Lack of Trex1 Causes Systemic Autoimmunity despite the Presence of Antiretroviral Drugs
| Autor: | Alexander Gerbaulet, Rayk Behrendt, Benjamin Gabriel, Martin Kleefisch, Min Ae Lee-Kirsch, Axel Roers, Martin Achleitner, Uwe Fiebig, Anastasia Polikarpova, Reinhard Oertel, Alexander Hennig, Livia Schulze, Katrin Peschke, Dirk Lindeman |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
DNA Complementary Retroelements Immunology Three prime repair exonuclease 1 Autoimmunity Retrotransposon Endogeny Inflammation Disease Biology Nervous System Malformations medicine.disease_cause Mice 03 medical and health sciences Autoimmune Diseases of the Nervous System 0302 clinical medicine Complementary DNA medicine Animals Humans Immunology and Allergy education education.field_of_study Reverse Transcription Phosphoproteins Reverse transcriptase Exodeoxyribonucleases 030104 developmental biology Interferon Type I Mutation Reverse Transcriptase Inhibitors medicine.symptom 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | The Journal of Immunology. 199:2261-2269 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1700714 |
| Popis: | Biallelic mutations of three prime repair exonuclease 1 (TREX1) cause the lupus-like disease Aicardi–Goutières syndrome in which accumulation of a yet unknown endogenous DNA substrate of TREX1 triggers a cyclic GMP–AMP synthase-dependent type I IFN response and systemic autoimmunity. Products of reverse transcription originating from endogenous retroelements have been suggested to be a major substrate for TREX1, and reverse transcriptase inhibitors (RTIs) were proposed as a therapeutic option in autoimmunity ensuing from defects of TREX1. In this study, we treated Trex1−/− mice with RTIs. The serum RTI levels reached were sufficient to block retrotransposition of endogenous retroelements. However, the treatment did not reduce the spontaneous type I IFN response and did not ameliorate lethal inflammation. Furthermore, long interspersed nuclear elements 1 retrotransposition was not enhanced in the absence of Trex1. Our data do not support the concept of retroelement-derived cDNA as key triggers of systemic autoimmunity in Trex1-deficient humans and mice and motivate the continuing search for the pathogenic IFN-inducing Trex1 substrate. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|