Lack of Trex1 Causes Systemic Autoimmunity despite the Presence of Antiretroviral Drugs

J Immunol. 2017 Oct 1;199(7):2261-2269. doi: 10.4049/jimmunol.1700714. Epub 2017 Aug 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases of the Nervous System / immunology
  • Autoimmunity*
  • DNA, Complementary
  • Exodeoxyribonucleases / deficiency
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism*
  • HeLa Cells
  • Humans
  • Inflammation
  • Interferon Type I / biosynthesis
  • Interferon Type I / immunology
  • Mice
  • Mutation
  • Nervous System Malformations / immunology
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Retroelements
  • Reverse Transcriptase Inhibitors / adverse effects
  • Reverse Transcriptase Inhibitors / blood*
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Reverse Transcription

Substances

  • DNA, Complementary
  • Interferon Type I
  • Phosphoproteins
  • Retroelements
  • Reverse Transcriptase Inhibitors
  • Exodeoxyribonucleases
  • three prime repair exonuclease 1

Supplementary concepts

  • Aicardi-Goutieres syndrome