The Toll-like Receptor 2 (TLR2)-related Immunopathological Responses in the Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

  • Abdollah Jafarzadeh Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran AND Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
  • Maryam Nemati Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
  • Hossain Khorramdelazad Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran AND Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
  • Abbas Mirshafiey Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
Keywords: Experimental autoimmune encephalomyelitis, Multiple sclerosis, Pathogenesis, Toll like receptor 2


Toll-like receptors (TLRs) play principle roles in recognition of autologous components which have been pointed as the danger-associated molecular patterns (DAMP) and microbial components which are identified as pathogen associated molecular patterns (PAMP).The infiltration of various inflammatory cells such as dendritic cells, lymphocytes (CD4+ T, CD8+ T as well as B cells), monocytes and macrophages occur into the central nervous sys­tem (CNS) during multiple sclerosis (MS) and its animal model named experimental autoimmune encephalomyelitis (EAE). The infiltrated leukocytes and residential cells of the CNS express several TLRs (especially TLR2) and their expression are elevated in MS and EAE. TLR2 recognizes a large variety DAMP and PAMP molecules due to its ability to create heterodimers with TLR1, TLR6 and probably TLR10. A wide spectrum of  DAMP molecules, including heat shock protein 60 (HSP60), HSP70, high mobility group box 1 (HMGB1), β-defensin 3, surfactant protein A and D, eosinophil-derived neurotoxin, gangliosides, serum amyloid A, hyaluronic acid and biglycan are identified by TLR2, whose their expression is increased in MS patients. TLR2 may contribute in the development of MS and EAE diseases through the reinforcement of Th1/Th17 cell-related responses, downregulation of regulatory T cells, induction of IL-17+ γδ T cells, inhibition of oligodendrocyte maturation, induction of poly ADP-ribose polymerase-1 (PARP-1)-dependent pathway in microglia, macrophages and astrocytes and inhibition of type I interferons expression. The contribution of TLR2-related immunopathological responses in the MS and EAE pathogenesis and its possible targeting as promising therapeutic potentials are considered in this review. 



1. Milo R, Miller A. Revised diagnostic criteria of multiple sclerosis. Autoimmun Rev. 2014;9972(14):012.

2. Anlar O. Treatment of multiple sclerosis. CNS Neurol Disord Drug Targets. 2009;8(3):167-74.

3. Jorg S, Grohme DA, Erzler M, Binsfeld M, Haghikia A, Muller DN, et al. Environmental factors in autoimmune diseases and their role in multiple sclerosis. Cell Mol Life Sci. 2016; 73: 4611-4622

4. Iwanowski P, Losy J. Immunological differences between classical phenothypes of multiple sclerosis. J Neurol Sci. 2015;349(1-2):10-4.

5. Robinson AP, Harp CT, Noronha A, Miller SD. The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment. Handb Clin Neurol. 2014;122:173-89.

6. Jafarzadeh A, Azizi SV, Nemati M, Khoramdel-Azad H, Shamsizadeh A, Ayoobi F, et al. Ginger Extract Reduces the Expression of IL-17 and IL-23 in the Sera and Central Nervous System of EAE Mice. Iran J Immunol. 2015;12(4):288-301.

7. Jafarzadeh A, Mohammadi-Kordkhayli M, Ahangar-Parvin R, Azizi V, Khoramdel-Azad H, Shamsizadeh A, et al. Ginger extracts influence the expression of IL-27 and IL-33 in the central nervous system in experimental autoimmune encephalomyelitis and ameliorates the clinical symptoms of disease. J Neuroimmunol. 2014;276(1-2):80-8.

8. Baker D, Amor S. Experimental autoimmune encephalomyelitis is a good model of multiple sclerosis if used wisely. Mult Scler Relat Disord. 2014;3(5):555-64.

9. Buc M. Role of regulatory T cells in pathogenesis and biological therapy of multiple sclerosis. Mediators Inflamm. 2013;2013:963748.

10. Garg N, Smith TW. An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain Behav. 2015;5(9):e00362.

11. Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74(1):5-17.

12. Jafarzadeh A, Mahdavi R, Jamali M, Hajghani H, Nemati M, Ebrahimi HA. Increased Concentrations of Interleukin-33 in the Serum and Cerebrospinal Fluid of Patients with Multiple Sclerosis. Oman Med J. 2016;31(1):40-5.

13. Jafarzadeh A, Jamali M, Mahdavi R, Ebrahimi HA, Hajghani H, Khosravimashizi A, et al. Circulating levels of interleukin-35 in patients with multiple sclerosis: evaluation of the influences of FOXP3 gene polymorphism and treatment program. J Mol Neurosci. 2015;55(4):891-7.

14. Jafarzadeh A, Bagherzadeh S, Ebrahimi HA, Hajghani H, Bazrafshani MR, Khosravimashizi A, et al. Higher circulating levels of chemokine CCL20 in patients with multiple sclerosis: evaluation of the influences of chemokine gene polymorphism, gender, treatment and disease pattern. J Mol Neurosci. 2014;53(3):500-5.

15. Mohammadi-Kordkhayli M, Ahangar-Parvin R, Azizi SV, Nemati M, Shamsizadeh A, Khaksari M, et al. Vitamin D Modulates the Expression of IL-27 and IL-33 in the Central Nervous System in Experimental Autoimmune Encephalomyelitis (EAE). Iran J Immunol. 2015;12(1):35-49.

16. Fernandez-Menendez S, Fernandez-Moran M, Fernandez-Vega I, Perez-Alvarez A, Villafani-Echazu J. Epstein-Barr virus and multiple sclerosis. From evidence to therapeutic strategies. J Neurol Sci. 2016;361:213-9.

17. Pormohammad A, Azimi T, Falah F, Faghihloo E. Relationship of Human Herpes Virus 6 and Multiple Sclerosis: A Systematic Review and Meta-analysis. J Cell Physiol. 2017; doi: 10.1002/jcp.26000.

18. Fainardi E, Castellazzi M, Seraceni S, Granieri E, Contini C. Under the microscope: focus on Chlamydia pneumoniae infection and multiple sclerosis. Curr Neurovasc Res. 2008;5(1):60-70.

19. Topkaya AE, Sahin S, Aksungar FB, Boru UT, Yildiz Z, Sur H. Is there any relationship between streptococcal infection and multiple sclerosis? Med Sci Monit. 2007;13(12):Cr567-9.

20. Nemati M, Larussa T, Khorramdelazad H, Mahmoodi M, Jafarzadeh A. Toll-like receptor 2: An important immunomodulatory molecule during Helicobacter pylori infection. Life Sci. 2017;178:17-29.

21. Farrugia M, Baron B. The Role of Toll-Like Receptors in Autoimmune Diseases through Failure of the Self-Recognition Mechanism. Int J Inflam, 2017; 2017: 8391230. doi: 10.1155/2017/8391230.

22. Miranda-Hernandez S, Baxter AG. Role of toll-like receptors in multiple sclerosis. Am J Clin Exp Immunol. 2013;2(1):75-93.

23. Uenishi H, Shinkai H. Porcine Toll-like receptors: the front line of pathogen monitoring and possible implications for disease resistance. Dev Comp Immunol. 2009;33(3):353-61.

24. Erridge C. Endogenous ligands of TLR2 and TLR4: agonists or assistants? J Leuk Biol. 2010;87(6):989-99.

25. Podda G, Nyirenda M, Crooks J, Gran B. Innate immune responses in the CNS: role of toll-like receptors, mechanisms, and therapeutic opportunities in multiple sclerosis. J Neuroimmune Pharmacol. 2013;8(4):791-806.

26. Hayward JH, Lee SJ. A Decade of Research on TLR2 Discovering Its Pivotal Role in Glial Activation and Neuroinflammation in Neurodegenerative Diseases. Exp Neurobiol. 2014;23(2):138-47.

27. Kumar H, Kawai T, Akira S. Pathogen recognition in the innate immune response. Biochem J. 2009;420(1):1-16.

28. Duthie MS, Windish HP, Fox CB, Reed SG. Use of defined TLR ligands as adjuvants within human vaccines. Immunol Rev. 2011;239(1):178-96.

29. Gibson J, Gow N, Wong S. Expression and functions of innate pattern recognition receptors in T and B cells. Immunol Endocr Metab Agents Med Chem. 2010;10(1):11-20.

30. Li J, Lee DS, Madrenas J. Evolving Bacterial Envelopes and Plasticity of TLR2-Dependent Responses: Basic Research and Translational Opportunities. Front Immunol. 2013;4:347.

31. Mukherjee S, Karmakar S, Babu SP. TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review. Braz J Infect Dis. 2016;20(2):193-204.

32. Picard C, Casanova J-L, Puel A. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Nat Cell Biol. 2011;24(3):490-7.

33. Chen ZJ. Ubiquitin signalling in the NF-κB pathway. Nat Cell Biol. 2005;7(8):758-65.

34. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J-i, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001;412(6844):346-51.

35. Ghosh S, May MJ, Kopp EB. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16(1):225-60.

36. Israël A. The IKK complex, a central regulator of NF-κB activation. Cold Spring Harb Perspect Biol. 2010;2(3):a000158.

37. Tak PP, Firestein GS. NF-κB: a key role in inflammatory diseases. J Clin Invest. 2001;107(1):7-11.

38. Santos‐Sierra S, Deshmukh SD, Kalnitski J, Küenzi P, Wymann MP, Golenbock DT, et al. Mal connects TLR2 to PI3Kinase activation and phagocyte polarization. EMBO J. 2009;28(14):2018-27.

39. Zanin-Zhorov A, Cohen IR. Signaling via TLR2 and TLR4 Directly Down-Regulates T Cell Effector Functions: The Regulatory Face of Danger Signals. Front Immunol. 2013;4:211.

40. Liu YC, Simmons DP, Li X, Abbott DW, Boom WH, Harding CV. TLR2 signaling depletes IRAK1 and inhibits induction of type I IFN by TLR7/9. J Immunol. 2012;188(3):1019-26.

41. Gooshe M, Abdolghaffari AH, Gambuzza ME, Rezaei N. The role of Toll-like receptors in multiple sclerosis and possible targeting for therapeutic purposes. Rev Neurosci. 2014;25(5):713-39.

42. Hemmer B, Kerschensteiner M, Korn T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. Lancet Neurol. 2015;14(4):406-19.

43. Fernandez-Paredes L, de Diego RP, de Andres C, Sanchez-Ramon S. Close Encounters of the First Kind: Innate Sensors and Multiple Sclerosis. Mol Neurobiol. 2016.

44. Carty M, Bowie AG. Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol. 2011;81(7):825-37.

45. Nyirenda MH, Morandi E, Vinkemeier U, Constantin-Teodosiu D, Drinkwater S, Mee M, et al. TLR2 stimulation regulates the balance between regulatory T cell and Th17 function: a novel mechanism of reduced regulatory T cell function in multiple sclerosis. J Immunol. 2015;194(12):5761-74.

46. Hasheminia SJ, Zarkesh-Esfahani SH, Tolouei S, Shaygannejad V, Shirzad H, Hashemzadeh Chaleshtory M. Toll like receptor 2 and 4 expression in peripheral blood mononuclear cells of multiple sclerosis patients. Iran J Immunol. 2014;11(2):74-83.

47. da Silva DJ, Borges AF, Souza PO, de Souza PR, Cardoso CR, Dorta ML, et al. Decreased Toll-Like Receptor 2 and Toll-Like Receptor 7/8-Induced Cytokines in Parkinson's Disease Patients. Neuroimmunomodulation. 2016;23(1):58-66.

48. McDonald CL, Hennessy E, Rubio-Araiz A, Keogh B, McCormack W, McGuirk P, et al. Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer's disease. Brain Behav Immun. 2016.

49. Farez MF, Quintana FJ, Gandhi R, Izquierdo G, Lucas M, Weiner HL. Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE. Nat Immunol. 2009;10(9):958-64.

50. Reynolds JM, Pappu BP, Peng J, Martinez GJ, Zhang Y, Chung Y, et al. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity. 2010;32(5):692-702.

51. Nagyoszi P, Wilhelm I, Farkas AE, Fazakas C, Dung NT, Hasko J, et al. Expression and regulation of toll-like receptors in cerebral endothelial cells. Neurochem Int. 2010;57(5):556-64.

52. Esser S, Gopfrich L, Bihler K, Kress E, Nyamoya S, Tauber SC, et al. Toll-Like Receptor 2-Mediated Glial Cell Activation in a Mouse Model of Cuprizone-Induced Demyelination. Mol Neurobiol. 2017; doi: 10.1007/s12035-017-0838-2.

53. van Noort JM, Bsibsi M. Toll-like receptors in the CNS: implications for neurodegeneration and repair. Prog Brain Res. 2009;175:139-48.

54. Bsibsi M, Nomden A, van Noort JM, Baron W. Toll-like receptors 2 and 3 agonists differentially affect oligodendrocyte survival, differentiation, and myelin membrane formation. J Neurosci Res. 2012;90(2):388-98.

55. Naegele M, Tillack K, Reinhardt S, Schippling S, Martin R, Sospedra M. Neutrophils in multiple sclerosis are characterized by a primed phenotype. J Neuroimmunol. 2012;242(1-2):60-71.

56. Andersson A, Covacu R, Sunnemark D, Danilov AI, Dal Bianco A, Khademi M, et al. Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. J Leuk Biol. 2008;84(5):1248-55.

57. Malhotra S, Fissolo N, Tintore M, Wing AC, Castillo J, Vidal-Jordana A, et al. Role of high mobility group box protein 1 (HMGB1) in peripheral blood from patients with multiple sclerosis. J Neuroinflammation. 2015;12:48.

58. Sternberg Z, Sternberg D, Chichelli T, Drake A, Patel N, Kolb C, et al. High-mobility group box 1 in multiple sclerosis. Immunol Res. 2016;64(2):385-91.

59. Mansilla MJ, Comabella M, Rio J, Castillo J, Castillo M, Martin R, et al. Up-regulation of inducible heat shock protein-70 expression in multiple sclerosis patients. Autoimmunity. 2014;47(2):127-33.

60. Mansilla MJ, Montalban X, Espejo C. Heat shock protein 70: roles in multiple sclerosis. Mol Med. 2012;18:1018-28.

61. Chang A, Staugaitis SM, Dutta R, Batt CE, Easley KE, Chomyk AM, et al. Cortical remyelination: a new target for repair therapies in multiple sclerosis. Ann Neurol. 2012;72(6):918-26.

62. Yokote H, Yagi Y, Watanabe Y, Amino T, Kamata T, Mizusawa H. Serum amyloid A level is increased in neuromyelitis optica and atypical multiple sclerosis with smaller T2 lesion volume in brain MRI. J Neuroimmunol. 2013;259(1-2):92-5.

63. Pender MP, Csurhes PA, Wolfe NP, Hooper KD, Good MF, McCombe PA, et al. Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary progressive multiple sclerosis. J Clin Neurosci. 2003;10(1):63-6.

64. Mohan H, Krumbholz M, Sharma R, Eisele S, Junker A, Sixt M, et al. Extracellular matrix in multiple sclerosis lesions: Fibrillar collagens, biglycan and decorin are upregulated and associated with infiltrating immune cells. Brain Pathol. 2010;20(5):966-75.

65. Thundyil J, Lim KL. DAMPs and neurodegeneration. Ageing Res Rev. 2015;24(Pt A):17-28.

66. Downer EJ, Johnston DG, Lynch MA. Differential role of Dok1 and Dok2 in TLR2-induced inflammatory signaling in glia. Mol Cell Neurosci. 2013;56:148-58.

67. Loebermann M, Winkelmann A, Hartung HP, Hengel H, Reisinger EC, Zettl UK. Vaccination against infection in patients with multiple sclerosis. Nat Rev Neurol. 2011;8(3):143-51.

68. Watad A, Azrielant S, Soriano A, Bracco D, Abu Much A, Amital H. Association between seasonal factors and multiple sclerosis. Eur J Epidemiol. 2016; 31(11):1081-1089.

69. McKay KA, Jahanfar S, Duggan T, Tkachuk S, Tremlett H. Factors associated with onset, relapses or progression in multiple sclerosis: A systematic review. Neurotoxicology. 2016.

70. Correale J, Farez M. Monocyte-derived dendritic cells in multiple sclerosis: the effect of bacterial infection. J Neuroimmunol. 2007;190(1-2):177-89.

71. Schrijver IA, van Meurs M, Melief MJ, Wim Ang C, Buljevac D, Ravid R, et al. Bacterial peptidoglycan and immune reactivity in the central nervous system in multiple sclerosis. Brain. 2001;124(Pt 8):1544-54.

72. Visser L, Melief MJ, van Riel D, van Meurs M, Sick EA, Inamura S, et al. Phagocytes containing a disease-promoting Toll-like receptor/Nod ligand are present in the brain during demyelinating disease in primates. Am J Pathol. 2006;169(5):1671-85.

73. Visser L, Jan de Heer H, Boven LA, van Riel D, van Meurs M, Melief MJ, et al. Proinflammatory bacterial peptidoglycan as a cofactor for the development of central nervous system autoimmune disease. J Immunol. 2005;174(2):808-16.

74. Herrmann I, Kellert M, Schmidt H, Mildner A, Hanisch UK, Bruck W, et al. Streptococcus pneumoniae Infection aggravates experimental autoimmune encephalomyelitis via Toll-like receptor 2. Infect Immun. 2006;74(8):4841-8.

75. Nichols FC, Yao X, Bajrami B, Downes J, Finegold SM, Knee E, et al. Phosphorylated dihydroceramides from common human bacteria are recovered in human tissues. PloS One. 2011;6(2):e16771.

76. Cogni G, Chiovato L. An overview of the pathogenesis of thyroid autoimmunity. Hormones. 2013;12(1):19-29.

77. Zhang Y, Zhang Y, Gu W, Sun B. TH1/TH2 cell differentiation and molecular signals. Adv Exp Med Biol. 2014;841:15-44.

78. Zhang Y, Zhang Y, Gu W, He L, Sun B. Th1/Th2 cell's function in immune system. Adv Exp Med Biol. 2014;841:45-65.

79. Safdari V, Alijani E, Nemati M, Jafarzadeh A. Imbalances in T Cell-Related Transcription Factors Among Patients with Hashimoto's Thyroiditis. Sultan Qaboos Univ Med J. 2017;17(2):e174-e80.

80. Rathore JS, Wang Y. Protective role of Th17 cells in pulmonary infection. Vaccine. 2016;34(13):1504-14.

81. Volpe E, Battistini L, Borsellino G. Advances in T Helper 17 Cell Biology: Pathogenic Role and Potential Therapy in Multiple Sclerosis. Mediators Inflamm. 2015;2015:475158.

82. Basu R, Hatton RD, Weaver CT. The Th17 family: flexibility follows function. Immunol Rev. 2013;252(1):89-103.

83. Etesam Z, Nemati M, Ebrahimizadeh MA, Ebrahimi HA, Hajghani H, Khalili T, et al. Altered Expression of Specific Transcription Factors of Th17 (RORgammat, RORalpha) and Treg Lymphocytes (FOXP3) by Peripheral Blood Mononuclear Cells from Patients with Multiple Sclerosis. J Mol Neurosci. 2016;60(1):94-101.

84. Jafarzadeh A, Azizi SV, Arabi Z, Ahangar-Parvin R, Mohammadi-Kordkhayli M, Larussa T, et al. Vitamin D down-regulates the expression of some Th17 cell-related cytokines, key inflammatory chemokines, and chemokine receptors in experimental autoimmune encephalomyelitis. Nutr Neurosci. 2018:1-13.

85. Ghaffari SA, Nemati M, Hajghani H, Ebrahimi H, Sheikhi A, Jafarzadeh A. Circulating concentrations of interleukin (IL)-17 in patients with multiple sclerosis: Evaluation of the effects of gender, treatment, disease patterns and IL-23 receptor gene polymorphisms. Iran J Neurol. 2017;16(1):15-25.

86. Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2010;162(1):1-11.

87. Kroenke MA, Carlson TJ, Andjelkovic AV, Segal BM. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med. 2008;205(7):1535-41.

88. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17 T Helper Cells. Cell. 2006;126(6):1121-33.

89. Bettelli E, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchroo VK. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. The J Exp Med. 2004;200(1):79-87.

90. Hirahara K, Nakayama T. CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm. Int Immunol. 2016.

91. Kostic M, Stojanovic I, Marjanovic G, Zivkovic N, Cvetanovic A. Deleterious versus protective autoimmunity in multiple sclerosis. Cell Immunol. 2015;296(2):122-32.

92. Kallaur AP, Oliveira SR, Colado Simao AN, Delicato de Almeida ER, Kaminami Morimoto H, Lopes J, et al. Cytokine profile in relapsingremitting multiple sclerosis patients and the association between progression and activity of the disease. Mol Med Rep. 2013;7(3):1010-20.

93. Uysal S, Meric Yilmaz F, Bogdaycioglu N, Mungan Ozturk S, Ak F. Increased serum levels of some inflammatory markers in patients with multiple sclerosis. Minerva Med. 2014;105(3):229-35.

94. van Hamburg JP, Asmawidjaja PS, Davelaar N, Mus AM, Colin EM, Hazes JM, et al. Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum. 2011;63(1):73-83.

95. Mirshafiey A, Asghari B, Ghalamfarsa G, Jadidi-Niaragh F, Azizi G. The significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis. Sultan Qaboos Univ Med J. 2014;14(1):e13-25.

96. Jafarzadeh A, Ebrahimi HA, Bagherzadeh S, Zarkesh F, Iranmanesh F, Najafzadeh A, et al. Lower serum levels of Th2-related chemokine CCL22 in women patients with multiple sclerosis: a comparison between patients and healthy women. Inflammation. 2014;37(2):604-10.

97. Yu Y, Zhang Y, Zhang J, Dou X, Yang H, Shao Y, et al. Impaired Toll-like receptor 2-mediated Th1 and Th17/22 cytokines secretion in human peripheral blood mononuclear cells from patients with atopic dermatitis. J Transl Med. 2015;13:384.

98. Zimmermann C, Weber A, Mausberg AK, Kieseier BC, Hartung HP, Hofstetter HH. T cell activation status determines the cytokine pattern induced by zymosan and bacterial DNA both in thymocytes and splenocytes. Clin Exp Immunol. 2013;172(2):245-53.

99. Miranda-Hernandez S, Gerlach N, Fletcher JM, Biros E, Mack M, Korner H, et al. Role for MyD88, TLR2 and TLR9 but not TLR1, TLR4 or TLR6 in experimental autoimmune encephalomyelitis. J Immunol. 2011;187(2):791-804.

100. Ferreira TB, Hygino J, Wing AC, Kasahara TM, Sacramento PM, Camargo S, et al. Different IL-17-secreting TLR(+) T cell subsets are associated with disease activity in multiple sclerosis. Immunology. 2017; doi: 10.1111/imm.12872.

101. Chen Y, Sun W, Gao R, Su Y, Umehara H, Dong L, et al. The role of high mobility group box chromosomal protein 1 in rheumatoid arthritis. Rheumatol. 2013;52(10):1739-47.

102. Sadat-Hatamnezhad L, Tanomand A, Mahmoudi J, Sandoghchian Shotorbani S. Activation of Toll-Like Receptors 2 by High-Mobility Group Box 1 in Monocytes from Patients with Ischemic Stroke. Iran Biomed J. 2016;20(4):223-8.

103. Zhao RR, Yang XF, Dong J, Zhao YY, Wei X, Huang CX, et al. Toll-like receptor 2 promotes T helper 17 cells response in hepatitis B virus infection. Int J Clin Exp Med. 2015;8(5):7315-23.

104. Rodriguez-Perea AL, Arcia ED, Rueda CM, Velilla PA. Phenotypic characterization of regulatory T cells in humans and rodents. Clin Exp Immunol. 2016; 185: 281-291.

105. Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmu Rev. 2014;13(6):668-77.

106. Gravano DM, Vignali DA. The battle against immunopathology: infectious tolerance mediated by regulatory T cells. Cell Mol Life Sci. 2012;69(12):1997-2008.

107. Nie J, Li YY, Zheng SG, Tsun A, Li B. FOXP3(+) Treg Cells and Gender Bias in Autoimmune Diseases. Front Immunol. 2015;6:493.

108. Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15(8):946-50.

109. Roses RE, Xu S, Xu M, Koldovsky U, Koski G, Czerniecki BJ. Differential production of IL-23 and IL-12 by myeloid-derived dendritic cells in response to TLR agonists. J Immunol. 2008;181(7):5120-7.

110. Nyirenda MH, Sanvito L, Darlington PJ, O'Brien K, Zhang GX, Constantinescu CS, et al. TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J Immunol. 2011;187(5):2278-90.

111. Schneider A, Long SA, Cerosaletti K, Ni CT, Samuels P, Kita M, et al. In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive T(regs) involves IL-6-mediated signaling. Sci Transl Med. 2013;5(170):170ra15.

112. Araki M, Matsuoka T, Miyamoto K, Kusunoki S, Okamoto T, Murata M, et al. Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology. 2014;82(15):1302-6.

113. Ho LJ, Luo SF, Lai JH. Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers. Biochem Pharmacol. 2015;97(1):16-26.

114. Malik S, Want MY, Awasthi A. The Emerging Roles of Gamma-Delta T Cells in Tissue Inflammation in Experimental Autoimmune Encephalomyelitis. Front Immunol. 2016;7:14.

115. Derkow K, Kruger C, Dembny P, Lehnardt S. Microglia Induce Neurotoxic IL-17+ gammadelta T Cells Dependent on TLR2, TLR4, and TLR9 Activation. PloS One. 2015;10(8):e0135898.

116. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31(2):331-41.

117. Raverdeau M, Breen CJ, Misiak A, Mills KH. Retinoic acid suppresses IL-17 production and pathogenic activity of gammadelta T cells in CNS autoimmunity. Immunol Cell Biol. 2016;94(8):763-73.

118. Verden D, Macklin WB. Neuroprotection by central nervous system remyelination: Molecular, cellular, and functional considerations. J Neurosci Res. 2016;94(12):1411-20.

119. Domingues HS, Portugal CC, Socodato R, Relvas JB. Corrigendum: Oligodendrocyte, Astrocyte and Microglia Crosstalk in Myelin Development, Damage, and Repair. Front Cell Dev Biol. 2016;4:79.

120. Sloane JA, Batt C, Ma Y, Harris ZM, Trapp B, Vartanian T. Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2. Proc Natl Acad Sci U S A. 2010;107(25):11555-60.

121. Sherman LS, Matsumoto S, Su W, Srivastava T, Back SA. Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases. Int J Cell Biol. 2015;2015:368584.

122. Hanafy KA, Sloane JA. Regulation of remyelination in multiple sclerosis. FEBS Lett. 2011;585(23):3821-8.

123. Schonberg DL, Popovich PG, McTigue DM. Oligodendrocyte generation is differentially influenced by toll-like receptor (TLR) 2 and TLR4-mediated intraspinal macrophage activation. J Neuropathol Exp Neurol. 2007;66(12):1124-35.

124. Lehnardt S, Lehmann S, Kaul D, Tschimmel K, Hoffmann O, Cho S, et al. Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J Neuroimmunol. 2007;190(1-2):28-33.

125. Ba X, Garg NJ. Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases. Am J Pathol. 2011;178(3):946-55.

126. Rom S, Zuluaga-Ramirez V, Dykstra H, Reichenbach NL, Ramirez SH, Persidsky Y. Poly(ADP-ribose) polymerase-1 inhibition in brain endothelium protects the blood-brain barrier under physiologic and neuroinflammatory conditions. J Cereb Blood Flow Metab. 2015;35(1):28-36.

127. Cavone L, Aldinucci A, Ballerini C, Biagioli T, Moroni F, Chiarugi A. PARP-1 inhibition prevents CNS migration of dendritic cells during EAE, suppressing the encephalitogenic response and relapse severity. Mult Scler. 2011;17(7):794-807.

128. Kamboj A, Lu P, Cossoy MB, Stobart JL, Dolhun BA, Kauppinen TM, et al. Poly(ADP-ribose) polymerase 2 contributes to neuroinflammation and neurological dysfunction in mouse experimental autoimmune encephalomyelitis. Journal of neuroinflammation. 2013;10:49.

129. Tao Y, Zhang X, Markovic-Plese S. Toll-like receptor (TLR)7 and TLR9 agonists enhance interferon (IFN) beta-1a's immunoregulatory effects on B cells in patients with relapsing-remitting multiple sclerosis (RRMS). J Neuroinflammation. 2016;298:181-8.

130. Guo B, Chang EY, Cheng G. The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J Clin Invest. 2008;118(5):1680-90.

131. Severa M, Rizzo F, Giacomini E, Salvetti M, Coccia EM. IFN-beta and multiple sclerosis: cross-talking of immune cells and integration of immunoregulatory networks. Cytokine Growth Factor Rev. 2015;26(2):229-39.

132. Schwab N, Zozulya AL, Kieseier BC, Toyka KV, Wiendl H. An imbalance of two functionally and phenotypically different subsets of plasmacytoid dendritic cells characterizes the dysfunctional immune regulation in multiple sclerosis. J Immunol. 2010;184(9):5368-74.

133. Xie ZX, Zhang HL, Wu XJ, Zhu J, Ma DH, Jin T. Role of the immunogenic and tolerogenic subsets of dendritic cells in multiple sclerosis. Mediators Inflamm. 2015;2015:513295.

134. Flannery S, Bowie AG. The interleukin-1 receptor-associated kinases: critical regulators of innate immune signalling. Biochem Pharmacol. 2010;80(12):1981-91.

135. Anstadt EJ, Fujiwara M, Wasko N, Nichols F, Clark RB. TLR Tolerance as a Treatment for Central Nervous System Autoimm J Immunol. 2016;197(6):2110-8.

136. van Noort JM, Bsibsi M, Nacken PJ, Verbeek R, Venneker EH. Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial. PloS One. 2015;10(11):e0143366.

137. Bsibsi M, Holtman IR, Gerritsen WH, Eggen BJ, Boddeke E, van der Valk P, et al. Alpha-B-crystallin induces an immune-regulatory and antiviral microglial response in preactive multiple sclerosis lesions. J Neuropathol Exp Neurol. 2013;72(10):970-9.

138. Bsibsi M, Peferoen LA, Holtman IR, Nacken PJ, Gerritsen WH, Witte ME, et al. Demyelination during multiple sclerosis is associated with combined activation of microglia/macrophages by IFN-gamma and alpha B-crystallin. Acta Neuropathol. 2014;128(2):215-29.

139. Holtman IR, Bsibsi M, Gerritsen WH, Boddeke HW, Eggen BJ, van der Valk P, et al. Identification of highly connected hub genes in the protective response program of human macrophages and microglia activated by alpha B-crystallin. Glia. 2017;65(3):460-73.

140. Correale J, Farez MF. Does helminth activation of toll-like receptors modulate immune response in multiple sclerosis patients? Front Cell Infect Microbiol. 2012;2:112.

141. Wang Y, Telesford KM, Ochoa-Reparaz J, Haque-Begum S, Christy M, Kasper EJ, et al. An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling. Nat Commun. 2014;5:4432.

142. Jafarzadeh A, Larussa T, Nemati M, Jalapour S. T cell subsets play an important role in the determination of the clinical outcome of Helicobacter pylori infection. Microb Pathog. 2018; 116:227-236.

143. Cook KW, Crooks J, Hussain K, O'Brien K, Braitch M, Kareem H, et al. Helicobacter pylori infection reduces disease severity in an experimental model of multiple sclerosis. Front Microbiol. 2015;6:52.

144. Pedrini MJ, Seewann A, Bennett KA, Wood AJ, James I, Burton J, et al. Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females. J Neurol Neurosurg Psychiatry. 2015;86(6):603-7.

145. Hossain MJ, Tanasescu R, Gran B. Innate immune regulation of autoimmunity in multiple sclerosis: Focus on the role of Toll-like receptor 2. Journal of neuroimmunology. 2017;304:11-20.

146. Stirling DP, Cummins K, Mishra M, Teo W, Yong VW, Stys P. Toll-like receptor 2-mediated alternative activation of microglia is protective after spinal cord injury. Brain. 2014;137(Pt 3):707-23.

147. Lobo-Silva D, Carriche GM, Castro AG, Roque S, Saraiva M. Interferon-beta regulates the production of IL-10 by toll-like receptor-activated microglia. Glia. 2017;65(9):1439-51.

148. Buwitt‐Beckmann U, Heine H, Wiesmüller KH, Jung G, Brock R, Akira S, et al. Toll‐like receptor 6‐independent signaling by diacylated lipopeptides. Eur J Immunol. 2005;35(1):282-9.

149. Frodermann V, Chau TA, Sayedyahossein S, Toth JM, Heinrichs DE, Madrenas J. A modulatory interleukin-10 response to staphylococcal peptidoglycan prevents Th1/Th17 adaptive immunity to Staphylococcus aureus. Journal Infect Dis. 2011;204(2):253-62.

150. Weber MS, Starck M, Wagenpfeil S, Meinl E, Hohlfeld R, Farina C. Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain. 2004;127(Pt 6):1370-8.

151. Gao D, Li W. Structures and recognition modes of toll-like receptors. Proteins. 2017;85(1):3-9.

152. Keogh B, Parker AE. Toll-like receptors as targets for immune disorders. Trends Pharmacol Sci. 2011;32(7):435-42.

153. Tsai YG, Yang KD, Niu DM, Chien JW, Lin CY. TLR2 agonists enhance CD8+Foxp3+ regulatory T cells and suppress Th2 immune responses during allergen immunotherapy. J Immunol. 2010;184(12):7229-37.

154. Liu X, Guan JH, Jiang BC, Li ZS, Zhu GZ. Toll-Like Receptor 2 Modulates the Balance of Regulatory T Cells and T Helper 17 Cells in Chronic Hepatitis C. Viral Immunol. 2016;29(6):322-31.

155. Deifl S, Kitzmuller C, Steinberger P, Himly M, Jahn-Schmid B, Fischer GF, et al. Differential activation of dendritic cells by toll-like receptors causes diverse differentiation of naive CD4+ T cells from allergic patients. Allergy. 2014;69(12):1602-9.

156. Koymans KJ, Feitsma LJ, Brondijk TH, Aerts PC, Lukkien E, Lossl P, et al. Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3). Proc Natl Acad Sci U S A. 2015;112(35):11018-23.

157. Mistry P, Laird MH, Schwarz RS, Greene S, Dyson T, Snyder GA, et al. Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain. Proc Natl Acad Sci U S A. 2015;112(17):5455-60.

158. Shmuel-Galia L, Aychek T, Fink A, Porat Z, Zarmi B, Bernshtein B, et al. Neutralization of pro-inflammatory monocytes by targeting TLR2 dimerization ameliorates colitis. EMBO J. 2016;35(6):685-98.

159. Henrick BM, Yao XD, Taha AY, German JB, Rosenthal KL. Insights into Soluble Toll-Like Receptor 2 as a Downregulator of Virally Induced Inflammation. Front Immunol. 2016;7:291.

160. Houssen ME, El-Mahdy RH, Shahin DA. Serum soluble toll-like receptor 2: a novel biomarker for systemic lupus erythematosus disease activity and lupus-related cardiovascular dysfunction. Int J Rheum Dis. 2016;19(7):685-92.

161. Tehrani M, Varasteh AR, Khakzad MR, Mirsadraee M, Sankian M. Decreased levels of soluble Toll-like Receptor 2 in patients with asthma. Rep Biochem Mol Biol. 2012;1(1):30-6.

162. Baroni A, Orlando M, Donnarumma G, Farro P, Iovene MR, Tufano MA, et al. Toll-like receptor 2 (TLR2) mediates intracellular signalling in human keratinocytes in response to Malassezia furfur. Arch Dermatol Res. 2006;297(7):280-8.

163. Lima CX, Souza DG, Amaral FA, Fagundes CT, Rodrigues IP, Alves-Filho JC, et al. Therapeutic Effects of Treatment with Anti-TLR2 and Anti-TLR4 Monoclonal Antibodies in Polymicrobial Sepsis. PloS One. 2015;10(7):e0132336.

164. Reilly M, Miller RM, Thomson MH, Patris V, Ryle P, McLoughlin L, et al. Randomized, double-blind, placebo-controlled, dose-escalating phase I, healthy subjects study of intravenous OPN-305, a humanized anti-TLR2 antibody. Clin Pharmacol Ther. 2013;94(5):593-600.

165. Achek A, Yesudhas D, Choi S. Toll-like receptors: promising therapeutic targets for inflammatory diseases. Arch Pharm Res. 2016;39(8):1032-49.

166. Kirschning CJ, Dreher S, Maass B, Fichte S, Schade J, Koster M, et al. Generation of anti-TLR2 intrabody mediating inhibition of macrophage surface TLR2 expression and TLR2-driven cell activation. BMC Biotechnol. 2010;10:31.

167. Guo H, Gao J, Wu X. Toll-like receptor 2 siRNA suppresses corneal inflammation and attenuates Aspergillus fumigatus keratitis in rats. Immunol Cell Biol. 2012;90(3):352-7.

168. Case SR, Martin RJ, Jiang D, Minor MN, Chu HW. MicroRNA-21 inhibits toll-like receptor 2 agonist-induced lung inflammation in mice. Exp Lung Res. 2011;37(8):500-8.

How to Cite
Jafarzadeh A, Nemati M, Khorramdelazad H, Mirshafiey A. The Toll-like Receptor 2 (TLR2)-related Immunopathological Responses in the Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis. Iran J Allergy Asthma Immunol. 18(3):230-250.
Review Article(s)