Autoimmunity Initiates in Nonhematopoietic Cells and Progresses via Lymphocytes in an Interferon-Dependent Autoimmune Disease
Open accessAbstract
The type I interferon (IFN) response initiated by detection of nucleic acids is important for antiviral defense but is also associated with specific autoimmune diseases. Mutations in the human 3' repair exonuclease 1 (Trex1) gene cause Aicardi-Goutières syndrome (AGS), an IFN-associated autoimmune disease. However, the source of the type I IFN response and the precise mechanisms of disease in AGS remain unknown. Here, we demonstrate that Trex1 is an essential negative regulator of the STING-dependent antiviral response. We used an in vivo reporter of IFN activity in Trex1-deficient mice to localize the initiation of disease to nonhematopoietic cells. These IFNs drove T cell-mediated inflammation and an autoantibody response that targeted abundant, tissue-restricted autoantigens. However, B cells contributed to mortality independently of T cell-mediated tissue damage. These findings reveal a stepwise progression of autoimmune disease in Trex1-deficient mice, with implications for the treatment of AGS and related disorders.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
These cytosolic DNA fragments are thought to trigger a cytosolic DNA sensor, leading to aberrant production of IFNs and eventually autoimmunity.
“These are then thought to trigger a cytosolic DNA sensor, leading to aberrant production of IFNs and, eventually, autoimmunity 29.”
From Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis (2013) · cites this paper as [29]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity
Ishikawa, H., Ma, Z., & Barber, G. N. (2009) · Nature · doi:10.1038/nature08476 · Cited by 2,759 · see citing works
Self-citationPlasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide
Lande, R., Gregorio, J., Facchinetti, V., Chatterjee, B., Wang, Y.-H., Homey, B., Cao, W., Wang, Y.-H., Su, B., Nestle, F. O., et al. (2007) · Nature · doi:10.1038/nature06116 · Cited by 1,910 · see citing works
Lee-Kirsch, M. A., Gong, M., Chowdhury, D., Senenko, L., Engel, K., Lee, Y.-A., de Silva, U., Bailey, S. L., Witte, T., Vyse, T. J., et al. (2007) · Nature Genetics · doi:10.1038/ng2091 · Cited by 730 · cited 2× · see citing works
“…of Trex1 mutations in AGS, dozens of distinct mutations within the human Trex1 open reading frame have been discovered in the context of several disease phenotypes, including chilblain lupus and SLE (de Vries et al., 2010; Lee-Kirsch et al., 2007; Namjou et al., 2011; Rice et al., 2007a).”
Rice, G., Newman, W. G., Dean, J., Patrick, T., Parmar, R., Flintoff, K., Robins, P., Harvey, S., Hollis, T., O’Hara, A., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/513443 · Cited by 410 · see citing works
Flagged first, then by citations
Research works printed but not linked: 32
- Ablasser A Bauernfeind F Hartmann G Latz E Fitzgerald KA Hornung V 2009 RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate Nat Immunol 10 1065 1072 19609254 PMC3878616
- Banchereau J Pascual V 2006 Type I interferon in systemic lupus erythematosus and other autoimmune diseases Immunity 25 383 392 16979570
- Barbalat R Ewald SE Mouchess ML Barton GM 2011 Nucleic acid recognition by the innate immune system Annu Rev Immunol 29 185 214 21219183
- Barrat FJ Meeker T Gregorio J Chan JH Uematsu S Akira S Chang B Duramad O Coffman RL 2005 Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus J Exp Med 202 1131 1139 16230478 PMC2213213
- Barton GM Kagan JC 2009 A cell biological view of Toll-like receptor function: regulation through compartmentalization Nat Rev Immunol 9 535 542 19556980 PMC3934928
- Chan O Shlomchik MJ 1998 A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice J Immunol 160 51 59 9551955
- Chiu YH Macmillan JB Chen ZJ 2009 RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway Cell 138 576 591 19631370 PMC2747301
- Christensen SR Shupe J Nickerson K Kashgarian M Flavell RA Shlomchik MJ 2006 Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus Immunity 25 417 428 16973389
- Crow YJ Hayward BE Parmar R Robins P Leitch A Ali M Black DN van Bokhoven H Brunner HG Hamel BC 2006 Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus Nat Genet 38 917 920 16845398
- de Vries B Steup-Beekman GM Haan J Bollen EL Luyendijk J Frants RR Terwindt GM van Buchem MA Huizinga TW van den Maagdenberg AM Ferrari MD 2009 TREX1 gene variant in neuropsychiatric systemic lupus erythematosus Ann Rheum Dis 69 1886 1887 19875384
- Harley IT Kaufman KM Langefeld CD Harley JB Kelly JA 2009 Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies Nat Rev Genet 10 285 290 19337289 PMC2737697
- Ishii KJ Coban C Kato H Takahashi K Torii Y Takeshita F Ludwig H Sutter G Suzuki K Hemmi H 2006 A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA Nat Immunol 7 40 48 16286919
- Jin L Xu LG Yang IV Davidson EJ Schwartz DA Wurfel MM Cambier JC 2011 Identification and characterization of a loss-of-function human MPYS variant Genes Immun 12 263 269 21248775 PMC3107388
- Kolumam GA Thomas S Thompson LJ Sprent J Murali-Krishna K 2005 Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection J Exp Med 202 637 650 16129706 PMC2212878
- Kuhn R Schwenk F Aguet M Rajewsky K 1995 Inducible gene targeting in mice Science 269 1427 1429 7660125
- Leadbetter EA Rifkin IR Hohlbaum AM Beaudette BC Shlomchik MJ Marshak-Rothstein A 2002 Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors Nature 416 603 607 11948342
- Lebon P Badoual J Ponsot G Goutieres F Hemeury-Cukier F Aicardi J 1988 Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy J Neurol Sci 84 201 208 2837539
- Looney RJ 2010 B cell-targeted therapies for systemic lupus erythematosus: an update on clinical trial data Drugs 70 529 540 20297867
- Martin DA Zhang K Kenkel J Hughes G Clark E Davidson A Elkon KB 2007 Autoimmunity stimulated by adoptively transferred dendritic cells is initiated by both alphabeta and gammadelta T cells but does not require MyD88 signaling J Immunol 179 5819 5828 17947655 PMC2601662
- Morita M Stamp G Robins P Dulic A Rosewell I Hrivnak G Daly G Lindahl T Barnes DE 2004 Gene-targeted mice lacking the Trex1 (DNase III) 3′-->5′ DNA exonuclease develop inflammatory myocarditis Mol Cell Biol 24 6719 6727 15254239 PMC444847
- Nagata S Hanayama R Kawane K 2010 Autoimmunity and the clearance of dead cells Cell 140 619 630 20211132
- Namjou B Kothari PH Kelly JA Glenn SB Ojwang JO Adler A Alarcon-Riquelme ME Gallant CJ Boackle SA Criswell LA 2011 Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort Genes Immun 12 270 279 21270825 PMC3107387
- Rice G Patrick T Parmar R Taylor CF Aeby A Aicardi J Artuch R Montalto SA Bacino CA Barroso B 2007b Clinical and molecular phenotype of Aicardi-Goutieres syndrome Am J Hum Genet 81 713 725 17846997 PMC2227922
- Srinivas S Watanabe T Lin CS William CM Tanabe Y Jessell TM Costantini F 2001 Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus BMC Dev Biol 1 4 11299042 PMC31338
- Stark GR Kerr IM Williams BR Silverman RH Schreiber RD 1998 How cells respond to interferons Annu Rev Biochem 67 227 264 9759489
- Stetson DB Ko JS Heidmann T Medzhitov R 2008 Trex1 prevents cell-intrinsic initiation of autoimmunity Cell 134 587 598 18724932 PMC2626626
- Stetson DB Medzhitov R 2006a Recognition of cytosolic DNA activates an IRF3-dependent innate immune response Immunity 24 93 103 16413926
- Stetson DB Medzhitov R 2006b Type I interferons in host defense Immunity 25 373 381 16979569
- Takahashi I Iijima H Katashima R Itakura M Kiyono H 1999 Clonal expansion of CD4+ TCRbetabeta+ T cells in TCR alpha-chain- deficient mice by gut-derived antigens J Immunol 162 1843 1850 9973450
- Theofilopoulos AN Baccala R Beutler B Kono DH 2005 Type I interferons (alpha/beta) in immunity and autoimmunity Annu Rev Immunol 23 307 336 15771573
- Yan N Regalado-Magdos AD Stiggelbout B Lee-Kirsch MA Lieberman J 2010 The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1 Nat Immunol 11 1005 1013 20871604 PMC2958248
- Yang YG Lindahl T Barnes DE 2007 Trex1 Exonuclease Degrades ssDNA to Prevent Chronic Checkpoint Activation and Autoimmune Disease Cell 131 873 886 18045533
Cited by
Sorted by citations
Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing
Chen, Q., Sun, L., & Chen, Z. J. (2016) · Nature Immunology · doi:10.1038/ni.3558 · Cited by 2,333 · see citing works
The cGAS–STING pathway as a therapeutic target in inflammatory diseases
Decout, A., Katz, J. D., Venkatraman, S., & Ablasser, A. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00524-z · Cited by 2,309 · see citing works
Molecular mechanisms and cellular functions of cGAS–STING signalling
Hopfner, K.-P., & Hornung, V. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0244-x · Cited by 2,052 · see citing works
DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity
Vanpouille-Box, C., Alard, A., Aryankalayil, M. J., Sarfraz, Y., Diamond, J. M., Schneider, R. J., Inghirami, G., Coleman, C. N., Formenti, S. C., & Demaria, S. (2017) · Nature Communications · doi:10.1038/ncomms15618 · Cited by 1,834 · see citing works
CGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING.
Ablasser, A., Goldeck, M., Cavlar, T., Deimling, T., Witte, G., Röhl, I., Hopfner, K.-P., Ludwig, J., & Hornung, V. (2013) · Nature · doi:10.1038/nature12306 · Cited by 1,695 · see citing works
DNA sensing by the cGAS–STING pathway in health and disease
Motwani, M., Pesiridis, S., & Fitzgerald, K. A. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0151-1 · Cited by 1,467 · see citing works
The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer
Li, T., & Chen, Z. J. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180139 · Cited by 1,293 · see citing works
STING: infection, inflammation and cancer.
Barber, G. N. (2015) · Nature Reviews Immunology · doi:10.1038/nri3921 · Cited by 1,313 · see citing works
Self-citationTargeting STING with covalent small-molecule inhibitors
Haag, S. M., Gulen, M. F., Reymond, L., Gibelin, A., Abrami, L., Decout, A., Heymann, M., van der Goot, F. G., Turcatti, G., Behrendt, R., et al. (2018) · Nature · doi:10.1038/s41586-018-0287-8 · Cited by 1,178 · see citing works
Aicardi–Goutières syndrome and the type I interferonopathies
Crow, Y. J., & Manel, N. (2015) · Nature Reviews Immunology · doi:10.1038/nri3850 · Cited by 925 · see citing works
Härtlova, A., Erttmann, S. F., Raffi, F. A., Schmalz, A. M., Resch, U., Anugula, S., Lienenklaus, S., Nilsson, L. M., Kröger, A., Nilsson, J. A., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.01.012 · Cited by 716 · see citing works
Recognition of Endogenous Nucleic Acids by the Innate Immune System
Roers, A., Hiller, B., & Hornung, V. (2016) · Immunity · doi:10.1016/j.immuni.2016.04.002 · Cited by 541 · see citing works
STING and the innate immune response to nucleic acids in the cytosol
Burdette, D. L., & Vance, R. E. (2013) · Nature Immunology · doi:10.1038/ni.2491 · Cited by 501 · see citing works
Taming lupus-a new understanding of pathogenesis is leading to clinical advances
Liu, Z., & Davidson, A. (2012) · Nature Medicine · doi:10.1038/nm.2752 · Cited by 433 · see citing works
Thomas, C. A., Tejwani, L., Trujillo, C. A., Negraes, P. D., Herai, R. H., Mesci, P., Macia, A., Crow, Y. J., & Muotri, A. R. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2017.07.009 · Cited by 330 · see citing works
Interleukin-1β Induces mtDNA Release to Activate Innate Immune Signaling via cGAS-STING
Aarreberg, L. D., Esser-Nobis, K., Driscoll, C., Shuvarikov, A., Roby, J. A., & Gale, M. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.02.038 · Cited by 328 · see citing works
Self-citationC9orf72 in myeloid cells suppresses STING-induced inflammation
McCauley, M. E., O’Rourke, J. G., Yáñez, A., Markman, J. L., Ho, R., Wang, X., Chen, S., Lall, D., Jin, M., Muhammad, A. K. M. G., et al. (2020) · Nature · doi:10.1038/s41586-020-2625-x · Cited by 298 · see citing works
Hartmann, G. (2017) · Advances in Immunology · doi:10.1016/bs.ai.2016.11.001 · Cited by 285 · see citing works
Cytosolic DNA Sensing in Organismal Tumor Control
Vanpouille-Box, C., Demaria, S., Formenti, S. C., & Galluzzi, L. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.05.013 · Cited by 250 · see citing works
USP18 lack in microglia causes destructive interferonopathy of the mouse brain
Goldmann, T., Zeller, N., Raasch, J., Kierdorf, K., Frenzel, K., Ketscher, L., Basters, A., Staszewski, O., Brendecke, S. M., Spiess, A., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490791 · Cited by 223 · see citing works
Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response
Mackenzie, K. J., Carroll, P., Lettice, L., Tarnauskaitė, Ž., Reddy, K., Dix, F., Revuelta, A., Abbondati, E., Rigby, R. E., Rabe, B., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201593339 · Cited by 248 · see citing works
Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity
Hiller, B., Achleitner, M., Glage, S., Naumann, R., Behrendt, R., & Roers, A. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20120876 · Cited by 245 · see citing works
Pokatayev, V., Hasin, N., Chon, H., Cerritelli, S. M., Sakhuja, K., Ward, J. M., Morris, H. D., Yan, N., & Crouch, R. J. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20151464 · Cited by 245 · see citing works
Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy
Lan, Y. Y., Londoño, D., Bouley, R., Rooney, M. S., & Hacohen, N. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.074 · Cited by 236 · see citing works
Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy
Bartsch, K., Knittler, K., Borowski, C., Rudnik, S., Damme, M., Aden, K., Spehlmann, M. E., Frey, N., Saftig, P., Chalaris, A., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx283 · Cited by 196 · see citing works
p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression
Ghosh, M., Saha, S., Li, J., Montrose, D. C., & Martinez, L. A. (2023) · Molecular Cell · doi:10.1016/j.molcel.2022.12.023 · Cited by 166 · see citing works
Pelka, K., Shibata, T., Miyake, K., & Latz, E. (2016) · Immunological Reviews · doi:10.1111/imr.12375 · Cited by 110 · see citing works
Wang, Y., Fu, Z., Li, X., Liang, Y., Pei, S., Hao, S., Zhu, Q., Yu, T., Pei, Y., Yuan, J., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.02.003 · Cited by 84 · see citing works
Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis
Young, G. R., Stoye, J. P., & Kassiotis, G. (2013) · BioEssays · doi:10.1002/bies.201300049 · Cited by 78 · see citing works
“These are then thought to trigger a cytosolic DNA sensor, leading to aberrant production of IFNs and, eventually, autoimmunity [29].”
BackgroundBartsch, K., Damme, M., Regen, T., Becker, L., Garrett, L., Hölter, S. M., Knittler, K., Borowski, C., Waisman, A., Glatzel, M., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00587 · Cited by 20 · see citing works
- Authors
- Gall, A., Treuting, P., Elkon, K. B., Loo, Y.-M., Gale, M., Barber, G. N., & Stetson, D. B.
- Affiliations
- University of Washington (US)
- University of Miami (US)
- Corresponding author
- Stetson, Daniel B.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 36
- Issue
- 1
- Pages
- 120-131
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3269499
- OpenAlex
- W2116778443
- Cited by
- 510
- References
- 4
- Citations by year
- 2026: 21 · 2025: 36 · 2024: 27 · 2023: 21 · 2022: 37 · 2021: 39 · 2020: 30 · 2019: 42 · 2018: 34 · 2017: 22 · 2016: 36 · 2015: 47 · 2014: 46 · 2013: 48 · 2012: 24
- FWCI
- 23.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI084914, R01AI084914)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR048796, AR48796)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- Aicardi-Goutières syndrome, TREX1, type I interferon, STING, autoimmunity, non-hematopoietic cells, T cell-mediated inflammation, autoantibodies, B cells, autoantigens, nucleic acid sensing, antiviral response
- MeSH terms
- Animals, Autoimmune Diseases, Exodeoxyribonucleases, Interferons, Lymphocytes, Models, Biological, Nervous System Malformations, Phosphoproteins, Signal Transduction, Autoimmunity, Mice, Knockout, Autoimmune Diseases of the Nervous System, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
