promise in disease models in vivo...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Marije E C Meuwissen, Rachel Schot, Sofija Buta, Grétel Oudesluijs, Sigrid Tinschert, Scott D Speer, Zhi Li, Leontine van Unen, Daphne Heijsman, Tobias Goldmann, Maarten H Lequin, Johan M Kros, Wendy Stam, Mark Hermann, Rob Willemsen, Rutger W W Brouwer, Wilfred F J Van IJcken, Marta Martin-Fernandez, Irenaeus de Coo, Jeroen Dudink, Femke A T de Vries, Aida Bertoli Avella, Marco Prinz, Yanick J Crow, Frans W Verheijen, Sandra Pellegrini, Dusan Bogunovic, Grazia M S Mancini
Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families...
June 27, 2016: Journal of Experimental Medicine
Stefano Volpi, Paolo Picco, Roberta Caorsi, Fabio Candotti, Marco Gattorno
Defective regulation of type I interferon response is associated with severe inflammatory phenotypes and autoimmunity. Type I interferonopathies are a clinically heterogenic group of Mendelian diseases with a constitutive activation of this pathway that might present as atypical, severe, early onset rheumatic diseases. Skin vasculopathy with chilblains and livedo reticularis, interstitial lung disease, and panniculitis are common. Recent studies have implicated abnormal responses to nucleic acid stimuli or defective regulation of downstream effector molecules in disease pathogenesis...
2016: Pediatric Rheumatology Online Journal
Sharon A Chung, Anthony K Shum
PURPOSE OF REVIEW: We review select studies of newly discovered rare variants in autoimmune diseases with a focus on newly described monogenic disorders, rheumatoid arthritis, and systemic lupus erythematosus. RECENT FINDINGS: Two new monogenic syndromes of inflammatory arthritis were discovered using whole exome sequencing: the coatomer subunit alpha syndrome because of rare mutations in coatomer subunit alpha and haploinsufficiency of A20 resulting from rare mutations in TNFAIP3...
July 2016: Current Opinion in Rheumatology
Jacki E Heraud-Farlow, Carl R Walkley
The innate immune system is the first line of the cellular defence against invading pathogens. A critical component of this defence is the capacity to discriminate foreign RNA molecules, which are distinct from most cellular RNAs in structure and/or modifications. However, a series of rare autoimmune/autoinflammatory diseases in humans highlight the propensity for the innate immune sensing system to be activated by endogenous cellular double-stranded RNAs (dsRNAs), underscoring the fine line between distinguishing self from non-self...
April 5, 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Insa Buers, Yvonne Nitschke, Frank Rutsch
Type I interferonopathies are a relatively new class of inherited autoimmune disorders associated with an inborn elevated interferon response. Activation of cytosolic receptors which recognize viral double stranded RNA including the RIG-I (retinoic acid-inducible gene I) like receptors RIG-I and MDA5 (melanoma differentiation-associated gene 5) has been shown to induce the transcription of type I interferon genes. Within recent years, with the help of next generation sequencing techniques in syndromic families, mutations in the genes encoding for RIG-I and MDA5 have been identified to cause rare diseases including Aicardi-Goutières syndrome, Systemic Lupus Erythematosus in certain individuals as well as classic and atypical Singleton-Merten syndrome...
March 11, 2016: Cytokine & Growth Factor Reviews
Karen J Mackenzie, Paula Carroll, Laura Lettice, Žygimantė Tarnauskaitė, Kaalak Reddy, Flora Dix, Ailsa Revuelta, Erika Abbondati, Rachel E Rigby, Björn Rabe, Fiona Kilanowski, Graeme Grimes, Adeline Fluteau, Paul S Devenney, Robert E Hill, Martin Am Reijns, Andrew P Jackson
Aicardi-Goutières syndrome (AGS) provides a monogenic model of nucleic acid-mediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease (RNase) H2 enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus. Reduced processing of eitherRNA:DNAhybrid or genome-embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid-sensing pathway...
April 15, 2016: EMBO Journal
Maroof Hasan, Nicole Dobbs, Shaheen Khan, Michael A White, Edward K Wakeland, Quan-Zhen Li, Nan Yan
TANK-binding kinase 1 (TBK1) is a serine/threonine protein kinase that plays a crucial role in innate immunity. Enhanced TBK1 function is associated with autoimmune diseases and cancer, implicating the potential benefit of therapeutically targeting TBK1. In this article, we examined a recently identified TBK1 inhibitor Compound II on treating autoimmune diseases. We found that Compound II is a potent and specific inhibitor of TBK1-mediated IFN response. Compound II inhibited polyinosinic-polycytidylic acid-induced immune activation in vitro and in vivo...
November 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Tobias Goldmann, Thomas Blank, Marco Prinz
Type I interferons (IFN) are pleiotropic cytokines originally described as molecules used for communication between cells to trigger the protective defenses against viral infections. Upon activation, type I IFN can be produced locally in the central nervous system (CNS) from a number of different cell types including microglia, the CNS-resident macrophages. Increased type I IFN production and signaling in microglia are critically important to limit viral infection and disease progression in multiple sclerosis...
February 2016: Current Opinion in Neurobiology
J Munoz, M Marque, M Dandurand, L Meunier, Y-J Crow, D Bessis
Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date, interferonopathies include Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, PRoteasome-associated auto-inflammatory syndrome (PRAAS) and Singleton-Merten syndrome. These diseases present phenotypic overlap including cutaneous features like chilblain lupus, that can be inaugural or present within the first months of life. This novel set of inborn errors of immunity is evolving rapidly, with recognition of new diseases and genes...
November 2015: Annales de Dermatologie et de Vénéréologie
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