1932

Abstract

Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. The existence of these sensors raises fundamental questions about self/nonself discrimination because of the abundance of self-DNA and self-RNA that occupy these same compartments. Recent advances have revealed that enzymes that metabolize or modify endogenous nucleic acids are essential for preventing inappropriate activation of the innate antiviral response. In this review, we discuss rare human diseases caused by dysregulated nucleic acid sensing, focusing primarily on intracellular sensors of nucleic acids. We summarize lessons learned from these disorders, we rationalize the existence of these diseases in the context of evolution, and we propose that this framework may also apply to a number of more common autoimmune diseases for which the underlying genetics and mechanisms are not yet fully understood.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-051116-052331
2017-04-26
2024-06-17
Loading full text...

Full text loading...

/deliver/fulltext/immunol/35/1/annurev-immunol-051116-052331.html?itemId=/content/journals/10.1146/annurev-immunol-051116-052331&mimeType=html&fmt=ahah

Literature Cited

  1. Burnet FMS. 1.  1969. Self and Not-Self Melbourne, Aust.: Melbourne Univ. Press [Google Scholar]
  2. Janeway CA Jr. 2.  1989. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54:Part 11–13 [Google Scholar]
  3. Barbalat R, Ewald SE, Mouchess ML, Barton GM. 3.  2011. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29:185–214 [Google Scholar]
  4. Goubau D, Deddouche S, Reis ESC. 4.  2013. Cytosolic sensing of viruses. Immunity 38:855–69 [Google Scholar]
  5. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S. 5.  et al. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408:740–45 [Google Scholar]
  6. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. 6.  2001. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413:732–38 [Google Scholar]
  7. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H. 7.  et al. 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3:196–200 [Google Scholar]
  8. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C. 8.  et al. 2004. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303:1526–29 [Google Scholar]
  9. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. 9.  2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–31 [Google Scholar]
  10. Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC. 10.  et al. 2004. Recognition of single-stranded RNA viruses by Toll-like receptor 7. PNAS 101:5598–603 [Google Scholar]
  11. Takeda K, Kaisho T, Akira S. 11.  2003. Toll-like receptors. Annu. Rev. Immunol. 21:335–76 [Google Scholar]
  12. Iwasaki A, Medzhitov R. 12.  2004. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5:987–95 [Google Scholar]
  13. Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P. 13.  et al. 2006. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat. Immunol. 7:156–64 [Google Scholar]
  14. Lee BL, Moon JE, Shu JH, Yuan L, Newman ZR. 14.  et al. 2013. UNC93B1 mediates differential trafficking of endosomal TLRs. eLife 2:e00291 [Google Scholar]
  15. Miyake K, Shibata T, Ohto U, Shimizu T. 15.  2017. Emerging roles of the processing of nucleic acids and Toll-like receptors in innate immune responses to nucleic acids. J. Leukoc. Biol. 101:135–42 [Google Scholar]
  16. Barton GM, Kagan JC, Medzhitov R. 16.  2006. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat. Immunol. 7:49–56 [Google Scholar]
  17. Mouchess ML, Arpaia N, Souza G, Barbalat R, Ewald SE. 17.  et al. 2011. Transmembrane mutations in Toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation. Immunity 35:721–32 [Google Scholar]
  18. Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP. 18.  et al. 2008. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456:658–62 [Google Scholar]
  19. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T. 19.  et al. 2005. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434:1035–40 [Google Scholar]
  20. Pichlmair A, Reis e Sousa C. 20.  2007. Innate recognition of viruses. Immunity 27:370–83 [Google Scholar]
  21. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ. 21.  et al. 2002. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603–7 [Google Scholar]
  22. Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. 22.  2006. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25:417–28 [Google Scholar]
  23. Teichmann LL, Schenten D, Medzhitov R, Kashgarian M, Shlomchik MJ. 23.  2013. Signals via the adaptor MyD88 in B cells and DCs make distinct and synergistic contributions to immune activation and tissue damage in lupus. Immunity 38:528–40 [Google Scholar]
  24. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T. 24.  et al. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5:730–37 [Google Scholar]
  25. Hornung V, Ellegast J, Kim S, Brzozka K, Jung A. 25.  et al. 2006. 5′-Triphosphate RNA is the ligand for RIG-I. Science 314:994–97 [Google Scholar]
  26. Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P. 26.  et al. 2006. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314:997–1001 [Google Scholar]
  27. Goubau D, Schlee M, Deddouche S, Pruijssers AJ, Zillinger T. 27.  et al. 2014. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates. Nature 514:372–75 [Google Scholar]
  28. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M. 28.  et al. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–5 [Google Scholar]
  29. Seth RB, Sun L, Ea CK, Chen ZJ. 29.  2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3. Cell 122:669–82 [Google Scholar]
  30. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M. 30.  et al. 2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–72 [Google Scholar]
  31. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB. 31.  2005. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19:727–40 [Google Scholar]
  32. Kawai T, Takahashi K, Sato S, Coban C, Kumar H. 32.  et al. 2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6:981–88 [Google Scholar]
  33. Stetson DB, Medzhitov R. 33.  2006. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24:93–103 [Google Scholar]
  34. Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y. 34.  et al. 2006. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. 7:40–48 [Google Scholar]
  35. Sun L, Wu J, Du F, Chen X, Chen ZJ. 35.  2013. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–91 [Google Scholar]
  36. Wu J, Sun L, Chen X, Du F, Shi H. 36.  et al. 2013. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339:826–30 [Google Scholar]
  37. Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL. 37.  et al. 2013. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153:1094–107 [Google Scholar]
  38. Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G. 38.  et al. 2013. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498:380–84 [Google Scholar]
  39. Diner EJ, Burdette DL, Wilson SC, Monroe KM, Kellenberger CA. 39.  et al. 2013. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep 3:1355–61 [Google Scholar]
  40. Ishikawa H, Barber GN. 40.  2008. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455:674–78 [Google Scholar]
  41. Zhong B, Yang Y, Li S, Wang YY, Li Y. 41.  et al. 2008. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29:538–50 [Google Scholar]
  42. Ishikawa H, Ma Z, Barber GN. 42.  2009. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–92 [Google Scholar]
  43. Gao D, Wu J, Wu YT, Du F, Aroh C. 43.  et al. 2013. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341:903–6 [Google Scholar]
  44. Chen Q, Sun L, Chen ZJ. 44.  2016. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat. Immunol. 17:1142–49 [Google Scholar]
  45. Rifkin IR, Leadbetter EA, Busconi L, Viglianti G, Marshak-Rothstein A. 45.  2005. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol. Rev. 204:27–42 [Google Scholar]
  46. Marshak-Rothstein A, Rifkin IR. 46.  2007. Immunologically active autoantigens: the role of Toll-like receptors in the development of chronic inflammatory disease. Annu. Rev. Immunol. 25:419–41 [Google Scholar]
  47. Christensen SR, Shlomchik MJ. 47.  2007. Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors. Semin. Immunol. 19:11–23 [Google Scholar]
  48. Rosen A, Casciola-Rosen L. 48.  2016. Autoantigens as partners in initiation and propagation of autoimmune rheumatic diseases. Annu. Rev. Immunol. 34:395–420 [Google Scholar]
  49. Crow YJ. 49.  2011. Type I interferonopathies: a novel set of inborn errors of immunity. Ann. N. Y. Acad. Sci. 1238:91–98 [Google Scholar]
  50. de Jesus AA, Canna SW, Liu Y, Goldbach-Mansky R. 50.  2015. Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling. Annu. Rev. Immunol. 33:823–74 [Google Scholar]
  51. Crow YJ, Manel N. 51.  2015. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15:429–40 [Google Scholar]
  52. Roers A, Hiller B, Hornung V. 52.  2016. Recognition of endogenous nucleic acids by the innate immune system. Immunity 44:739–54 [Google Scholar]
  53. Aicardi J, Goutières F. 53.  1984. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann. Neurol. 15:49–54 [Google Scholar]
  54. Lebon P, Badoual J, Ponsot G, Goutières F, Hemeury-Cukier F, Aicardi J. 54.  1988. Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J. Neurol. Sci. 84:201–8 [Google Scholar]
  55. McGonagle D, McDermott MF. 55.  2006. A proposed classification of the immunological diseases. PLOS Med 3:e297 [Google Scholar]
  56. Masters SL, Simon A, Aksentijevich I, Kastner DL. 56.  2009. Horror Autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu. Rev. Immunol. 27:621–68 [Google Scholar]
  57. Brydges SD, Mueller JL, McGeough MD, Pena CA, Misaghi A. 57.  et al. 2009. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30:875–87 [Google Scholar]
  58. Cuadrado E, Vanderver A, Brown KJ, Sandza A, Takanohashi A. 58.  et al. 2015. Aicardi-Goutières syndrome harbours abundant systemic and brain-reactive autoantibodies. Ann. Rheum. Dis. 74:1931–39 [Google Scholar]
  59. Stetson DB, Ko JS, Heidmann T, Medzhitov R. 59.  2008. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134:587–98 [Google Scholar]
  60. Gall A, Treuting P, Elkon KB, Loo YM, Gale M Jr.. 60.  et al. 2012. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36:120–31 [Google Scholar]
  61. Crow YJ, Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GM. 61.  et al. 2015. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am. J. Med. Genet. A 167A296–312 [Google Scholar]
  62. Livingston JH, Crow YJ. 62.  2016. Neurologic phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutières syndrome and beyond. Neuropediatrics 47:355–60 [Google Scholar]
  63. Lindahl T, Gally JA, Edelman GM. 63.  1969. Properties of deoxyribonuclease 3 from mammalian tissues. J. Biol. Chem. 244:5014–19 [Google Scholar]
  64. Hoss M, Robins P, Naven TJ, Pappin DJ, Sgouros J, Lindahl T. 64.  1999. A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein. EMBO J 18:3868–75 [Google Scholar]
  65. Mazur DJ, Perrino FW. 65.  1999. Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3′→5′ exonucleases. J. Biol. Chem. 274:19655–60 [Google Scholar]
  66. Chowdhury D, Beresford PJ, Zhu P, Zhang D, Sung JS. 66.  et al. 2006. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol. Cell 23:133–42 [Google Scholar]
  67. Mazur DJ, Perrino FW. 67.  2001. Excision of 3′ termini by the Trex1 and TREX2 3′→5′ exonucleases: characterization of the recombinant proteins. J. Biol. Chem. 276:17022–29 [Google Scholar]
  68. Lehtinen DA, Harvey S, Mulcahy MJ, Hollis T, Perrino FW. 68.  2008. The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease. J. Biol. Chem. 283:31649–56 [Google Scholar]
  69. Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A. 69.  et al. 2006. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat. Genet. 38:917–20 [Google Scholar]
  70. Rice G, Newman WG, Dean J, Patrick T, Parmar R. 70.  et al. 2007. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutières syndrome. Am. J. Hum. Genet. 80:811–15 [Google Scholar]
  71. Gray EE, Treuting PM, Woodward JJ, Stetson DB. 71.  2015. Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutières syndrome. J. Immunol. 195:1939–43 [Google Scholar]
  72. Gao D, Li T, Li XD, Chen X, Li QZ. 72.  et al. 2015. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. PNAS 112:E5699–705 [Google Scholar]
  73. Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA, Lieberman J. 73.  2010. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat. Immunol. 11:1005–13 [Google Scholar]
  74. Beck-Engeser GB, Eilat D, Wabl M. 74.  2011. An autoimmune disease prevented by anti-retroviral drugs. Retrovirology 8:91 [Google Scholar]
  75. Yang YG, Lindahl T, Barnes DE. 75.  2007. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873–86 [Google Scholar]
  76. Ahn J, Ruiz P, Barber GN. 76.  2014. Intrinsic self-DNA triggers inflammatory disease dependent on STING. J. Immunol. 193:4634–42 [Google Scholar]
  77. Hasan M, Fermaintt CS, Gao N, Sakai T, Miyazaki T. 77.  et al. 2015. Cytosolic nuclease TREX1 regulates oligosaccharyltransferase activity independent of nuclease activity to suppress immune activation. Immunity 43:463–74 [Google Scholar]
  78. Crow YJ, Leitch A, Hayward BE, Garner A, Parmar R. 78.  et al. 2006. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nat. Genet. 38:910–16 [Google Scholar]
  79. Perrino FW, Harvey S, Shaban NM, Hollis T. 79.  2009. RNaseH2 mutants that cause Aicardi-Goutières syndrome are active nucleases. J. Mol. Med. 87:25–30 [Google Scholar]
  80. Reijns MA, Rabe B, Rigby RE, Mill P, Astell KR. 80.  et al. 2012. Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell 149:1008–22 [Google Scholar]
  81. Hiller B, Achleitner M, Glage S, Naumann R, Behrendt R, Roers A. 81.  2012. Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity. J. Exp. Med. 209:1419–26 [Google Scholar]
  82. Mackenzie KJ, Carroll P, Lettice L, Tarnauskaite Z, Reddy K. 82.  et al. 2016. Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response. EMBO J 35:831–44 [Google Scholar]
  83. Pokatayev V, Hasin N, Chon H, Cerritelli SM, Sakhuja K. 83.  et al. 2016. RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J. Exp. Med. 213:329–36 [Google Scholar]
  84. Gunther C, Kind B, Reijns MA, Berndt N, Martinez-Bueno M. 84.  et al. 2015. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J. Clin. Investig. 125:413–24 [Google Scholar]
  85. Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW. 85.  et al. 2009. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat. Genet. 41:829–32 [Google Scholar]
  86. Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C. 86.  et al. 2011. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474:654–57 [Google Scholar]
  87. Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M. 87.  et al. 2011. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474:658–61 [Google Scholar]
  88. Goldstone DC, Ennis-Adeniran V, Hedden JJ, Groom HC, Rice GI. 88.  et al. 2011. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480:379–82 [Google Scholar]
  89. Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC. 89.  et al. 2012. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat. Immunol. 13:223–28 [Google Scholar]
  90. Beloglazova N, Flick R, Tchigvintsev A, Brown G, Popovic A. 90.  et al. 2013. Nuclease activity of the human SAMHD1 protein implicated in the Aicardi-Goutières syndrome and HIV-1 restriction. J. Biol. Chem. 288:8101–10 [Google Scholar]
  91. Ryoo J, Choi J, Oh C, Kim S, Seo M. 91.  et al. 2014. The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat. Med. 20:936–41 [Google Scholar]
  92. Choi J, Ryoo J, Oh C, Hwang S, Ahn K. 92.  2015. SAMHD1 specifically restricts retroviruses through its RNase activity. Retrovirology 12:46 [Google Scholar]
  93. Ryoo J, Hwang SY, Choi J, Oh C, Ahn K. 93.  2016. SAMHD1, the Aicardi-Goutières syndrome gene and retroviral restriction factor, is a phosphorolytic ribonuclease rather than a hydrolytic ribonuclease. Biochem. Biophys. Res. Commun. 477:977–81 [Google Scholar]
  94. Seamon KJ, Sun Z, Shlyakhtenko LS, Lyubchenko YL, Stivers JT. 94.  2015. SAMHD1 is a single-stranded nucleic acid binding protein with no active site-associated nuclease activity. Nucleic Acids Res 43:6486–99 [Google Scholar]
  95. Antonucci JM, St. Gelais C, de Silva S, Yount JS, Tang C. 95.  et al. 2016. SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity. Nat. Med. 22:1072–74 [Google Scholar]
  96. Maelfait J, Bridgeman A, Benlahrech A, Cursi C, Rehwinkel J. 96.  2016. Restriction by SAMHD1 limits cGAS/STING-dependent innate and adaptive immune responses to HIV-1. Cell Rep 16:1492–501 [Google Scholar]
  97. Rehwinkel J, Maelfait J, Bridgeman A, Rigby R, Hayward B. 97.  et al. 2013. SAMHD1-dependent retroviral control and escape in mice. EMBO J 32:2454–62 [Google Scholar]
  98. Zhao K, Du J, Han X, Goodier JL, Li P. 98.  et al. 2013. Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutières syndrome-related SAMHD1. Cell Rep 4:1108–15 [Google Scholar]
  99. Kretschmer S, Wolf C, König N, Staroske W, Guck J. 99.  et al. 2015. SAMHD1 prevents autoimmunity by maintaining genome stability. Ann. Rheum. Dis. 74:e17 [Google Scholar]
  100. Clifford R, Louis T, Robbe P, Ackroyd S, Burns A. 100.  et al. 2014. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood 123:1021–31 [Google Scholar]
  101. Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K. 101.  et al. 2013. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152:714–26 [Google Scholar]
  102. Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM. 102.  et al. 2012. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat. Genet. 44:1243–48 [Google Scholar]
  103. Bass BL. 103.  2002. RNA editing by adenosine deaminases that act on RNA. Annu. Rev. Biochem. 71:817–46 [Google Scholar]
  104. Patterson JB, Samuel CE. 104.  1995. Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Mol. Cell. Biol. 15:5376–88 [Google Scholar]
  105. Hartner JC, Walkley CR, Lu J, Orkin SH. 105.  2009. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat. Immunol. 10:109–15 [Google Scholar]
  106. Mannion NM, Greenwood SM, Young R, Cox S, Brindle J. 106.  et al. 2014. The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep 9:1482–94 [Google Scholar]
  107. Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M. 107.  et al. 2015. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349:1115–20 [Google Scholar]
  108. Pestal K, Funk CC, Snyder JM, Price ND, Treuting PM, Stetson DB. 108.  2015. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity 43:933–44 [Google Scholar]
  109. Kim DD, Kim TT, Walsh T, Kobayashi Y, Matise TC. 109.  et al. 2004. Widespread RNA editing of embedded Alu elements in the human transcriptome. Genome Res 14:1719–25 [Google Scholar]
  110. Goodier JL, Kazazian HH Jr. 110.  2008. Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell 135:23–35 [Google Scholar]
  111. Smyth DJ, Cooper JD, Bailey R, Field S, Burren O. 111.  et al. 2006. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat. Genet. 38:617–19 [Google Scholar]
  112. Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA. 112.  et al. 2009. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41:1228–33 [Google Scholar]
  113. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA. 113.  2009. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324:387–89 [Google Scholar]
  114. Sutherland A, Davies J, Owen CJ, Vaikkakara S, Walker C. 114.  et al. 2007. Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Graves’ disease susceptibility. J. Clin. Endocrinol. Metab. 92:3338–41 [Google Scholar]
  115. Rice GI, del Toro Duany Y, Jenkinson EM, Forte GM, Anderson BH. 115.  et al. 2014. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat. Genet. 46:503–9 [Google Scholar]
  116. Garneau NL, Wilusz J, Wilusz CJ. 116.  2007. The highways and byways of mRNA decay. Nat. Rev. Mol. Cell Biol. 8:113–26 [Google Scholar]
  117. Eckard SC, Rice GI, Fabre A, Badens C, Gray EE. 117.  et al. 2014. The SKIV2L RNA exosome limits activation of the RIG-I-like receptors. Nat. Immunol. 15:839–45 [Google Scholar]
  118. Fabre A, Charroux B, Martinez-Vinson C, Roquelaure B, Odul E. 118.  et al. 2012. SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome. Am. J. Hum. Genet. 90:689–92 [Google Scholar]
  119. Kawane K, Fukuyama H, Kondoh G, Takeda J, Ohsawa Y. 119.  et al. 2001. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science 292:1546–49 [Google Scholar]
  120. Yoshida H, Okabe Y, Kawane K, Fukuyama H, Nagata S. 120.  2005. Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat. Immunol. 6:49–56 [Google Scholar]
  121. Okabe Y, Kawane K, Akira S, Taniguchi T, Nagata S. 121.  2005. Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation. J. Exp. Med. 202:1333–39 [Google Scholar]
  122. Ahn J, Gutman D, Saijo S, Barber GN. 122.  2012. STING manifests self DNA-dependent inflammatory disease. PNAS 109:19386–91 [Google Scholar]
  123. Singleton EB, Merten DF. 123.  1973. An unusual syndrome of widened medullary cavities of the metacarpals and phalanges, aortic calcification and abnormal dentition. Pediatr. Radiol. 1:2–7 [Google Scholar]
  124. Jang MA, Kim EK, Now H, Nguyen NT, Kim WJ. 124.  et al. 2015. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am. J. Hum. Genet. 96:266–74 [Google Scholar]
  125. Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O. 125.  et al. 2015. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am. J. Hum. Genet. 96:275–82 [Google Scholar]
  126. Bursztejn AC, Briggs TA, del Toro Duany Y, Anderson BH, O'Sullivan J. 126.  et al. 2015. Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutières and Singleton-Merten syndromes. Br. J. Dermatol. 173:1505–13 [Google Scholar]
  127. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE. 127.  et al. 2014. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371:507–18 [Google Scholar]
  128. Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S. 128.  et al. 2014. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J. Clin. Investig. 124:5516–20 [Google Scholar]
  129. König N, Fiehn C, Wolf C, Schuster M, Cura Costa E. 129.  et al. 2017. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann. Rheum. Dis. 76:468–72 [Google Scholar]
  130. Kim H, Sanchez GA, Goldbach-Mansky R. 130.  2016. Insights from Mendelian interferonopathies: comparison of CANDLE, SAVI with AGS, monogenic lupus. J. Mol. Med. 94:1111–27 [Google Scholar]
  131. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T. 131.  2000. Features of systemic lupus erythematosus in DNase1-deficient mice. Nat. Genet. 25:177–81 [Google Scholar]
  132. Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C. 132.  et al. 2001. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat. Genet. 28:313–14 [Google Scholar]
  133. Al-Mayouf SM, Sunker A, Abdwani R, Abrawi SA, Almurshedi F. 133.  et al. 2011. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat. Genet. 43:1186–88 [Google Scholar]
  134. Ozcakar ZB, 2nd Foster J, Diaz-Horta O, Kasapcopur O, Fan YS. 134.  et al. 2013. DNASE1L3 mutations in hypocomplementemic urticarial vasculitis syndrome. Arthritis Rheum 65:2183–89 [Google Scholar]
  135. Sisirak V, Sally B, D'Agati V, Martinez-Ortiz W, Ozcakar ZB. 135.  et al. 2016. Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell 166:88–101 [Google Scholar]
  136. Briggs TA, Rice GI, Daly S, Urquhart J, Gornall H. 136.  et al. 2011. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat. Genet. 43:127–31 [Google Scholar]
  137. An J, Briggs TA, Dumax-Vorzet A, Alarcon-Riquelme ME, Belot A. 137.  et al. 2017. Tartrate-resistant acid phosphatase deficiency in the predisposition to systemic lupus erythematosus. Arthritis Rheumatol 69:131–42 [Google Scholar]
  138. Zhang X, Bogunovic D, Payelle-Brogard B, Francois-Newton V, Speer SD. 138.  et al. 2015. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. Nature 517:89–93 [Google Scholar]
  139. Meuwissen ME, Schot R, Buta S, Oudesluijs G, Tinschert S. 139.  et al. 2016. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J. Exp. Med. 213:1163–74 [Google Scholar]
  140. Daugherty MD, Malik HS. 140.  2012. Rules of engagement: molecular insights from host-virus arms races. Annu. Rev. Genet. 46:677–700 [Google Scholar]
  141. Hancks DC, Hartley MK, Hagan C, Clark NL, Elde NC. 141.  2015. Overlapping patterns of rapid evolution in the nucleic acid sensors cGAS and OAS1 suggest a common mechanism of pathogen antagonism and escape. PLOS Genet 11:e1005203 [Google Scholar]
  142. Mozzi A, Pontremoli C, Forni D, Clerici M, Pozzoli U. 142.  et al. 2015. OASes and STING: adaptive evolution in concert. Genome Biol. Evol. 7:1016–32 [Google Scholar]
  143. Lemos de Matos A, McFadden G, Esteves PJ. 143.  2013. Positive evolutionary selection on the RIG-I-like receptor genes in mammals. PLOS ONE 8:e81864 [Google Scholar]
  144. Patel MR, Loo YM, Horner SM, Gale M Jr., Malik HS. 144.  2012. Convergent evolution of escape from hepaciviral antagonism in primates. PLOS Biol 10:e1001282 [Google Scholar]
  145. Elde NC, Child SJ, Geballe AP, Malik HS. 145.  2009. Protein kinase R reveals an evolutionary model for defeating viral mimicry. Nature 457:485–89 [Google Scholar]
  146. Compton AA, Malik HS, Emerman M. 146.  2013. Host gene evolution traces the evolutionary history of ancient primate lentiviruses. Philos. Trans. R. Soc. Lond. B 368:20120496 [Google Scholar]
  147. Kaiser SM, Malik HS, Emerman M. 147.  2007. Restriction of an extinct retrovirus by the human TRIM5α antiviral protein. Science 316:1756–58 [Google Scholar]
  148. Hochberg MC. 148.  1997. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725 [Google Scholar]
  149. Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K. 149.  et al. 2007. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet. 39:1065–67 [Google Scholar]
  150. Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO. 150.  et al. 2011. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 12:270–79 [Google Scholar]
  151. Danchenko N, Satia JA, Anthony MS. 151.  2006. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus 15:308–18 [Google Scholar]
  152. Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. 152.  2010. Epidemiology of type 1 diabetes. Endocrinol. Metab. Clin. North Am. 39:481–97 [Google Scholar]
  153. Deapen D, Escalante A, Weinrib L, Horwitz D, Bachman B. 153.  et al. 1992. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 35:311–18 [Google Scholar]
  154. Risch N, Merikangas K. 154.  1996. The future of genetic studies of complex human diseases. Science 273:1516–17 [Google Scholar]
  155. Anderson MS, Casanova JL. 155.  2015. More than meets the eye: monogenic autoimmunity strikes again. Immunity 42:986–88 [Google Scholar]
  156. Cavalli-Sforza LL, Feldman MW. 156.  2003. The application of molecular genetic approaches to the study of human evolution. Nat. Genet. 33:Suppl.266–75 [Google Scholar]
  157. McClellan J, King MC. 157.  2010. Genetic heterogeneity in human disease. Cell 141:210–17 [Google Scholar]
  158. Sun C, Molineros JE, Looger LL, Zhou XJ, Kim K. 158.  et al. 2016. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat. Genet. 48:323–30 [Google Scholar]
  159. Crow YJ. 159.  2011. Lupus: how much “complexity” is really (just) genetic heterogeneity?. Arthritis Rheum 63:3661–64 [Google Scholar]
  160. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA. 160.  et al. 2003. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. PNAS 100:2610–15 [Google Scholar]
  161. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J. 161.  et al. 2003. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197:711–23 [Google Scholar]
  162. McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA. 162.  2005. Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat. Med. 11:85–89 [Google Scholar]
  163. James JA, Harley JB, Scofield RH. 163.  2006. Epstein-Barr virus and systemic lupus erythematosus. Curr. Opin. Rheumatol. 18:462–67 [Google Scholar]
  164. Gratama JW, Ernberg I. 164.  1995. Molecular epidemiology of Epstein-Barr virus infection. Adv. Cancer Res. 67:197–255 [Google Scholar]
  165. Merrill JT, Buyon JP, Utset T. 165.  2014. A 2014 update on the management of patients with systemic lupus erythematosus. Semin. Arthritis Rheum. 44:e1–2 [Google Scholar]
  166. Banchereau R, Hong S, Cantarel B, Baldwin N, Baisch J. 166.  et al. 2016. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell 165:1548–50 [Google Scholar]
  167. Borba HH, Funke A, Wiens A, Utiyama SR, Perlin CM, Pontarolo R. 167.  2016. Update on biologic therapies for systemic lupus erythematosus. Curr. Rheumatol. Rep. 18:44 [Google Scholar]
  168. Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V. 168.  2014. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J. Immunol. 192:5993–97 [Google Scholar]
  169. Sharma S, Campbell AM, Chan J, Schattgen SA, Orlowski GM. 169.  et al. 2015. Suppression of systemic autoimmunity by the innate immune adaptor STING. PNAS 112:E710–17 [Google Scholar]
/content/journals/10.1146/annurev-immunol-051116-052331
Loading
/content/journals/10.1146/annurev-immunol-051116-052331
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error