Advertisement

Cellular and Molecular Life Sciences

, Volume 68, Issue 3, pp 407–416 | Cite as

Janus head: the dual role of HLA-G in CNS immunity

  • Yu-Hwa Huang
  • Laura Airas
  • Nicholas Schwab
  • Heinz Wiendl
Multi-Author Review

Abstract

The central nervous system (CNS) is considered an immune-privileged organ that maintains an adaptable immune surveillance system. Dysregulated immune function within the CNS contributes to the development of brain tumor growth, and robust immune activation results in excessive inflammation. Human lymphocyte antigen-G (HLA-G) proteins with tolerogenic immunoreactivity have been implicated in various pathophysiological processes including immune surveillance, governing homeostasis and immune regulation. In this review, we describe the wealth of evidence for the involvement of HLA-G in the CNS under physiological and pathological conditions. Further, we review regulatory functions that may be applicable as beneficial strategies in the therapeutic manipulation of immune-mediated CNS immune responses. Additionally, we try to understand how this molecule cooperates with other CNS-resident cells to maintain normal immune homeostasis, while still facilitating the development of the appropriate immune responses.

Keywords

Multiple sclerosis Central nervous system Human lymphocyte antigen-G Immune surveillance Blood–brain barrier Immune tolerance 

Notes

Acknowledgments

This work was supported by grants from the German Research Foundation (DFG, Wi 1722/6-1 to H.W.) and the German Ministry for Education and Research (BMBF, “German Competence Network of MS” (KKNMS), UNDERSTANDMS, 01GI0907, to H.W.).

References

  1. 1.
    Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R (1990) A class I antigen, HLA-G, expressed in human trophoblasts. Science 248:220–223CrossRefPubMedGoogle Scholar
  2. 2.
    Le Bouteiller P (1995) Regulation of the expression of HLA class I genes in human trophoblasts. Pathol Biol (Paris) 43:628–635Google Scholar
  3. 3.
    Apps R, Gardner L, Moffett A (2008) A critical look at HLA-G. Trends Immunol 29:313–321CrossRefPubMedGoogle Scholar
  4. 4.
    Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N (2003) HLA-G molecules: from maternal-fetal tolerance to tissue acceptance. Adv Immunol 81:199–252CrossRefPubMedGoogle Scholar
  5. 5.
    Arnaiz-Villena A, Martinez-Laso J, Serrano-Vela JI, Reguera R, Moscoso J (2007) HLA-G polymorphism and evolution. Tissue Antigens 69(Suppl 1):156–159CrossRefPubMedGoogle Scholar
  6. 6.
    Onno M, Guillaudeux T, Amiot L, Renard I, Drenou B, Hirel B, Girr M, Semana G, Le Bouteiller P, Fauchet R (1994) The HLA-G gene is expressed at a low mRNA level in different human cells and tissues. Hum Immunol 41:79–86CrossRefPubMedGoogle Scholar
  7. 7.
    Hickey WF (2001) Basic principles of immunological surveillance of the normal central nervous system. Glia 36:118–124CrossRefPubMedGoogle Scholar
  8. 8.
    Becher B, Bechmann I, Greter M (2006) Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain. J Mol Med 84:532–543CrossRefPubMedGoogle Scholar
  9. 9.
    Zipp F, Aktas O (2006) The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci 29:518–527CrossRefPubMedGoogle Scholar
  10. 10.
    Ueno M (2009) Mechanisms of the penetration of blood-borne substances into the brain. Curr Neuropharmacol 7:142–149CrossRefPubMedGoogle Scholar
  11. 11.
    Hickey WF (1991) Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol 1:97–105CrossRefPubMedGoogle Scholar
  12. 12.
    Hickey WF, Hsu BL, Kimura H (1991) T lymphocyte entry into the central nervous system. J Neurosci Res 28:254–260CrossRefPubMedGoogle Scholar
  13. 13.
    Raine CS, Cannella B, Duijvestijn AM, Cross AH (1990) Homing to central nervous system vasculature by antigen-specific lymphocytes. II. Lymphocyte/endothelial cell adhesion during the initial stages of autoimmune demyelination. Lab Invest 63:476–489PubMedGoogle Scholar
  14. 14.
    Campbell JJ, Bowman EP, Murphy K, Youngman KR, Siani MA, Thompson DA, Wu L, Zlotnik A, Butcher EC (1998) 6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonist for the MIP-3beta receptor CCR7. J Cell Biol 141:1053–1059CrossRefPubMedGoogle Scholar
  15. 15.
    Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN (1998) Expression of monocyte chemoattractant protein-1 and other beta-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions. J Neuroimmunol 84:238–249CrossRefPubMedGoogle Scholar
  16. 16.
    McManus CM, Brosnan CF, Berman JW (1998) Cytokine induction of MIP-1 alpha and MIP-1 beta in human fetal microglia. J Immunol 160:1449–1455PubMedGoogle Scholar
  17. 17.
    Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36:180–190CrossRefPubMedGoogle Scholar
  18. 18.
    Vajtr D, Benada O, Kukacka J, Prusa R, Houstava L, Toupalik P, Kizek R (2009) Correlation of ultrastructural changes of endothelial cells and astrocytes occurring during blood-brain barrier damage after traumatic brain injury with biochemical markers of BBB leakage and inflammatory response. Physiol Res 58:263–268PubMedGoogle Scholar
  19. 19.
    Hailer NP, Heppner FL, Haas D, Nitsch R (1998) Astrocytic factors deactivate antigen-presenting cells that invade the central nervous system. Brain Pathol 8:459–474CrossRefPubMedGoogle Scholar
  20. 20.
    Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS (1998) Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282:103–107CrossRefPubMedGoogle Scholar
  21. 21.
    Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE, Kolbeck R, Hoppe E, Oropeza-Wekerle RL, Bartke I, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R (1999) Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189:865–870CrossRefPubMedGoogle Scholar
  22. 22.
    Liu Y, Teige I, Birnir B, Issazadeh-Navikas S (2006) Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat Med 12:518–525CrossRefPubMedGoogle Scholar
  23. 23.
    Jurewicz A, Biddison WE, Antel JP (1998) MHC class I-restricted lysis of human oligodendrocytes by myelin basic protein peptide-specific CD8 T lymphocytes. J Immunol 160:3056–3059PubMedGoogle Scholar
  24. 24.
    D′Souza S, Alinauskas K, McCrea E, Goodyer C, Antel JP (1995) Differential susceptibility of human CNS-derived cell populations to TNF-dependent and independent immune-mediated injury. J Neurosci 15:7293–7300PubMedGoogle Scholar
  25. 25.
    Bonetti B, Raine CS (1997) Multiple sclerosis: oligodendrocytes display cell death-related molecules in situ but do not undergo apoptosis. Ann Neurol 42:74–84CrossRefPubMedGoogle Scholar
  26. 26.
    Akassoglou K, Bauer J, Kassiotis G, Pasparakis M, Lassmann H, Kollias G, Probert L (1998) Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy. Am J Pathol 153:801–813PubMedGoogle Scholar
  27. 27.
    Jung DY, Lee H, Jung BY, Ock J, Lee MS, Lee WH, Suk K (2005) TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia: a critical role of IFN-beta as a decision maker. J Immunol 174:6467–6476PubMedGoogle Scholar
  28. 28.
    Alarcon R, Fuenzalida C, Santibanez M, von Bernhardi R (2005) Expression of scavenger receptors in glial cells. Comparing the adhesion of astrocytes and microglia from neonatal rats to surface-bound beta-amyloid. J Biol Chem 280:30406–30415CrossRefPubMedGoogle Scholar
  29. 29.
    Ulvestad E, Williams K, Vedeler C, Antel J, Nyland H, Mork S, Matre R (1994) Reactive microglia in multiple sclerosis lesions have an increased expression of receptors for the Fc part of IgG. J Neurol Sci 121:125–131CrossRefPubMedGoogle Scholar
  30. 30.
    Wiendl H, Feger U, Mittelbronn M, Jack C, Schreiner B, Stadelmann C, Antel J, Brueck W, Meyermann R, Bar-Or A, Kieseier BC, Weller M (2005) Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity. Brain 128:2689–2704CrossRefPubMedGoogle Scholar
  31. 31.
    Fainardi E, Rizzo R, Melchiorri L, Stignani M, Castellazzi M, Tamborino C, Paolino E, Tola MR, Granieri E, Baricordi OR (2008) CSF levels of soluble HLA-G and Fas molecules are inversely associated to MRI evidence of disease activity in patients with relapsing-remitting multiple sclerosis. Mult Scler 14:446–454CrossRefPubMedGoogle Scholar
  32. 32.
    Fainardi E, Rizzo R, Melchiorri L, Vaghi L, Castellazzi M, Marzola A, Govoni V, Paolino E, Tola MR, Granieri E, Baricordi OR (2003) Presence of detectable levels of soluble HLA-G molecules in CSF of relapsing-remitting multiple sclerosis: relationship with CSF soluble HLA-I and IL-10 concentrations and MRI findings. J Neuroimmunol 142:149–158CrossRefPubMedGoogle Scholar
  33. 33.
    Zozulya AL, Wiendl H (2008) The role of regulatory T cells in multiple sclerosis. Nat Clin Pract Neurol 4:384–398CrossRefPubMedGoogle Scholar
  34. 34.
    Huang YH, Zozulya AL, Weidenfeller C, Metz I, Buck D, Toyka KV, Bruck W, Wiendl H (2009) Specific central nervous system recruitment of HLA-G(+) regulatory T cells in multiple sclerosis. Ann Neurol 66:171–183CrossRefPubMedGoogle Scholar
  35. 35.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMedGoogle Scholar
  36. 36.
    Nyberg P, Salo T, Kalluri R (2008) Tumor microenvironment and angiogenesis. Front Biosci 13:6537–6553CrossRefPubMedGoogle Scholar
  37. 37.
    Carosella ED, Horuzsko A (2007) HLA-G and cancer. Semin Cancer Biol 17:411–412CrossRefPubMedGoogle Scholar
  38. 38.
    Sheu JJ, Shih IeM (2007) Clinical and biological significance of HLA-G expression in ovarian cancer. Semin Cancer Biol 17:436–443CrossRefPubMedGoogle Scholar
  39. 39.
    Rouas-Freiss N, Moreau P, Ferrone S, Carosella ED (2005) HLA-G proteins in cancer: do they provide tumor cells with an escape mechanism? Cancer Res 65:10139–10144CrossRefPubMedGoogle Scholar
  40. 40.
    Rouas-Freiss N, Moreau P, Menier C, Carosella ED (2003) HLA-G in cancer: a way to turn off the immune system. Semin Cancer Biol 13:325–336CrossRefPubMedGoogle Scholar
  41. 41.
    Urosevic M, Dummer R (2003) HLA-G in skin cancer: a wolf in sheep’s clothing? Hum Immunol 64:1073–1080CrossRefPubMedGoogle Scholar
  42. 42.
    Urosevic M, Trojan A, Dummer R (2002) HLA-G and its KIR ligands in cancer – another enigma yet to be solved? J Pathol 196:252–253CrossRefPubMedGoogle Scholar
  43. 43.
    Wiendl H, Mitsdoerffer M, Weller M (2003) Hide and seek in the brain: a role for HLA-G mediating immune privilege for glioma cells. Semin Cancer Biol 13:343–351CrossRefPubMedGoogle Scholar
  44. 44.
    Wiendl H, Mitsdoerffer M, Weller M (2002) A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol 168:4772–4780PubMedGoogle Scholar
  45. 45.
    Morandi F, Levreri I, Bocca P, Galleni B, Raffaghello L, Ferrone S, Prigione I, Pistoia V (2007) Human neuroblastoma cells trigger an immunosuppressive program in monocytes by stimulating soluble HLA-G release. Cancer Res 67:6433–6441CrossRefPubMedGoogle Scholar
  46. 46.
    Lafon M, Prehaud C, Megret F, Lafage M, Mouillot G, Roa M, Moreau P, Rouas-Freiss N, Carosella ED (2005) Modulation of HLA-G expression in human neural cells after neurotropic viral infections. J Virol 79:15226–15237CrossRefPubMedGoogle Scholar
  47. 47.
    Hafler DA (2004) Multiple sclerosis. J Clin Invest 113:788–794PubMedGoogle Scholar
  48. 48.
    Steinman L, Zamvil S (2003) Transcriptional analysis of targets in multiple sclerosis. Nat Rev Immunol 3:483–492CrossRefPubMedGoogle Scholar
  49. 49.
    Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–952CrossRefPubMedGoogle Scholar
  50. 50.
    Hafler DA, Slavik JM, Anderson DE, O′Connor KC, De Jager P, Baecher-Allan C (2005) Multiple sclerosis. Immunol Rev 204:208–231CrossRefPubMedGoogle Scholar
  51. 51.
    Gonzalez-Rey E, Chorny A, Delgado M (2007) Regulation of immune tolerance by anti-inflammatory neuropeptides. Nat Rev Immunol 7:52–63CrossRefPubMedGoogle Scholar
  52. 52.
    Hohlfeld R, Kerschensteiner M, Meinl E (2007) Dual role of inflammation in CNS disease. Neurology 68:S58–S63; discussion S91–S96CrossRefPubMedGoogle Scholar
  53. 53.
    Kalled SL (2005) The role of BAFF in immune function and implications for autoimmunity. Immunol Rev 204:43–54CrossRefPubMedGoogle Scholar
  54. 54.
    Meinl E, Krumbholz M, Hohlfeld R (2006) B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation. Ann Neurol 59:880–892CrossRefPubMedGoogle Scholar
  55. 55.
    Kerschensteiner M, Stadelmann C, Dechant G, Wekerle H, Hohlfeld R (2003) Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases. Ann Neurol 53:292–304CrossRefPubMedGoogle Scholar
  56. 56.
    Aarli JA, Mork SJ, Myrseth E, Larsen JL (1989) Glioblastoma associated with multiple sclerosis: coincidence or induction? Eur Neurol 29:312–316CrossRefPubMedGoogle Scholar
  57. 57.
    Khan OA, Bauserman SC, Rothman MI, Aldrich EF, Panitch HS (1997) Concurrence of multiple sclerosis and brain tumor: clinical considerations. Neurology 48:1330–1333PubMedGoogle Scholar
  58. 58.
    Paydarfar D, de la Monte SM (1997) Case records of the Massachusetts General Hospital weekly clinicopathological exercises: Case 12-1997: a 50-year-old woman with multiple sclerosis and an enlarging frontal-lobe mass. N Engl J Med 336:1163–1171CrossRefPubMedGoogle Scholar
  59. 59.
    Shuangshoti S, Hjardermaal GM, Ahmad Y, Arden JL, Herman MM (2003) Concurrence of multiple sclerosis and intracranial glioma: report of a case and review of the literature. Clin Neuropathol 22:304–308PubMedGoogle Scholar
  60. 60.
    Frisullo G, Patanella AK, Nociti V, Cianfoni A, Iorio R, Bianco A, Marti A, Tonali PA, Batocchi AP (2009) Glioblastoma in multiple sclerosis: a case report. J Neurooncol 94:141–144CrossRefPubMedGoogle Scholar
  61. 61.
    Warner CM, Comiskey M, Clisham PR, Brenner CA (2004) Soluble HLA-G (sHLA-G) a predictor of IVF outcome? J Assist Reprod Genet 21:315–316CrossRefPubMedGoogle Scholar
  62. 62.
    Noci I, Fuzzi B, Rizzo R, Melchiorri L, Criscuoli L, Dabizzi S, Biagiotti R, Pellegrini S, Menicucci A, Baricordi OR (2005) Embryonic soluble HLA-G as a marker of developmental potential in embryos. Hum Reprod 20:138–146CrossRefPubMedGoogle Scholar
  63. 63.
    Carosella ED, Moreau P, Lemaoult J, Rouas-Freiss N (2008) HLA-G: from biology to clinical benefits. Trends Immunol 29:125–132CrossRefPubMedGoogle Scholar
  64. 64.
    Wiendl H (2007) HLA-G in the nervous system. Hum Immunol 68:286–293CrossRefPubMedGoogle Scholar
  65. 65.
    Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, Colone M, Tatti M, Sargiacomo M, Fais S (2009) Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 284:34211–34222CrossRefPubMedGoogle Scholar
  66. 66.
    Schorey JS, Bhatnagar S (2008) Exosome function: from tumor immunology to pathogen biology. Traffic 9:871–881CrossRefPubMedGoogle Scholar
  67. 67.
    Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659CrossRefPubMedGoogle Scholar
  68. 68.
    Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ (2006) Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20:847–856CrossRefPubMedGoogle Scholar
  69. 69.
    Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476CrossRefPubMedGoogle Scholar
  70. 70.
    Riteau B, Faure F, Menier C, Viel S, Carosella ED, Amigorena S, Rouas-Freiss N (2003) Exosomes bearing HLA-G are released by melanoma cells. Hum Immunol 64:1064–1072CrossRefPubMedGoogle Scholar
  71. 71.
    Borchers AT, Naguwa SM, Keen CL, Gershwin ME (2010) The implications of autoimmunity and pregnancy. J Autoimmun 34(3):J287–J299CrossRefPubMedGoogle Scholar
  72. 72.
    Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group. N Engl J Med 339:285–291CrossRefPubMedGoogle Scholar
  73. 73.
    Saraste M, Vaisanen S, Alanen A, Airas L (2007) Clinical and immunologic evaluation of women with multiple sclerosis during and after pregnancy. Gend Med 4:45–55CrossRefPubMedGoogle Scholar
  74. 74.
    Paavilainen T, Kurki T, Parkkola R, Farkkila M, Salonen O, Dastidar P, Elovaara I, Airas L (2007) Magnetic resonance imaging of the brain used to detect early post-partum activation of multiple sclerosis. Eur J Neurol 14:1216–1221CrossRefPubMedGoogle Scholar
  75. 75.
    Thellin O, Heinen E (2003) Pregnancy and the immune system: between tolerance and rejection. Toxicology 185:179–184CrossRefPubMedGoogle Scholar
  76. 76.
    Luppi P (2003) How immune mechanisms are affected by pregnancy. Vaccine 21:3352–3357CrossRefPubMedGoogle Scholar
  77. 77.
    Hunt JS, Petroff MG, McIntire RH, Ober C (2005) HLA-G and immune tolerance in pregnancy. FASEB J 19:681–693CrossRefPubMedGoogle Scholar
  78. 78.
    Airas L, Saraste M, Rinta S, Elovaara I, Huang YH, Wiendl H (2008) Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells. Clin Exp Immunol 151:235–243CrossRefPubMedGoogle Scholar
  79. 79.
    Gilmore JH, Jarskog LF (1997) Exposure to infection and brain development: cytokines in the pathogenesis of schizophrenia. Schizophr Res 24:365–367CrossRefPubMedGoogle Scholar
  80. 80.
    Wegmann TG, Lin H, Guilbert L, Mosmann TR (1993) Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14:353–356CrossRefPubMedGoogle Scholar
  81. 81.
    Saraste M, Ryynanen J, Alanen A, Multanen J, Farkkila M, Kaaja R, Airas L (2006) Cerebrospinal fluid findings in multiple sclerosis patients before, during and after pregnancy. J Neurol Neurosurg Psychiatry 77:1195–1196CrossRefPubMedGoogle Scholar
  82. 82.
    Kim S, Liva SM, Dalal MA, Verity MA, Voskuhl RR (1999) Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis. Neurology 52:1230–1238PubMedGoogle Scholar
  83. 83.
    Polanczyk MJ, Hopke C, Huan J, Vandenbark AA, Offner H (2005) Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol 170:85–92CrossRefPubMedGoogle Scholar
  84. 84.
    Airas L, Nikula T, Huang YH, Lahesmaa R, Wiendl H (2007) Postpartum-activation of multiple sclerosis is associated with down-regulation of tolerogenic HLA-G. J Neuroimmunol 187:205–211CrossRefPubMedGoogle Scholar
  85. 85.
    Clark DA (2005) Tolerance signaling molecules. Chem Immunol Allergy 89:36–48CrossRefPubMedGoogle Scholar
  86. 86.
    Bebo BF Jr, Dveksler GS (2005) Evidence that pregnancy specific glycoproteins regulate T cell function and inflammatory autoimmune disease during pregnancy. Curr Drug Targets Inflamm Allergy 4:231–237CrossRefPubMedGoogle Scholar
  87. 87.
    Irony-Tur-Sinai M, Grigoriadis N, Lourbopoulos A, Pinto-Maaravi F, Abramsky O, Brenner T (2006) Amelioration of autoimmune neuroinflammation by recombinant human alpha-fetoprotein. Exp Neurol 198:136–144CrossRefPubMedGoogle Scholar
  88. 88.
    Feger U, Tolosa E, Huang YH, Waschbisch A, Biedermann T, Melms A, Wiendl H (2007) HLA-G expression defines a novel regulatory T cell subset present in human peripheral blood and sites of inflammation. Blood 110:568–577CrossRefPubMedGoogle Scholar
  89. 89.
    Huang YH, Zozulya AL, Weidenfeller C, Schwab N, Wiendl H (2009) T cell suppression by naturally occurring HLA-G-expressing regulatory CD4+ T cells is IL-10-dependent and reversible. J Leukoc Biol 86:273–281CrossRefPubMedGoogle Scholar
  90. 90.
    Weiner HL, Selkoe DJ (2002) Inflammation and therapeutic vaccination in CNS diseases. Nature 420:879–884CrossRefPubMedGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Yu-Hwa Huang
    • 1
  • Laura Airas
    • 2
  • Nicholas Schwab
    • 1
  • Heinz Wiendl
    • 1
  1. 1.Department of Neurology, Inflammatory Disorders of the Nervous System and NeurooncologyUniversity of MüensterMüensterGermany
  2. 2.Department of Neurology, MediCity Research LaboratoryTurku University HospitalTurkuFinland

Personalised recommendations