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Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease.

ABSTRACT: The TREX1 gene encodes a potent DNA exonuclease, and mutations in TREX1 cause a spectrum of lupus-like autoimmune diseases. Most lupus patients develop autoantibodies to double-stranded DNA (dsDNA), but the source of DNA antigen is unknown. The TREX1 D18N mutation causes a monogenic, cutaneous form of lupus called familial chilblain lupus, and the TREX1 D18N enzyme exhibits dysfunctional dsDNA-degrading activity, providing a link between dsDNA degradation and nucleic acid-mediated autoimmune disease. We determined the structure of the TREX1 D18N protein in complex with dsDNA, revealing how this exonuclease uses a novel DNA-unwinding mechanism to separate the polynucleotide strands for single-stranded DNA (ssDNA) loading into the active site. The TREX1 D18N dsDNA interactions coupled with catalytic deficiency explain how this mutant nuclease prevents dsDNA degradation. We tested the effects of TREX1 D18N in vivo by replacing the TREX1 WT gene in mice with the TREX1 D18N allele. The TREX1 D18N mice exhibit systemic inflammation, lymphoid hyperplasia, vasculitis, and kidney disease. The observed lupus-like inflammatory disease is associated with immune activation, production of autoantibodies to dsDNA, and deposition of immune complexes in the kidney. Thus, dysfunctional dsDNA degradation by TREX1 D18N induces disease in mice that recapitulates many characteristics of human lupus. Failure to clear DNA has long been linked to lupus in humans, and these data point to dsDNA as a key substrate for TREX1 and a major antigen source in mice with dysfunctional TREX1 enzyme.

SUBMITTER: Grieves JL

PROVIDER: S-EPMC4413332 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease.

Grieves Jessica L JL Fye Jason M JM Harvey Scott S Grayson Jason M JM Hollis Thomas T Perrino Fred W FW

Proceedings of the National Academy of Sciences of the United States of America 20150406 16

The TREX1 gene encodes a potent DNA exonuclease, and mutations in TREX1 cause a spectrum of lupus-like autoimmune diseases. Most lupus patients develop autoantibodies to double-stranded DNA (dsDNA), but the source of DNA antigen is unknown. The TREX1 D18N mutation causes a monogenic, cutaneous form of lupus called familial chilblain lupus, and the TREX1 D18N enzyme exhibits dysfunctional dsDNA-degrading activity, providing a link between dsDNA degradation and nucleic acid-mediated autoimmune dis ...[more]

PMID: 25848017

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Project description:ObjectiveElevated double-stranded DNA (dsDNA) antibody levels in blood serum are considered a disease-specific marker in systemic lupus erythematosus (SLE), correlate with disease activity and the incidence of lupus nephritis, and can be detected in up to 86% of all SLE cases. Despite the high clinical relevance, the variety of dsDNA antibody testing methods with heterogenous performance in clinical use remains challenging. This study is the first to prospectively investigate the performance of two of today's most commonly applied anti-dsDNA testing methods head-to-head under real-world conditions, as well as their correlation with other clinical and serological disease parameters in SLE patients.MethodsIn this prospective study, all SLE patients undergoing treatment at the Department of Rheumatology at the University Hospital Bonn within a 13-months period (n=41) and control patients without connective-tissue disease (n=51) were consecutively enrolled and examined. For all study participants' serum samples both anti-dsDNA-NcX enzyme-linked immunoassay testing EUROIMMUN, Luebeck, Germany) and the fluorescence immunoassay ELiA dsDNA (Thermo Fisher Scientific, Waltham, USA) were performed. In addition, demographic data, further laboratory values and disease activity parameters were recorded. Clinical disease activity was assessed by SLEDAI-2K.ResultsBoth assays showed high specificity (anti-dsDNA-NcX ELISA: 0.9, ELiA dsDNA: 0.959), but there were notable differences in sensitivity (anti-dsDNA-NcX ELISA: 0.51, ELiA dsDNA: 0.38). Pearsons's correlation yielded a positive correlation between anti-dsDNA concentrations and CRP concentrations for the anti-dsDNA-NcX ELISA (R=0.22; p=0.038) and a mild-to-moderate inverse correlation between concentrations of anti-dsDNA and complement C4 for the ELiA dsDNA test (R=-0.22; p=0.045) when SLE and control patients were considered together. Other than, no significant correlation between anti-dsDNA concentrations and clinical or laboratory findings was found for either test procedure.ConclusionBoth anti-dsDNA antibody assays represent reliable examination methods with high specificity for the diagnosis of SLE that fulfill EULAR/ACR requirements. However, the anti-dsDNA-NcX ELISA showed superior sensitivity and significant correlation with disease activity (as measured by CRP concentrations).

Dataset Information

Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease.

Publications

Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease.

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