Toll-like receptors 7, 8, and 9: Linking innate immunity to autoimmunity

Immunological Reviews

Volumn 220, Issue 1, 2007, Pages 251-269

  Krieg, Arthur M ^a   Vollmer, Jörg ^a  

^a PFIZER INC   (United States)

Author keywords

Autoimmunity; Innate immunity; Oligodeoxynucleotide; Toll like receptor

Indexed keywords

ALPHA INTERFERON; ANTIGEN; ANTIVIRUS AGENT; CHLOROQUINE; CPG OLIGODEOXYNUCLEOTIDE; DNA ANTIBODY; DNA VACCINE; FREUND ADJUVANT; GAMMA INTERFERON INDUCIBLE PROTEIN 10; GUANOSINE DERIVATIVE; HYDROXYCHLOROQUINE; IMIDAZOQUINOLINE DERIVATIVE; IMIQUIMOD; INTERLEUKIN 10; MYELIN; OLIGORIBONUCLEOTIDE; PROTEOLIPID PROTEIN; RECEPTOR BLOCKING AGENT; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8; TOLL LIKE RECEPTOR 9;

AUTOIMMUNE DISEASE; AUTOIMMUNE HEPATITIS; AUTOIMMUNITY; CARDITIS; CELL COMPARTMENTALIZATION; CLINICAL TRIAL; CYTOKINE RELEASE; DRUG MEGADOSE; DRUG WITHDRAWAL; ENDOSOME; ENTERITIS; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; INFLAMMATION; INNATE IMMUNITY; NONHUMAN; PRIORITY JOURNAL; REVIEW; RHEUMATOID ARTHRITIS; SYSTEMIC LUPUS ERYTHEMATOSUS; TRANSGENIC MOUSE; VITILIGO;

ANIMALS; AUTOIMMUNE DISEASES; AUTOIMMUNITY; CPG ISLANDS; DNA; DRUG DESIGN; HUMANS; IMMUNITY, NATURAL; MICE; RNA; TOLL-LIKE RECEPTOR 7; TOLL-LIKE RECEPTOR 8; TOLL-LIKE RECEPTOR 9; TOLL-LIKE RECEPTORS;

EID: 35748964708     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/j.1600-065X.2007.00572.x     Document Type: Review

References (224)

1. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003 21 : 335 376.
2. Kariko K, Buckstein M, Ni H, Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005 23 : 165 175.
3. Krieg AM, et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995 374 : 546 549.
4. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 2002 416 : 603 607.
5. Viglianti GA, Lau CM, Hanley TM, Miko BA, Shlomchik MJ, Marshak-Rothstein A. Activation of autoreactive B cells by CpG dsDNA. Immunity 2003 19 : 837 847.
6. Krieg AM. A role for Toll in autoimmunity. Nat Immunol 2002 3 : 423 424.
7. Baccala R, Hoebe K, Kono DH, Beutler B, Theofilopoulos AN. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat Med 2007 13 : 543 551.
8. Heil F, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004 303 : 1526 1529.
9. Wang JP, Liu P, Latz E, Golenbock DT, Finberg RW, Libraty DH. Flavivirus activation of plasmacytoid dendritic cells delineates key elements of TLR7 signaling beyond endosomal recognition. J Immunol 2006 177 : 7114 7121.
10. Melchjorsen J, et al. Activation of innate defense against a paramyxovirus is mediated by RIG-I and TLR7 and TLR8 in a cell-type-specific manner. J Virol 2005 79 : 12944 12951.
11. Lund JM, et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA 2004 101 : 5598 5603.
12. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004 303 : 1529 1531.
13. Diebold SS, Massacrier C, Akira S, Paturel C, Morel Y, Reis e Sousa C. Nucleic acid agonists for Toll-like receptor 7 are defined by the presence of uridine ribonucleotides. Eur J Immunol 2006 36 : 3256 3267.
14. Forsbach A, Montino C, Muller C, Vollmer J, Bauer S, Lipford G. Identification of ssRNA sequences that stimulate innate immunity through TLRs [Abstract]. Clin Immunol 2005 115 (Suppl. 1 5161.
15. Hornung V, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 2005 11 : 263 270.
16. Forsbach A, et al. Identification of conserved viral leader RNA sequences that stimulate innate immunity through TLRs. Oligonucleotides 2007, in press.
17. Conzelmann KK. Nonsegmented negative-strand RNA viruses: genetics and manipulation of viral genomes. Annu Rev Genet 1998 32 : 123 162.
18. 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 2005 202 : 1575 1585.
19. Sioud M. Single-stranded small interfering RNA are more immunostimulatory than their double-stranded counterparts: a central role for 2′-hydroxyl uridines in immune responses. Eur J Immunol 2006 36 : 1222 1230.
20. Judge AD, Sood V, Shaw JR, Fang D, McClintock K, MacLachlan I. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol 2005 23 : 457 462.
21. Sioud M. Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization. J Mol Biol 2005 348 : 1079 1090.
22. Nishiya T, DeFranco AL. Ligand-regulated chimeric receptor approach reveals distinctive subcellular localization and signaling properties of the Toll-like receptors. J Biol Chem 2004 279 : 19008 19017.
23. Nishiya T, Kajita E, Miwa S, DeFranco AL. TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements. J Biol Chem 2005 280 : 37107 37117.
24. Barton GM, Kagan JC, Medzhitov R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 2006 7 : 49 56.
25. Probst J, et al. Characterization of the ribonuclease activity on the skin surface. Genet Vaccines Ther 2006 4 : 4.
26. Le B, et al. Endosome-to-cytosol transport of viral nucleocapsids. Nat Cell Biol 2005 7 : 653 664.
27. Boulo S, Akarsu H, Ruigrok RW, Baudin F. Nuclear traffic of influenza virus proteins and ribonucleoprotein complexes. Virus Res 2007 124 : 12 21.
28. Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 2007 315 : 1398 1401.
29. Scheel B, et al. Immunostimulating capacities of stabilized RNA molecules. Eur J Immunol 2004 34 : 537 547.
30. Bourquin C, et al. Immunostimulatory RNA oligonucleotides trigger an antigen-specific cytotoxic T-cell and IgG2a response. Blood 2007 109 : 2953 2960.
31. Hamm S, et al. Immunostimulatory RNA is a potent inducer of antigen-specific cytotoxic and humoral immune response in vivo. Int Immunol 2007 19 : 297 304.
32. Tokunaga T, Yamamoto T, Yamamoto S. How BCG led to the discovery of immunostimulatory DNA. Jpn J Infect Dis 1999 52 : 1 11.
33. Messina JP, Gilkeson GS, Pisetsky DS. Stimulation of in vitro murine lymphocyte proliferation by bacterial DNA. J. Immunol 1991 147 : 1759 1764.
34. Hemmi H, et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000 408 : 740 745.
35. Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 2006 5 : 471 484.
36. Kawai T, Akira S. Antiviral signaling through pattern recognition receptors. J Biochem (Tokyo) 2007 141 : 137 145.
37. Vollmer J. TLR9 in health and disease. Int Rev Immunol 2006 25 : 155 181.
38. Heil F, et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 2003 33 : 2987 2997.
39. Gorden KB, et al. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 2005 174 : 1259 1268.
40. Jurk M, et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 2002 3 : 499.
41. Zarember KA, Godowski PJ. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 2002 168 : 554 561.
42. Hornung V, et al. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 2002 168 : 4531 4537.
43. Ito T, et al. Interferon-alpha and interleukin-12 are induced differentially by Toll- like receptor 7 ligands in human blood dendritic cell subsets. J Exp Med 2002 195 : 1507 1512.
44. Renn CN, et al. TLR activation of Langerhans cell-like dendritic cells triggers an antiviral immune response. J Immunol 2006 177 : 298 305.
45. Miettinen M, Sareneva T, Julkunen I, Matikainen S. IFNs activate toll-like receptor gene expression in viral infections. Genes Immun 2001 2 : 349 355.
46. Bauer S, et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci USA 2001 98 : 9237 9242.
47. Kadowaki N, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 2001 194 : 863 870.
48. Krug A, et al. Identification of CpG oligonucleotide sequences with high induction of IFN-alpha/beta in plasmacytoid dendritic cells. Eur J Immunol 2001 31 : 2154 2163.
49. Duramad O, et al. IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 2003 102 : 4487 4492.
50. Kadowaki N, Antonenko S, Liu YJ. Distinct CpG DNA and polyinosinic-polycytidylic acid double-stranded RNA, respectively, stimulate CD11c(-) type 2 dendritic cell precursors and CD11c(+) dendritic cells to produce type I IFN. J Immunol 2001 166 : 2291 2295.
51. Boonstra A, et al. Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation. J Exp Med 2003 197 : 101 109.
52. Ishii KJ, Akira S. Innate immune recognition of, and regulation by, DNA. Trends Immunol 2006 27 : 525 532.
53. Blackwell SE, Krieg AM. CpG-A-induced monocyte IFN-gamma-inducible protein-10 production is regulated by plasmacytoid dendritic cell-derived IFN-alpha. J Immunol 2003 170 : 4061 4068.
54. Hartmann G, Weiner GJ, Krieg AM. CpG DNA: a potent signal for growth, activation, and maturation of human dendritic cells. Proc Natl Acad Sci USA 1999 96 : 9305 9310.
55. Bauer M, et al. Bacterial CpG-DNA triggers activation and maturation of human CD11c(-), CD123(+) dendritic cells. J Immunol 2001 166 : 5000 5007.
56. Rui L, Vinuesa CG, Blasioli J, Goodnow CC. Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling. Nat Immunol 2003 4 : 594 600.
57. Redford TW, Yi AK, Ward CT, Krieg AM. Cyclosporin A enhances IL-12 production by CpG motifs in bacterial DNA and synthetic oligodeoxynucleotides. J Immunol 1998 161 : 3930 3935.
58. Yi AK, Yoon JG, Yeo SJ, Hong SC, English BK, Krieg AM. Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J Immunol 2002 168 : 4711 4720.
59. Chen Y, et al. CpG DNA induces cyclooxygenase-2 expression and prostaglandin production. Int Immunol 2001 13 : 1013 1020.
60. Wingender G, et al. Systemic application of CpG-rich DNA suppresses adaptive T cell immunity via induction of IDO. Eur J Immunol 2006 36 : 12 20.
61. Mellor AL, Baban B, Chandler PR, Manlapat A, Kahler DJ, Munn DH. Cutting edge: CpG oligonucleotides induce splenic CD19+ dendritic cells to acquire potent indoleamine 2,3-dioxygenase-dependent T cell regulatory functions via IFN type 1 signaling. J Immunol 2005 175 : 5601 5605.
62. Moseman EA, et al. Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells. J Immunol 2004 173 : 4433 4442.
63. Wald D, et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 2003 4 : 920 927.
64. Dalpke AH, Opper S, Zimmermann S, Heeg K. Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs. J Immunol 2001 166 : 7082 7089.
65. Yeo SJ, Yoon JG, Hong SC, Yi AK. CpG DNA induces self and cross-hyporesponsiveness of RAW264.7 cells in response to CpG DNA and lipopolysaccharide: alterations in IL-1 receptor-associated kinase expression. J Immunol 2003 170 : 1052 1061.
66. Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 2006 6 : 823 835.
67. Martin DA, Elkon KB. Autoantibodies make a U-turn: the toll hypothesis for autoantibody specificity. J Exp Med 2005 202 : 1465 1469.
68. Tian J, et al. Regulation of TLR9 dependent DNA immune complex mediated cell activation by high mobility group box protein 1 (HMGB1) and the receptor for advanced glycation end products (RAGE). Nat Immunol 2007 8 : 780.
69. Rumore PM, Steinman CR. Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone. J Clin Invest 1990 86 : 69 74.
70. Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR. Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 1998 41 : 1241 1250.
71. Amoura Z, et al. Circulating plasma levels of nucleosomes in patients with systemic lupus erythematosus: correlation with serum antinucleosome antibody titers and absence of clear association with disease activity. Arthritis Rheum 1997 40 : 2217 2225.
72. Botto M, et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 1998 19 : 56 59.
73. Bickerstaff MC, et al. Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 1999 5 : 694 697.
74. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 2000 25 : 177 181.
75. Yasutomo K, et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet 2001 28 : 313 314.
76. Scott RS, et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 2001 411 : 207 211.
77. Cohen PL, et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med 2002 196 : 135 140.
78. Qian Y, Wang H, Clarke SH. Impaired clearance of apoptotic cells induces the activation of autoreactive anti-Sm marginal zone and B-1 B cells. J Immunol 2004 172 : 625 635.
79. Choi JJ, Reich CF III., Pisetsky DS. Release of DNA from dead and dying lymphocyte and monocyte cell lines in vitro. Scand J Immunol 2004 60 : 159 166.
80. Sato Y, Miyata M, Sato Y, Nishimaki T, Kochi H, Kasukawa R. CpG motif-containing DNA fragments from sera of patients with systemic lupus erythematosus proliferate mononuclear cells in vitro. J Rheumatol 1999 26 : 294 301.
81. Magnusson M, Magnusson S, Vallin H, Ronnblom L, Alm GV. Importance of CpG dinucleotides in activation of natural IFN-alpha-producing cells by a lupus-related oligodeoxynucleotide. Scand J Immunol 2001 54 : 543 550.
82. Bave U, Alm GV, Ronnblom L. The combination of apoptotic U937 cells and lupus IgG is a potent IFN-alpha inducer. J Immunol 2000 165 : 3519 3526.
83. Lovgren T, Eloranta ML, Bave U, Alm GV, Ronnblom L. Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum 2004 50 : 1861 1872.
84. Hardin JA. Directing autoimmunity to nucleoprotein particles: the impact of dendritic cells and interferon alpha in lupus. J Exp Med 2003 197 : 681 685.
85. Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK. Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum 2005 52 : 1491 1503.
86. Barrat FJ, 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 2005 202 : 1131 1139.
87. Yasuda K, et al. Murine dendritic cell type I IFN production induced by human IgG-RNA immune complexes is IFN regulatory factor (IRF)5 and IRF7 dependent and is required for IL-6 production. J Immunol 2007 178 : 6876 6885.
88. Hoffman RW, et al. U1 RNA induces innate immunity signaling. Arthritis Rheum 2004 50 : 2891 2896.
89. Kim DH, Longo M, Han Y, Lundberg P, Cantin E, Rossi JJ. Interferon induction by siRNAs and ssRNAs synthesized by phage polymerase. Nat Biotechnol 2004 22 : 321 325.
90. Hornung V, et al. 5′-triphosphate RNA is the ligand for RIG-I. Science 2006 314 : 994 997.
91. Pichlmair A, et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 2006 314 : 997 1001.
92. Baechler EC, Gregersen PK, Behrens TW. The emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol 2004 16 : 801 807.
93. Baechler EC, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA 2003 100 : 2610 2615.
94. Crow MK. Interferon-alpha: a new target for therapy in systemic lupus erythematosus? Arthritis Rheum 2003 48 : 2396 2401.
95. Ioannou Y, Isenberg DA. Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum 2000 43 : 1431 1442.
96. Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 2001 294 : 1540 1543.
97. Ronnblom L, Alm GV. A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus. J Exp Med 2001 194 : F59 F63.
98. Tuetken R, Yi AK, Krieg AM. The Immune effects of bacterial DNA and their possible role in the pathogenesis of lupus. In : Tsokos GC, Kammer G, eds. Lupus: Molecular and Cellular Pathogenesis. Totowana : Humana Press, 1999 : 79 100.
99. Vallin H, Perers A, Alm GV, Ronnblom L. Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-α inducer in systemic lupus erythematosus. J Immunol 1999 163 : 6306 6313.
100. Papadimitraki ED, et al. Expansion of toll-like receptor 9-expressing B cells in active systemic lupus erythematosus: implications for the induction and maintenance of the autoimmune process. Arthritis Rheum 2006 54 : 3601 3611.
101. Gorden KK, Qiu X, Battiste JJ, Wightman PP, Vasilakos JP, Alkan SS. Oligodeoxynucleotides differentially modulate activation of TLR7 and TLR8 by imidazoquinolines. J Immunol 2006 177 : 8164 8170.
102. Lenert P, Brummel R, Field EH, Ashman RF. TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production. J Clin Immunol 2005 25 : 29 40.
103. Wang J, Shao Y, Bennett TA, Shankar RA, Wightman PD, Reddy LG. The functional effects of physical interactions among Toll-like receptors 7, 8, and 9. J Biol Chem 2006 281 : 37427 37434.
104. Ghosh TK, et al. Toll-like receptor (TLR) 2-9 agonists-induced cytokines and chemokines: I. Comparison with T cell receptor-induced responses. Cell Immunol 2006 243 : 48 57.
105. Jurk M, et al. Modulating responsiveness of human TLR7 and 8 to small molecule ligands with T-rich phosphorothiate oligodeoxynucleotides. Eur J Immunol 2006 36 : 1815 1826.
106. Vielhauer V, Mayadas TN. Functions of TNF and its receptors in renal disease: distinct roles in inflammatory tissue injury and immune regulation. Semin Nephrol 2007 27 : 286 308.
107. De Bandt M. Lessons for lupus from tumour necrosis factor blockade. Lupus 2006 15 : 762 767.
108. Gottenberg JE, et al. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjogren's syndrome. Proc Natl Acad Sci USA 2006 103 : 2770 2775.
109. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol 2001 2 : 777 780.
110. Berghofer B, Frommer T, Haley G, Fink L, Bein G, Hackstein H. TLR7 ligands induce higher IFN-alpha production in females. J Immunol 2006 177 : 2088 2096.
111. Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 2006 312 : 1669 1672.
112. Subramanian S, et al. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci USA 2006 103 : 9970 9975.
113. Lau CM, et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 2005 202 : 1171 1177.
114. Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, Shlomchik MJ. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 2005 202 : 321 331.
115. Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 2006 25 : 417 428.
116. Wu X, Peng SL. Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum 2006 54 : 336 342.
117. Yu P, et al. Toll-like receptor 9-independent aggravation of glomerulonephritis in a novel model of SLE. Int Immunol 2006 18 : 1211 1219.
118. Ma Z, Chen F, Madaio MP, Cohen PL, Eisenberg RA. Modulation of autoimmunity by TLR9 in the chronic graft-vs-host model of systemic lupus erythematosus. J Immunol 2006 177 : 7444 7450.
119. Pawar RD, Ramanjaneyulu A, Kulkarni OP, Lech M, Segerer S, Anders HJ. Inhibition of Toll-like receptor-7 (TLR-7) or TLR-7 plus TLR-9 attenuates glomerulonephritis and lung injury in experimental lupus. J Am Soc Nephrol 2007 18 : 1721 1731.
120. Rutz M, et al. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol 2004 34 : 2541 2550.
121. Lafyatis R, York M, Marshak-Rothstein A. Antimalarial agents: closing the gate on Toll-like receptors? Arthritis Rheum 2006 54 : 3068 3070.
122. Krieg AM, et al. Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc Natl Acad Sci USA 1998 95 : 12631 12636.
123. Yamada H, et al. Effect of suppressive DNA on CpG-induced immune activation. J Immunol 2002 169 : 5590 5594.
124. Lenert P, Stunz LL, Yi AK, Krieg AM, Ashman RF. CpG stimulation of primary mouse B cells is blocked by inhibitory oligodeoxyribonucleotides at a site proximal to NF-κB activation. Antisense Nucleic Acid Drug Dev 2001 11 : 247 256.
125. Shirota H, Gursel I, Gursel M, Klinman DM. Suppressive oligodeoxynucleotides protect mice from lethal endotoxic shock. J Immunol 2005 174 : 4579 4583.
126. Lenert P, Goeken AJ, Ashman RF. Extended sequence preferences for oligodeoxyribonucleotide activity. Immunology 2006 117 : 474 481.
127. Patole PS, et al. Viral double-stranded RNA aggravates lupus nephritis through Toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells. J Am Soc Nephrol 2005 16 : 1326 1338.
128. Dong L, Ito S, Ishii KJ, Klinman DM. Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus-prone NZB × NZW mice. Arthritis Rheum 2005 52 : 651 658.
129. Zeuner RA, Verthelyi D, Gursel M, Ishii KJ, Klinman DM. Influence of stimulatory and suppressive DNA motifs on host susceptibility to inflammatory arthritis. Arthritis Rheum 2003 48 : 1701 1707.
130. Mor G, Singla M, Steinberg AD, Hoffman SL, Okuda K, Klinman DM. Do DNA vaccines induce autoimmune disease? Hum Gene Ther 1997 8 : 293 300.
131. Gilkeson GS, Conover J, Halpern M, Pisetsky DS, Feagin A, Klinman DM. Effects of bacterial DNA on cytokine production by (NZB/NZW)F1 mice. J Immunol 1998 161 : 3890 3895.
132. Gilkeson GS, Ruiz P, Pippen AM, Alexander AL, Lefkowith JB, Pisetsky DS. Modulation of renal disease in autoimmune NZB/NZW mice by immunization with bacterial DNA. J Exp Med 1996 183 : 1389 1397.
133. Hasegawa K, Hayashi T. Synthetic CpG oligodeoxynucleotides accelerate the development of lupus nephritis during preactive phase in NZB × NZWF1 mice. Lupus 2003 12 : 838 845.
134. Anders HJ, et al. Bacterial CpG-DNA aggravates immune complex glomerulonephritis: role of TLR9-mediated expression of chemokines and chemokine receptors. J Am Soc Nephrol 2003 14 : 317 326.
135. Pawar RD, et al. Ligands to nucleic acid-specific toll-like receptors and the onset of lupus nephritis. J Am Soc Nephrol 2006 17 : 3365 3373.
136. Pawar RD, Patole PS, Wornle M, Anders HJ. Microbial nucleic acids pay a Toll in kidney disease. Am J Physiol Renal Physiol 2006 291 : F509 F516.
137. Segal BM, Klinman DM, Shevach EM. Microbial products induce autoimmune disease by an IL-12-dependent pathway. J Immunol 1997 158 : 5087 5090.
138. Ichikawa HT, Williams LP, Segal BM. Activation of APCs through CD40 or Toll-like receptor 9 overcomes tolerance and precipitates autoimmune disease. J Immunol 2002 169 : 2781 2787.
139. Segal BM, Chang JT, Shevach EM. CpG oligonucleotides are potent adjuvants for the activation of autoreactive encephalitogenic T cells in vivo. J Immunol 2000 164 : 5683 5688.
140. Boccaccio GL, Mor F, Steinman L. Non-coding plasmid DNA induces IFN-γ in vivo and suppresses autoimmune encephalomyelitis. Int Immunol 1999 11 : 289 296.
141. Deng GM, Liu ZQ, Tarkowski A. Intracisternally localized bacterial DNA containing CpG motifs induces meningitis. J Immunol 2001 167 : 4616 4626.
142. Schluesener HJ, Seid K, Deininger M, Schwab J. Transient in vivo activation of rat brain macrophages/microglial cells and astrocytes by immunostimulatory multiple CpG oligonucleotides. J Neuroimmunol 2001 113 : 89 94.
143. Carpentier AF, Chen L, Maltonti F, Delattre JY. Oligodeoxynucleotides containing CpG motifs can induce rejection of a neuroblastoma in mice. Cancer Res 1999 59 : 5429 5432.
144. Carpentier AF, Xie J, Mokhtari K, Delattre JY. Successful treatment of intracranial gliomas in rat by oligodeoxynucleotides containing CpG motifs. Clin Cancer Res 2000 6 : 2469 2473.
145. Carpentier AF, Auf G, Delattre JY. CpG-oligonucleotides for cancer immunotherapy: review of the literature and potential applications in malignant glioma. Front Biosci 2003 8 : 115 127.
146. Auf G, Chen L, Fornes P, Le Clanche C, Delattre JY, Carpentier AF. CpG-oligodeoxynucleotide rejection of a neuroblastoma in A/J mice does not induce a paraneoplastic disease. Neurosci Lett 2002 327 : 189 192.
147. Darabi K, et al. The third signal in T cell-mediated autoimmune disease? J Immunol 2004 173 : 92 99.
148. Prinz M, et al. Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J Clin Invest 2006 116 : 456 464.
149. Su SB, et al. Essential role of the MyD88 pathway, but nonessential roles of TLRs 2, 4, and 9, in the adjuvant effect promoting Th1-mediated autoimmunity. J Immunol 2005 175 : 6303 6810.
150. Carpentier A, et al. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro Oncol 2006 8 : 60 66.
151. Ronaghy A, et al. Immunostimulatory DNA sequences influence the course of adjuvant arthritis. J Immunol 2002 168 : 51 56.
152. Svelander L, Erlandsson HH, Lorentzen JC, Trollmo C, Klareskog L, Bucht A. Oligodeoxynucleotides containing CpG motifs can induce T cell-dependent arthritis in rats. Arthritis Rheum 2004 50 : 297 304.
153. Miyata M, Kobayashi H, Sasajima T, Sato Y, Kasukawa R. Unmethylated oligo-DNA containing CpG motifs aggravates collagen- induced arthritis in mice. Arthritis Rheum 2000 43 : 2578 2582.
154. Deng GM, Nilsson IM, Verdrengh M, Collins LV, Tarkowski A. Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat Med 1999 5 : 702 705.
155. Deng GM, Tarkowski A. The features of arthritis induced by CpG motifs in bacterial DNA. Arthritis Rheum 2000 43 : 356 364.
156. Deng GM, Verdrengh M, Liu ZQ, Tarkowski A. The major role of macrophages and their product tumor necrosis factor α in the induction of arthritis triggered by bacterial DNA containing CpG motifs. Arthritis Rheum 2000 43 : 2283 2289.
157. Kyburz D, et al. Bacterial peptidoglycans but not CpG oligodeoxynucleotides activate synovial fibroblasts by toll-like receptor signaling. Arthritis Rheum 2003 48 : 642 650.
158. Cavanagh LL, et al. Rheumatoid arthritis synovium contains plasmacytoid dendritic cells. Arthritis Res Ther 2005 7 : R230 R240.
159. Gattorno M, et al. Distinct expression pattern of IFN-alpha and TNF-alpha in juvenile idiopathic arthritis synovial tissue. Rheumatology (Oxford) 2007 46 : 657 665.
160. Roelofs MF, et al. The expression of toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells. Arthritis Rheum 2005 52 : 2313 2322.
161. Quintana FJ, Rotem A, Carmi P, Cohen IR. Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in nonobese diabetic mice: modulation of spontaneous 60-kDa heat shock protein autoimmunity. J Immunol 2000 165 : 6148 6155.
162. Bot A, et al. Plasmid vaccination with insulin B chain prevents autoimmune diabetes in nonobese diabetic mice. J Immunol 2001 167 : 2950 2955.
163. Coon B, An LL, Whitton JL, von Herrath MG. DNA immunization to prevent autoimmune diabetes. J Clin Invest 1999 104 : 189 194.
164. Seifarth C, Pop S, Liu B, Wong CP, Tisch R. More stringent conditions of plasmid DNA vaccination are required to protect grafted versus endogenous islets in nonobese diabetic mice. J Immunol 2003 171 : 469 476.
165. Quintana FJ, Carmi P, Cohen IR. DNA vaccination with heat shock protein 60 inhibits cyclophosphamide-accelerated diabetes. J Immunol 2002 169 : 6030 6035.
166. Serra P, et al. CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 2003 19 : 877 889.
167. Hayashi T, Yoshinaka K, Hasegawa K, Maeda K, Onodera T. CpG oligodeoxynucleotides accelerate reovirus type 2-triggered insulitis in DBA/1 suckling mice. Int J Exp Pathol 2002 83 : 217 223.
168. Ohashi PS, et al. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 1991 65 : 305 317.
169. Lang KS, et al. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat Med 2005 11 : 138 145.
170. Bach JF. A Toll-like trigger for autoimmune disease. Nat Med 2005 11 : 120 121.
171. Wen L, Peng J, Li Z, Wong FS. The effect of innate immunity on autoimmune diabetes and the expression of Toll-like receptors on pancreatic islets. J Immunol 2004 172 : 3173 3180.
172. Lee J, et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol 2006 8 : 1327 1336.
173. Obermeier F, et al. In vivo CpG DNA/toll-like receptor 9 interaction induces regulatory properties in CD4+CD62L+ T cells which prevent intestinal inflammation in the SCID transfer model of colitis. Gut 2005 54 : 1428 1436.
174. Obermeier F, et al. CpG motifs of bacterial DNA essentially contribute to the perpetuation of chronic intestinal inflammation. Gastroenterology 2005 129 : 913 927.
175. Obermeier F, Dunger N, Deml L, Herfarth H, Scholmerich J, Falk W. CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur J Immunol 2002 32 : 2084 2092.
176. Rachmilewitz D, et al. Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 2002 122 : 1428 1441.
177. Obermeier F, et al. Contrasting activity of cytosin-guanosin dinucleotide oligonucleotides in mice with experimental colitis. Clin Exp Immunol 2003 134 : 217 224.
178. Katakura K, Lee J, Rachmilewitz D, Li G, Eckmann L, Raz E. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J Clin Invest 2005 115 : 695 702.
179. Bachmaier K, Neu N, de la Maza LM, Pal S, Hessel A, Penninger JM. Chlamydia infections and heart disease linked through antigenic mimicry. Science 1999 283 : 1335 1339.
180. Eriksson U, et al. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat Med 2003 9 : 1484 1490.
181. Mancini M, Hadchouel M, Davis HL, Whalen RG, Tiollais P, Michel ML. DNA-mediated immunization in a transgenic mouse model of the hepatitis B surface antigen chronic carrier state. Proc Natl Acad Sci USA 1996 93 : 12496 12501.
182. Schirmbeck R, et al. Breaking tolerance in hepatitis B surface antigen (HBsAg) transgenic mice by vaccination with cross-reactive, natural HBsAg variants. Eur J Immunol 2003 33 : 3342 3352.
183. Mancini M, Hadchouel M, Tiollais P, Michel ML. Regulation of hepatitis B virus mRNA expression in a hepatitis B surface antigen transgenic mouse model by IFN-γ-secreting T cells after DNA-based immunization. J Immunol 1998 161 : 5564 5570.
184. Malanchere-Bres E, Payette PJ, Mancini M, Tiollais P, Davis HL, Michel ML. CpG oligodeoxynucleotides with hepatitis B surface antigen (HBsAg) for vaccination in HBsAg-transgenic mice. J Virol 2001 75 : 6482 6491.
185. Sacher T, Knolle P, Nichterlein T, Arnold B, Hammerling GJ, Limmer A. CpG-ODN-induced inflammation is sufficient to cause T-cell-mediated autoaggression against hepatocytes. Eur J Immunol 2002 32 : 3628 3637.
186. Lang KS, et al. Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling. J Clin Invest 2006 116 : 2456 2463.
187. Kouskoff V, Lacaud G, Nemazee D. T cell-independent rescue of B lymphocytes from peripheral immune tolerance. Science 2000 287 : 2501 2503.
188. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol 2004 172 : 2731 2738.
189. Gorden KK, Qiu XX, Binsfeld CC, Vasilakos JP, Alkan SS. Cutting edge: activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and polyT oligodeoxynucleotides. J Immunol 2006 177 : 6584 6587.
190. Krug A, et al. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol 2001 31 : 3026 3037.
191. Dalpke AH, et al. Immunostimulatory CpG-DNA activates murine microglia. J. Immunol 2002 168 : 4854 4863.
192. Pillarisetty VG, Shah AB, Miller G, Bleier JI, DeMatteo RP. Liver dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition. J Immunol 2004 172 : 1009 1017.
193. Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 2002 20 : 709 760.
194. Zhao Q, Temsamani J, Zhou RZ, Agrawal S. Pattern and kinetics of cytokine production following administration of phosphorothioate oligonucleotides in mice. Antisense Nucleic Acid Drug Dev 1997 7 : 495 502.
195. Yi AK, Klinman DM, Martin TL, Matson S, Krieg AM. Rapid immune activation by CpG motifs in bacterial DNA. Systemic induction of IL-6 transcription through an antioxidant-sensitive pathway. J Immunol 1996 157 : 5394 5402.
196. Krieg AM, Efler SM, Wittpoth M, Al Adhami MJ, Davis HL. Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. J Immunother 2004 27 : 460 471.
197. Friedberg JW, et al. Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-alpha/beta-inducible gene expression, without significant toxicity. Blood 2005 105 : 489 495.
198. Krieg AM. CpG DNA: trigger of sepsis, mediator of protection, or both? Scand J Infect Dis 2003 35 : 653 659.
199. Levin AA, Henry S, Monteith D. Toxicity of antisense oligonucleotides. In : Crooke ST, ed. Antisense Drug Technology. New York : Marcel Dekker Inc., 2001 : 201 267.
200. Dorr A, Glover JG, Kwoh TJ. Clinical safety of phosphorothioate oligodeoxynucleotides. In : Crooke ST, ed. Antisense Drug Technology. New York : Marcel Dekker Inc., 2001 : 269 290.
201. Henry SP, Templin MV, Gillett N, Rojko J, Levin AA. Correlation of toxicity and pharmacokinetic properties of a phosphorothioate oligonucleotide designed to inhibit ICAM-1. Toxicol Pathol 1999 27 : 95 100.
202. Sparwasser T, Hultner L, Koch ES, Luz A, Lipford GB, Wagner H. Immunostimulatory CpG-oligodeoxynucleotides cause extramedullary murine hemopoiesis. J Immunol 1999 162 : 2368 2374.
203. Heikenwalder M, et al. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med 2004 10 : 187 192.
204. Hartmann G, et al. Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 2000 164 : 1617 1624.
205. Brown CA, Lesher JL Jr., Peterson CM. Tuberous and tendinous xanthomata secondary to ritonavir-associated hyperlipidemia. J Am Acad Dermatol 2005 52 : S86 S89.
206. Bong AB, Gollnick H, Schon MP. Treatment of vitiligo with topical imiquimod. J Eur Acad Dermatol Venereol 2004 18 : 741 742.
207. Gerdsen R, Wenzel J, Uerlich M, Bieber T, Petrow W. Successful treatment of chronic discoid lupus erythematosus of the scalp with imiquimod. Dermatology 2002 205 : 416 418.
208. Krieg AM. Direct immunologic activities of CpG DNA and implications for gene therapy. J Gene Med 1999 1 : 56 63.
209. Krieg AM. Minding the Cs and Gs [comment]. Mol Ther 2000 1 : 209 210.
210. Agrawal S, Kandimalla ER. Role of Toll-like receptors in antisense and siRNA. Nat Biotechnol 2004 22 : 1533 1537.
211. Klasa RJ, Gillum AM, Klem RE, Frankel SR. Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 2002 12 : 193 213.
212. Cooper CL, et al. CpG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind Phase I/II study. J Clin Immunol 2004 24 : 693 702.
213. Cooper CL, et al. Safety and immunogenicity of CpG 7909 injection as an adjuvant to fluarix influenza vaccine. Vaccine 2004 22 : 3136 3143.
214. Halperin SA, Van Nest G, Smith B, Abtahi S, Whiley H, Eiden JJ. A phase I study of the safety and immunogenicity of recombinant hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant. Vaccine 2003 21 : 2461 2467.
215. Speiser DE, et al. Rapid and strong human CD8(+) T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 2005 115 : 739 746.
216. Halperin SA, et al. Comparison of the safety and immunogenicity of hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide and a licensed hepatitis B vaccine in healthy young adults. Vaccine 2006 24 : 20 26.
217. Valmori D, et al. Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming. Proc Natl Acad Sci USA 2007 104 : 8947 8952.
218. Creticos PS, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 2006 355 : 1445 1455.
219. Macfarlane DE, Manzel L. Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds. J Immunol 1998 160 : 1122 1131.
220. Yi AK, Tuetken R, Redford T, Waldschmidt M, Kirsch J, Krieg AM. CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J Immunol 1998 160 : 4755 4761.
221. Hacker H, et al. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J 1998 17 : 6230 6240.
222. Strekowski L, et al. Structure-activity relationship analysis of substituted 4-quinolinamines, antagonists of immunostimulatory CpG-oligodeoxynucleotides. Bioorg Med Chem Lett 1999 9 : 1819 1824.
223. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003 299 : 1033 1036.
224. Steinman RM, Nussenzweig MC. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA 2002 99 : 351 358.