Publikationsserver der Universitätsbibliothek Marburg
Titel:Epigenetische Regulation Th1/Th2-relevanter Gene in CD4+-T-Zellen als Mechanismus der Allergie-Prävention bei experimentellem Asthma
Autor:Brand, Stephanie
Weitere Beteiligte: Garn, Holger (Dr.)
Veröffentlicht:2010
URI:https://archiv.ub.uni-marburg.de/diss/z2010/0358
URN: urn:nbn:de:hebis:04-z2010-03580
DOI: https://doi.org/10.17192/z2010.0358
DDC: Medizin
Titel (trans.):Epigenetic regulation of Th1/Th2 relevant genes in CD4+ T-cells as a mechanism of allergy prevention in experimental asthma
Publikationsdatum:2010-07-08
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
allergisches Asthma, T-Zellen, Hygiene Hypothese, Allergisches Asthma, Epigenetik, Hygiene Hypothesis, Epigenetics, Asthma, Epigenetik, T-cells

Zusammenfassung:
Epigenetische Modulation ist assoziiert mit der Differenzierung von T-Helfer (Th)1- und Th2-Zellen, wobei letzere für die Dirigierung der allergischen Immunantwort eine bedeutende Rolle spielen. In dieser Arbeit wurde mittels des DNA-Methyltransferase-Inhibitors 5-Aza-2´-Deoxycytidin (5Aza) zunächst untersucht, ob eine veränderte epigenetische Signatur in CD4+-T-Zellen den asthmatischen Phänotyp in einem Tiermodell des experimentellen Asthmas beeinflussen kann. Dazu wurde ein adoptiver Transfer von CD4+-T-Zellen aus 5Aza- oder PBS-behandelten sensibilisierten Ovalbumin (OVA)-T-Zell-Rezeptor transgenen (DO11.10)-Donormäusen durchgeführt und der asthmatische Phänotyp in OVA-provozierten Wildtyp-Balb/c-Rezipienten analysiert. Hier resultierte die Behandlung der Donoren mit 5Aza in einer signifikanten Reduktion des asthmatischen Phänotyps in den Rezipienten. Diese Ergebnisse zeigen, dass der DNA-Methylierungsgrad in CD4+-T-Zellen einen Einfluss auf die Entwicklung des asthmatischen Phänotyps in diesem Modell hat. Da bekannt ist, dass epigenetische Regulation durch komplexe Gen-Umwelt-Interaktionen moduliert werden kann, wurde im zweiten Teil dieser Arbeit die Rolle epigenetischer Regulation bei der mikrobiell-vermittelten transmaternalen Asthma-Protektion untersucht. Dazu wurden Balb/c-Mäuse während der Schwangerschaft mit dem apathogenen, gram-negativen Bakterium Acinetobacter lwoffii F78 (A. lwoffii F78) exponiert und die Nachkommen dieser Tiere anschließend mit OVA sensibilisiert und provoziert. Die pränatale A. lwoffii F78-Exposition führte zu einer Veränderung der Th1/Th2-Balance, da die Interferon gamma (IFNg)-Produktion von mononukleären Zellen (MNCs) aus der Milz erhöht und die Produktion der Interleukine (IL)-4, IL-5 und IL-13 erniedrigt war, einhergehend mit einer signifikanten Reduktion des asthmatischen Phänotyps in diesen Tieren. Dieser Effekt scheint von der erhöhten IFNg-Produktion und damit der verschobenen Th1/Th2-Balance abhängig zu sein, da die funktionelle Inhibition von IFNg mit einem neutralisierenden Antikörper zur Wiederherstellung des asthmatischen Phänotyps führte. Daher wurden DNA-Methylierung und posttranslationale Histonmodifikationen in Th1- und Th2-regulatorischen Genregionen von CD4+CD25--T-Zellen aus der Milz von Nachkommen A. lwoffii F78-exponierter Mütter nach OVA-Sensibilisierung und -Provokation analysiert. Hier zeigte sich am IFNg-Promotor eine signifikante Erhöhung der Histon H4-Acetylierung. Um die Relevanz der veränderten H4-Acetylierung am IFNg-Promotor weiter zu untersuchen, wurden die Nachkommen während der OVA-Provokation zusätzlich mit einem Histonacetyltransferase-Inhibitor behandelt. Diese Behandlung resultierte in der Aufhebung der Asthma-Protektion einhergehend mit der Inhibierung der H4-Acetylierung am IFNg-Promotor. Die hier erhaltenen Daten liefern somit einen ersten Hinweis, das epigenetische Regulation innerhalb von Th1/Th2-Zytokin-Genen von CD4+-T-Zellen, insbesondere am IFNg-Promotor, eine wichtige Rolle bei der Asthmaprotektion spielt, welche vermittelt wird durch die pränatale Exposition mit dem Modellkeim A. lwoffii F78.

Bibliographie / References

  1. Wills-Karp, M., Luyimbazi, J., Xu, X., Schofield, B., Neben, T. Y., Karp, C. L., and Donaldson, D. D. Interleukin-13: central mediator of allergic asthma. 1998. Science 282:2258-2261.
  2. Fedulov, A. V., Leme, A., Yang, Z., Dahl, M., Lim, R., Mariani, T. J., and Kobzik, L. Pulmonary exposure to particles during pregnancy causes increased neonatal asthma susceptibility. 2008. Am J Respir Cell Mol Biol. 38:57-67.
  3. Ibanez, de Caceres, I, Dulaimi, E., Hoffman, A. M., Al Saleem, T., Uzzo, R. G., and Cairns, P. Identification of novel target genes by an epigenetic reactivation screen of renal cancer. 2006. Cancer Res. 66:5021-5028.
  4. Yang, S. R., Valvo, S., Yao, H., Kode, A., Rajendrasozhan, S., Edirisinghe, I., Caito, S., Adenuga, D., Henry, R., Fromm, G., Maggirwar, S., Li, J. D., Bulger, M., and Rahman, I. IKK alpha causes chromatin modification on pro-inflammatory genes by cigarette smoke in mouse lung. 2008. Am J Respir Cell Mol Biol. 38:689-698.
  5. Lei, H., Oh, S. P., Okano, M., Juttermann, R., Goss, K. A., Jaenisch, R., and Li, E. De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. 1996. Development 122:3195-3205.
  6. Pfefferle, P. I., Buchele, G., Blumer, N., Roponen, M., Ege, M. J., Krauss-Etschmann, S., Genuneit, J., Hyvarinen, A., Hirvonen, M. R., Lauener, R., Pekkanen, J., Riedler, J., Dalphin, J. C. , Brunekeef, B., Braun-Fahrlander, C., von Mutius, E., and Renz, H. Cord blood cytokines are modulated by maternal farming activities and consumption of farm dairy products during pregnancy: The PASTURE Study. 2010. J Allergy Clin Immunol 125:108-115.
  7. Jones, P. A. and Baylin, S. B. The fundamental role of epigenetic events in cancer. 2002. Nat.Rev Genet 3:415-428.
  8. von Mutius, E. Gene-environment interactions in asthma. 2009. J Allergy Clin Immunol 123:3- 11.
  9. Pan, Y. and Sawalha, A. H. Epigenetic regulation and the pathogenesis of systemic lupus erythematosus. 2009. Transl.Res. 153:4-10.
  10. Lau, S., Nickel, R., Niggemann, B., Gruber, C., Sommerfeld, C., Illi, S. , Kulig, M., Forster, J. , Wahn, U., Groeger, M., Zepp, F., Kamin, W., Bieber, I., Tacke, U., Wahn, V., Bauer, C. P., Bergmann, R., and von Mutius, E. The development of childhood asthma: lessons from the German Multicentre Allergy Study (MAS). 2002. Paediatr.Respir Rev 3:265-272.
  11. Maziak, W., Behrens, T., Brasky, T. M., Duhme, H., Rzehak, P., Weiland, S. K., and Keil, U. Are asthma and allergies in children and adolescents increasing? Results from ISAAC phase I and phase III surveys in Munster, Germany. 2003. Allergy 58:572-579.
  12. Takemoto, N., Koyano-Nakagawa, N., Yokota, T., Arai, N., Miyatake, S., and Arai, K. Th2- specific DNase I-hypersensitive sites in the murine IL-13 and IL-4 intergenic region. 1998. Int Immunol 10:1981-1985.
  13. Nakanishi, K., Yoshimoto, T., Chu, C. C., Matsumoto, H., Hase, K., Nagai, N., Tanaka, T., Miyasaka, M., Paul, W. E., and Shinka, S. IL-2 inhibits IL-4-dependent IgE and IgG1 production in vitro and in vivo. 1995. Int Immunol 7:259-268.
  14. Herceg, Z. Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors. 2007. Mutagenesis 22:91-103.
  15. Iguchi-Ariga, S. M. and Schaffner, W. CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation. 1989. Genes Dev. 3:612-619.
  16. Mantelingu, K., Reddy, B. A., Swaminathan, V., Kishore, A. H., Siddappa, N. B., Kumar, G. V., Nagashankar, G., Natesh, N., Roy, S., Sadhale, P. P., Ranga, U., Narayana, C., and Kundu, T. K. Specific inhibition of p300-HAT alters global gene expression and represses HIV replication. 2007. Chem.Biol. 14:645-657.
  17. Huh, J. C., Strickland, D. H., Jahnsen, F. L., Turner, D. J., Thomas, J. A., Napoli, S., Tobagus, I., Stumbles, P. A., Sly, P. D., and Holt, P. G. Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma. 2003. J Exp Med 198:19-30.
  18. Rowe, J., Heaton, T., Kusel, M., Suriyaarachchi, D., Serralha, M., Holt, B. J., de Klerk, N., Sly, P. D., and Holt, P. G. High IFN-gamma production by CD8+ T cells and early sensitization among infants at high risk of atopy. 2004. J Allergy Clin Immunol 113:710-716.
  19. Kass, S. U., Landsberger, N., and Wolffe, A. P. DNA methylation directs a time-dependent repression of transcription initiation. 1997. Curr.Biol. 7:157-165.
  20. Jones, B. and Chen, J. Inhibition of IFN-gamma transcription by site-specific methylation during T helper cell development. 2006. EMBO J 25:2443-2452.
  21. Vermaelen, K. and Pauwels, R. Accelerated airway dendritic cell maturation, trafficking, and elimination in a mouse model of asthma. 2003. Am J Respir Cell Mol Biol. 29:405-409.
  22. Coyle, A. J., Tsuyuki, S., Bertrand, C., Huang, S. , Aguet, M., Alkan, S. S., and Anderson, G. P. Mice lacking the IFN-gamma receptor have impaired ability to resolve a lung eosinophilic inflammatory response associated with a prolonged capacity of T cells to exhibit a Th2 cytokine profile. 1996. J Immunol 156:2680-2685.
  23. Coffman, R. L., Savelkoul, H. F., and Lebman, D. A. Cytokine regulation of immunoglobulin isotype switching and expression. 1989. Semin.Immunol 1:55-63.
  24. Abb. 3.11 5Aza beeinflusst den IFNγ-Promotor (Th1) und CNS-1(Th2) unterschiedlich stark: Differenz zwischen PBS-und 5Aza-behandelten Tieren _______________________ 75
  25. Abb. 1.1 Sensibilisierungsphase (modifiziert nach Valenta 2002) ________________________ 10
  26. Abb. 3.12 Migration der transferierten CD4 + -T-Zellen in die Lymphknoten der Lunge wird nicht durch 5Aza beeinflusst _________________________________________________ 76
  27. Abb. 1.2 Sofortreaktion (modifiziert nach Valenta 2002, Galli 2008) _____________________ 11
  28. Abb. 1.3 Spätreaktion (modifiziert nach Valenta 2002, Galli 2008) ______________________ 12
  29. Abb. 3.14 5-Aza-2´-Deoxycytidinbehandlung verhindert inflammatorische Reaktion im Lungengewebe nach Transfer CD4 + -T-Zellen ________________________________ 79
  30. Abb. 1.5 Regulation der Transkription durch DNA-Methylierung (modifiziert nach Barros 2009) _________________________________________________________ 20
  31. Abb. 1.7 Aufbau und Modifikationen des murinen IFNγ-Lokus (modifiziert nach Wilson 2009) 25
  32. Abb. 3.20 Unveränderte CpG-Methylierung am IFNγ-Promotor nach pränataler A. lwoffii F78- Exposition ___________________________________________________________ 86
  33. Tab. 2.1 AK-Konzentrationen und Verdünnungsfaktoren für Ig-ELISAs _________________ 39
  34. Abb. 3.21 Pränatale A. lwoffii F78-Exposition führt zu einer erhöhten H4-Acetylierung am IFNγ-Promotor ________________________________________________________ 87
  35. Abb. 3.22 CpG-Methylierung des IL-4-und IL-5-Promotors sowie der Th2-reglatorischen Region CNS-1 nach pränataler A. lwoffii F78-Exposition _______________________ 89
  36. Abb. 2.5 Protokoll der anti-IFNγ-und Garcinol-Behandlung ___________________________ 33
  37. Abb. 3.26 Garcinol inhibiert erhöhte H4-Acetylierung am IFNγ-Promotor nach pränataler A. lwoffii F78-Exposition ________________________________________________ 94
  38. Abb. 3.27 Erniedrigte IFNγ-und erhöhte IL-5-Produktion nach Garcinol-Behandlung von pränatal A. lwoffii F78-exponierten Mäusen _________________________________ 95
  39. Abb. 3.18 Anti-IFNγ-Behandlung führt zur Wiederherstellung des asthmatischen Phänotyps ___ 84
  40. Abb. 3.19 Wiederherstellung der IL-5-Produktion von Milz-MNCs nach anti-IFNγ-Behandlung 85
  41. Abb. 3.23 Veränderte Histonmodifikationen am Th2-Lokus nach pränataler A. lwoffii F78- Exposition ___________________________________________________________ 90
  42. Abb. 3.6 5-Aza-2´-Deoxycytidinbehandlung verhindert inflammatorische Reaktion im Lungengewebe ________________________________________________________ 70
  43. Lantry, L. E., Zhang, Z., Crist, K. A., Wang, Y., Kelloff, G. J., Lubet, R. A., and You, M. 5-Aza- 2'-deoxycytidine is chemopreventive in a 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone- induced primary mouse lung tumor model. 1999. Carcinogenesis 20:343-346.
  44. Christman, J. K. 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. 2002. Oncogene 21:5483-5495.
  45. Abb. 3.9 5-Aza-2´-Deoxycytidinbehandlung führt zu einem erhöhten Anteil OVA-spezifischer IgG2a-Antikörper, sowie zu einer Erniedrigung Th2-induzierter IgE-und IgG1- Antikörper ___________________________________________________________ 73
  46. Lee, P. P., Fitzpatrick, D. R., Beard, C., Jessup, H. K., Lehar, S., Makar, K. W., Perez-Melgosa, M., Sweetser, M. T., Schlissel, M. S., Nguyen, S., Cherry, S. R., Tsai, J. H., Tucker, S. M., Weaver, W. M., Kelso, A., Jaenisch, R., and Wilson, C. B. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. 2001. Immunity 15:763-774.
  47. Hatton, R. D., Harrington, L. E., Luther, R. J., Wakefield, T., Janowski, K. M., Oliver, J. R., Lallone, R. L., Murphy, K. M., and Weaver, C. T. A distal conserved sequence element controls Ifng gene expression by T cells and NK cells. 2006. Immunity 25:717-729.
  48. Lee, D. U., Avni, O., Chen, L., and Rao, A. A distal enhancer in the interferon-gamma (IFN- gamma) locus revealed by genome sequence comparison. 2004. J Biol.Chem. 279:4802-4810.
  49. Winders, B. R., Schwartz, R. H., and Bruniquel, D. A distinct region of the murine IFN-gamma promoter is hypomethylated from early T cell development through mature naive and Th1 cell differentiation, but is hypermethylated in Th2 cells. 2004. J Immunol 173:7377-7384.
  50. Daniels, S. E., Bhattacharrya, S., James, A., Leaves, N. I., Young, A., Hill, M. R., Faux, J. A., Ryan, G. F., le Souef, P. N., Lathrop, G. M., Musk, A. W., and Cookson, W. O. A genome-wide search for quantitative trait loci underlying asthma. 1996. Nature 383:247-250.
  51. Vignola, A. M., Mirabella, F., Costanzo, G., Di Giorgi, R., Gjomarkaj, M., Bellia, V., and Bonsignore, G. Airway remodeling in asthma. 2003. Chest 123:417S-422S.
  52. von Mutius, E. Allergies, infections and the hygiene hypothesis--the epidemiological evidence. 2007. Immunobiology 212:433-439.
  53. Wise, J. T., Baginski, T. J., and Mobley, J. L. An adoptive transfer model of allergic lung inflammation in mice is mediated by CD4+CD62LlowCD25+ T cells. 1999. J Immunol 162:5592- 5600.
  54. Johansson, S. G., Hourihane, J. O., Bousquet, J., Bruijnzeel-Koomen, C., Dreborg, S., Haahtela, T., Kowalski, M. L., Mygind, N., Ring, J., van Cauwenberge, P., Hage-Hamsten, M., and Wuthrich, B. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. 2001. Allergy 56:813-824.
  55. von Mutius, E. Asthma and allergies in rural areas of Europe. 2007. Proc.Am Thorac.Soc 4:212- 216.
  56. Ober, C. and Hoffjan, S. Asthma genetics 2006: the long and winding road to gene discovery. 2006. Genes Immun. 7:95-100.
  57. Cohn, L., Elias, J. A., and Chupp, G. L. Asthma: mechanisms of disease persistence and progression. 2004. Annu.Rev Immunol 22:789-815.
  58. Conrad, M.L., Teich, R., Ferstl, R., Brand, S., Yildirim, A.Ö., Kirschning, C., Garn, H., Renz, H., Asthma protective effects are induced by prenatal Acinetobacter lwoffii application and dependent on functional maternal toll-like receptors, Allergo J., 18(1) (2009) – Mainzer Allergie Workshop 2009
  59. Marone, G. Asthma: recent advances. 1998. Immunol Today 19:5-9.
  60. Janson, P. C., Winerdal, M. E., and Winqvist, O. At the crossroads of T helper lineage commitment-Epigenetics points the way. 2009. Biochim.Biophys.Acta 1790:906-919.
  61. Riedler, J., Eder, W., Oberfeld, G., and Schreuer, M. Austrian children living on a farm have less hay fever, asthma and allergic sensitization. 2000. Clin Exp Allergy 30:194-200.
  62. Lambrecht, B. N. and Hammad, H. Biology of lung dendritic cells at the origin of asthma. 2009. Immunity 31:412-424.
  63. Levine, S. J. Bronchial epithelial cell-cytokine interactions in airway inflammation. 1995. J Investig.Med 43:241-249.
  64. Ozdemir, C., Sel, S., Scholl, I., Yildirim, A. O. , Bluemer, N., Garn, H., Ackermann, U., Wegmann, M., Barlan, I. B., Renz, H., and Sel, S. CD4+ T cells from mice with intestinal immediate-type hypersensitivity induce airway hyperreactivity. 2007. Clin Exp Allergy 37:1419- 1426.
  65. Smale, S. T. and Fisher, A. G. Chromatin structure and gene regulation in the immune system. 2002. Annu.Rev Immunol 20:427-462.
  66. Heinzmann, A., Blattmann, S., Forster, J., Kuehr, J., and Deichmann, K. A. Common polymorphisms and alternative splicing in the ILT3 gene are not associated with atopy. 2000. Eur.J Immunogenet. 27:121-127.
  67. R., Stamatoyannopoulos, J. A., and Wilson, C. B. Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma. 2007. Nat.Immunol 8:732-742.
  68. Rabe, K. F., Munoz, N. M., Vita, A. J., Morton, B. E., Magnussen, H., and Leff, A. R. Contraction of human bronchial smooth muscle caused by activated human eosinophils. 1994. Am J Physiol 267:L326-L334 .
  69. Ober, C. and Moffatt, M. F. Contributing factors to the pathobiology. The genetics of asthma. 2000. Clin Chest Med 21:245-261.
  70. White, G. P., Hollams, E. M., Yerkovich, S. T., Bosco, A., Holt, B. J., Bassami, M. R., Kusel, M., Sly, P. D., and Holt, P. G. CpG methylation patterns in the IFNgamma promoter in naive T cells: variations during Th1 and Th2 differentiation and between atopics and non-atopics. 2006.
  71. CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic asthma. 2002. J Allergy Clin Immunol 110:867-872.
  72. Flaishon, L., Topilski, I. , Shoseyov, D., Hershkoviz, R., Fireman, E., Levo, Y., Marmor, S., and Shachar, I. Cutting edge: anti-inflammatory properties of low levels of IFN-gamma. 2002. J Immunol 168:3707-3711.
  73. Fields, P. E., Kim, S. T., and Flavell, R. A. Cutting edge: changes in histone acetylation at the IL- 4 and IFN-gamma loci accompany Th1/Th2 differentiation. 2002. J Immunol 169:647-650.
  74. Fitzpatrick, D. R., Shirley, K. M., and Kelso, A. Cutting edge: stable epigenetic inheritance of regional IFN-gamma promoter demethylation in CD44highCD8+ T lymphocytes. 1999. J Immunol 162:5053-5057.
  75. Celedon, J. C., Litonjua, A. A., Weiss, S. T., and Gold, D. R. Day care attendance in the first year of life and illnesses of the upper and lower respiratory tract in children with a familial history of atopy. 1999. Pediatrics 104:495-500.
  76. Mohrs, M., Blankespoor, C. M., Wang, Z. E., Loots, G. G., Afzal, V., Hadeiba, H., Shinkai, K., Rubin, E. M., and Locksley, R. M. Deletion of a coordinate regulator of type 2 cytokine expression in mice. 2001. Nat.Immunol 2:842-847.
  77. Mellman, I. and Steinman, R. M. Dendritic cells: specialized and regulated antigen processing machines. 2001. Cell 106:255-258.
  78. Fogarty, A., Lewis, S., Weiss, S., and Britton, J. Dietary vitamin E, IgE concentrations, and atopy. 2000. Lancet 356:1573-1574.
  79. White, G. P., Watt, P. M., Holt, B. J., and Holt, P. G. Differential patterns of methylation of the IFN-gamma promoter at CpG and non-CpG sites underlie differences in IFN-gamma gene expression between human neonatal and adult CD. 2002. J Immunol 168:2820-2827.
  80. Young, H. A., Ghosh, P., Ye, J., Lederer, J., Lichtman, A., Gerard, J. R. , Penix, L., Wilson, C. B., Melvin, A. J., McGurn, M. E., and . Differentiation of the T helper phenotypes by analysis of the methylation state of the IFN-gamma gene. 1994. J Immunol 153:3603-3610.
  81. Fitzpatrick, D. R., Shirley, K. M., McDonald, L. E., Bielefeldt-Ohmann, H., Kay, G. F., and Kelso, A. Distinct methylation of the interferon gamma (IFN-gamma) and interleukin 3 (IL-3) genes in newly activated primary CD8+ T lymphocytes: regional IFN-gamma promoter 6. LITERATURVERZEICHNIS [123] demethylation and mRNA expression are heritable in CD44(high)CD8+ T cells. 1998. J Exp Med 188:103-117.
  82. Tost, J. and Gut, I. G. DNA methylation analysis by pyrosequencing. 2007. Nat.Protoc. 2:2265- 2275.
  83. Kwon, N. H., Kim, J. S., Lee, J. Y., Oh, M. J., and Choi, D. C. DNA methylation and the expression of IL-4 and IFN-gamma promoter genes in patients with bronchial asthma. 2008. J Clin Immunol 28:139-146.
  84. Yang, A. S., Doshi, K. D., Choi, S. W., Mason, J. B., Mannari, R. K., Gharybian, V., Luna, R., Rashid, A., Shen, L., Estecio, M. R., Kantarjian, H. M., Garcia-Manero, G., and Issa, J. P. DNA methylation changes after 5-aza-2'-deoxycytidine therapy in patients with leukemia. 2006. Cancer Res. 66:5495-5503.
  85. Jones, C. A., Holloway, J. A., and Warner, J. O. Does atopic disease start in foetal life? 2000. Allergy 55:2-10.
  86. Chang, S. and Aune, T. M. Dynamic changes in histone-methylation 'marks' across the locus encoding interferon-gamma during the differentiation of T helper type 2 cells. 2007. Nat.Immunol 8:723-731.
  87. von Mutius, E. and le Souef, P. N. Early gene-environment interactions: can they inform primary preventive strategies for asthma? 2007. Semin.Respir Crit Care Med 28:255-263.
  88. Ein großer Dank betreffend der technischen Unterstützung geht an Lydia Lerch für die vielen ELISAs, die ich auf sie " abschieben " durfte, sowie an Thomas Ruppersberg, Sophia Bernhardt, Nicole Disser, Anja Spies-Naumann und unsere Azubis. Ein Dank auch an alle anderen Mitglieder der Arbeitsgruppe und des Instituts, die mir durch gute Zusammenarbeit und Ratschläge geholfen haben.
  89. Huehn, J., Polansky, J. K. , and Hamann, A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? 2009. Nat.Rev Immunol 9:83-89.
  90. Wilson, C. B., Rowell, E., and Sekimata, M. Epigenetic control of T-helper-cell differentiation. 2009. Nat.Rev Immunol 9:91-105.
  91. Sigalotti, L., Fratta, E., Coral, S., Cortini, E., Covre, A., Nicolay, H. J., Anzalone, L., Pezzani, L., Di Giacomo, A. M., Fonsatti, E., Colizzi, F., Altomonte, M., Calabro, L., and Maio, M. Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications. 2007. J Cell Physiol 212:330-344.
  92. van der Maarel, S. M. Epigenetic mechanisms in health and disease. 2008. Ann.Rheum.Dis. 67 Suppl 3:iii97-100.
  93. Urdinguio, R. G., Sanchez-Mut, J. V., and Esteller, M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. 2009. Lancet Neurol. 8:1056-1072.
  94. Teich, R., Brand, S., Blümer, N., Pfefferle, P.I., Garn, H., Renz, H., Epigenetic regulation of asthma preventive effects mediated by stable-derived bacteria, J. Allergy.
  95. Jaenisch, R. and Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. 2003. Nat.Genet 33 Suppl:245-254.
  96. Für solche netten Aktionen wie die " Eppendorf-Love-Story " , die ein wenig Ablenkung in den grauen Laboralltag gebracht hat, sei natürlich auch Eva-Maria Wittmann und
  97. Shnyreva, M., Weaver, W. M., Blanchette, M., Taylor, S. L., Tompa, M., Fitzpatrick, D. R., and Wilson, C. B. Evolutionarily conserved sequence elements that positively regulate IFN-gamma expression in T cells. 2004. Proc.Natl.Acad.Sci U.S.A 101:12622-12627.
  98. von Mutius, E., Braun-Fahrlander, C., Schierl, R., Riedler, J., Ehlermann, S., Maisch, S., Waser, M., and Nowak, D. Exposure to endotoxin or other bacterial components might protect against the development of atopy. 2000. Clin Exp Allergy 30:1230-1234.
  99. Riedler, J., Braun-Fahrlander, C., Eder, W., Schreuer, M., Waser, M., Maisch, S., Carr, D., Schierl, R., Nowak, D., and von Mutius, E. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. 2001. Lancet 358:1129-1133.
  100. Koyanagi, M., Baguet, A., Martens, J., Margueron, R., Jenuwein, T., and Bix, M. EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. 2005. J Biol.Chem. 280:31470-31477.
  101. Trojer, P. and Reinberg, D. Facultative heterochromatin: is there a distinctive molecular signature? 2007. Mol Cell 28:1-13.
  102. Burke, W., Fesinmeyer, M., Reed, K., Hampson, L., and Carlsten, C. Family history as a predictor of asthma risk. 2003. Am J Prev.Med 24:160-169.
  103. Strachan, D. P. Family size, infection and atopy: the first decade of the "hygiene hypothesis". 2000. Thorax 55 Suppl 1:S2-10.
  104. Fontenot, J. D., Gavin, M. A., and Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. 2003. Nat.Immunol 4:330-336.
  105. Bousquet, J., Jeffery, P. K., Busse, W. W., Johnson, M., and Vignola, A. M. Asthma. From bronchoconstriction to airways inflammation and remodeling. 2000. Am J Respir Crit Care Med 161:1720-1745.
  106. Stresemann, C., Brueckner, B., Musch, T., Stopper, H., and Lyko, F. Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. 2006. Cancer Res. 66:2794-2800.
  107. GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. 2000. J Exp Med 192:105-115.
  108. Skadhauge, L. R., Christensen, K., Kyvik, K. O., and Sigsgaard, T. Genetic and environmental influence on asthma: a population-based study of 11,688 Danish twin pairs. 1999. Eur.Respir J 13:8-14.
  109. Holgate, S. T. Genetic and environmental interaction in allergy and asthma. 1999. J Allergy Clin Immunol 104:1139-1146.
  110. Moffatt, M. F., Kabesch, M., Liang, L., Dixon, A. L., Strachan, D., Heath, S., Depner, M., von Berg, A., Bufe, A., Rietschel, E., Heinzmann, A., Simma, B., Frischer, T., Willis-Owen, S. A., Wong, K. C., Illig, T., Vogelberg, C., Weiland, S. K., von Mutius, E., Abecasis, G. R., Farrall, M., Gut, I. G., Lathrop, G. M., and Cookson, W. O. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. 2007. Nature 448:470-473.
  111. Moffatt, M. F., Schou, C., Faux, J. A., and Cookson, W. O. Germline TCR-A restriction of immunoglobulin E responses to allergen. 1997. Immunogenetics 46:226-230.
  112. Strachan, D. P. Hay fever, hygiene, and household size. 1989. BMJ 299:1259-1260.
  113. Lee, G. R., Spilianakis, C. G., and Flavell, R. A. Hypersensitive site 7 of the TH2 locus control region is essential for expressing TH2 cytokine genes and for long-range intrachromosomal interactions. 2005. Nat.Immunol 6:42-48.
  114. Melvin, A. J., McGurn, M. E., Bort, S. J., Gibson, C., and Lewis, D. B. Hypomethylation of the interferon-gamma gene correlates with its expression by primary T-lineage cells. 1995. Eur.J Immunol 25:426-430.
  115. Loots, G. G., Locksley, R. M., Blankespoor, C. M., Wang, Z. E., Miller, W., Rubin, E. M., and Frazer, K. A. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. 2000. Science 288:136-140.
  116. H., Fish, J. E., and Peters, S. P. Immunoglobulin E-mediated increase in vascular permeability correlates with eosinophilic inflammation. 1993. Am Rev Respir Dis. 147:677-683.
  117. Klinman, D. M. Immunotherapeutic uses of CpG oligodeoxynucleotides. 2004. Nat.Rev Immunol 4:249-258.
  118. Stenvinkel, P., Karimi, M. , Johansson, S., Axelsson, J., Suliman, M., Lindholm, B., Heimburger, O., Barany, P., Alvestrand, A., Nordfors, L., Qureshi, A. R., Ekstrom, T. J., and Schalling, M. Impact of inflammation on epigenetic DNA methylation -a novel risk factor for cardiovascular disease? 2007. J Intern.Med 261:488-499.
  119. von Mutius, E., Weiland, S. K., Fritzsch, C., Duhme, H., and Keil, U. Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany . 1998. Lancet 351 :862-866.
  120. Wahn, U., Lau, S., Bergmann, R., Kulig, M., Forster, J., Bergmann, K., Bauer, C. P., and Guggenmoos-Holzmann, I. Indoor allergen exposure is a risk factor for sensitization during the first three years of life. 1997. J Allergy Clin Immunol 99:763-769.
  121. Corry, D. B. and Kheradmand, F. Induction and regulation of the IgE response. 1999. Nature 402:B18-B23.
  122. Constant, S. L. and Bottomly, K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. 1997. Annu.Rev Immunol 15:297-322.
  123. Leff, A. R. Inflammatory mediation of airway hyperresponsiveness by peripheral blood granulocytes. The case for the eosinophil. 1994. Chest 106:1202-1208.
  124. Wills-Karp, M. Interleukin-13 in asthma pathogenesis. 2004. Immunol Rev 202:175-190.
  125. P. Interleukin-4 is required for the induction of lung Th2 mucosal immunity. 1995. Am J Respir Cell Mol Biol. 13:54-59.
  126. Wehbe, H., Henson, R., Meng, F., Mize-Berge, J., and Patel, T. Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. 2006. Cancer Res. 66:10517-10524
  127. Hodge, D. R., Xiao, W., Clausen, P. A., Heidecker, G., Szyf, M., and Farrar, W. L. Interleukin-6 regulation of the human DNA methyltransferase (HDNMT) gene in human erythroleukemia cells. 2001. J Biol.Chem 276:39508-39511.
  128. Hodge, D. R., Peng, B., Cherry, J. C., Hurt, E. M. , Fox, S. D., Kelley, J. A., Munroe, D. J., and Farrar, W. L. Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. 2005. Cancer Res. 65:4673-4682.
  129. Hackanson, B., Robbel, C., Wijermans, P., and Lubbert, M. In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies. 2005.
  130. Keine Beeinflussung von Tregs nach pränataler A. lwoffii F78-Exposition _________ 83
  131. Vignola, A. M., Merendino, A. M., Chiappara, G., Chanez, P., Pace, E., Siena, L., Profita, M., Bousquet, J., and Bonsignore, G. Markers of acute airway inflammation. 1997. Monaldi Arch Chest Dis. 52:83-85.
  132. Busse, W. W. and Rosenwasser, L. J. Mechanisms of asthma. 2003. J Allergy Clin Immunol 111:S799-S804.
  133. Jones, P. L., Veenstra, G. J., Wade, P. A., Vermaak, D., Kass, S. U., Landsberger, N., Strouboulis, J., and Wolffe, A. P. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. 1998. Nat.Genet 19:187-191.
  134. Thu, K. L., Pikor, L. A., Kennett, J. Y., Alvarez, C. E., and Lam, W. L. Methylation analysis by DNA immunoprecipitation. 2010. J Cell Physiol 222:522-531.
  135. Michael Lohoff für den Vorschlag zur Bestimmung der in vivo Proliferation.
  136. Gottardo, R. Modeling and analysis of ChIP-chip experiments. 2009. Methods Mol Biol. 567:133-143.
  137. Mucosal IFN-gamma gene transfer inhibits pulmonary allergic responses in mice. 1996. J Immunol 157:3216-3219.
  138. Rose, S., Lichtenheld, M., Foote, M. R., and Adkins, B. Murine neonatal CD4+ cells are poised for rapid Th2 effector-like function. 2007. J Immunol 178:2667-2678.
  139. Lack, G., Renz, H., Saloga, J., Bradley, K. L., Loader, J., Leung, D. Y., Larsen, G., and Gelfand, E. W. Nebulized but not parenteral IFN-gamma decreases IgE production and normalizes airways function in a murine model of allergen sensitization. 1994. J Immunol 152:2546-2554.
  140. Stirling, R. G. and Chung, K. F. New immunological approaches and cytokine targets in asthma and allergy. 2000. Eur.Respir J 16:1158-1174.
  141. Issa, J. P. Optimizing therapy with methylation inhibitors in myelodysplastic syndromes: dose, duration, and patient selection. 2005. Nat.Clin Pract.Oncol. 2 Suppl 1:S24-S29.
  142. Zhou, L., Chong, M. M., and Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. 2009. Immunity 30:646-655.
  143. Gold, D. R. and Wright, R. Population disparities in asthma. 2005. Annu.Rev Public Health 26:89-113.
  144. Kulig, M., Bergmann, R., Niggemann, B., Burow, G., and Wahn, U. Prediction of sensitization to inhalant allergens in childhood: evaluating family history, atopic dermatitis and sensitization to food allergens. The MAS Study Group. Multicentre Allergy Study. 1998. Clin Exp Allergy 28:1397-1403.
  145. Robinson, D. S., Hamid, Q. , Ying, S., Tsicopoulos, A., Barkans, J., Bentley, A. M., Corrigan, C., Durham, S. R., and Kay, A. B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. 1992. N.Engl.J Med 326:298-304.
  146. E., Greer, S., Orntoft, T. F., Thykjaer, T., and Jones, P. A. Preferential response of cancer cells to zebularine. 2004. Cancer Cell 6:151-158.
  147. Prevalence of asthma and atopy in two areas of West and East Germany. 1994. Am J Respir Crit Care Med 149:358-364.
  148. Prinzip: Chromatin-Immuno-Präzipitation (http://visiscience.com; modifiziert) _____ 54
  149. Prescott, S. L. and Bjorksten, B. Probiotics for the prevention or treatment of allergic diseases.
  150. Lee, G. R., Fields, P. E., and Flavell, R. A. Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. 2001. Immunity 14:447-459.
  151. McKenzie, A. N. Regulation of T helper type 2 cell immunity by interleukin-4 and interleukin-13. 2000. Pharmacol.Ther. 88:143-151.
  152. Nakajima, H. and Takatsu, K. Role of cytokines in allergic airway inflammation. 2007. Int Arch Allergy Immunol 142:265-273.
  153. Weisenberger, D. J., Velicescu, M., Cheng, J. C., Gonzales, F. A., Liang, G., and Jones, P. A. Role of the DNA methyltransferase variant DNMT3b3 in DNA methylation. 2004. Mol Cancer Res. 2:62-72.
  154. Lohoff, M. and Mak, T. W. Roles of interferon-regulatory factors in T-helper-cell differentiation. 2005. Nat.Rev Immunol 5:125-135.
  155. Martino, D. J. and Prescott, S. L. Silent mysteries: epigenetic paradigms could hold the key to conquering the epidemic of allergy and immune disease. 2010. Allergy 65:7-15.
  156. von Mutius, E., Martinez, F. D., Fritzsch, C., Nicolai, T., Reitmeir, P., and Thiemann, H. H. Skin test reactivity and number of siblings. 1994. BMJ 308:692-695.
  157. Ouyang, W., Lohning, M., Gao, Z., Assenmacher, M., Ranganath, S., Radbruch, A., and Murphy, K. M. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. 2000. Immunity 12:27-37.
  158. Weiterhin sei auch Dr. Susanne Weber und Prof. Dr. Uta-Maria Bauer gedankt, mit deren Hilfe und Unterstützung die Etablierung des ChIP-Assays möglich war, sowie Prof.
  159. Dow, S. W., Schwarze, J., Heath, T. D., Potter, T. A., and Gelfand, E. W. Systemic and local interferon gamma gene delivery to the lungs for treatment of allergen-induced airway hyperresponsiveness in mice. 1999. Hum Gene Ther. 10:1905-1914.
  160. Tab. 2.3 ChIP-Primer _________________________________________________________ 62
  161. Tab. 2.5 Pyrosequenzier-Primer _________________________________________________ 62
  162. Tab. 2.6 qPCR-Primer _________________________________________________________ 62
  163. Tabellen Tab. 1.1 Chromatinmodifikationen _______________________________________________ 23
  164. Li, E., Bestor, T. H., and Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. 1992. Cell 69:915-926.
  165. Lee, D. U., Agarwal, S., and Rao, A. Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. 2002. Immunity 16:649-660.
  166. Cookson, W. The alliance of genes and environment in asthma and allergy. 1999. Nature 402:B5- 11.
  167. Hershey, G. K., Friedrich, M. F., Esswein, L. A., Thomas, M. L., and Chatila, T. A. The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. 1997. N.Engl.J Med 337:1720-1725.
  168. Jarvis, D., Chinn, S., Luczynska, C., and Burney, P. The association of family size with atopy and atopic disease. 1997. Clin Exp Allergy 27:240-245.
  169. Burney, P. The changing prevalence of asthma? 2002. Thorax 57 Suppl 2:II36-II39.
  170. Galli, S. J., Tsai, M., and Piliponsky, A. M. The development of allergic inflammation. 2008. Nature 454:445-454.
  171. Feinberg, A. P., Ohlsson, R., and Henikoff, S. The epigenetic progenitor origin of human cancer. 2006. Nat.Rev Genet 7:21-33.
  172. Valenta, R. The future of antigen-specific immunotherapy of allergy. 2002. Nat.Rev Immunol 2:446-453.
  173. Cookson, W. The immunogenetics of asthma and eczema: a new focus on the epithelium. 2004. Nat.Rev Immunol 4:978-988.
  174. Devereux, G. The increase in the prevalence of asthma and allergy: food for thought. 2006. Nat.Rev Immunol 6:869-874.
  175. Margueron, R., Trojer, P., and Reinberg, D. The key to development: interpreting the histone code? 2005. Curr.Opin.Genet Dev. 15:163-176.
  176. Murphy, K. M. and Reiner, S. L. The lineage decisions of helper T cells. 2002. Nat.Rev Immunol 2:933-944.
  177. O'Garra, A. and Arai, N. The molecular basis of T helper 1 and T helper 2 cell differentiation. 2000. Trends Cell Biol. 10:542-550.
  178. Geha, R. S., Jabara, H. H. , and Brodeur, S. R. The regulation of immunoglobulin E class-switch recombination. 2003. Nat.Rev Immunol 3:721-732.
  179. Holt, P. G., Macaubas, C., Stumbles, P. A., and Sly, P. D. The role of allergy in the development of asthma. 1999. Nature 402:B12-B17.
  180. Romagnani, S. The role of lymphocytes in allergic disease. 2000. J Allergy Clin Immunol 105:399-408.
  181. Romagnani, S. The Th1/Th2 paradigm. 1997. Immunol Today 18:263-266.
  182. Mrabet-Dahbi, S., Dalpke, A.H., Niebuhr, M., Frey, M., Draing, C., Brand, S., Heeg, K., Werfel, T., Renz, H., The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis, J. Allergy Clin. Immunol. 121(4):1013-1019 (2007) 11. DANKSAGUNG [142]
  183. Wills-Karp, M. and Ewart, S. L. Time to draw breath: asthma-susceptibility genes are identified. 2004. Nat.Rev Genet 5:376-387.
  184. Rengarajan, J., Szabo, S. J., and Glimcher, L. H. Transcriptional regulation of Th1/Th2 polarization. 2000. Immunol Today 21:479-483.
  185. Cottrez, F., Hurst, S. D., Coffman, R. L., and Groux, H. T regulatory cells 1 inhibit a Th2-specific response in vivo. 2000. J Immunol 165:4848-4853.
  186. Choi, J. H., Oh, S. W., Kang, M. S., Kwon, H. J., Oh, G. T., and Kim, D. Y. Trichostatin A attenuates airway inflammation in mouse asthma model. 2005. Clin Exp Allergy 35:89-96.
  187. Fireman, P. Understanding asthma pathophysiology. 2003. Allergy Asthma Proc. 24:79-83.
  188. Karimi, M., Johansson, S., and Ekstrom, T. J. Using LUMA: a Luminometric-based assay for global DNA-methylation. 2006. Epigenetics. 1:45-48.
  189. Melanie Abram gedankt. Wenn es auch nicht für die Laborparty gereicht hat, so gab es doch wenigstens eine Torte mit 14 verschiedenen Geschmacksrichtungen. *g*
  190. Bauer, Bernd, Dalpke, Daut, Eilers, Elsässer, Feußer, Garn, Garten, Gudermann, Hasilik, Hassel, Huber, Jacob, Jungclas, Kirchner, Klenk, Knöller, Koolmann, Kunz, Lang, Lill, Löffler, Lohoff, Lorberth, Moll, Müller, Renkawitz-Pohl, Renz, Röhm, Schäfer, Schulz, Schwarz, Voigt, Weihe, Westermann 10. PUBLIKATIONEN [141] effects in offspring that are dependent on functional maternal toll-like receptors, Allergy 64 (Suppl. 90):88 (2009) – EAACI 2009 in Warschau Brand, S., Teich, R., Conrad, M.L., Pfefferle, P.I., Garn, H., Renz, H. Methylierung des IFNγ-Promotors als möglicher Mechanismus mikrobiell vermittelter Asthma- Protektion, Allergo J., 18(1) (2009) – Mainzer Allergie Workshop 2009
  191. Korthals, M., Ege, M. J., Tebbe, C. C., von Mutius, E., and Bauer, J. Application of PCR-SSCP for molecular epidemiological studies on the exposure of farm children to bacteria in environmental dust. 2008. J Microbiol.Methods 73:49-56.
  192. Conrad, M. L., Ferstl, R., Teich, R., Brand, S., Blumer, N., Yildirim, A. O., Patrascan, C. C., Hanuszkiewicz, A., Akira, S., Wagner, H., Holst, O., von Mutius, E., Pfefferle, P. I., Kirschning, C. J., Garn, H., and Renz, H. Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. 2009. J Exp Med 206:2869-2877.
  193. Mosmann, T. R. and Sad, S. The expanding universe of T-cell subsets: Th1, Th2 and more. 1996. Immunol Today 17:138-146.
  194. Ronmark, E., Lundback, B., Jonsson, E., Jonsson, A. C., Lindstrom, M., and Sandstrom, T. Incidence of asthma in adults--report from the Obstructive Lung Disease in Northern Sweden Study. 1997. Allergy 52:1071-1078.
  195. Marsh, D. G., Neely, J. D. , Breazeale, D. R., Ghosh, B., Freidhoff, L. R., Ehrlich-Kautzky, E., Schou, C., Krishnaswamy, G., and Beaty, T. H. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. 1994. Science 264:1152-1156.
  196. Altered early infant gut microbiota in children developing allergy up to 5 years of age. 2009. Clin Exp Allergy 39:518-526.
  197. Sepp, E., Naaber, P., Voor, T., Mikelsaar, M., and Bjorksten, B. Development of intestinal microflora during the first month of life in Estonian and Swedish infants. 2000. Micr Ecol Health Dis 12:22-26.
  198. D'Amato, G., Liccardi, G., and D'Amato, M. Environmental risk factors (outdoor air pollution and climatic changes) and increased trend of respiratory allergy. 2000. J Investig.Allergol.Clin Immunol 10:123-128.
  199. Strahl, B. D. and Allis, C. D. The language of covalent histone modifications. 2000. Nature 403:41-45.
  200. Schubeler, D., Lorincz, M. C., Cimbora, D. M., Telling, A., Feng, Y. Q., Bouhassira, E. E., and Groudine, M. Genomic targeting of methylated DNA: influence of methylation on transcription, replication, chromatin structure, and histone acetylation. 2000. Mol Cell Biol. 20:9103-9112.
  201. Kearley, J., Barker, J. E. , Robinson, D. S., and Lloyd, C. M. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. 2005. J Exp Med 202:1539-1547.
  202. Heinrich, J., Popescu, M. A., Wjst, M., Goldstein, I. F., and Wichmann, H. E. Atopy in children and parental social class. 1998. Am J Public Health 88:1319-1324.
  203. Kim, S. T., Fields, P. E., and Flavell, R. A. Demethylation of a specific hypersensitive site in the Th2 locus control region. 2007. Proc.Natl.Acad.Sci U.S.A 104:17052-17057.
  204. Iwamoto, I., Nakajima, H., Endo, H., and Yoshida, S. Interferon gamma regulates antigen- induced eosinophil recruitment into the mouse airways by inhibiting the infiltration of CD4+ T cells . 1993. J Exp Med 177:573-576.
  205. Locksley, R. M. Th2 cells: help for helminths. 1994. J Exp Med 179:1405-1407.
  206. Foster, P. S., Hogan, S. P., Ramsay, A. J., Matthaei, K. I., and Young, I. G. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. 1996. J Exp Med 183:195-201.
  207. Palii, S. S., Van Emburgh, B. O., Sankpal, U. T., Brown, K. D., and Robertson, K. D. DNA methylation inhibitor 5-Aza-2'-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. 2008. Mol Cell Biol. 28:752-771.
  208. Liu, J., Ballaney, M., Al alem, U., Quan, C., Jin, X., Perera, F., Chen, L. C., and Miller, R. L. Combined inhaled diesel exhaust particles and allergen exposure alter methylation of T helper genes and IgE production in vivo. 2008. Toxicol Sci 102:76-81.
  209. Li, C. R., Santoso, S., and Lo, D. D. Quantitative analysis of T cell homeostatic proliferation. 2007. Cell Immunol 250:40-54.
  210. Hahn, M. A., Hahn, T., Lee, D. H., Esworthy, R. S. , Kim, B. W., Riggs, A. D., Chu, F. F., and Pfeifer, G. P. Methylation of polycomb target genes in intestinal cancer is mediated by inflammation. 2008. Cancer Res. 68:10280-10289.
  211. Hollingsworth, J. W., Maruoka, S., Boon, K., Garantziotis, S., Li, Z., Tomfohr, J., Bailey, N., Potts, E. N., Whitehead, G., Brass, D. M., and Schwartz, D. A. In utero supplementation with methyl donors enhances allergic airway disease in mice. 2008. J Clin Invest 118:3462-3469.
  212. Perera, F., Tang, W. Y., Herbstman, J., Tang, D., Levin, L., Miller, R., and Ho, S. M. Relation of DNA methylation of 5'-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. 2009. PLoS.One. 4:e4488.
  213. Hewagama, A. and Richardson, B. The genetics and epigenetics of autoimmune diseases. 2009.
  214. Pene, J., Rousset, F., Briere, F., Chretien, I., Bonnefoy, J. Y., Spits, H., Yokota, T., Arai, N. , Arai, K., Banchereau, J.,. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. 1988. Proc.Natl.Acad.Sci U.S.A 85:6880-6884.
  215. Jirtle, R. L. and Skinner, M. K. Environmental epigenomics and disease susceptibility. 2007.
  216. Rountree, M. R. and Selker, E. U. DNA methylation inhibits elongation but not initiation of transcription in Neurospora crassa. 1997. Genes Dev. 11:2383-2395.
  217. Kearley, J., Robinson, D. S., and Lloyd, C. M. CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling. 2008. J Allergy Clin Immunol 122:617-624.
  218. Vaissiere, T., Sawan, C., and Herceg, Z. Epigenetic interplay between histone modifications and DNA methylation in gene silencing. 2008. Mutat.Res. 659:40-48.
  219. Michalowsky, L. A. and Jones, P. A. Differential nuclear protein binding to 5-azacytosine- containing DNA as a potential mechanism for 5-aza-2'-deoxycytidine resistance. 1987. Mol Cell Biol. 7:3076-3083.
  220. Juttermann, R., Li, E., and Jaenisch, R. Toxicity of 5-aza-2'-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. 1994. Proc.Natl.Acad.Sci U.S.A 91:11797-11801.
  221. Holgate, S. Mediator and cytokine mechanisms in asthma. 1993. Thorax 48:103-109.
  222. Debarry, J., Garn, H., Hanuszkiewicz, A., Dickgreber, N., Blumer, N., von Mutius, E., Bufe, A., Gatermann, S., Renz, H., Holst, O., and Heine, H. Acinetobacter lwoffii and Lactococcus lactis strains isolated from farm cowsheds possess strong allergy-protective properties. 2007. J Allergy Clin Immunol 119:1514-1521.
  223. Egger, G., Liang, G., Aparicio, A., and Jones, P. A. Epigenetics in human disease and prospects for epigenetic therapy. 2004. Nature 429:457-463.

* Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten
© UB Marburg 1997 - 2024 Universitätsbibliothek Marburg