Skip to main content
SpringerLink
Log in

Nucleic Acid Recognition Receptors in Autoimmunity

  • Chapter
Toll-Like Receptors (TLRs) and Innate Immunity

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 183))

Recent studies in mouse models of systemic autoimmune diseases have drawn attention to the involvement of Toll-like receptors (TLRs) in the generation of autoreactive immune responses. The endosomally localized TLRs7 and 9 are activated by autoimmune complexes containing self DNA and RNA in B lymphocytes and dendritic cells. These endogenous TLR ligands act as autoadjuvants providing a stimulatory signal together with the autoantigen and thus contribute to break peripheral tolerance against self antigens in systemic lupus erythematosus (SLE), for example. In vivo studies in SLE mouse models demonstrate an essential role for TLR7 in the generation of RNA-containing antinuclear antibodies and deposition of pathogenic immune complexes in the kidney. TLR9, however, appears to have immunostimulatory as well as regulatory functions in SLE mouse models. Type I Interferon, which is produced by plasmacytoid dendritic cells in response to autoimmune complexes containing RNA and DNA recognized by TLR7 and 9 acts as a potent amplifier of the autoimmune response. TLR-independent recognition of self nucleic acids by cytosolic RNA and DNA sensors may also play a role in the generation of autoimmune responses. Defects in protective mechanisms, which normally prevent immunostimulation by self nucleic acids in healthy individuals, promote the development of autoimmune diseases. For example, defects in nucleases that clear nucleic acids derived from apoptotic material, changes in the level and localization of TLR expression, defects in negative regulators of TLR signaling, or changes in the posttranscriptional modification of mammalian DNA and RNA may contribute to autoreactive responses. A better understanding of the exact function of different nucleic acid recognition receptors in the development of systemic autoimmunity will allow targeting of these innate immune receptors for the therapy of patients with systemic autoimmune diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124: 783-801

    Article  CAS  PubMed  Google Scholar 

  • Akwa Y, Hassett DE, Eloranta ML, Sandberg K, Masliah E, Powell H, Whitton JL, Bloom FE, Campbell IL (1998) Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. J Immunol 161: 5016-526

    CAS  PubMed  Google Scholar 

  • Alarcon-Riquelme ME (2005) The genetics of systemic lupus erythematosus. J Autoimmun 25 Suppl: 46-48

    Article  CAS  PubMed  Google Scholar 

  • 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: 732-738

    Article  CAS  PubMed  Google Scholar 

  • Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA 100: 2610-2615

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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: 1131-1139

    Article  CAS  PubMed  Google Scholar 

  • 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: 49-56

    Article  CAS  PubMed  Google Scholar 

  • Bave U, Alm GV, Ronnblom L (2000) The combination of apoptotic U937 cells and lupus IgG is a potent IFN-alpha inducer. J Immunol 165: 3519-3526

    CAS  PubMed  Google Scholar 

  • Bave U, Magnusson M, Eloranta ML, Perers A, Alm GV, Ronnblom L (2003) Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG. J Immunol 171: 3296-3302

    CAS  PubMed  Google Scholar 

  • Bave U, Vallin H, Alm GV, Ronnblom L (2001) Activation of natural interferon-alpha producing cells by apoptotic U937 cells combined with lupus IgG and its regulation by cytokines. J Autoimmun 17: 71-80

    Article  CAS  PubMed  Google Scholar 

  • Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V (2003) Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197: 711-723

    Article  CAS  PubMed  Google Scholar 

  • Berghofer B, Frommer T, Haley G, Fink L, Bein G, Hackstein H (2006) TLR7 ligands induce higher IFN-alpha production in females. J Immunol 177: 2088-2096

    PubMed  Google Scholar 

  • Berkeredjian-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: 4043-4050

    CAS  PubMed  Google Scholar 

  • Berland R, Fernandez L, Kari E, Han JH, Lomakin I, Akira S, Wortis HH, Kearney JF, Ucci AA, Imanishi-Kari T (2006) Toll-like Receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity 25: 429-440

    Article  CAS  PubMed  Google Scholar 

  • Blasius A, Vermi W, Krug A, Facchetti F, Cella M, Colonna M (2004) A cell-surface molecule selectively expressed on murine natural interferon-producing cells that blocks secretion of interferon-alpha. Blood 103: 4201-4206

    Article  CAS  PubMed  Google Scholar 

  • 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: 1631-1640

    Article  CAS  PubMed  Google Scholar 

  • Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, Scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27: 68-73

    Article  CAS  PubMed  Google Scholar 

  • Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J (2003) Regulatory T cells selectively express Toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197: 403-411

    Article  CAS  PubMed  Google Scholar 

  • Caron G, Duluc D, Fremaux I, Jeannin P, David C, Gascan H, Delneste Y (2005) Direct stimulation of human T cells via TLR5 and TLR7/8: Flagellin and R-848 up-regulate proliferation and IFNgamma production by memory CD4+T cells. J Immunol 175: 1551-1557

    CAS  PubMed  Google Scholar 

  • Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ (2006) Tolllike receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25: 417-428

    Article  CAS  PubMed  Google Scholar 

  • Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, van Bokhoven H, Brunner HG, Hamel BC, Corry PC, Cowan FM, Frints SG, Klepper J, Livingston JH, Lynch SA, Massey RF, Meritet JF, Michaud JL, Ponsot G, Voit T, Lebon P, Bonthron DT, Jackson AP, Barnes DE, Lindahl T (2006a) Mutations in the gene encoding the 3′ -5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat Genet 38: 917-920

    Article  CAS  Google Scholar 

  • Crow YJ, Leitch A, Hayward BE, Garner A, Parmar R, Griffith E, Ali M, Semple C, Aicardi J, Babul-Hirji R, Baumann C, Baxter P, Bertini E, Chandler KE, Chitayat D, Cau D, Dery C, Fazzi E, Goizet C, King MD, Klepper J, Lacombe D, Lanzi G, Lyall H, Martinez-Frias ML, Mathieu M, McKeown C, Monier A, Oade Y, Quarrell OW, Rittey CD, Rogers RC, Sanchis A, Stephenson JB, Tacke U, Till M, Tolmie JL, Tomlin P, Voit T, Weschke B, Woods CG, Lebon P, Bonthron DT, Ponting CP, Jackson AP (2006b) Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat Genet 38: 910-916

    Article  CAS  Google Scholar 

  • De Bouteiller O, Merck E, Hasan UA, Hubac S, Benguigui B, Trinchieri G, Bates EE, Caux C (2005) Recognition of double-stranded RNA by human Toll-like receptor 3 and downstream receptor signaling requires multimerization and an acidic pH. J Biol Chem 280: 3813-3845

    Article  CAS  Google Scholar 

  • 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: 1279-1282

    Article  CAS  PubMed  Google Scholar 

  • De Laet C, Goyens P, Christophe C, Ferster A, Mascart F, Dan B (2005) Phenotypic overlap between infantile systemic lupus erythematosus and Aicardi-Goutieres syndrome. Neuropediatrics 36: 399-402

    Article  CAS  PubMed  Google Scholar 

  • Decker P, Singh-Jasuja H, Haager S, Kotter I, Rammensee HG (2005) 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

    CAS  PubMed  Google Scholar 

  • Diebold SS, Kaisho T, Hemmi H, Akira S, Reis ESC (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303: 1529-1531

    Article  CAS  PubMed  Google Scholar 

  • Ding C, Wang L, Al-Ghawi H, Marroquin J, Mamula M, Yan J (2006) Toll-like receptor engagement stimulates anti-snRNP autoreactive B cells for activation. Eur J Immunol 36: 2013-2024

    Article  CAS  PubMed  Google Scholar 

  • Dong L, Ito S, Ishii KJ, Klinman DM (2005) Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus-prone NZB × NZW mice. Arthritis Rheum 52: 651-658

    Article  CAS  PubMed  Google Scholar 

  • Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F, Gunther G, Johnston I, Lanzavecchia A, Nagasaka T, Okada T, Vermi W, Winkels G, Yamamoto T, Zysk M, Yamaguchi Y, Schmitz J (2001) BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J Exp Med 194: 1823-1834

    Article  CAS  PubMed  Google Scholar 

  • 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: 553-561

    Article  CAS  PubMed  Google Scholar 

  • Fields ML, Metzgar MH, Hondowicz BD, Kang SA, Alexander ST, Hazard KD, Hsu AC, Du YZ, Prak EL, Monestier M, Erikson J (2006) Exogenous and endogenous TLR ligands activate anti-chromatin and polyreactive B cells. J Immunol 176: 6491-6502

    CAS  PubMed  Google Scholar 

  • Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol 4: 330-336

    Article  CAS  PubMed  Google Scholar 

  • Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B, Flavell RA, Diamond MS, Colonna M (2006) 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

    Article  CAS  PubMed  Google Scholar 

  • Goutieres F (2005) Aicardi-Goutieres syndrome. Brain Dev 27: 201-206

    Article  PubMed  Google Scholar 

  • Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S, Wagner H, Bauer S (2003) The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 33: 2987-2997

    Article  CAS  PubMed  Google Scholar 

  • 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: 1526-1529

    Article  CAS  PubMed  Google Scholar 

  • Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3: 196-200

    Article  CAS  PubMed  Google Scholar 

  • Honda K, Yanai H, Mizutani T, Negishi H, Shimada N, Suzuki N, Ohba Y, Takaoka A, Yeh WC, Taniguchi T (2004) Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci USA 101: 15416-15421

    Article  CAS  PubMed  Google Scholar 

  • Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, Endres S, Hartmann G (2006) 5′ triphosphate RNA is the ligand for RIG-I. Science 314: 994-997

    Article  PubMed  Google Scholar 

  • 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: 266-270

    Article  CAS  PubMed  Google Scholar 

  • Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, Ludwig H, Sutter G, Suzuki K, Hemmi H, Sato S, Yamamoto M, Uematsu S, Kawai T, Takeuchi O, Akira S (2006) A Tolllike receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol 7: 40-48

    Article  CAS  PubMed  Google Scholar 

  • Ishii KJ, Suzuki K, Coban C, Takeshita F, Itoh Y, Matoba H, Kohn LD, Klinman DM (2001) Genomic DNA released by dying cells induces the maturation of APCs. J Immunol 167: 2602-2607

    CAS  PubMed  Google Scholar 

  • Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A (2001) Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 31: 3388-3393

    Article  CAS  PubMed  Google Scholar 

  • 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: 863-869

    Article  CAS  PubMed  Google Scholar 

  • Kariko K, Buckstein M, Ni H, Weissman D (2005) Suppression of RNA recognition by Tolllike receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23: 165-175

    Article  CAS  PubMed  Google Scholar 

  • 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: 12542-12550

    Article  CAS  PubMed  Google Scholar 

  • Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S (2006) Differential roles of mda5 and RIG-I helicases in the recognition of RNA viruses. Nature 441: 101-105

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, Terai K, Matsuda M, Inoue J, Uematsu S, Takeuchi O, Akira S (2004) Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5: 1061-1068

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S (2005) IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6: 981-988

    Article  CAS  PubMed  Google Scholar 

  • Kawane K, Fukuyama H, Yoshida H, Nagase H, Ohsawa Y, Uchiyama Y, Okada K, Iida T, Nagata S (2003) Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation. Nat Immunol 4: 138-144

    Article  CAS  PubMed  Google Scholar 

  • Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y, Yoshioka Y, Yoshikawa H, Nagata S (2006) Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443: 998-1002

    Article  CAS  PubMed  Google Scholar 

  • Kerkmann M, Rothenfusser S, Hornung V, Towarowski A, Wagner M, Sarris A, Giese T, Endres S, Hartmann G (2003) Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J Immunol 170: 4465-4474

    CAS  PubMed  Google Scholar 

  • Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK (2005) Activation of the interferonalpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum 52: 1491-1503

    Article  CAS  PubMed  Google Scholar 

  • Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, Bals R, Giese T, Engelmann H, Endres S, Krieg AM, Hartmann G (2001) 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 31: 3026-3037

    Article  CAS  PubMed  Google Scholar 

  • Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, Hamann A, Wagner H, Huehn J, Sparwasser T (2007) Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med 204: 57-63

    Article  CAS  PubMed  Google Scholar 

  • Lartigue A, Courville P, Auquit I, Francois A, Arnoult C, Tron F, Gilbert D, Musette P (2006) Role of TLR9 in anti-nucleosome and anti-DNA antibody production in lpr mutation-induced murine lupus. J Immunol 177: 1349-1354

    CAS  PubMed  Google Scholar 

  • 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: 190-198

    Article  CAS  PubMed  Google Scholar 

  • 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: 1171-1177

    Article  CAS  PubMed  Google Scholar 

  • 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: 603-607

    Article  CAS  PubMed  Google Scholar 

  • Lebon P, Badoual J, Ponsot G, Goutieres F, Hemeury-Cukier F, Aicardi J (1988) Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci 84: 201-208

    Article  CAS  PubMed  Google Scholar 

  • Lee HK, Dunzendorfer S, Soldau K, Tobias PS (2006) Double-stranded RNA-mediated TLR3 activation is enhanced by CD14. Immunity 24: 153-163

    Article  CAS  PubMed  Google Scholar 

  • Liew FY, Xu D, Brint EK, O’Neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5: 446-458

    Article  CAS  PubMed  Google Scholar 

  • 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: 1861-1872

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA (2005) Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med 11: 85-89

    Article  CAS  PubMed  Google Scholar 

  • 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: 407-417

    CAS  PubMed  Google Scholar 

  • Mellor AL, Baban B, Chandler PR, Manlapat A, Kahler DJ, Munn DH (2005) 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 175: 5601-5605

    CAS  PubMed  Google Scholar 

  • Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437: 1167-1172

    Article  CAS  PubMed  Google Scholar 

  • Morita M, Stamp G, Robins P, Dulic A, Rosewell I, Hrivnak G, Daly G, Lindahl T, Barnes DE (2004) Gene-targeted mice lacking the Trex1 (DNase III) 3′ - > 5′ DNA exonuclease develop inflammatory myocarditis. Mol Cell Biol 24: 6719-6727

    Article  CAS  PubMed  Google Scholar 

  • Moseman EA, Liang X, Dawson AJ, Panoskaltsis-Mortari A, Krieg AM, Liu YJ, Blazar BR, Chen W (2004) Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+ CD25+ regulatory T cells. J Immunol 173: 4433-4442

    CAS  PubMed  Google Scholar 

  • Mudd PA, Teague BN, Farris AD (2006) Regulatory T cells and systemic lupus erythematosus. Scand J Immunol 64: 211-218

    Article  CAS  PubMed  Google Scholar 

  • Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T (2000) Features of systemic lupus erythematosus in Dnase-1-deficient mice. Nat Genet 25: 177-181

    Article  CAS  PubMed  Google Scholar 

  • Nishiya T, Kajita E, Miwa S, Defranco AL (2005) TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements. J Biol Chem 280: 37107-37117

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+ CD25+ T cellmediated suppression by dendritic cells. Science 299: 1033-1036

    Article  CAS  PubMed  Google Scholar 

  • Pashenkov M, Teleshova N, Kouwenhoven M, Smirnova T, Jin YP, Kostulas V, Huang YM, Pinegin B, Boiko A, Link H (2002) Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections. J Neuroimmunol 122: 106-116

    Article  CAS  PubMed  Google Scholar 

  • Patole PS, Grone HJ, Segerer S, Ciubar R, Belemezova E, Henger A, Kretzler M, Schlondorff D, Anders HJ (2005a) 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: 1326-1338

    Article  CAS  Google Scholar 

  • Patole PS, Zecher D, Pawar RD, Grone HJ, Schlondorff D, Anders HJ (2005b) G-rich DNA suppresses systemic lupus. J Am Soc Nephrol 16: 3273-3280

    Article  CAS  Google Scholar 

  • Pawar RD, Patole PS, Wornle M, Anders HJ (2006) Microbial nucleic acids pay a Toll in kidney disease. Am J Physiol Renal Physiol 291: F509-516

    Article  CAS  PubMed  Google Scholar 

  • Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF (2005) Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309: 1380-1384

    Article  CAS  PubMed  Google Scholar 

  • Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, Reis ESC (2006) RIG-Imediated antiviral responses to single-stranded RNA bearing 5′ phosphates. Science 314: 997-1001

    Article  CAS  PubMed  Google Scholar 

  • 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 duplication. Science 312: 1669-1672

    Article  CAS  PubMed  Google Scholar 

  • Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33: 1665-1673

    Article  CAS  PubMed  Google Scholar 

  • Ronnefarth VM, Erbacher AI, Lamkemeyer T, Madlung J, Nordheim A, Rammensee HG, Decker P (2006) TLR2/TLR4-independent neutrophil activation and recruitment upon endocytosis of nucleosomes reveals a new pathway of innate immunity in systemic lupus erythematosus. J Immunol 177: 7740-7749

    PubMed  Google Scholar 

  • Rutz M, Metzger J, Gellert T, Luppa P, Lipford GB, Wagner H, Bauer S (2004) Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol 34: 2541-2550

    Article  CAS  PubMed  Google Scholar 

  • 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: 1341-1345

    CAS  PubMed  Google Scholar 

  • Santiago-Raber ML, Baccala R, Haraldsson KM, Choubey D, Stewart TA, Kono DH, Theofilopou-los AN (2003) Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med 197: 777-788

    Article  CAS  PubMed  Google Scholar 

  • Savarese E, Chae OW, Trowitzsch S, Weber G, Kastner B, Akira S, Wagner H, Schmid RM, Bauer S, Krug A (2006) U1 small nuclear ribonucleoprotein immune complexes induce Type I interferon in plasmacytoid dendritic cells through TLR7. Blood 107: 3229-3234

    Article  CAS  PubMed  Google Scholar 

  • Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljestrom P, Reis e Sousa C (2005) Toll-like receptor 3 promotes cross-priming to virusinfected cells. Nature 433: 887-892

    Article  CAS  PubMed  Google Scholar 

  • Seth RB, Sun L, Ea CK, Chen ZJ (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122: 669-682

    Article  CAS  PubMed  Google Scholar 

  • Shi SN, Feng SF, Wen YM, He LF, Huang YX (1987) Serum interferon in systemic lupus erythematosus. Br J Dermatol 117: 155-159

    Article  CAS  PubMed  Google Scholar 

  • Shin HD, Park BL, Cheong HS, Lee HS, Jun JB, Bae SC (2005) DNase II polymorphisms associated with risk of renal disorder among systemic lupus erythematosus patients. J Hum Genet 50: 107-111

    Article  CAS  PubMed  Google Scholar 

  • Shin HD, Park BL, Kim LH, Lee HS, Kim TY, Bae SC (2004) Common DNase I polymorphism associated with autoantibody production among systemic lupus erythematosus patients. Hum Mol Genet 13: 2343-2350

    Article  CAS  PubMed  Google Scholar 

  • Stetson DB, Medzhitov R (2006) Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24: 93-103

    Article  CAS  PubMed  Google Scholar 

  • Subramanian S, Tus K, Li QZ, Wang A, Tian XH, Zhou J, Liang C, Bartov G, McDaniel LD, Zhou XJ, Schultz RA, Wakeland EK (2006) A TLR7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci USA 103: 9970-9975

    Article  CAS  PubMed  Google Scholar 

  • Suri-Payer E, Fritzsching B (2006) Regulatory T cells in experimental autoimmune disease. Springer Semin Immunopathol 28: 3-16

    Article  CAS  PubMed  Google Scholar 

  • Tissari J, Siren J, Meri S, Julkunen I, Matikainen S (2005) IFN-alpha enhances TLR3-mediated antiviral cytokine expression in human endothelial and epithelial cells by up-regulating TLR3 expression. J Immunol 174: 4289-4294

    CAS  PubMed  Google Scholar 

  • Vallin H, Blomberg S, Alm GV, Cederblad B, Ronnblom L (1999) Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-alpha (IFN-alpha) production acting on leucocytes resembling immature dendritic cells. Clin Exp Immunol 115: 196-202

    Article  CAS  PubMed  Google Scholar 

  • Viglianti GA, Lau CM, Hanley TM, Miko BA, Shlomchik MJ, Marshak-Rothstein A (2003) Activation of autoreactive B cells by CpG dsDNA. Immunity 19: 837-847

    Article  CAS  PubMed  Google Scholar 

  • 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: 1575-1585

    Article  CAS  PubMed  Google Scholar 

  • Wingender G, Garbi N, Schumak B, Jungerkes F, Endl E, von Bubnoff D, Steitz J, Striegler J, Moldenhauer G, Tuting T, Heit A, Huster KM, Takikawa O, Akira S, Busch DH, Wagner H, Hammerling GJ, Knolle PA, Limmer A (2006) Systemic application of CpG-rich DNA suppresses adaptive T cell immunity via induction of IDO. Eur J Immunol 36: 12-20

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Peng SL (2006) Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum 54: 336-42

    Article  CAS  PubMed  Google Scholar 

  • Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB (2005) VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19: 727-740

    Article  CAS  PubMed  Google Scholar 

  • 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: 313-314

    Article  CAS  PubMed  Google Scholar 

  • Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo YM, Gale M, Jr., Akira S, Yonehara S, Kato A, Fujita T (2005) Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 175: 2851-2858

    CAS  PubMed  Google Scholar 

  • Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T (2004) The RNA helicase RIG-I has an essential function in double-stranded RNAinduced innate antiviral responses. Nat Immunol 5: 730-737

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Yu P, Wellmann U, Kunder S, Quintanilla-Martinez L, Jennen L, Dear N, Amann K, Bauer S, Win-kler TH, Wagner H (2006) Toll-like receptor 9-independent aggravation of glomerulonephritis in a novel model of SLE. Int Immunol 18: 1211-1219

    Article  CAS  PubMed  Google Scholar 

  • Yurasov S, Wardemann H, Hammersen J, Tsuiji M, Meffre E, Pascual V, Nussenzweig MC (2005) Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med 201: 703-711

    Article  CAS  PubMed  Google Scholar 

  • Zhuang H, Kosboth M, Lee P, Rice A, Driscoll DJ, Zori R, Narain S, Lyons R, Satoh M, Sobel E, Reeves WH (2006) Lupus-like disease and high interferon levels corresponding to trisomy of the Type I interferon cluster on chromosome 9p. Arthritis Rheum 54: 1573-1579

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. II. Medizinische Klinik, Klinkum Rechts der Isar, Technische Universität München, Trogerstr. 32, D-81675, München, Germany

    Anne Krug

Authors
  1. Anne Krug
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institut für Immunologie BMFZ, Philipps-Universität Marburg, Hans-Meerwein-Str. 2, D-35043, Marburg, Germany

    Stefan Bauer

  2. Abteilung für Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, D-53105, Bonn, Germany

    Gunther Hartmann

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Krug, A. (2008). Nucleic Acid Recognition Receptors in Autoimmunity. In: Bauer, S., Hartmann, G. (eds) Toll-Like Receptors (TLRs) and Innate Immunity. Handbook of Experimental Pharmacology, vol 183. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-72167-3_7

Download citation

Publish with us

Policies and ethics

Search

Navigation