1932

Abstract

An important concept in immunology is the classification of immune responses as either innate or adaptive, based on whether the antigen receptors are encoded in the germline or generated somatically by gene rearrangement. The innate immune system is an ancient mode of immunity, and by being a first layer in our defense against infectious agents, it is essential for our ability to develop rapid and sustained responses to pathogens. We discuss the importance of nucleic acid recognition by the innate immune system to mounting an appropriate immune response to pathogens and also how inflammation driven by uncontrolled recognition of self-nucleic acids can lead to autoimmune diseases. We also summarize current efforts to either harness the immune system using agonists of nucleic acid–specific innate sensors or, on the contrary, by using inhibitors in autoimmune situations.

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2016-01-14
2024-03-29
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Literature Cited

  1. Janeway CA Jr, Medzhitov R. 1.  2002. Innate immune recognition. Annu. Rev. Immunol. 20:197–216 [Google Scholar]
  2. Hemmi H, Takeuchi O, Kawai T. 2.  et al. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408:740–45 [Google Scholar]
  3. Akira S, Uematsu S, Takeuchi O. 3.  2006. Pathogen recognition and innate immunity. Cell 124:783–801 [Google Scholar]
  4. Hoebe K, Jiang Z, Georgel P. 4.  et al. 2006. TLR signaling pathways: opportunities for activation and blockade in pursuit of therapy. Curr. Pharm. Des. 12:4123–34 [Google Scholar]
  5. Akira S, Takeda K. 5.  2004. Toll-like receptor signalling. Nat. Rev. Immunol. 4:499–511 [Google Scholar]
  6. Hoffmann JA. 6.  2003. The immune response of Drosophila. Nature 426:33–38 [Google Scholar]
  7. Lemaitre B, Nicolas E, Michaut L. 7.  et al. 1996. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–83 [Google Scholar]
  8. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. 8.  1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–97 [Google Scholar]
  9. Roach JC, Glusman G, Rowen L. 9.  et al. 2005. The evolution of vertebrate Toll-like receptors. PNAS 102:9577–82 [Google Scholar]
  10. Rock FL, Hardiman G, Timans JC. 10.  et al. 1998. A family of human receptors structurally related to Drosophila Toll. PNAS 95:588–93 [Google Scholar]
  11. Akira S, Hemmi H. 11.  2003. Recognition of pathogen-associated molecular patterns by TLR family. Immunol. Lett. 85:85–95 [Google Scholar]
  12. Kanzler H, Barrat FJ, Hessel EM, Coffman RL. 12.  2007. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat. Med. 13:552–59 [Google Scholar]
  13. Barrat FJ, Coffman RL. 13.  2008. Development of TLR inhibitors for the treatment of autoimmune diseases. Immunol. Rev. 223:271–83 [Google Scholar]
  14. Hayashi F, Means TK, Luster AD. 14.  2003. Toll-like receptors stimulate human neutrophil function. Blood 102:2660–69 [Google Scholar]
  15. Schroder M, Bowie AG. 15.  2005. TLR3 in antiviral immunity: key player or bystander?. Trends Immunol. 26:462–68 [Google Scholar]
  16. Zhang SY, Jouanguy E, Ugolini S. 16.  et al. 2007. TLR3 deficiency in patients with herpes simplex encephalitis. Science 317:1522–27 [Google Scholar]
  17. Hattermann K, Picard S, Borgeat M. 17.  et al. 2007. The Toll-like receptor 7/8-ligand resiquimod (R-848) primes human neutrophils for leukotriene B4, prostaglandin E2 and platelet-activating factor biosynthesis. FASEB J. 21:1575–85 [Google Scholar]
  18. Forsbach A, Nemorin JG, Montino C. 18.  et al. 2008. Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses. J. Immunol. 180:3729–38 [Google Scholar]
  19. Janke M, Poth J, Wimmenauer V. 19.  et al. 2009. Selective and direct activation of human neutrophils but not eosinophils by Toll-like receptor 8. J. Allergy Clin. Immunol. 123:1026–33 [Google Scholar]
  20. Guiducci C, Gong M, Cepika AM. 20.  et al. 2013. RNA recognition by human TLR8 can lead to autoimmune inflammation. J. Exp. Med. 210:2903–19 [Google Scholar]
  21. Kaisho T, Akira S. 21.  2006. Toll-like receptor function and signaling. J. Allergy Clin. Immunol. 117:979–87; quiz 88 [Google Scholar]
  22. Barreiro LB, Ben-Ali M, Quach H. 22.  et al. 2009. Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense. PLOS Genet. 5:e1000562 [Google Scholar]
  23. Goubau D, Deddouche S, Reis e Sousa C. 23.  2013. Cytosolic sensing of viruses. Immunity 38:855–69 [Google Scholar]
  24. Goubau D, Schlee M, Deddouche S. 24.  et al. 2014. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates. Nature 514:372–75 [Google Scholar]
  25. Dempsey A, Bowie AG. 25.  2015. Innate immune recognition of DNA: a recent history. Virology 479–480:146–52 [Google Scholar]
  26. Kim T, Pazhoor S, Bao M. 26.  et al. 2010. Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. PNAS 107:15181–86 [Google Scholar]
  27. Kawai T, Akira S. 27.  2011. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–50 [Google Scholar]
  28. Honda K, Yanai H, Negishi H. 28.  et al. 2005. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434:772–77 [Google Scholar]
  29. Guiducci C, Ghirelli C, Marloie-Provost MA. 29.  et al. 2008. PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation. J. Exp. Med. 205:315–22 [Google Scholar]
  30. Wang J, Lau KY, Jung J. 30.  et al. 2014. Bruton's tyrosine kinase regulates TLR9 but not TLR7 signaling in human plasmacytoid dendritic cells. Eur. J. Immunol. 44:1130–6 [Google Scholar]
  31. Honda K, Ohba Y, Yanai H. 31.  et al. 2005. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434:1035–40 [Google Scholar]
  32. Guiducci C, Ott G, Chan JH. 32.  et al. 2006. Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J. Exp. Med. 203:1999–2008 [Google Scholar]
  33. Ku CL, von Bernuth H, Picard C. 33.  et al. 2007. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J. Exp. Med. 204:2407–22 [Google Scholar]
  34. Tabeta K, Georgel P, Janssen E. 34.  et al. 2004. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. PNAS 101:3516–21 [Google Scholar]
  35. Hoebe K, Du X, Georgel P. 35.  et al. 2003. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743–48 [Google Scholar]
  36. Her Z, Teng TS, Tan JJ. 36.  et al. 2015. Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus-specific neutralizing antibody response. EMBO Mol. Med. 7:24–41 [Google Scholar]
  37. Edelmann KH, Richardson-Burns S, Alexopoulou L. 37.  et al. 2004. Does Toll-like receptor 3 play a biological role in virus infections?. Virology 322:231–38 [Google Scholar]
  38. Wang T, Town T, Alexopoulou L. 38.  et al. 2004. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med. 10:1366–73 [Google Scholar]
  39. Gowen BB, Hoopes JD, Wong MH. 39.  et al. 2006. TLR3 deletion limits mortality and disease severity due to Phlebovirus infection. J. Immunol. 177:6301–7 [Google Scholar]
  40. Alagarasu K, Bachal RV, Memane RS. 40.  et al. 2015. Polymorphisms in RNA sensing toll like receptor genes and its association with clinical outcomes of dengue virus infection. Immunobiology 220:164–68 [Google Scholar]
  41. Diebold SS, Kaisho T, Hemmi H. 41.  et al. 2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–31 [Google Scholar]
  42. Lund JM, Alexopoulou L, Sato A. 42.  et al. 2004. Recognition of single-stranded RNA viruses by Toll-like receptor 7. PNAS 101:5598–603 [Google Scholar]
  43. Lee HK, Lund JM, Ramanathan B. 43.  et al. 2007. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315:1398–401 [Google Scholar]
  44. Lund J, Sato A, Akira S. 44.  et al. 2003. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med. 198:513–20 [Google Scholar]
  45. Fiola S, Gosselin D, Takada K, Gosselin J. 45.  2010. TLR9 contributes to the recognition of EBV by primary monocytes and plasmacytoid dendritic cells. J. Immunol. 185:3620–31 [Google Scholar]
  46. Hornung V, Latz E. 46.  2010. Intracellular DNA recognition. Nat. Rev. Immunol. 10:123–30 [Google Scholar]
  47. Kanneganti TD. 47.  2010. Central roles of NLRs and inflammasomes in viral infection. Nat. Rev. Immunol. 10:688–98 [Google Scholar]
  48. Dinarello CA. 48.  2010. IL-1: discoveries, controversies and future directions. Eur. J. Immunol. 40:599–606 [Google Scholar]
  49. Burckstummer T, Baumann C, Bluml S. 49.  et al. 2009. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat. Immunol. 10:266–72 [Google Scholar]
  50. Fernandes-Alnemri T, Yu JW, Datta P. 50.  et al. 2009. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458:509–13 [Google Scholar]
  51. Hornung V, Ablasser A, Charrel-Dennis M. 51.  et al. 2009. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458:514–18 [Google Scholar]
  52. Roberts TL, Idris A, Dunn JA. 52.  et al. 2009. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323:1057–60 [Google Scholar]
  53. Rathinam VA, Jiang Z, Waggoner SN. 53.  et al. 2010. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11:395–402 [Google Scholar]
  54. Ishikawa H, Ma Z, Barber GN. 54.  2009. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–92 [Google Scholar]
  55. Li XD, Wu J, Gao D. 55.  et al. 2013. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341:1390–94 [Google Scholar]
  56. Dai P, Wang W, Cao H. 56.  et al. 2014. Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. PLOS Pathog. 10:e1003989 [Google Scholar]
  57. Lam E, Stein S, Falck-Pedersen E. 57.  2014. Adenovirus detection by the cGAS/STING/TBK1 DNA sensing cascade. J. Virol. 88:974–81 [Google Scholar]
  58. Lahaye X, Satoh T, Gentili M. 58.  et al. 2013. The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA by the innate sensor cGAS in dendritic cells. Immunity 39:1132–42 [Google Scholar]
  59. Gao D, Wu J, Wu YT. 59.  et al. 2013. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341:903–6 [Google Scholar]
  60. Krieg AM. 60.  2002. CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol. 20:709–60 [Google Scholar]
  61. Kariko K, Buckstein M, Ni H, Weissman D. 61.  2005. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23:165–75 [Google Scholar]
  62. Nestle FO, Kaplan DH, Barker J. 62.  2009. Psoriasis.. N. Engl. J. Med. 361:496–509 [Google Scholar]
  63. Morizane S, Yamasaki K, Muhleisen B. 63.  et al. 2012. Cathelicidin antimicrobial peptide LL-37 in psoriasis enables keratinocyte reactivity against TLR9 ligands. J. Investig. Dermatol. 132:135–43 [Google Scholar]
  64. Ronnblom L, Eloranta ML, Alm GV. 64.  2006. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. 54:408–20 [Google Scholar]
  65. van der Fits L, Mourits S, Voerman JS. 65.  et al. 2009. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182:5836–45 [Google Scholar]
  66. Yokogawa M, Takaishi M, Nakajima K. 66.  et al. 2014. Epicutaneous application of Toll-like receptor 7 agonists leads to systemic autoimmunity in wild-type mice: a new model of systemic lupus erythematosus. Arthritis Rheumatol. 66:694–706 [Google Scholar]
  67. Tsokos GC. 67.  2011. Systemic lupus erythematosus. N. Engl. J. Med. 365:2110–21 [Google Scholar]
  68. Christensen SR, Shupe J, Nickerson K. 68.  et al. 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]
  69. Garcia-Romo GS, Caielli S, Vega B. 69.  et al. 2011. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3:73ra20 [Google Scholar]
  70. Barrat FJ, Meeker T, Gregorio J. 70.  et al. 2005. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J. Exp. Med. 202:1131–39 [Google Scholar]
  71. Elkon KB, Wiedeman A. 71.  2012. Type I IFN system in the development and manifestations of SLE. Curr. Opin. Rheumatol. 24:499–505 [Google Scholar]
  72. Means TK, Latz E, Hayashi F. 72.  et al. 2005. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Investig. 115:407–17 [Google Scholar]
  73. von Wussow P, Jakschies D, Hochkeppel H. 73.  et al. 1989. MX homologous protein in mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum. 32:914–18 [Google Scholar]
  74. Blanco P, Palucka AK, Gill M. 74.  et al. 2001. Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science 294:1540–43 [Google Scholar]
  75. Bennett L, Palucka AK, Arce E. 75.  et al. 2003. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197:711–23 [Google Scholar]
  76. Baechler EC, Batliwalla FM, Karypis G. 76.  et al. 2003. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. PNAS 100:2610–15 [Google Scholar]
  77. Kirou KA, Lee C, George S. 77.  et al. 2004. Coordinate overexpression of interferon-α-induced genes in systemic lupus erythematosus. Arthritis Rheum. 50:3958–67 [Google Scholar]
  78. Crow YJ. 78.  2015. Type I interferonopathies: Mendelian type I interferon up-regulation. Curr. Opin. Immunol. 32:7–12 [Google Scholar]
  79. Liu Y, Jesus AA, Marrero B. 79.  et al. 2014. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371:507–18 [Google Scholar]
  80. Sharma S, Campbell AM, Chan J. 80.  et al. 2015. Suppression of systemic autoimmunity by the innate immune adaptor STING. PNAS 112:E710–17 [Google Scholar]
  81. Wagstaff AJ, Perry CM. 81.  2007. Topical imiquimod: a review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions. Drugs 67:2187–210 [Google Scholar]
  82. Wenzel J, Tuting T. 82.  2008. An IFN-associated cytotoxic cellular immune response against viral, self-, or tumor antigens is a common pathogenetic feature in “interface dermatitis”. J. Investig. Dermatol. 128:2392–402 [Google Scholar]
  83. Geary RS, Yu RZ, Levin AA. 83.  2001. Pharmacokinetics of phosphorothioate antisense oligodeoxynucleotides. Curr. Opin. Investig. Drugs 2:562–73 [Google Scholar]
  84. Dubensky TW Jr, Kanne DB, Leong ML. 84.  2013. Rationale, progress and development of vaccines utilizing STING-activating cyclic dinucleotide adjuvants. Ther. Adv. Vaccines 1:131–43 [Google Scholar]
  85. Temizoz B, Kuroda E, Ohata K. 85.  et al. 2015. TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN. Eur. J. Immunol. 45:1159–69 [Google Scholar]
  86. Kulkarni RR, Rasheed MA, Bhaumik SK. 86.  et al. 2014. Activation of the RIG-I pathway during influenza vaccination enhances the germinal center reaction, promotes T follicular helper cell induction, and provides a dose-sparing effect and protective immunity. J. Virol. 88:13990–4001 [Google Scholar]
  87. Ueno H, Klechevsky E, Morita R. 87.  et al. 2007. Dendritic cell subsets in health and disease. Immunol. Rev. 219:118–42 [Google Scholar]
  88. Guiducci C, Coffman RL, Barrat FJ. 88.  2009. Signalling pathways leading to IFN-α production in human plasmacytoid dendritic cell and the possible use of agonists or antagonists of TLR7 and TLR9 in clinical indications. J. Intern. Med. 265:43–57 [Google Scholar]
  89. Hooks JJ, Moutsopoulos HM, Geis SA. 89.  et al. 1979. Immune interferon in the circulation of patients with autoimmune disease. N. Engl. J. Med. 301:5–8 [Google Scholar]
  90. Ytterberg SR, Schnitzer TJ. 90.  1982. Serum interferon levels in patients with systemic lupus erythematosus. Arthritis Rheum. 25:401–6 [Google Scholar]
  91. Bengtsson AA, Sturfelt G, Truedsson L. 91.  et al. 2000. Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus 9:664–71 [Google Scholar]
  92. Ronnblom L, Alm GV. 92.  2003. Systemic lupus erythematosus and the type I interferon system. Arthritis Res. Ther. 5:68–75 [Google Scholar]
  93. An J, Woodward JJ, Sasaki T. 93.  et al. 2015. Cutting edge: antimalarial drugs inhibit IFN-β production through blockade of cyclic GMP-AMP synthase-DNA interaction. J. Immunol. 194:4089–93 [Google Scholar]
  94. Sun X, Wiedeman A, Agrawal N. 94.  et al. 2013. Increased RNase expression reduces inflammation and prolongs survival in TLR7 transgenic mice. J. Immunol. 190:2536–43 [Google Scholar]
  95. Chow J, Franz KM, Kagan JC. 95.  2015. PRRs are watching you: localization of innate sensing and signaling regulators. Virology 479–480:104–9 [Google Scholar]
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