Springer Seminars in Immunopathology

, Volume 28, Issue 2, pp 131–143 | Cite as

The role of toll-like receptors in systemic lupus erythematosus

Review

Abstract

Systemic lupus erythematosus is an autoimmune disease characterized by the production of autoantibodies against a relatively limited range of nuclear antigens. These autoantibodies result in the formation of immune complexes that deposit in tissues and induce inflammation, thereby contributing to disease pathology. Growing evidence suggests that recognition of nucleic acid motifs by Toll-like receptors may play a role in both the activation of antinuclear B cells and in the subsequent disease progression after immune complex formation. The endosomal localization of the nucleic acid-sensing Toll-like receptors (TLRs), TLR3, 7, and 9, is believed to contribute to the distinction between endogenous nucleic acids and those of foreign origin. In this article we review recent work that suggests a role for the B-cell receptor and Fcγ receptors in delivering nuclear antigens to intracellular compartments allowing TLR activation by endogenous nucleic acids. A number of in vitro studies have presented evidence supporting a role for TLRs in SLE pathology. However, recent studies that have examined the contributions of individual TLRs to SLE by using TLR-deficient mice suggest that the situation is far more complicated in vivo. These studies show that under different circumstances TLR signaling may either exacerbate or protect against SLE-associated pathology. Further understanding of the role of TLRs in pathological autoreactivity of the adaptive immune system will likely lead to important insights into the etiopathogenesis of SLE and potential targets for novel therapies.

Keywords

TLR7 TLR9 Autoimmunity Chromatin Ribonucleoprotein 

References

  1. 1.
    Plotz PH (2003) The autoantibody repertoire: searching for order. Nat Rev Immunol 3:73–78PubMedCrossRefGoogle Scholar
  2. 2.
    Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB (2003). Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349:1526–1533PubMedCrossRefGoogle Scholar
  3. 3.
    ter Borg EJ, Groen H, Horst G, Limburg PC, Wouda AA, Kallenberg CG (1990) Clinical associations of antiribonucleoprotein antibodies in patients with systemic lupus erythematosus. Semin Arthritis Rheum 20:164–173PubMedCrossRefGoogle Scholar
  4. 4.
    Shlomchik M, Mascelli M, Shan H, Radic MZ, Pisetsky D, Marshak-Rothstein A, Weigert M (1990) Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J Exp Med 171:265–292PubMedCrossRefGoogle Scholar
  5. 5.
    Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603–607PubMedCrossRefGoogle Scholar
  6. 6.
    Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376PubMedCrossRefGoogle Scholar
  7. 7.
    Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, Lien E, Nilsen NJ, Espevik T, Golenbock DT (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 5:190–198PubMedCrossRefGoogle Scholar
  8. 8.
    Barton GM, Kagan JC, Medzhitov R (2006) Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 7:49–56PubMedCrossRefGoogle Scholar
  9. 9.
    Yamamoto M, Takeda K, Akira S (2004) TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol 40:861–868PubMedCrossRefGoogle Scholar
  10. 10.
    Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S (2003) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301:640–643PubMedCrossRefGoogle Scholar
  11. 11.
    Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes PF, Rollinghoff M, Bolcskei PL, Wagner M, Akira S, Norgard MV, Belisle JT, Godowski PJ, Bloom BR, Modlin RL (2001) Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291:1544–1547PubMedCrossRefGoogle Scholar
  12. 12.
    Blander JM, Medzhitov R (2006) Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440 (E-pub ahead of print; DOI 10.1038/nature04596)
  13. 13.
    Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995PubMedCrossRefGoogle Scholar
  14. 14.
    Anders HJ, Vielhauer V, Eis V, Linde Y, Kretzler M, Perez de Lema G, Strutz F, Bauer S, Rutz M, Wagner H, Grone HJ, Schlondorff D (2004) Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice. Faseb J 18:534–536PubMedGoogle Scholar
  15. 15.
    Anders HJ, Banas B, Linde Y, Weller L, Cohen CD, Kretzler M, Martin S, Vielhauer V, Schlondorff D, Grone HJ (2003) Bacterial CpG-DNA aggravates immune complex glomerulonephritis: role of TLR9-mediated expression of chemokines and chemokine receptors. J Am Soc Nephrol 14:317–326PubMedCrossRefGoogle Scholar
  16. 16.
    Patole PS, Grone HJ, Segerer S, Ciubar R, Belemezova E, Henger A, Kretzler M, Schlondorff D, Anders HJ (2005) Viral double-stranded RNA aggravates lupus nephritis through Toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells. J Am Soc Nephrol 16:1326–1338PubMedCrossRefGoogle Scholar
  17. 17.
    Meyers CM, Seeff LB, Stehman-Breen CO, Hoofnagle JH (2003) Hepatitis C and renal disease: an update. Am J Kidney Dis 42:631PubMedCrossRefGoogle Scholar
  18. 18.
    Wornle M, Schmid H, Banas B, Merkle M, Henger A, Roeder M, Blattner S, Bock E, Kretzler M, Grone HJ, Schlondorff D (2006) Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis. Am J Pathol 168:370–385PubMedGoogle Scholar
  19. 19.
    Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745PubMedCrossRefGoogle Scholar
  20. 20.
    Stacey KJ, Young GR, Clark F, Sester DP, Roberts TL, Naik S, Sweet MJ, Hume DA (2003) The molecular basis for the lack of immunostimulatory activity of vertebrate DNA. J Immunol 170:3614–3620PubMedGoogle Scholar
  21. 21.
    Yamamoto S, Yamamoto T, Shimada S, Kuramoto E, Yano O, Kataoka T, Tokunaga T (1992) DNA from bacteria, but not from vertebrates, induces interferons, activates natural killer cells and inhibits tumor growth. Microbiol Immunol 36:983–997PubMedGoogle Scholar
  22. 22.
    Viglianti GA, Lau CM, Hanley TM, Miko BA, Shlomchik MJ, Marshak-Rothstein A (2003) Activation of autoreactive B cells by CpG dsDNA. Immunity 19:837–947PubMedCrossRefGoogle Scholar
  23. 23.
    Cross SH, Bird AP (1995) CpG islands and genes. Curr Opin Genet Dev 5:309–314PubMedCrossRefGoogle Scholar
  24. 24.
    Krystosek A (1999) Preferential sites of early DNA cleavage in apoptosis and the pathway of nuclear damage. Histochem Cell Biol 111:265–276PubMedCrossRefGoogle Scholar
  25. 25.
    Sano H, Morimoto C (1982) Dna isolated from DNA/anti-DNA antibody immune complexes in systemic lupus erythematosus is rich in guanine-cytosine content. J Immunol 128:1341–1345PubMedGoogle Scholar
  26. 26.
    Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T (2000) Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 25:177–181PubMedCrossRefGoogle Scholar
  27. 27.
    Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C, Urushihara M, Kuroda Y (2001) Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet 28:313–314PubMedCrossRefGoogle Scholar
  28. 28.
    Cohen PL, Caricchio R, Abraham V, Camenisch TD, Jennette JC, Roubey, Earp HS, Matsushima G, Reap EA (2002) Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med 196:135–140PubMedCrossRefGoogle Scholar
  29. 29.
    Manderson AP, Botto M, Walport MJ (2004) The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 22:431–436PubMedCrossRefGoogle Scholar
  30. 30.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738PubMedCrossRefGoogle Scholar
  31. 31.
    Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA 101:5598–5603PubMedCrossRefGoogle Scholar
  32. 32.
    Barrat FJ, Meeker T, Gregorio J, Chan JH, Uematsu S, Akira S, Chang B, Duramad O, Coffman RL (2005) Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 202:1131–1139PubMedCrossRefGoogle Scholar
  33. 33.
    Kariko K, Ni H, Capodici J, Lamphier M, Weissman D (2004) mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem 279:12542–12550PubMedCrossRefGoogle Scholar
  34. 34.
    Stark H, Dube P, Luhrmann R, Kastner B (2001) Arrangement of RNA and proteins in the spliceosomal U1 small nuclear ribonucleoprotein particle. Nature 409:539–542PubMedCrossRefGoogle Scholar
  35. 35.
    Hoffman RW, Gazitt T, Foecking MF, Ortmann RA, Misfeldt M, Jorgenson R, Young SL, Greidinger EL (2004) U1 RNA induces innate immunity signaling. Arthritis Rheum 50:2891–2896PubMedCrossRefGoogle Scholar
  36. 36.
    Kelly KM, Zhuang H, Nacionales DC, Scumpia PO, Lyons R, Akaogi J, Lee P, Williams B, Yamamoto M, Akira S, Satoh M, Reeves WH (2006) “Endogenous adjuvant” activity of the RNA components of lupus autoantigens Sm/RNP and Ro 60. Arthritis Rheum 54:1557–1567PubMedCrossRefGoogle Scholar
  37. 37.
    Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, Endres S, Hartmann G (2002) 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 168:4531–4537PubMedGoogle Scholar
  38. 38.
    Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S (1999) Cutting edge: toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162:3749PubMedGoogle Scholar
  39. 39.
    Tomai MA, Imbertson LM, Stanczak TL, Tygrett LT, Waldschmidt TJ (2000) The immune response modifiers imiquimod and R-848 are potent activators of B lymphocytes. Cell Immunol 203:55–65PubMedCrossRefGoogle Scholar
  40. 40.
    Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549PubMedCrossRefGoogle Scholar
  41. 41.
    Bekeredjian-Ding IB, Wagner M, Hornung V, Giese T, Schnurr M, Endres S, Hartmann G (2005) Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN. J Immunol 174:4043–4050PubMedGoogle Scholar
  42. 42.
    Bernasconi NL, Onai N, Lanzavecchia A (2003) A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 101:4500–4504PubMedCrossRefGoogle Scholar
  43. 43.
    Peng SL (2005) Signaling in B cells via Toll-like receptors. Curr Opin Immunol 17:230–236PubMedCrossRefGoogle Scholar
  44. 44.
    Pasare C, Medzhitov R (2005) Control of B-cell responses by Toll-like receptors. Nature 438:364–368PubMedCrossRefGoogle Scholar
  45. 45.
    Ruprecht CR, Lanzavecchia A (2006) Toll-like receptor stimulation as a third signal required for activation of human naive B cells. Eur J Immunol 36:810–816PubMedCrossRefGoogle Scholar
  46. 46.
    Yi AK, Klinman DM, Martin TL, Matson S, Krieg AM (1996) Rapid immune activation by CpG motifs in bacterial DNA. Systemic induction of IL-6 transcription through an antioxidant-sensitive pathway. J Immunol 157:5394–5402PubMedGoogle Scholar
  47. 47.
    Lenert P, Brummel R, Field EH, Ashman RF (2005) TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production. J Clin Immunol 25:29–40PubMedCrossRefGoogle Scholar
  48. 48.
    Han SS, Chung ST, Robertson DA, Chelvarajan RL, Bondada S (1999) CpG oligodeoxynucleotides rescue BKS-2 immature B cell lymphoma from anti-IgM-mediated growth inhibition by up-regulation of egr-1. Int Immunol 11:871–879PubMedCrossRefGoogle Scholar
  49. 49.
    Yi AK, Chang M, Peckham DW, Krieg AM, Ashman RF (1998) CpG oligodeoxyribonucleotides rescue mature spleen B cells from spontaneous apoptosis and promote cell cycle entry. J Immunol 160:5898–5906PubMedGoogle Scholar
  50. 50.
    Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529PubMedCrossRefGoogle Scholar
  51. 51.
    Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, Mamula MJ, Christensen SR, Shlomchik MJ, Viglianti GA, Rifkin IR, Marshak-Rothstein A (2005) RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 202:1171–1177PubMedCrossRefGoogle Scholar
  52. 52.
    Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, Liu YJ (2001) Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194:863–869PubMedCrossRefGoogle Scholar
  53. 53.
    Boule MW, Broughton C, Mackay F, Akira S, Marshak-Rothstein A, Rifkin IR (2004) Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J Exp Med 199:1121–1131CrossRefGoogle Scholar
  54. 54.
    Lovgren T, Eloranta ML, Bave U, Alm GV, Ronnblom L (2004) 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 50:1861–1872PubMedCrossRefGoogle Scholar
  55. 55.
    Zhuang H, Narain S, Sobel E, Lee PY, Nacionales DC, Kelly KM, Richards HB, Segal M, Stewart C, Satoh M, Reeves WH (2005) Association of anti-nucleoprotein autoantibodies with upregulation of Type I interferon-inducible gene transcripts and dendritic cell maturation in systemic lupus erythematosus. Clin Immunol 117:238–250PubMedCrossRefGoogle Scholar
  56. 56.
    Means TK, Latz E, Hayashi F, Murali MR, Golenbock DT, Luster AD (2005) Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest 115:407–417PubMedCrossRefGoogle Scholar
  57. 57.
    Salmon JE, Millard S, Schachter LA, Arnett FC, Ginzler EM, Gourley MF, Ramsey-Goldman R, Peterson MG, Kimberly RP (1996) Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 97:1348–1354PubMedGoogle Scholar
  58. 58.
    Coggeshall KM (2000) Positive and negative signaling in B lymphocytes. Curr Top Microbiol Immunol 245:213–260PubMedGoogle Scholar
  59. 59.
    Brauweiler A, Tamir I, Marschner S, Helgason CD, Cambier JC (2001). Partially distinct molecular mechanisms mediate inhibitory FcgammaRIIB signaling in resting and activated B cells. J Immunol 167:204–211PubMedGoogle Scholar
  60. 60.
    Bjersing JL, Tarkowski A, Lundin S, Collins LV (2005) Synergistic action of immunostimulatory DNA and fcgamma receptor IIB-crosslinking on B-cell phenotype and function. Immunobiology 210:23–32PubMedCrossRefGoogle Scholar
  61. 61.
    Bolland S, Ravetch JV (2000) Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 13:277–285PubMedCrossRefGoogle Scholar
  62. 62.
    McGaha TL, Sorrentino B, Ravetch JV (2005) Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 307:590–593PubMedCrossRefGoogle Scholar
  63. 63.
    Ravetch JV, Bolland S (2001) IgG Fc receptors. Annu Rev Immunol 19:275–290PubMedCrossRefGoogle Scholar
  64. 64.
    Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV (2005) FcgammaRIV: a novel FcR with distinct IgG subclass specificity. Immunity 23:41–51PubMedCrossRefGoogle Scholar
  65. 65.
    Savarese E, Chae OW, Trowitzsch S, Weber G, Kastner B, Akira S, Wagner H, Schmid RM, Bauer S, Krug A (2005) U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells via TLR7. Blood 107:3229–3234PubMedCrossRefGoogle Scholar
  66. 66.
    Vollmer J, Tluk S, Schmitz C, Hamm S, Jurk M, Forsbach A, Akira S, Kelly KM, Reeves WH, Bauer S, Krieg AM (2005) Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J Exp Med 202:1575–1585PubMedCrossRefGoogle Scholar
  67. 67.
    Crow MK, Kirou KA (2004) Interferon-alpha in systemic lupus erythematosus. Curr Opin Rheumatol 16:541–547PubMedCrossRefGoogle Scholar
  68. 68.
    Tackey E, Lipsky PE, Illei GG (2004) Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus 13:339–343PubMedCrossRefGoogle Scholar
  69. 69.
    Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–1036PubMedCrossRefGoogle Scholar
  70. 70.
    Horii Y, Iwano M, Hirata E, Shiiki M, Fujii Y, Dohi K, Ishikawa H (1993) Role of interleukin-6 in the progression of mesangial proliferative glomerulonephritis. Kidney Int Suppl 39:S71–S75PubMedGoogle Scholar
  71. 71.
    Ryffel B, Car BD, Gunn H, Roman D, Hiestand P, Mihatsch MJ (1994) Interleukin-6 exacerbates glomerulonephritis in (NZB x NZW)F1 mice. Am J Pathol 144:927–937PubMedGoogle Scholar
  72. 72.
    Finck BK, Chan B, Wofsy D (1994) Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. J Clin Invest 94:585–591PubMedGoogle Scholar
  73. 73.
    Mihara M, Takagi N, Takeda Y, Ohsugi Y (1998) IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. Clin Exp Immunol 112:397–402PubMedCrossRefGoogle Scholar
  74. 74.
    Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, Shlomchik MJ (2005) Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 202:321–331PubMedCrossRefGoogle Scholar
  75. 75.
    Vyse TJ, Drake CG, Rozzo SJ, Roper E, Izui S, Kotzin BL (1996) Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice. J Clin Invest 98:1762–1772PubMedCrossRefGoogle Scholar
  76. 76.
    Izui S, Lambert PH, Miescher PA (1977) Failure to detect circulating DNA-anti-DNA complexes by four radioimmunological methods in patients with systemic lupus erythematosus. Clin Exp Immunol 30:384–392PubMedGoogle Scholar
  77. 77.
    Wu X, Peng SL (2006) Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum 54:336–342PubMedCrossRefGoogle Scholar
  78. 78.
    Ehlers M, Fukuyama H, McGaha TL, Aderem A, Ravetch JV (2006) TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE. J Exp Med 203:553–561PubMedCrossRefGoogle Scholar
  79. 79.
    Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S (2006) Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplicaton. Science 312:1669–1672PubMedCrossRefGoogle Scholar
  80. 80.
    Bolland S, Yim YS, Tus K, Wakeland EK, Ravetch JV (2002) Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(−/−) mice. J Exp Med 195:1167–1174PubMedCrossRefGoogle Scholar
  81. 81.
    Lazarus R, Klimecki WT, Raby BA, Vercelli D, Palmer LJ, Kwiatkowski DJ, Silverman EK, Martinez F, Weiss ST (2003) Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies. Genomics 81:85–91PubMedCrossRefGoogle Scholar
  82. 82.
    Torok HP, Glas J, Tonenchi L, Bruennler G, Folwaczny M, Folwaczny C (2004) Crohn’s disease is associated with a toll-like receptor-9 polymorphism. Gastroenterology 127:365–366PubMedCrossRefGoogle Scholar
  83. 83.
    Hur JW, Shin HD, Park BL, Kim LH, Kim SY, Bae SC (2005) Association study of Toll-like receptor 9 gene polymorphism in Korean patients with systemic lupus erythematosus. Tissue Antigens 65:266–270PubMedCrossRefGoogle Scholar
  84. 84.
    Ng MW, Lau CS, Chan TM, Wong WH, Lau YL (2005) Polymorphisms of the toll-like receptor 9 (TLR9) gene with systemic lupus erythematosus in Chinese. Rheumatology (Oxford) 44:1456–1457CrossRefGoogle Scholar
  85. 85.
    De Jager PL, Richardson A, Vyse TJ, Rioux JD (2006) Genetic variation in toll-like receptor 9 and susceptibility to systemic lupus erythematosus. Arthritis Rheum 54:1279–1282PubMedCrossRefGoogle Scholar
  86. 86.
    Hawn TR, Wu H, Grossman JM, Hahn BH, Tsao BP, Aderem A (2005) A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Proc Natl Acad Sci USA 102:10593–10597PubMedCrossRefGoogle Scholar
  87. 87.
    Krieg AM (2001) From bugs to drugs: therapeutic immunomodulation with oligodeoxynucleotides containing CpG sequences from bacterial DNA. Antisense Nucleic Acid Drug Dev 11:181–188PubMedCrossRefGoogle Scholar
  88. 88.
    Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB, Schroeder L, Aderem A (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA 97:13766–13771PubMedCrossRefGoogle Scholar
  89. 89.
    Iwaki D, Mitsuzawa H, Murakami S, Sano H, Konishi M, Akino T, Kuroki Y (2002) The extracellular toll-like receptor 2 domain directly binds peptidoglycan derived from Staphylococcus aureus. J Biol Chem 277:24315–24320PubMedCrossRefGoogle Scholar
  90. 90.
    Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD, Klimpel GR, Godowski P, Zychlinsky A (1999) Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285:736–739PubMedCrossRefGoogle Scholar
  91. 91.
    Muzio M, Bosisio D, Polentarutti N, D’Amico G, Stoppacciaro A, Mancinelli R, van’t Veer C, Penton-Rol G, Ruco LP, Allavena P, Mantovani A (2000) Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 164:5998–6004PubMedGoogle Scholar
  92. 92.
    Jiang Q, Akashi S, Miyake K, Petty HR (2000) Lipopolysaccharide induces physical proximity between CD14 and toll-like receptor 4 (TLR4) prior to nuclear translocation of NF-kappa B. J Immunol 165:3541–3544PubMedGoogle Scholar
  93. 93.
    Akashi S, Shimazu R, Ogata H, Nagai Y, Takeda K, Kimoto M, Miyake K (2000) Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages. J Immunol 164:3471–3475PubMedGoogle Scholar
  94. 94.
    Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099–1103PubMedCrossRefGoogle Scholar
  95. 95.
    Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL (2001) Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 167:1882–1885PubMedGoogle Scholar
  96. 96.
    Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3:499PubMedCrossRefGoogle Scholar
  97. 97.
    Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S (2004) A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303:1522–1526PubMedCrossRefGoogle Scholar
  98. 98.
    Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S, Sher A (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308:1626–1629PubMedCrossRefGoogle Scholar
  99. 99.
    Ma Z, Chen Z, Madaio M, Cohen PL, Eisenberg RA (2006) Modulation of Autoimmunity by TLR9 in the Chronic GVH Model of SLE (in press)Google Scholar

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© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Division of Rheumatology, Department of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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