Advertisement

Immune Tolerance in Autoimmune Central Nervous System Disorders

  • Sundararajan Jayaraman
  • Bellur S. PrabhakarEmail author
Chapter
Part of the Contemporary Clinical Neuroscience book series (CCNE)

Abstract

Multiple sclerosis (MS) afflicts genetically predisposed individuals and is associated with T lymphocyte-mediated damage to the myelin sheath of neurons in the central nervous system, resulting in severely impaired signal transmission. The mechanisms of the induction and manifestation of MS are not entirely understood. The control of autoimmune disorders is accomplished by both central tolerance in which autoreactive T lymphocytes are eliminated in the thymus and by tolerance mechanisms that operate in the periphery. Among the many mechanisms described, T regulatory (Treg) cells derived from the thymus (tTregs) and induced (iTregs) in the periphery as well as T regulatory type 1 cells (Tr1) are involved in many disease models. However, the precise details of the generation and perpetuation of these various Treg subsets and their relevance to the regulation of autoimmune diseases remain elusive. In this review, we critically analyze the current knowledge of the tolerance mechanisms involved in the regulation of MS and its animal model, experimental autoimmune encephalomyelitis.

Keywords

Anergy Autoimmune diseases Blood-brain barrier Central nervous system Cerebrospinal fluid Foxp3 GM-CSF Human leukocyte antigen Interferon-γ Interleukin 17 Myelin basic protein Multiple sclerosis Myelin oligodendrocyte glycoprotein Neuromyelitis optica Proteolipid protein Th1 Th17 T regulatory cells Trichostatin A Tumor necrosis factor-α, Tolerance 

Notes

Acknowledgments

Arathi Jayaraman is acknowledged for comments on the manuscript.

References

  1. 1.
    Alderson MR, Lynch DH. Receptors and ligands that mediate activation-induced death of T cells. Springer Semin Immunopathol. 1998;19(3):289–300. PMID:9540157PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Tracey KJ, Cerami A. Tumor necrosis factor: an updated review of its biology. Crit Care Med. 1993;21(10 Suppl):S415–22. PMID:8403979PubMedPubMedCentralGoogle Scholar
  3. 3.
    Dorf ME, Benacerraf B. Suppressor cells and immunoregulation. Annu Rev Immunol. 1984;2:127–57. PMID:6242348PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Germain RN. Special regulatory T-cell review: A rose by any other name: from suppressor T cells to Tregs, approbation to unbridled enthusiasm. Immunology. 2008;123(1):20–7. PMID:18154615PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Kleinewietfeld M, Hafler DA. Regulatory T cells in autoimmune neuroinflammation. Immunol Rev. 2014;259(1):231–44. PMID:24712469PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017;14(1):117. PMID:28599652PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Dominguez-Villar M, Hafler DA. Regulatory T cells in autoimmune disease. Nat Immunol. 2018;19:665.  https://doi.org/10.1038/s41590-018-0120-4. PMID:29925983CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Shevach EM. Foxp3+ T regulatory cells: still many unanswered questions-A perspective after 20 years of study. Front Immunol. 2018;9:1048. PMID:29868011PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Jasiak-Zatonska M, Kalinowska-Lyszczarz A, Michalak S, Kozubski W. The immunology of neuromyelitis optica-current knowledge, clinical implications, controversies and future perspectives. Int J Mol Sci. 2016;17(3):273. PMID:26950113PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Bar-Or A, Steinman L, Behne JM, Benitez-Ribas D, Chin PS, Clare-Salzler M, et al. Restoring immune tolerance in neuromyelitis optica: Part II. Neurol Neuroimmunol Neuroinflamm. 2016;3(5):e277. PMID:27648464PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    D’Andrea MR. Add Alzheimer’s disease to the list of autoimmune diseases. Med Hypotheses. 2005;64(3):458–63. PMID:15617848PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Fukata M, Yokoi N, Fukata Y. Neurobiology of autoimmune encephalitis. Curr Opin Neurobiol. 2018;48:1–8. PMID:28829986PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Alexopoulos H, Dalakas MC. Immunology of stiff person syndrome and other GAD-associated neurological disorders. Expert Rev Clin Immunol. 2013;9(11):1043–53. PMID:24168411PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58. PMID:26250739.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Legroux L, Arbour N. Multiple sclerosis and T Lymphocytes: an entangled story. J Neuroimmune Pharmacol. 2015;10(4):528–46. PMID:25946987PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Lassmann H. Targets of therapy in progressive MS. Mult Scler. 2017;23(12):1593–9. PMID:29041864PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Correale J, Gaitán MI, Ysrraelit MC, Fiol MP. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain. 2017;140(3):527–46. PMID:27794524PubMedPubMedCentralGoogle Scholar
  18. 18.
    Chaudhuri A, Behan PO. Multiple sclerosis is not an autoimmune disease. Arch Neurol. 2004;61(10):1610–2. PMID:15477520PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci. 2008;31:247–69. PMID:18558855PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc. 2014;89(2):225–40. PMID:24485135PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Tintore M, Vidal-Jordana A, Sastre-Garriga J. Treatment of multiple sclerosis - success from bench to bedside. Nat Rev Neurol. 2019;15:53–8.  https://doi.org/10.1038/s41582-018-0082-z. PMID:30315270CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Engelhardt B, Vajkoczy P, Weller RO. The movers and shapers in immune privilege of the CNS. Nat Immunol. 2017;18(2):123–31. PMID:28092374PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Domingues HS, Portugal CC, Socodato R, Relvas JB. Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol. 2016;4:71. PMID:27551677PubMedPubMedCentralGoogle Scholar
  24. 24.
    Scheu S, Ali S, Ruland C, Arolt V, Alferink J. The C-C chemokines CCL17 and CCL22 and their receptor CCR4 in CNS autoimmunity. Int J Mol Sci. 2017;18(11):pii:E2306. PMID:29099057CrossRefGoogle Scholar
  25. 25.
    Parnell GP, Booth DR. The Multiple Sclerosis (MS) genetic risk factors indicate both acquired and innate immune cell subsets contribute to MS pathogenesis and identify novel therapeutic opportunities. Front Immunol. 2017;8:425. PMID:28458668PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Harkiolaki M, Holmes SL, Svendsen P, Gregersen JW, Jensen LT, McMahon R, et al. T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity. 2009;30(3):348–57. Erratum in: Immunity. 2009;30(4):610. PMID:19303388PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Ramadan A, Lucca LE, Carrié N, Desbois S, Axisa PP, Hayder M, et al. In situ expansion of T cells that recognize distinct self-antigens sustains autoimmunity in the CNS. Brain. 2016;139.(Pt 5:1433–46.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Fredrikson S, Söderström M, Hillert J, Sun JB, Käll TB, Link H. Multiple sclerosis: occurrence of myelin basic protein peptide-reactive T cells in healthy family members. Acta Neurol Scand. 1994;89(3):184–9. PMID:7518178PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Hellings N, Barée M, Verhoeven C, D’hooghe MB, Medaer R, Bernard CC, et al. T-cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls. J Neurosci Res. 2001;63(3):290–302. PMID:11170179PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Raddassi K, Kent SC, Yang J, Bourcier K, Bradshaw EM, Seyfert-Margolis V, et al. Increased frequencies of myelin oligodendrocyte glycoprotein/MHC class II-binding CD4 cells in patients with multiple sclerosis. J Immunol. 2011;187(2):1039–46. PMID:21653833PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Kebir H, Ifergan I, Alvarez JI, Bernard M, Poirier J, Arbour N, et al. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol. 2009;66(3):390–402. PMID:19810097PubMedCrossRefGoogle Scholar
  32. 32.
    Alvermann S, Hennig C, Stüve O, Wiendl H, Stangel M. Immunophenotyping of cerebrospinal fluid cells in multiple sclerosis: in search of biomarkers. JAMA Neurol. 2014;71(7):905–12. PMID:24818670PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    van Langelaar J, van der Vuurst de Vries RM, Janssen M, Wierenga-Wolf AF, Spilt IM, Siepman TA, et al. T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention. Brain. 2018;141(5):1334–49. PMID:29659729PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Willing A, Leach OA, Ufer F, Attfield KE, Steinbach K, Kursawe N, et al. CD8+ MAIT cells infiltrate into the CNS and alterations in their blood frequencies correlate with IL-18 serum levels in multiple sclerosis. Eur J Immunol. 2014;44(10):3119–28. PMID:25043505PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Li R, Patterson KR, Bar-Or A. Reassessing B cell contributions in multiple sclerosis. Nat Immunol 2018.  https://doi.org/10.1038/s41590-018-0135-x. [Epub ahead of print]. PMID:29925992.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Wurth S, Kuenz B, Bsteh G, Ehling R, Di Pauli F, Hegen H, et al. Cerebrospinal fluid B cells and disease progression in multiple sclerosis – A longitudinal prospective study. PLoS One. 2017;12(8):e0182462. PMID:28777826PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Rivers TM, Sprunt DH, Berry GP. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J Exp Med. 1933;58(1):39–53. PMID:19870180PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Sabin AB, Wright AM. Acute ascending myelitis following a monkey bite, with the isolation of a virus capable of reproducing the disease. J Exp Med. 1934;59(2):115–36. PMID:19870235PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Constantinescu CS, Farooqi N, O’Brien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol. 2011;164(4):1079–106. PMID:21371012PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Lassmann H, Bradl M. Multiple sclerosis: experimental models and reality. Acta Neuropathol. 2017;133(2):223–44. PMID:27766432PubMedCrossRefGoogle Scholar
  41. 41.
    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. PMID:26265267PubMedCrossRefGoogle Scholar
  42. 42.
    McGeachy MJ, Stephens LA, Anderton SM. Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system. J Immunol. 2005;175(5):3025–32. PMID:16116190PubMedCrossRefGoogle Scholar
  43. 43.
    Shetty A, Gupta SG, Varrin-Doyer M, Weber MS, Prod’homme T, Molnarfi N, et al. Immunodominant T-cell epitopes of MOG reside in its transmembrane and cytoplasmic domains in EAE. Neurol Neuroimmunol Neuroinflamm. 2014;1(2):e22. PMID:25340074PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Pham H, Doerrbecker J, Ramp AA, D’Souza CS, Gorasia DG, Purcell AW, Ayers MM, Orian JM. Experimental autoimmune encephalomyelitis (EAE) in C57Bl/6 mice is not associated with astrogliosis. J Neuroimmunol. 2011;232(1–2):51–62. PMID:21056916PubMedCrossRefGoogle Scholar
  45. 45.
    Kipp M, Nyamoya S, Hochstrasser T, Amor S. Multiple sclerosis animal models: a clinical and histopathological perspective. Brain Pathol. 2017;27(2):123–37. PMID:27792289PubMedCrossRefGoogle Scholar
  46. 46.
    Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petrovic-Stojkovic S, Puckett L, et al. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J Clin Invest. 2008;118(4):1532–43. PMID:18340379PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Jayaraman A, Soni A, Prabhakar BS, Holterman M, Jayaraman S. The epigenetic drug Trichostatin A ameliorates experimental autoimmune encephalomyelitis via T cell tolerance induction and impaired influx of T cells into the spinal cord. Neurobiol Dis. 2017;108:1–12. PMID:28736194PubMedCrossRefGoogle Scholar
  48. 48.
    Jayaraman A, Sharma M, Prabhakar B, Holterman M, Jayaraman S. Amelioration of progressive autoimmune encephalomyelitis by epigenetic regulation involves selective repression of mature neutrophils during the preclinical phase. Exp Neurol. 2018;304:14–20. PMID:29453977PubMedCrossRefGoogle Scholar
  49. 49.
    Slavin A, Ewing C, Liu J, Ichikawa M, Slavin J, Bernard CC. Induction of a multiple sclerosis-like disease in mice with an immunodominant epitope of myelin oligodendrocyte glycoprotein. Autoimmunity. 1998;28(2):109–20. PMID:9771980PubMedCrossRefGoogle Scholar
  50. 50.
    Hidaka Y, Inaba Y, Matsuda K, Itoh M, Kaneyama T, Nakazawa Y, et al. Cytokine production profiles in chronic relapsing-remitting experimental autoimmune encephalomyelitis: IFN-γ and TNF-α are essential participants in the first attack but not in the relapse. J Neurol Sci. 2014;340(1–2):117–22. PMID:24655735PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Dang PT, Bui Q, D’Souza CS, Orian JM. Modelling MS: chronic-relapsing EAE in the NOD/Lt mouse strain. Curr Top Behav Neurosci. 2015;26:143–77. PMID:26126592PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    McRae BL, Kennedy MK, Tan LJ, Dal Canto MC, Picha KS, Miller SD. Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid protein. J Neuroimmunol. 1992;38(3):229–40. PMID:1376328PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Behan PO, Chaudhuri A. EAE is not a useful model for demyelinating disease. Mult Scler Relat Disord. 2014;3(5):565–74.PMID:26265268.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Muller DM, Pender MP, Greer JM. A neuropathological analysis of experimental autoimmune encephalomyelitis with predominant brain stem and cerebellar involvement and differences between active and passive induction. Acta Neuropathol. 2000;100(2):174–82. PMID:10963365PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Abromson-Leeman S, Bronson R, Luo Y, Berman M, Leeman R, Leeman J, et al. T-cell properties determine disease site, clinical presentation, and cellular pathology of experimental autoimmune encephalomyelitis. Am J Pathol. 2004;165(5):1519–33. PMID:15509523PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Stromnes IM, Cerretti LM, Liggitt D, Harris RA, Goverman JM. Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med. 2008;14(3):337–42. PMID:18278054PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Lowther DE, Chong DL, Ascough S, Ettorre A, Ingram RJ, Boyton RJ, et al. Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response. Acta Neuropathol. 2013;126(4):501–15. PMID:23934116PubMedCrossRefGoogle Scholar
  58. 58.
    O’Connor RA, Prendergast CT, Sabatos CA, Lau CW, Leech MD, Wraith DC, et al. Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. J Immunol. 2008;181(6):3750–4. PMID:18768826PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Murphy AC, Lalor SJ, Lynch SJ, Mills KH. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun. 2010;24(4):641–51. PMID:20138983PubMedCrossRefGoogle Scholar
  60. 60.
    Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011;12(3):255–63. PMID:21278737PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011;12(6):560–7. PMID:21516112PubMedCrossRefGoogle Scholar
  62. 62.
    Stadhouders R, Lubberts E, Hendriks RW. A cellular and molecular view of T helper 17 cell plasticity in autoimmunity. J Autoimmun. 2018;87:1–15. PMID:29275836PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Haak S, Croxford AL, Kreymborg K, Heppner FL, Pouly S, Becher B, et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest. 2009;119(1):61–9. PMID:19075395PubMedGoogle Scholar
  64. 64.
    McQualter JL, Darwiche R, Ewing C, Onuki M, Kay TW, Hamilton JA, et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J Exp Med. 2001;194(7):873–82. PMID:11581310PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Pierson ER, Goverman JM. GM-CSF is not essential for experimental autoimmune encephalomyelitis but promotes brain-targeted disease. JCI Insight. 2017;2(7):e92362. PMID:28405624PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Duncker PC, Stoolman JS, Huber AK, Segal BM. GM-CSF promotes chronic disability in experimental autoimmune encephalomyelitis by altering the composition of central nervous system-infiltrating cells, but is dispensable for disease induction. J Immunol. 2018;200(3):966–73. PMID:29288202PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Ifergan I, Davidson TS, Kebir H, Xu D, Palacios-Macapagal D, Cann J, et al. Targeting the GM-CSF rece2017ptor for the treatment of CNS autoimmunity. J Autoimmun. 84:1–11. PMID:28641926Google Scholar
  68. 68.
    Marrack P, Lo D, Brinster R, Palmiter R, Burkly L, Flavell RH, et al. The effect of thymus environment on T cell development and tolerance. Cell. 1988;53(4):627–34. PMID:3259471PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Fredrikson S, Söderström M, Hillert J, Sun JB, Käll TB, Link H. Multiple sclerosis: occurrence of myelin basic protein peptide-reactive T cells in healthy family members. Acta Neurol Scand. 1994;89(3):184–9. PMID:7518178PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Hellings N, Barée M, Verhoeven C, D’hooghe MB, Medaer R, Bernard CC, et al. T-cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls. J Neurosci Res. 2001;63(3):290–302. PMID:11170179PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Raddassi K, Kent SC, Yang J, Bourcier K, Bradshaw EM, Seyfert-Margolis V, et al. Increased frequencies of myelin oligodendrocyte glycoprotein/MHC class II-binding CD4 cells in patients with multiple sclerosis. J Immunol. 2011;187(2):1039–46. PMID:21653833PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Jayaraman S. Novel methods of type 1 diabetes treatment. Discov Med. 2014;17(96):347–55. PMID:24979255PubMedPubMedCentralGoogle Scholar
  73. 73.
    Lutterotti A, Martin R. Antigen-specific tolerization approaches in multiple sclerosis. Expert Opin Investig Drugs. 2014;23(1):9–20. PMID:24151958PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Steinman L. The re-emergence of antigen-specific tolerance as a potential therapy for MS. Mult Scler. 2015;21(10):1223–38. PMID:25921045PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Schwartz RH, Mueller DL, Jenkins MK, Quill H. T-cell clonal anergy. Cold Spring Harb Symp Quant Biol. 1989;54 Pt 2:605–10. PMID:2534840PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Beverly B, Kang SM, Lenardo MJ, Schwartz RH. Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int Immunol. 1992;4(6):661–71. PMID:1616898PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Jayaraman S, Luo Y, Dorf ME. Tolerance induction in T helper (Th1) cells by thymic macrophages. J Immunol. 1992;148(9):2672–81. PMID:1533409PubMedPubMedCentralGoogle Scholar
  78. 78.
    Jayaraman S, Bellone CJ. Interaction of idiotype-specific T suppressor factor with the hapten-specific third-order T suppressor subset results in antigen-nonspecific suppression. Cell Immunol. 1986;101(1):72–81. PMID:3489537PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med. 1985;161(1):72–87. PMID:3871469PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151–64. PMID:21422251PubMedPubMedCentralGoogle Scholar
  81. 81.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61. PMID:12522256CrossRefGoogle Scholar
  82. 82.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–6. PMID: 12612578PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911. PMID:19464196PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A. Induced regulatory T cells: their development, stability, and applications. Trends Immunol. 2016;37(11):803–11. PMID:27623114PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev. 2001;182:68–79. PMID:11722624PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity. 2009;30(5):626–35. PMID:19464985PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164(1):183–90. PMID:10605010PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167(3):1245–53. PMID:11466340PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Stephens LA, Mottet C, Mason D, Powrie F. Human CD4 + CD25 + thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur J Immunol. 2001;31(4):1247–54. PMID:11298351PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4 + CD25 + regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199(7):971–9. PMID: 15067033PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Putheti P, Pettersson A, Soderstorm M, Link H, Huang YM. Circulating CD4 + CD25 + T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs. J Clin Immunol. 2004;24(2):155–61. PMID:15024182PubMedCrossRefGoogle Scholar
  92. 92.
    Haas J, Hug A, Viehöver A, Fritzsching B, Falk CS, Filser A, et al. Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Immunol. 2005;35(11):3343–52. PMID:16206232PubMedCrossRefGoogle Scholar
  93. 93.
    Michel L, Berthelot L, Pettré S, Wiertlewski S, Lefrère F, Braudeau C, et al. Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor α-chain are excluded from the analysis. J Clin Invest. 2008;118(10):3411–9. PMID:18769633PubMedPubMedCentralGoogle Scholar
  94. 94.
    Feger U, Luther C, Poeschel S, Melms A, Tolosa E, Wiendl H. Increased frequency of CD4 + CD25 + regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin Exp Immunol. 2007;147(3):412–8. PMID:17302889PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Venken K, Hellings N, Broekmans T, Hensen K, Rummens JL, Stinissen P. Natural naive CD4 + CD25 + CD127 low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory T reg homeostasis during disease progression. J Immunol. 2008;180(9):6411–20. PMID:18424765PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Kumar M, Putzki N, Limmroth V, Remus R, Lindemann M, Knop D, et al. CD4 + CD25 + FoxP3 + T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis. J Neuroimmunol. 2006;180(1–2):178–84. PMID:17011048PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Venken K, Hellings N, Thewissen M, Somers V, Hensen K, Rummens JL, et al. Compromised CD4 + CD25 high regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology. 2008;123(1):79–89. PMID:17897326PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Frisullo G, Nociti V, Iorio R, Patanella AK, Caggiula M, Marti A, et al. Regulatory T cells fail to suppress CD4T+-bet+ T cells in relapsing multiple sclerosis patients. Immunology. 2009;127(3):418–28. PMID:19016907PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Haas J, Fritzsching B, Trübswetter P, Korporal M, Milkova L, Fritz B, et al. Prevalence of newly generated naive regulatory T cells (T reg) is critical for T suppressive function and determines T reg dysfunction in multiple sclerosis. J Immunol. 2007;179(2):1322–30. PMID:17617625PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, et al. Expression of ectonucleotidase CD39 by Foxp3 + Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood. 2007;110(4):1225–32. PMID: 17449799PubMedCrossRefGoogle Scholar
  101. 101.
    Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O’Farrelly C, et al. CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol. 2009;183(11):7602–10. PMID: 19917691PubMedCrossRefGoogle Scholar
  102. 102.
    Powell BR, Buist NR, Stenzel P. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediar. 1982;100(5):731–7. PMID:7040622CrossRefGoogle Scholar
  103. 103.
    Tan QKG, Louie RJ, Sleasman JW. IPEX Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington; 2004. Seattle; 1993–2018. [updated 2018 Jul 19]. PMID:20301297.Google Scholar
  104. 104.
    Zavattari P, Deidda E, Pitzalis M, Zoa B, Moi L, Lampis R, et al. No association between variation of the FOXP3 gene and common type 1 diabetes in the Sardinian population. Diabetes. 2004;53(7):1911–4. PMID:15220219PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18–20. PMID:11137992PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–1. PMID:11137993PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest. 2006;116(6):1713–22. PMID:16741580PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Krishnamoorthy G, Holz A, Wekerle H. Experimental models of spontaneous autoimmune disease in the central nervous system. J Mol Med (Berl). 2007;85(11):1161–73. PMID:17569024CrossRefGoogle Scholar
  109. 109.
    Koutrolos M, Berer K, Kawakami N, Wekerle H, Krishnamoorthy G. Treg cells mediate recovery from EAE by controlling effector T cell proliferation and motility in the CNS. Acta Neuropathol Commun. 2014;2:163.. PMID:25476447.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Korn T, Reddy J, Gao W, Bettelli E, Awasthi A, Petersen TR, et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med. 2007;13(4):423–31.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Montero E, Nussbaum G, Kaye JF, Perez R, Lage A, Ben-Nun A, Cohen IR. Regulation of experimental autoimmune encephalomyelitis by CD4+, CD25+ and CD8+ T cells: analysis using depleting antibodies. J Autoimmun. 2004;23(1):1–7. PMID:15236747PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Gärtner D, Hoff H, Gimsa U, Burmester GR, Brunner-Weinzierl MC. CD25 regulatory T cells determine secondary but not primary remission in EAE: impact on long-term disease progression. J Neuroimmunol. 2006;172(1–2):73–84. PMID:16360886PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Rudra D, de Roos P, Chaudhry A, Niec RE, Arvey A, Samstein RM, et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol. 2012;13(10):1010–9. PMID:22922362PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Bettini ML, Pan F, Bettini M, Finkelstein D, Rehg JE, Floess S, et al. Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity. 2012;36(5):717–30. PMID:22579476PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Dominguez-Villar M, Baecher-Allan CM, Hafler DA. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat Med. 2011;17(6):673–5. PMID:21540856PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, et al. Pathogenic conversion of Foxp3 + T cells into T H 17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62–8. PMID: 24362934PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Zhang Z, Zhang W, Guo J, Gu Q, Zhu X, Zhou X. Activation and functional specialization of regulatory T cells Lead to the generation of Foxp3 instability. J Immunol. 2017;198(7):2612–25. PMID:28228556PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Jin HS, Park Y, Elly C, Liu YC. Itch expression by Treg cells controls Th2 inflammatory responses. J Clin Invest. 2013;123(11):4923–34. PMID:24135136PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Panduro M, Benoist C, Mathis D. Tissue Tregs. Annu Rev Immunol. 2016;34:609–33. PMID:27168246PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H, et al. Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity. 2013;39(5):949–62. PMID:24238343PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Huan J, Culbertson N, Spencer L, Bartholomew R, Burrows GG, Chou YK, et al. Decreased FoxP3 levels in multiple sclerosis patients. J Neurosci Res. 2005;81(1):45–52. PMID:15952173PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol. 2008;172(1):146–55.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Venken K, Hellings N, Hensen K, Rummens JL, Medaer R, D’hooghe MB, et al. Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FoxP3 expression. J Neurosci Res. 2006;83(8):1432–46. PMID:16583400PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010;10(12):849–59. PMID:21107346PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    de Andrés C, Aristimuño C, de Las Heras V, Martínez-Ginés ML, Bartolomé M, Arroyo R, et al. Interferon β-1a therapy enhances CD4 + regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis. J Neuroimmunol. 2007;182(1–2):204–11. PMID:17157927PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Haas J, Korporal M, Balint B, Fritzsching B, Schwarz A, Wildemann B. Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4(+)CD25(+)FoxP3(+)CD31(+) T-cells in patients with multiple sclerosis. J Neuroimmunol. 2009;216(1–2):113–7. PMID:19646767PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Chiarini M, Serana F, Zanotti C, Capra R, Rasia S, Rottoli M, et al. Modulation of the central memory and Tr1-like regulatory T cells in multiple sclerosis patients responsive to interferon-beta therapy. Multi Scler. 2012;18(6):788–98. PMID:22086901CrossRefGoogle Scholar
  128. 128.
    Stenner MP, Waschbisch A, Buck D, Doerck S, Einsele H, Toyka KV, et al. Effects of natalizumab treatment on Foxp3+ T regulatory cells. PLoS One. 2008;3(10):e3319.. PMID:18836525PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet. 2016;17(8):487–500. PMID:27346641PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Lal G, Bromberg JS. Epigenetic mechanisms of regulation of Foxp3 expression. Blood. 2009;114(18):3727–35. PMID:19641188PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med. 2007;13(11):1299–307. PMID:17922010PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Patel T, Patel V, Singh R, Jayaraman S. Chromatin remodeling resets the immune system to protect against autoimmune diabetes in mice. Immunol Cell Biol. 2011;89(5):640–9. PMID:21321581PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Jayaraman S, Patel A, Jayaraman A, Patel V, Holterman M, Prabhakar B. Transcriptome analysis of epigenetically modulated genome indicates signature genes in manifestation of type 1 diabetes and its prevention in NOD mice. PLoS One. 2013;8(1):e55074. PMID:23383062PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Akimova T, Ge G, Golovina T, Mikheeva T, Wang L, Riley JL, et al. Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs. Clin Immunol. 2010;136(3):348–63. PMID:20478744PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Weber MS, Prod’homme T, Youssef S, Dunn SE, Steinman L, Zamvil SS. Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity. J Neuroinflammation. 2014;11:29. PMID:24498870PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Ulivieri C, Baldari CT. Statins: from cholesterol-lowering drugs to novel immunomodulators for the treatment of Th17-mediated autoimmune diseases. Pharmacol Res. 2014;88:41–52. PMID:24657239PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study Group, Krischer JP, Schatz DA, Bundy B, Skyler JS, Greenbaum CJ. Effect of Oral insulin on prevention of diabetes in relatives of patients with type 1 diabetes: a randomized clinical trial. JAMA. 2017;318(19):1891–902. PMID:29164254PubMedCentralCrossRefPubMedGoogle Scholar
  138. 138.
    Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med. 2000;6(10):1167–75. PMID:11017150PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Phillips BE, Garciafigueroa Y, Trucco M, Giannoukakis N. Clinical Tolerogenic dendritic cells: exploring therapeutic impact on human autoimmune disease. Front Immunol. 2017;8:1279. PMID:29075262PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Pearson RM, Podojil JR, Shea LD, King NJ, Miller SD, Getts DR. Overcoming challenges in treating autoimmuntity: development of tolerogenic immune-modifying nanoparticles. Nanomedicine. 2018; pii: S1549–9634(18)30538–0. PMID:30352312.Google Scholar
  141. 141.
    Fritzsching B, Haas J, König F, Kunz P, Fritzsching E, Pöschl J, et al. Intracerebral human regulatory T cells: analysis of CD4+ CD25+ FOXP3+ T cells in brain lesions and cerebrospinal fluid of multiple sclerosis patients. PLoS One. 2011;6(3):e17988. PMID:21437244PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Martinez-Forero I, Garcia-Munoz R, Martinez-Pasamar S, Inoges S, Lopez-Diaz de Cerio A, Palacios R, et al. IL-10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis. Eur J Immunol. 2008;38(2):576–86. PMID:18200504PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of SurgeryUniversity of Illinois College of MedicinePeoriaUSA
  2. 2.Department of Microbiology & ImmunologyUniversity of Illinois College of MedicineChicagoUSA

Personalised recommendations