| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Crow, Yanick J. Kasher, Paul R. Briolat, Valérie Zeef, Leo A. H. Levraud, Jean-Pierre Jenkinson, Emma M. Gent, David Morrissey, Catherine Rice, Gillian I. |
| Description |
Author Affiliation: Kasher PR ( Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom); Jenkinson EM ( Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom); Briolat V ( Institut Pasteur, Macrophages et Développement de l'Immunité, F-75015 Paris, France); Gent D ( Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom); Morrissey C ( Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom); Zeef LA ( Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom); Rice GI ( Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom); Levraud JP ( Institut Pasteur, Macrophages et Développement de l'Immunité, F-75015 Paris, France); Crow YJ ( Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom) |
| Abstract |
In humans, loss of function mutations in the SAMHD1 (AGS5) gene cause a severe form of Aicardi-Goutières syndrome (AGS), an inherited inflammatory-mediated encephalopathy characterized by increased type I IFN activity and upregulation of IFN-stimulated genes (ISGs). In particular, SAMHD1-related AGS is associated with a distinctive cerebrovascular pathology that commonly leads to stroke. Although inflammatory responses are observed in immune cells cultured from Samhd1 null mouse models, these mice are physically healthy, specifically lacking a brain phenotype. We have investigated the use of zebrafish as an alternative system for generating a clinically relevant model of SAMHD1-related AGS. Using temporal gene knockdown of zebrafish samhd1, we observe hindbrain ventricular swelling and brain hemorrhage. Furthermore, loss of samhd1 or of another AGS-associated gene, adar, leads to a significant upregulation of innate immune-related genes and an increase in the number of cells expressing the zebrafish type I IFN ifnphi1. To our knowledge, this is the first example of an in vivo model of AGS that recapitulates features of both the innate immune and neurological characteristics of the disease. The phenotypes associated with loss of samhd1 and adar suggest a function of these genes in controlling innate immune processes conserved to zebrafish, thereby also contributing to our understanding of antiviral signaling in this model organism. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| Journal |
The Journal of Immunology |
| Issue Number |
6 |
| Volume Number |
194 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2015-03-15 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Acid Anhydride Hydrolases Genetics Autoimmune Diseases Of The Nervous System Gene Knockdown Techniques Interferon Type I Nervous System Malformations Zebrafish Proteins Metabolism Adenosine Deaminase Amino Acid Sequence Animals Animals, Genetically Modified Embryology Blotting, Western Cerebral Ventricles Abnormalities Disease Models, Animal Gene Expression Regulation, Developmental Immunity, Innate Interferons Intracranial Hemorrhages Microscopy, Fluorescence Molecular Sequence Data Reverse Transcriptase Polymerase Chain Reaction Rhombencephalon Sequence Homology, Amino Acid Zebrafish Deficiency Research Support, Non-u.s. Gov't Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
