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TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity

Nature Medicine volume 13, pages 543–551 (2007)Cite this article

Abstract

We formulate a two-phase paradigm of autoimmunity associated with systemic lupus erythematosus, the archetypal autoimmune disease. The initial Toll-like receptor (TLR)-independent phase is mediated by dendritic cell uptake of apoptotic cell debris and associated nucleic acids, whereas the subsequent TLR-dependent phase serves an amplification function and is mediated by uptake of TLR ligands derived from self-antigens (principally nucleic acids) complexed with autoantibodies. Both phases depend on elaboration of type I interferons (IFNs), and therapeutic interruption of induction or activity of these cytokines in predisposed individuals might have a substantial mitigating effect in lupus and other autoimmune diseases.

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Figure 1
Figure 2: TLR-dependent pathways of IFN-α/β induction.
Figure 3: TLR-independent pathways of IFN-α/β induction.
Figure 4: Endogenous stimuli promoting IFN-α/β production by pDCs and conventional DCs, and activation of B cells.
Figure 5: The paradigm of the two-phase IFN-α/β induction in systemic autoimmunity.

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References

  1. Kono, D.H., Baccala, R. & Theofilopoulos, A.N. Genes and genetics of murine lupus. in Systemic Lupus Erythematosus (ed. Lahita, R.G.) 225–263 (Academic Press, San Diego, 2004).

    Google Scholar 

  2. Goodnow, C.C., Sprent, J., Fazekas de St Groth, B. & Vinuesa, C.G. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 435, 590–597 (2005).

    CAS  PubMed  Google Scholar 

  3. Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 6, 644–658 (2006).

    CAS  PubMed  Google Scholar 

  4. Platanias, L.C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5, 375–386 (2005).

    CAS  PubMed  Google Scholar 

  5. Liu, Y.J. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275–306 (2005).

    CAS  PubMed  Google Scholar 

  6. Theofilopoulos, A.N., Baccala, R., Beutler, B. & Kono, D.H. Type I interferons (α/β) in immunity and autoimmunity. Annu. Rev. Immunol. 23, 307–335 (2005).

    CAS  PubMed  Google Scholar 

  7. Banchereau, J. & Pascual, V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25, 383–392 (2006).

    CAS  PubMed  Google Scholar 

  8. Zhuang, H. et al. Lupus-like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p. Arthritis Rheum. 54, 1573–1579 (2006).

    CAS  PubMed  Google Scholar 

  9. Sigurdsson, S. et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am. J. Hum. Genet. 76, 528–537 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Graham, R.R. et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat. Genet. 38, 550–555 (2006).

    CAS  PubMed  Google Scholar 

  11. Santiago-Raber, M.L. et al. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J. Exp. Med. 197, 777–788 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Braun, D., Geraldes, P., Demengeot, J. Type I interferon controls the onset and severity of autoimmune manifestations in lpr mice. J. Autoimmun. 20, 15–25 (2003).

    CAS  PubMed  Google Scholar 

  13. Hron, J.D. & Peng, S.L. Type I IFN protects against murine lupus. J. Immunol. 173, 2134–2142 (2004).

    CAS  PubMed  Google Scholar 

  14. Schwarting, A. et al. Interferon-β: a therapeutic for autoimmune lupus in MRL-Faslpr mice. J. Am. Soc. Nephrol. 16, 3264–3272 (2005).

    CAS  PubMed  Google Scholar 

  15. Baccala, R., Kono, D.H. & Theofilopoulos, A.N. Interferons as pathogenic effectors in autoimmunity. Immunol. Rev. 204, 9–26 (2005).

    CAS  PubMed  Google Scholar 

  16. Zhu, J. et al. T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells. J. Clin. Invest. 115, 1869–1878 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen, M. et al. Dendritic cell apoptosis in the maintenance of immune tolerance. Science 311, 1160–1164 (2006).

    CAS  PubMed  Google Scholar 

  18. Le Bon, A. et al. Cutting edge: enhancement of antibody responses through direct stimulation of B and T cells by type I IFN. J. Immunol. 176, 2074–2078 (2006).

    CAS  PubMed  Google Scholar 

  19. Lin, Q., Dong, C. & Cooper, M.D. Impairment of T and B cell development by treatment with a type I interferon. J. Exp. Med. 187, 79–87 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kawai, T. & Akira, S. TLR signaling. Cell Death Differ. 13, 816–825 (2006).

    CAS  PubMed  Google Scholar 

  21. Beutler, B. et al. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24, 353–389 (2006).

    CAS  PubMed  Google Scholar 

  22. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987–995 (2004).

    CAS  PubMed  Google Scholar 

  23. Fitzgerald, K.A. & Chen, Z.J. Sorting out Toll signals. Cell 125, 834–836 (2006).

    CAS  PubMed  Google Scholar 

  24. Liew, F.Y., Xu, D., Brint, E.K. & O'Neill, L.A. Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5, 446–458 (2005).

    CAS  PubMed  Google Scholar 

  25. O'Neill, L.A. DisSARMing Toll-like receptor signaling. Nat. Immunol. 7, 1023–1025 (2006).

    CAS  PubMed  Google Scholar 

  26. Meylan, E. & Tschopp, J. Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses. Mol. Cell 22, 561–569 (2006).

    CAS  PubMed  Google Scholar 

  27. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).

    CAS  PubMed  Google Scholar 

  28. Hornung, V. et al. 5′-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006).

    PubMed  Google Scholar 

  29. Pichlmair, A. et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′ phosphates. Science 314, 997–1001 (2006).

    CAS  PubMed  Google Scholar 

  30. Gitlin, L. et al. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl. Acad. Sci. USA 103, 8459–8464 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Yoneyama, M. et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. 175, 2851–2858 (2005).

    CAS  PubMed  Google Scholar 

  32. Rothenfusser, S. et al. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J. Immunol. 175, 5260–5268 (2005).

    CAS  PubMed  Google Scholar 

  33. Stetson, D.B. & Medzhitov, R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93–103 (2006).

    CAS  PubMed  Google Scholar 

  34. Marshak-Rothstein, A. Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 6, 823–835 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ronnblom, L., Eloranta, M.L. & Alm, G.V. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. 54, 408–420 (2006).

    PubMed  Google Scholar 

  36. Vollmer, J. et al. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J. Exp. Med. 202, 1575–1585 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Barrat, F.J. et al. 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 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Savarese, E. et al. U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood 107, 3229–3234 (2006).

    CAS  PubMed  Google Scholar 

  39. Martin, D.A. & Elkon, K.B. Autoantibodies make a U-turn: the toll hypothesis for autoantibody specificity. J. Exp. Med. 202, 1465–1469 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wagner, H. Endogenous TLR ligands and autoimmunity. Adv. Immunol. 91, 159–173 (2006).

    CAS  PubMed  Google Scholar 

  41. Boule, M.W. et al. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J. Exp. Med. 199, 1631–1640 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Means, T.K. et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407–417 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sano, H. & Morimoto, C. Dna isolated from DNA/anti-DNA antibody immune complexes in systemic lupus erythematosus is rich in guanine-cytosine content. J. Immunol. 128, 1341–1345 (1982).

    CAS  PubMed  Google Scholar 

  44. Ishii, K.J. et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. 7, 40–48 (2006).

    CAS  PubMed  Google Scholar 

  45. Martin, D.A. & Elkon, K.B. Intracellular mammalian DNA stimulates myeloid dendritic cells to produce type I interferons predominantly through a toll-like receptor 9-independent pathway. Arthritis Rheum. 54, 951–962 (2006).

    CAS  PubMed  Google Scholar 

  46. Decker, P., Singh-Jasuja, H., Haager, S., Kotter, I. & Rammensee, H.G. Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation. J. Immunol. 174, 3326–3334 (2005).

    CAS  PubMed  Google Scholar 

  47. Cortez-Gonzalez, X. et al. TLR9-independent activation of B lymphocytes by bacterial DNA. DNA Cell Biol. 25, 253–261 (2006).

    CAS  PubMed  Google Scholar 

  48. Sun, Q. et al. The specific and essential role of MAVS in antiviral innate immune responses. Immunity 24, 633–642 (2006).

    CAS  PubMed  Google Scholar 

  49. Napirei, M. et al. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat. Genet. 25, 177–181 (2000).

    CAS  PubMed  Google Scholar 

  50. Tsukumo, S. & Yasutomo, K. DNaseI in pathogenesis of systemic lupus erythematosus. Clin. Immunol. 113, 14–18 (2004).

    CAS  PubMed  Google Scholar 

  51. Bodano, A., Amarelo, J., Gonzalez, A., Gomez-Reino, J.J. & Conde, C. Novel DNASE I mutations related to systemic lupus erythematosus. Arthritis Rheum. 50, 4070–4071 (2004).

    CAS  PubMed  Google Scholar 

  52. Yoshida, H., Okabe, Y., Kawane, K., Fukuyama, H. & Nagata, S. Lethal anemia caused by interferon-β produced in mouse embryos carrying undigested DNA. Nat. Immunol. 6, 49–56 (2005).

    CAS  PubMed  Google Scholar 

  53. Okabe, Y., Kawane, K., Akira, S., Taniguchi, T. & Nagata, S. Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation. J. Exp. Med. 202, 1333–1339 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kawane, K. et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998–1002 (2006).

    CAS  PubMed  Google Scholar 

  55. Janssen, E. et al. Efficient T cell activation via a Toll-Interleukin 1 Receptor-independent pathway. Immunity 24, 787–799 (2006).

    CAS  PubMed  Google Scholar 

  56. Fritz, J.H., Ferrero, R.L., Philpott, D.J. & Girardin, S.E. Nod-like proteins in immunity, inflammation and disease. Nat. Immunol. 7, 1250–1257 (2006).

    CAS  PubMed  Google Scholar 

  57. Andrade, F., Casciola-Rosen, L. & Rosen, A. Apoptosis in systemic lupus erythematosus. Clinical implications. Rheum. Dis. Clin. North Am. 26, 215–227, v (2000).

    CAS  PubMed  Google Scholar 

  58. Gaipl, U.S. et al. Inefficient clearance of dying cells and autoreactivity. Curr. Top. Microbiol. Immunol. 305, 161–176 (2006).

    CAS  PubMed  Google Scholar 

  59. Ogden, C.A. & Elkon, K.B. Role of complement and other innate immune mechanisms in the removal of apoptotic cells. Curr. Dir. Autoimmun. 9, 120–142 (2006).

    CAS  PubMed  Google Scholar 

  60. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat. Genet. 19, 56–59 (1998).

    CAS  PubMed  Google Scholar 

  61. Lu, Q. & Lemke, G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 293, 306–311 (2001).

    CAS  PubMed  Google Scholar 

  62. Mevorach, D., Zhou, J.L., Song, X. & Elkon, K.B. Systemic exposure to irradiated apoptotic cells induces autoantibody production. J. Exp. Med. 188, 387–392 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Denny, M.F. et al. Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus. J. Immunol. 176, 2095–2104 (2006).

    CAS  PubMed  Google Scholar 

  64. Takemura, Y. et al. Adiponectin modulates inflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies. J. Clin. Invest. 117, 375–386 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nat. Med. 5, 1249–1255 (1999).

    CAS  PubMed  Google Scholar 

  66. Winau, F. et al. Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. Immunity 24, 105–117 (2006).

    CAS  PubMed  Google Scholar 

  67. Albert, M.L., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86–89 (1998).

    CAS  PubMed  Google Scholar 

  68. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    CAS  PubMed  Google Scholar 

  69. Waldner, H., Collins, M. & Kuchroo, V.K. Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease. J. Clin. Invest. 113, 990–997 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Lang, K.S. et al. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat. Med. 11, 138–145 (2005).

    CAS  PubMed  Google Scholar 

  71. Lang, K.S. et al. Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling. J. Clin. Invest. 116, 2456–2463 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Eriksson, U. et al. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat. Med. 9, 1484–1490 (2003).

    CAS  PubMed  Google Scholar 

  73. Krieg, A.M. CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol. 20, 709–760 (2002).

    CAS  PubMed  Google Scholar 

  74. Seya, T. et al. Role of toll-like receptors and their adaptors in adjuvant immunotherapy for cancer. Anticancer Res. 23, 4369–4376 (2003).

    CAS  PubMed  Google Scholar 

  75. Poole, B.D., Scofield, R.H., Harley, J.B. & James, J.A. Epstein-Barr virus and molecular mimicry in systemic lupus erythematosus. Autoimmunity 39, 63–70 (2006).

    CAS  PubMed  Google Scholar 

  76. Pawar, R.D., Patole, P.S., Wornle, M. & Anders, H.J. Microbial nucleic acids pay a Toll in kidney disease. Am. J. Physiol. Renal Physiol. 291, F509–F516 (2006).

    CAS  PubMed  Google Scholar 

  77. Mathian, A., Weinberg, A., Gallegos, M., Banchereau, J. & Koutouzov, S. IFN-α induces early lethal lupus in preautoimmune (New Zealand Black x New Zealand White) F1 but not in BALB/c mice. J. Immunol. 174, 2499–2506 (2005).

    CAS  PubMed  Google Scholar 

  78. Mohty, M. et al. IFN-α skews monocyte differentiation into Toll-like receptor 7-expressing dendritic cells with potent functional activities. J. Immunol. 171, 3385–3393 (2003).

    CAS  PubMed  Google Scholar 

  79. Bekeredjian-Ding, I.B. et al. Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN. J. Immunol. 174, 4043–4050 (2005).

    PubMed  Google Scholar 

  80. Hang, L. et al. Induction of murine autoimmune disease by chronic polyclonal B cell activation. J. Exp. Med. 157, 874–883 (1983).

    CAS  PubMed  Google Scholar 

  81. Christensen, S.R. et al. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J. Exp. Med. 202, 321–331 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Ehlers, M., Fukuyama, H., McGaha, T.L., Aderem, A. & Ravetch, J.V. TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE. J. Exp. Med. 203, 553–561 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Wu, X. & Peng, S.L. Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum. 54, 336–342 (2006).

    CAS  PubMed  Google Scholar 

  84. Lartigue, A. et al. Role of TLR9 in anti-nucleosome and anti-DNA antibody production in lpr mutation-induced murine lupus. J. Immunol. 177, 1349–1354 (2006).

    CAS  PubMed  Google Scholar 

  85. Yu, P. et al. Toll-like receptor 9-independent aggravation of glomerulonephritis in a novel model of SLE. Int. Immunol. 18, 1211–1219 (2006).

    CAS  PubMed  Google Scholar 

  86. Christensen, S.R. et al. 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 (2006).

    CAS  PubMed  Google Scholar 

  87. Bagavant, H., Deshmukh, U.S., Gaskin, F. & Fu, S.M. Lupus glomerulonephritis revisited 2004: autoimmunity and end-organ damage. Scand. J. Immunol. 60, 52–63 (2004).

    CAS  PubMed  Google Scholar 

  88. Avrameas, S. Natural autoantibodies: from 'horror autotoxicus' to 'gnothi seauton'. Immunol. Today 12, 154–159 (1991).

    CAS  PubMed  Google Scholar 

  89. Lau, C.M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171–1177 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Berland, R. et al. Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity 25, 429–440 (2006).

    CAS  PubMed  Google Scholar 

  91. Pisitkun, P. et al. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669–1672 (2006).

    CAS  PubMed  Google Scholar 

  92. Subramanian, S. et al. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc. Natl. Acad. Sci. USA 103, 9970–9975 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Tabeta, K. et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat. Immunol. 7, 156–164 (2006).

    CAS  PubMed  Google Scholar 

  94. Maldonado, M.A. et al. The role of environmental antigens in the spontaneous development of autoimmunity in MRL-lpr mice. J. Immunol. 162, 6322–6330 (1999).

    CAS  PubMed  Google Scholar 

  95. Dong, L., Ito, S., Ishii, K.J. & Klinman, D.M. Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus-prone NZB x NZW mice. Arthritis Rheum. 52, 651–658 (2005).

    CAS  PubMed  Google Scholar 

  96. Rezaei, N. Therapeutic targeting of pattern-recognition receptors. Int. Immunopharmacol. 6, 863–869 (2006).

    CAS  PubMed  Google Scholar 

  97. Nordmark, G., Alm, G.V. & Ronnblom, L. Mechanisms of disease: primary Sjogren's syndrome and the type I interferon system. Nat. Clin. Pract. Rheumatol. 2, 262–269 (2006).

    CAS  PubMed  Google Scholar 

  98. Stewart, T.A. Neutralizing interferon α as a therapeutic approach to autoimmune diseases. Cytokine Growth Factor Rev. 14, 139–154 (2003).

    CAS  PubMed  Google Scholar 

  99. Nestle, F.O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J. Exp. Med. 202, 135–143 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Wenzel, J. et al. Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis. Clin. Exp. Dermatol. 31, 576–582 (2006).

    CAS  PubMed  Google Scholar 

  101. Ishii, K.J., Uematsu, S. & Akira, S. 'Toll' gates for future immunotherapy. Curr. Pharm. Des. 12, 4135–4142 (2006).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize that space limitations preclude citation of all original articles. We thank K. Occhipinti-Bender for editorial assistance. The work of the authors has been supported by the US National Institutes of Health.

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  1. Department of Immunology, The Scripps Research Institute, La Jolla, 93037, California, USA

    Roberto Baccala, Kasper Hoebe, Dwight H Kono, Bruce Beutler & Argyrios N Theofilopoulos

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Baccala, R., Hoebe, K., Kono, D. et al. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat Med 13, 543–551 (2007). https://doi.org/10.1038/nm1590

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