Skip to main content

Advertisement

Log in

Toll-Like Receptor Pathways in Autoimmune Diseases

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Several studies suggest that Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. TLRs belong to the family of pattern recognition receptors (PRRs) that recognize a wide range of pathogen-associated molecular patterns (PAMPs). TLRs are type I transmembrane proteins and located on various cellular membranes. Two main groups have been classified based on their location; the extracelluar group referred to the ones located on the plasma membrane while the intracellular group all located in endosomal compartments responsible for the recognition of nucleic acids. They are released by the host cells and trigger various intracellular pathways which results in the production of proinflammatory cytokines, chemokines, as well as the expression of co-stimulatory molecules to protect against invading microorganisms. In particular, TLR pathway-associated proteins, such as IRAK, TRAF, and SOCS, are often dysregulated in this group of diseases. TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases. In this review, we summarize recent findings on TLR pathway regulation in various autoimmune diseases, including Sjögren’s syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis.

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

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Amital H, Govoni M, Maya R et al (2008) Role of infectious agents in systemic rheumatic diseases. Clin Exp Rheumatol 26:S27–32

    PubMed  CAS  Google Scholar 

  2. Liu Y, Yin H, Zhao M, Lu Q (2014) TLR2 and TLR4 in autoimmune diseases: a comprehensive review. Clin Rev Allergy Immunol 47:136–147. doi:10.1007/s12016-013-8402-y

    Article  PubMed  CAS  Google Scholar 

  3. Thwaites R, Chamberlain G, Sacre S (2014) Emerging role of endosomal toll-like receptors in rheumatoid arthritis. Front Immunol 5:1. doi:10.3389/fimmu.2014.00001

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801. doi:10.1016/j.cell.2006.02.015

    Article  PubMed  CAS  Google Scholar 

  5. Santegoets KCM, van Bon L, van den Berg WB et al (2011) Toll-like receptors in rheumatic diseases: are we paying a high price for our defense against bugs? FEBS Lett 585:3660–3666. doi:10.1016/j.febslet.2011.04.028

    Article  PubMed  CAS  Google Scholar 

  6. Mogensen TH, Paludan SR (2005) Reading the viral signature by Toll-like receptors and other pattern recognition receptors. J Mol Med Berl Ger 83:180–192. doi:10.1007/s00109-004-0620-6

    Article  CAS  Google Scholar 

  7. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511. doi:10.1038/nri1391

    Article  PubMed  CAS  Google Scholar 

  8. Bowie A, O’Neill LA (2000) The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products. J Leukoc Biol 67:508–514

    PubMed  CAS  Google Scholar 

  9. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650. doi:10.1016/j.immuni.2011.05.006

    Article  PubMed  CAS  Google Scholar 

  10. Roach JC, Glusman G, Rowen L et al (2005) The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A 102:9577–9582. doi:10.1073/pnas.0502272102

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  11. Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–14. doi:10.1093/intimm/dxh186

    Article  PubMed  CAS  Google Scholar 

  12. Yamamoto M, Sato S, Mori K et al (2002) Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol 169:6668–6672

    Article  PubMed  CAS  Google Scholar 

  13. Yamamoto M, Sato S, Hemmi H et al (2003) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301:640–643. doi:10.1126/science.1087262

    Article  PubMed  CAS  Google Scholar 

  14. Horng T, Barton GM, Flavell RA, Medzhitov R (2002) The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420:329–333. doi:10.1038/nature01180

    Article  PubMed  CAS  Google Scholar 

  15. Honda K, Yanai H, Mizutani T et al (2004) Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci U S A 101:15416–15421. doi:10.1073/pnas.0406933101

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Negishi H, Fujita Y, Yanai H et al (2006) Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program. Proc Natl Acad Sci U S A 103:15136–15141. doi:10.1073/pnas.0607181103

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Takaoka A, Yanai H, Kondo S et al (2005) Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434:243–249. doi:10.1038/nature03308

    Article  PubMed  CAS  Google Scholar 

  18. Kagan JC, Su T, Horng T et al (2008) TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol 9:361–368. doi:10.1038/ni1569

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384. doi:10.1038/ni.1863

    Article  PubMed  CAS  Google Scholar 

  20. Shimazu R, Akashi S, Ogata H et al (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189:1777–1782

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Kurt-Jones EA, Popova L, Kwinn L et al (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1:398–401. doi:10.1038/80833

    Article  PubMed  CAS  Google Scholar 

  22. Cao Z, Henzel WJ, Gao X (1996) IRAK: a kinase associated with the interleukin-1 receptor. Science 271:1128–1131

    Article  PubMed  CAS  Google Scholar 

  23. Janssens S, Beyaert R (2003) Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol Cell 11:293–302

    Article  PubMed  CAS  Google Scholar 

  24. O’Neill LAJ, Bryant CE, Doyle SL (2009) Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev 61:177–197. doi:10.1124/pr.109.001073

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Wang C, Deng L, Hong M et al (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412:346–351. doi:10.1038/35085597

    Article  PubMed  CAS  Google Scholar 

  26. Hsu H, Xiong J, Goeddel DV (1995) The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 81:495–504

    Article  PubMed  CAS  Google Scholar 

  27. Youn J, Kim H-Y, Park JH et al (2002) Regulation of TNF-alpha-mediated hyperplasia through TNF receptors, TRAFs, and NF-kappaB in synoviocytes obtained from patients with rheumatoid arthritis. Immunol Lett 83:85–93

    Article  PubMed  CAS  Google Scholar 

  28. Rothe M, Sarma V, Dixit VM, Goeddel DV (1995) TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40. Science 269:1424–1427

    Article  PubMed  CAS  Google Scholar 

  29. Ihnatko R, Kubes M (2007) TNF signaling: early events and phosphorylation. Gen Physiol Biophys 26:159–167

    PubMed  CAS  Google Scholar 

  30. Chung JY, Lu M, Yin Q et al (2007) Molecular basis for the unique specificity of TRAF6. Adv Exp Med Biol 597:122–130. doi:10.1007/978-0-387-70630-6_10

    Article  PubMed  Google Scholar 

  31. Lee NK, Lee SY (2002) Modulation of life and death by the tumor necrosis factor receptor-associated factors (TRAFs). J Biochem Mol Biol 35:61–66

    Article  PubMed  Google Scholar 

  32. Bradley JR, Pober JS (2001) Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene 20:6482–6491. doi:10.1038/sj.onc.1204788

    Article  PubMed  CAS  Google Scholar 

  33. Wu H, Arron JR (2003) TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays News Rev Mol Cell Dev Biol 25:1096–1105. doi:10.1002/bies.10352

    Article  CAS  Google Scholar 

  34. Naito A, Azuma S, Tanaka S et al (1999) Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells Devoted Mol Cell Mech 4:353–362

    Article  CAS  Google Scholar 

  35. Endo TA, Masuhara M, Yokouchi M et al (1997) A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387:921–924. doi:10.1038/43213

    Article  PubMed  CAS  Google Scholar 

  36. Starr R, Willson TA, Viney EM et al (1997) A family of cytokine-inducible inhibitors of signalling. Nature 387:917–921. doi:10.1038/43206

    Article  PubMed  CAS  Google Scholar 

  37. Naka T, Narazaki M, Hirata M et al (1997) Structure and function of a new STAT-induced STAT inhibitor. Nature 387:924–929. doi:10.1038/43219

    Article  PubMed  CAS  Google Scholar 

  38. Li YC, Chen Y, Liu W, Thadhani R (2014) MicroRNA-mediated mechanism of vitamin D regulation of innate immune response. J Steroid Biochem Mol Biol 144(Pt A):81–86. doi:10.1016/j.jsbmb.2013.09.014

    Article  PubMed  CAS  Google Scholar 

  39. Mansell A, Smith R, Doyle SL et al (2006) Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol 7:148–155. doi:10.1038/ni1299

    Article  PubMed  CAS  Google Scholar 

  40. Zeher M, Szodoray P (2009) Sjögren’s syndrome and associated disorders. Transworld Research Network, Kerala

    Google Scholar 

  41. Szanto A, Szodoray P, Kiss E et al (2006) Clinical, serologic, and genetic profiles of patients with associated Sjögren’s syndrome and systemic lupus erythematosus. Hum Immunol 67:924–930. doi:10.1016/j.humimm.2006.06.006

    Article  PubMed  CAS  Google Scholar 

  42. Zheng L, Zhang Z, Yu C, Yang C (2010) Expression of Toll-like receptors 7, 8, and 9 in primary Sjögren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 109:844–850. doi:10.1016/j.tripleo.2010.01.006

    Article  PubMed  Google Scholar 

  43. Spachidou MP, Bourazopoulou E, Maratheftis CI et al (2007) Expression of functional Toll-like receptors by salivary gland epithelial cells: increased mRNA expression in cells derived from patients with primary Sjögren’s syndrome. Clin Exp Immunol 147:497–503. doi:10.1111/j.1365-2249.2006.03311.x

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Kawakami A, Nakashima K, Tamai M et al (2007) Toll-like receptor in salivary glands from patients with Sjögren’s syndrome: functional analysis by human salivary gland cell line. J Rheumatol 34:1019–1026

    PubMed  CAS  Google Scholar 

  45. Kwok S-K, Cho M-L, Her Y-M et al (2012) TLR2 ligation induces the production of IL-23/IL-17 via IL-6, STAT3 and NF-kB pathway in patients with primary Sjogren’s syndrome. Arthritis Res Ther 14:R64. doi:10.1186/ar3780

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  46. Zilahi E, Tarr T, Papp G et al (2012) Increased microRNA-146a/b, TRAF6 gene and decreased IRAK1 gene expressions in the peripheral mononuclear cells of patients with Sjögren’s syndrome. Immunol Lett 141:165–168. doi:10.1016/j.imlet.2011.09.006

    Article  PubMed  CAS  Google Scholar 

  47. Bhaumik D, Scott GK, Schokrpur S et al (2008) Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. Oncogene 27:5643–5647. doi:10.1038/onc.2008.171

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  48. Szodoray P, Gal I, Barath S et al (2008) Immunological alterations in newly diagnosed primary Sjögren’s syndrome characterized by skewed peripheral T-cell subsets and inflammatory cytokines. Scand J Rheumatol 37:205–212. doi:10.1080/03009740801910361

    Article  PubMed  CAS  Google Scholar 

  49. Rothfield N (1989) Clinical aspects and treatment of systemic lupus erythematosus. Curr Opin Rheumatol 1:327–331

    Article  PubMed  CAS  Google Scholar 

  50. Savarese E, Chae O, Trowitzsch S et al (2006) U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood 107:3229–3234. doi:10.1182/blood-2005-07-2650

    Article  PubMed  CAS  Google Scholar 

  51. Vollmer J, Tluk S, Schmitz C et al (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. doi:10.1084/jem.20051696

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  52. Means TK, Latz E, Hayashi F et al (2005) Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest 115:407–417. doi:10.1172/JCI23025

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  53. Barrat FJ, Meeker T, Gregorio J et al (2005) Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 202:1131–1139. doi:10.1084/jem.20050914

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  54. Bengtsson AA, Sturfelt G, Truedsson L et al (2000) Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus 9:664–671

    Article  PubMed  CAS  Google Scholar 

  55. Baechler EC, Batliwalla FM, Karypis G et al (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100:2610–2615. doi:10.1073/pnas.0337679100

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  56. Honda K, Ohba Y, Yanai H et al (2005) Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434:1035–1040. doi:10.1038/nature03547

    Article  PubMed  CAS  Google Scholar 

  57. Napolitani G, Rinaldi A, Bertoni F et al (2005) Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol 6:769–776. doi:10.1038/ni1223

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  58. Dennehy KM, Willment JA, Williams DL, Brown GD (2009) Reciprocal regulation of IL-23 and IL-12 following co-activation of Dectin-1 and TLR signaling pathways. Eur J Immunol 39:1379–1386. doi:10.1002/eji.200838543

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  59. Lyn-Cook BD, Xie C, Oates J et al (2014) Increased expression of Toll-like receptors (TLRs) 7 and 9 and other cytokines in systemic lupus erythematosus (SLE) patients: ethnic differences and potential new targets for therapeutic drugs. Mol Immunol 61:38–43. doi:10.1016/j.molimm.2014.05.001

    Article  PubMed  CAS  Google Scholar 

  60. Castiblanco J, Varela D-C, Castaño-Rodríguez N et al (2008) TIRAP (MAL) S180L polymorphism is a common protective factor against developing tuberculosis and systemic lupus erythematosus. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis 8:541–544. doi:10.1016/j.meegid.2008.03.001

    Article  CAS  Google Scholar 

  61. Zhang J, Zhu Q, Meng F et al (2014) Association study of TLR-9 polymorphisms and systemic lupus erythematosus in northern Chinese Han population. Gene 533:385–388. doi:10.1016/j.gene.2013.08.051

    Article  PubMed  CAS  Google Scholar 

  62. Wang C-M, Chang S-W, Wu Y-JJ et al (2014) Genetic variations in Toll-like receptors (TLRs 3/7/8) are associated with systemic lupus erythematosus in a Taiwanese population. Sci Rep 4:3792. doi:10.1038/srep03792

    PubMed Central  PubMed  Google Scholar 

  63. Zhou X-J, Lv J-C, Cheng W-R et al (2010) Association of TLR9 gene polymorphisms with lupus nephritis in a Chinese Han population. Clin Exp Rheumatol 28:397–400

    PubMed  Google Scholar 

  64. Laska MJ, Troldborg A, Hansen B et al (2014) Polymorphisms within Toll-like receptors are associated with systemic lupus erythematosus in a cohort of Danish females. Rheumatol Oxf Engl 53:48–55. doi:10.1093/rheumatology/ket316

    Article  CAS  Google Scholar 

  65. Sánchez E, García-Bermúdez M, Jiménez-Alonso J et al (2012) Association study of IRAK-M and SIGIRR genes with SLE in a large European-descent population. Lupus 21:1166–1171. doi:10.1177/0961203312449494

    Article  PubMed  CAS  Google Scholar 

  66. Zhu L, Yang X, Chen W et al (2007) Decreased expressions of the TNF-alpha signaling adapters in peripheral blood mononuclear cells (PBMCs) are correlated with disease activity in patients with systemic lupus erythematosus. Clin Rheumatol 26:1481–1489. doi:10.1007/s10067-006-0531-8

    Article  PubMed  Google Scholar 

  67. Tsao J-T, Kuo C-C, Lin S-C (2008) The analysis of CIS, SOCS1, SOSC2 and SOCS3 transcript levels in peripheral blood mononuclear cells of systemic lupus erythematosus and rheumatoid arthritis patients. Clin Exp Med 8:179–185. doi:10.1007/s10238-008-0006-0

    Article  PubMed  CAS  Google Scholar 

  68. Li J, Zhao S, Yi M et al (2011) Activation of JAK-STAT1 signal transduction pathway in lesional skin and monocytes from patients with systemic lupus erythematosus. Zhong Nan Da Xue Xue Bao Yi Xue Ban 36:109–115. doi:10.3969/j.issn. 1672-7347.2011.02.003

    PubMed  CAS  Google Scholar 

  69. Pierangeli SS, Vega‐Ostertag ME, Raschi E et al (2007) Toll‐like receptor and antiphospholipid mediated thrombosis: in vivo studies. Ann Rheum Dis 66:1327–1333. doi:10.1136/ard.2006.065037

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  70. Polman CH, Reingold SC, Edan G et al (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.”. Ann Neurol 58:840–846. doi:10.1002/ana.20703

    Article  PubMed  Google Scholar 

  71. Gveric D, Kaltschmidt C, Cuzner ML, Newcombe J (1998) Transcription factor NF-kappaB and inhibitor I kappaBalpha are localized in macrophages in active multiple sclerosis lesions. J Neuropathol Exp Neurol 57:168–178

    Article  PubMed  CAS  Google Scholar 

  72. Christophi GP, Panos M, Hudson CA et al (2009) Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype. Lab Investig J Tech Methods Pathol 89:742–759. doi:10.1038/labinvest.2009.32

    Article  CAS  Google Scholar 

  73. Reynolds JM, Martinez GJ, Chung Y, Dong C (2012) Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc Natl Acad Sci U S A 109:13064–13069. doi:10.1073/pnas.1120585109

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  74. Rolls A, Shechter R, London A et al (2007) Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 9:1081–1088. doi:10.1038/ncb1629

    Article  PubMed  CAS  Google Scholar 

  75. Kostjuk S, Loseva P, Chvartatskaya O et al (2012) Extracellular GC-rich DNA activates TLR9- and NF-kB-dependent signaling pathways in human adipose-derived mesenchymal stem cells (haMSCs). Expert Opin Biol Ther 12(Suppl 1):S99–111. doi:10.1517/14712598.2012.690028

    Article  PubMed  CAS  Google Scholar 

  76. Sloane JA, Batt C, Ma Y et al (2010) Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2. Proc Natl Acad Sci U S A 107:11555–11560. doi:10.1073/pnas.1006496107

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  77. Hanafy KA, Sloane JA (2011) Regulation of remyelination in multiple sclerosis. FEBS Lett 585:3821–3828. doi:10.1016/j.febslet.2011.03.048

    Article  PubMed  CAS  Google Scholar 

  78. Hirotani M, Niino M, Fukazawa T et al (2010) Decreased IL-10 production mediated by Toll-like receptor 9 in B cells in multiple sclerosis. J Neuroimmunol 221:95–100. doi:10.1016/j.jneuroim.2010.02.012

    Article  PubMed  CAS  Google Scholar 

  79. Liu Y-J (2005) IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 23:275–306. doi:10.1146/annurev.immunol.23.021704.115633

    Article  PubMed  CAS  Google Scholar 

  80. Compton T, Kurt-Jones EA, Boehme KW et al (2003) Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol 77:4588–4596

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  81. Dolganiuc A, Oak S, Kodys K et al (2004) Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology 127:1513–1524

    Article  PubMed  CAS  Google Scholar 

  82. Bieback K, Lien E, Klagge IM et al (2002) Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol 76:8729–8736

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  83. Rizzo R, Gentili V, Casetta I et al (2012) Altered natural killer cells’ response to herpes virus infection in multiple sclerosis involves KIR2DL2 expression. J Neuroimmunol 251:55–64. doi:10.1016/j.jneuroim.2012.07.004

    Article  PubMed  CAS  Google Scholar 

  84. Hernández-Pedro NY, Espinosa-Ramirez G, de la Cruz VP et al (2013) Initial immunopathogenesis of multiple sclerosis: innate immune response. Clin Dev Immunol 2013:413465. doi:10.1155/2013/413465

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  85. Giacomini E, Severa M, Rizzo F et al (2013) IFN-β therapy modulates B-cell and monocyte crosstalk via TLR7 in multiple sclerosis patients. Eur J Immunol 43:1963–1972. doi:10.1002/eji.201243212

    Article  PubMed  CAS  Google Scholar 

  86. Vandenbroeck K, Alvarez J, Swaminathan B et al (2012) A cytokine gene screen uncovers SOCS1 as genetic risk factor for multiple sclerosis. Genes Immunol 13:21–28. doi:10.1038/gene.2011.44

    Article  CAS  Google Scholar 

  87. Baker BJ, Akhtar LN, Benveniste EN (2009) SOCS1 and SOCS3 in the control of CNS immunity. Trends Immunol 30:392–400. doi:10.1016/j.it.2009.07.001

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  88. Sedeño-Monge V, Arcega-Revilla R, Rojas-Morales E et al (2014) Quantitative analysis of the suppressors of cytokine signaling 1 and 3 in peripheral blood leukocytes of patients with multiple sclerosis. J Neuroimmunol 273:117–119. doi:10.1016/j.jneuroim.2014.05.013

    Article  PubMed  CAS  Google Scholar 

  89. Wesemann DR, Dong Y, O’Keefe GM et al (2002) Suppressor of cytokine signaling 1 inhibits cytokine induction of CD40 expression in macrophages. J Immunol 169:2354–2360

    Article  PubMed  CAS  Google Scholar 

  90. Frisullo G, Mirabella M, Angelucci F et al (2007) The effect of disease activity on leptin, leptin receptor and suppressor of cytokine signalling-3 expression in relapsing-remitting multiple sclerosis. J Neuroimmunol 192:174–183. doi:10.1016/j.jneuroim.2007.08.008

    Article  PubMed  CAS  Google Scholar 

  91. Matarese G, Carrieri PB, la Cava A et al (2005) Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells. Proc Natl Acad Sci U S A 102:5150–5155. doi:10.1073/pnas.0408995102

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  92. Bjørbaek C, Elmquist JK, Frantz JD et al (1998) Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1:619–625

    Article  PubMed  Google Scholar 

  93. Sha Y, Markovic-Plese S (2011) A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases. Self/Nonself 2:35–42. doi:10.4161/self.2.1.15639

    Article  PubMed Central  PubMed  Google Scholar 

  94. Ramgolam VS, Markovic-Plese S (2010) Interferon-beta inhibits Th17 cell differentiation in patients with multiple sclerosis. Endocr Metab Immune Disord Drug Targets 10:161–167

    Article  PubMed  CAS  Google Scholar 

  95. Zhang X, Jin J, Peng X et al (2008) Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol 180:6988–6996

    Article  PubMed  CAS  Google Scholar 

  96. Chen Z, Laurence A, Kanno Y et al (2006) Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A 103:8137–8142. doi:10.1073/pnas.0600666103

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  97. Weber MS, Zamvil SS (2008) Statins and demyelination. Curr Top Microbiol Immunol 318:313–324

    PubMed  CAS  Google Scholar 

  98. Mancuso R, Saresella M, Hernis A et al (2013) Torque teno virus (TTV) in multiple sclerosis patients with different patterns of disease. J Med Virol 85:2176–2183. doi:10.1002/jmv.23707

    Article  PubMed  CAS  Google Scholar 

  99. Gibofsky A (2012) Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J Manag Care 18:S295–302

    PubMed  Google Scholar 

  100. Coenen MJH, Enevold C, Barrera P et al (2010) Genetic variants in toll-like receptors are not associated with rheumatoid arthritis susceptibility or anti-tumour necrosis factor treatment outcome. PLoS One 5:e14326. doi:10.1371/journal.pone.0014326

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  101. Jaen O, Petit-Teixeira E, Kirsten H et al (2009) No evidence of major effects in several Toll-like receptor gene polymorphisms in rheumatoid arthritis. Arthritis Res Ther 11:R5. doi:10.1186/ar2589

    Article  PubMed Central  PubMed  Google Scholar 

  102. Etem EO, Elyas H, Ozgocmen S et al (2011) The investigation of toll-like receptor 3, 9 and 10 gene polymorphisms in Turkish rheumatoid arthritis patients. Rheumatol Int 31:1369–1374. doi:10.1007/s00296-010-1472-8

    Article  PubMed  CAS  Google Scholar 

  103. Enevold C, Radstake TRD, Coenen MJH et al (2010) Multiplex screening of 22 single-nucleotide polymorphisms in 7 Toll-like receptors: an association study in rheumatoid arthritis. J Rheumatol 37:905–910. doi:10.3899/jrheum.090775

    Article  PubMed  CAS  Google Scholar 

  104. Sacre SM, Andreakos E, Kiriakidis S et al (2007) The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. Am J Pathol 170:518–525. doi:10.2353/ajpath.2007.060657

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  105. Kim K-W, Cho M-L, Oh H-J et al (2009) TLR-3 enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis. Immunol Lett 124:9–17. doi:10.1016/j.imlet.2009.02.006

    Article  PubMed  CAS  Google Scholar 

  106. Brentano F, Schorr O, Gay RE et al (2005) RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3. Arthritis Rheum 52:2656–2665. doi:10.1002/art.21273

    Article  PubMed  CAS  Google Scholar 

  107. Sacre SM, Lo A, Gregory B et al (2008) Inhibitors of TLR8 reduce TNF production from human rheumatoid synovial membrane cultures. J Immunol 181:8002–8009

    Article  PubMed  CAS  Google Scholar 

  108. Ospelt C, Brentano F, Rengel Y et al (2008) Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum 58:3684–3692. doi:10.1002/art.24140

    Article  PubMed  CAS  Google Scholar 

  109. Roelofs MF, Wenink MH, Brentano F et al (2009) Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA). Ann Rheum Dis 68:1486–1493. doi:10.1136/ard.2007.086421

    Article  PubMed  CAS  Google Scholar 

  110. Tamaki Y, Takakubo Y, Hirayama T et al (2011) Expression of Toll-like receptors and their signaling pathways in rheumatoid synovitis. J Rheumatol 38:810–820. doi:10.3899/jrheum.100732

    Article  PubMed  CAS  Google Scholar 

  111. Radstake TRDJ, Roelofs MF, Jenniskens YM et al (2004) Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma. Arthritis Rheum 50:3856–3865. doi:10.1002/art.20678

    Article  PubMed  CAS  Google Scholar 

  112. Seibl R, Birchler T, Loeliger S et al (2003) Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am J Pathol 162:1221–1227. doi:10.1016/S0002-9440(10)63918-1

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  113. Pierer M, Rethage J, Seibl R et al (2004) Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. J Immunol 172:1256–1265

    Article  PubMed  CAS  Google Scholar 

  114. Roelofs MF, Joosten LA, Abdollahi-Roodsaz S et al (2005) 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 52:2313–2322. doi:10.1002/art.21278

    Article  PubMed  CAS  Google Scholar 

  115. Maksymowych W, Russell AS (1987) Antimalarials in rheumatology: efficacy and safety. Semin Arthritis Rheum 16:206–221

    Article  PubMed  CAS  Google Scholar 

  116. Khraishi MM, Singh G (1996) The role of anti-malarials in rheumatoid arthritis—the American experience. Lupus 5(Suppl 1):S41–44

    Article  PubMed  CAS  Google Scholar 

  117. Sanjuan MA, Rao N, Lai K-TA et al (2006) CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion. J Cell Biol 172:1057–1068. doi:10.1083/jcb.200508058

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  118. Kuznik A, Bencina M, Svajger U et al (2011) Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol 186:4794–4804. doi:10.4049/jimmunol.1000702

    Article  PubMed  CAS  Google Scholar 

  119. Isomäki P, Alanärä T, Isohanni P et al (2007) The expression of SOCS is altered in rheumatoid arthritis. Rheumatol Oxf Engl 46:1538–1546. doi:10.1093/rheumatology/kem198

    Article  CAS  Google Scholar 

  120. Raghav SK, Gupta B, Agrawal C et al (2006) Expression of TNF-alpha and related signaling molecules in the peripheral blood mononuclear cells of rheumatoid arthritis patients. Mediat Inflamm 2006:12682. doi:10.1155/MI/2006/12682

    Google Scholar 

  121. Potter C, Eyre S, Cope A et al (2007) Investigation of association between the TRAF family genes and RA susceptibility. Ann Rheum Dis 66:1322–1326. doi:10.1136/ard.2006.065706

    Article  PubMed Central  PubMed  Google Scholar 

  122. Lee A, Qiao Y, Grigoriev G et al (2013) Tumor necrosis factor α induces sustained signaling and a prolonged and unremitting inflammatory response in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 65:928–938. doi:10.1002/art.37853

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  123. Casale R, Buonocore M, Matucci-Cerinic M (1997) Systemic sclerosis (scleroderma): an integrated challenge in rehabilitation. Arch Phys Med Rehabil 78:767–773

    Article  PubMed  CAS  Google Scholar 

  124. van Bon L, Cossu M, Loof A et al (2014) Proteomic analysis of plasma identifies the Toll-like receptor agonists S100A8/A9 as a novel possible marker for systemic sclerosis phenotype. Ann Rheum Dis 73:1585–1589. doi:10.1136/annrheumdis-2013-205013

    Article  PubMed  CAS  Google Scholar 

  125. Broen JCA, Bossini-Castillo L, van Bon L et al (2012) A rare polymorphism in the gene for Toll-like receptor 2 is associated with systemic sclerosis phenotype and increases the production of inflammatory mediators. Arthritis Rheum 64:264–271. doi:10.1002/art.33325

    Article  PubMed  CAS  Google Scholar 

  126. York MR, Nagai T, Mangini AJ et al (2007) A macrophage marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists. Arthritis Rheum 56:1010–1020. doi:10.1002/art.22382

    Article  PubMed  CAS  Google Scholar 

  127. van Lieshout AWT, Vonk MC, Bredie SJH et al (2009) Enhanced interleukin-10 production by dendritic cells upon stimulation with Toll-like receptor 4 agonists in systemic sclerosis that is possibly implicated in CCL18 secretion. Scand J Rheumatol 38:282–290. doi:10.1080/03009740802572467

    Article  PubMed  CAS  Google Scholar 

  128. Fineschi S, Goffin L, Rezzonico R et al (2008) Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll-like receptor 4. Arthritis Rheum 58:3913–3923. doi:10.1002/art.24049

    Article  PubMed  CAS  Google Scholar 

  129. Farina A, Cirone M, York M et al (2014) Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma. J Invest Dermatol 134:954–964. doi:10.1038/jid.2013.423

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  130. Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92:827–839. doi:10.1161/01.RES.0000070112.80711.3D

    Article  PubMed  CAS  Google Scholar 

  131. Woessner JF (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J Off Publ Fed Am Soc Exp Biol 5:2145–2154

    CAS  Google Scholar 

  132. Kikuchi K, Kubo M, Hoashi T, Tamaki K (2002) Decreased MMP-9 activity in the serum of patients with diffuse cutaneous systemic sclerosis. Clin Exp Dermatol 27:301–305

    Article  PubMed  CAS  Google Scholar 

  133. Montagnana M, Volpe A, Lippi G et al (2007) Relationship between matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases systems and autoantibody patterns in systemic sclerosis. Clin Biochem 40:837–842. doi:10.1016/j.clinbiochem.2007.03.023

    Article  PubMed  CAS  Google Scholar 

  134. Kikuchi K, Kubo M, Sato S et al (1995) Serum tissue inhibitor of metalloproteinases in patients with systemic sclerosis. J Am Acad Dermatol 33:973–978

    Article  PubMed  CAS  Google Scholar 

  135. Iredale JP, Benyon RC, Arthur MJ et al (1996) Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis. Hepatolgy 24:176–184. doi:10.1002/hep.510240129, Baltim Md

    Article  CAS  Google Scholar 

  136. Ciechomska M, Huigens CA, Hügle T et al (2013) Toll-like receptor-mediated, enhanced production of profibrotic TIMP-1 in monocytes from patients with systemic sclerosis: role of serum factors. Ann Rheum Dis 72:1382–1389. doi:10.1136/annrheumdis-2012-201958

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  137. Christophers E (2001) Psoriasis–epidemiology and clinical spectrum. Clin Exp Dermatol 26:314–320

    Article  PubMed  CAS  Google Scholar 

  138. Baker BS, Ovigne J-M, Powles AV et al (2003) Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol 148:670–679

    Article  PubMed  CAS  Google Scholar 

  139. Seung NR, Park EJ, Kim CW et al (2007) Comparison of expression of heat-shock protein 60, Toll-like receptors 2 and 4, and T-cell receptor gammadelta in plaque and guttate psoriasis. J Cutan Pathol 34:903–911. doi:10.1111/j.1600-0560.2007.00756.x

    Article  PubMed  Google Scholar 

  140. Curry JL, Qin J-Z, Bonish B et al (2003) Innate immune-related receptors in normal and psoriatic skin. Arch Pathol Lab Med 127:178–186. doi:10.1043/0003-9985(2003)127<178:IIRRIN>2.0.CO;2

    PubMed  CAS  Google Scholar 

  141. Gaspari AA (2006) Innate and adaptive immunity and the pathophysiology of psoriasis. J Am Acad Dermatol 54:S67–80. doi:10.1016/j.jaad.2005.10.057

    Article  PubMed  Google Scholar 

  142. Miller LS, Sørensen OE, Liu PT et al (2005) TGF-alpha regulates TLR expression and function on epidermal keratinocytes. J Immunol 174:6137–6143

    Article  PubMed  CAS  Google Scholar 

  143. Hüffmeier U, Uebe S, Ekici AB et al (2010) Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat Genet 42:996–999. doi:10.1038/ng.688

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  144. Böhm B, Burkhardt H, Uebe S et al (2012) Identification of low-frequency TRAF3IP2 coding variants in psoriatic arthritis patients and functional characterization. Arthritis Res Ther 14:R84. doi:10.1186/ar3807

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  145. Eriksen KW, Woetmann A, Skov L et al (2010) Deficient SOCS3 and SHP-1 expression in psoriatic T cells. J Invest Dermatol 130:1590–1597. doi:10.1038/jid.2010.6

    Article  PubMed  CAS  Google Scholar 

  146. Madonna S, Scarponi C, Pallotta S et al (2012) Anti-apoptotic effects of suppressor of cytokine signaling 3 and 1 in psoriasis. Cell Death Dis 3:e334. doi:10.1038/cddis.2012.69

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  147. Sonkoly E, Wei T, Janson PCJ et al (2007) MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS One 2:e610. doi:10.1371/journal.pone.0000610

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  148. Federici M, Giustizieri ML, Scarponi C et al (2002) Impaired IFN-gamma-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1. J Immunol 169:434–442

    Article  PubMed  CAS  Google Scholar 

  149. Kubo M (2013) Therapeutic hope for psoriasis offered by SOCS (suppressor of cytokine signaling) mimetic peptide. Eur J Immunol 43:1702–1705. doi:10.1002/eji.201343748

    Article  PubMed  CAS  Google Scholar 

  150. Begon E, Michel L, Flageul B et al (2007) Expression, subcellular localization and cytokinic modulation of Toll-like receptors (TLRs) in normal human keratinocytes: TLR2 up-regulation in psoriatic skin. Eur J Dermatol EJD 17:497–506. doi:10.1684/ejd.2007.0264

    PubMed  CAS  Google Scholar 

  151. Rappersberger K, Komar M, Ebelin M-E et al (2002) Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated. J Invest Dermatol 119:876–887. doi:10.1046/j.1523-1747.2002.00694.x

    Article  PubMed  CAS  Google Scholar 

  152. Kang SSW, Kauls LS, Gaspari AA (2006) Toll-like receptors: applications to dermatologic disease. J Am Acad Dermatol 54:951–983. doi:10.1016/j.jaad.2005.05.004, quiz 983–986

    Article  PubMed  Google Scholar 

  153. Litjens NHR, Rademaker M, Ravensbergen B et al (2004) Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses. Eur J Immunol 34:565–575. doi:10.1002/eji.200324174

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Chinese Scholarship Council, the grants of the Hungarian National Scientific Research Fund (OTKA) and TÁMOP-4.2.2.A-11/1/KONV-2012-0023 project, which is co-financed by the European Union and European Social Fund.

Conflict of interest

No disclosure to report.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Margit Zeher.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, JQ., Szodoray, P. & Zeher, M. Toll-Like Receptor Pathways in Autoimmune Diseases. Clinic Rev Allerg Immunol 50, 1–17 (2016). https://doi.org/10.1007/s12016-015-8473-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-015-8473-z

Keywords

Navigation