Skip to main content

Progress in Understanding the Epigenetic Basis for Immune Development, Immune Function, and the Rising Incidence of Allergic Disease

Abstract

The profile of allergic disease worldwide continues to change as the number of severe IgE-mediated allergies increases. This phenomenon is thought to reflect the outcome of combined genetic/environmental/developmental/stochastic effects on immune development, but understanding this remains a challenge. Epigenetic disruption at key immune genes during development has been proposed as a potential explanation for how environmental exposures may alter immune cell development and function. This represents an emerging area of research with the potential to yield new understanding of how disease risk is modified. Here, we examine recent developments in this field that are defining new epigenetic paradigms of allergic disease.

This is a preview of subscription content, access via your institution.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Poulos LM, Waters A-M, Correll PK, Loblay RH, Marks GB. Trends in hospitalizations for anaphylaxis, angioedema, and urticaria in Australia, 1993–1994 to 2004–2005. Journal of allergy and clinical immunology. 2007;120:878–84.

    PubMed  Article  Google Scholar 

  2. Tang MLK, Osborne N, Allen K. Epidemiology of anaphylaxis. Curr Opin Allergy Clin Immunol. 2009;9:351–6.

    PubMed  Article  Google Scholar 

  3. Lin RY, Anderson AS, Shah SN, Nurruzzaman F. Increasing anaphylaxis hospitalizations in the first 2 decades of life: New York State, 1990–2006. Ann Allergy Asthma Immunol. 2008;101:387–93.

    PubMed  Article  Google Scholar 

  4. Lee JK, Vadas P. Anaphylaxis: mechanisms and management. Clin Exp Allergy. 2011;41:923–38.

    PubMed  Article  CAS  Google Scholar 

  5. Allen KJ, Koplin JJ. The epidemiology of IgE-mediated food allergy and anaphylaxis. Immunol Allergy Clin North Am. 2012;32:35–50.

    PubMed  Article  Google Scholar 

  6. Koplin JJ, Martin PE, Allen KJ. An update on epidemiology of anaphylaxis in children and adults. Curr Opin Allergy Clin Immunol. 2011;11:492–6.

    PubMed  Article  Google Scholar 

  7. Cianferoni A, Muraro A. Food-induced anaphylaxis. Immunol Allergy Clin North Am. 2012;32:165–95.

    PubMed  Article  Google Scholar 

  8. Prescott S, Allen KJ. Food allergy: Riding the second wave of the allergy epidemic. Pediatr Allergy Immunol. 2011;22:155–60.

    PubMed  Article  Google Scholar 

  9. Mullins RJ, Dear KBG, Tang MLK. Characteristics of childhood peanut allergy in the Australian Capital Territory, 1995 to 2007. J Allergy Clin Immunol. 2009;123:689–93.

    PubMed  Article  Google Scholar 

  10. Fazekas de St Groth B. Regulatory T-cell abnormalities and the global epidemic of immuno-inflammatory disease. Immunol Cell Biol. 2012;90:256–9.

    Article  CAS  Google Scholar 

  11. Kondilis-Mangum HD, Wade PA. Epigenetics and the adaptive immune response. Mol Aspects Med. 2012. doi:10.1016/j.mam.2012.06.008.

  12. Suarez-Alvarez B, Rodriguez RM, Fraga MF, López-Larrea C. DNA methylation: a promising landscape for immune system-related diseases. Trends Genet 2012, In press.

  13. Palm NW, Rosenstein RK, Medzhitov R. Allergic host defenses. Nature. 2012;484:465–72.

    PubMed  Article  CAS  Google Scholar 

  14. North ML. Ellis AK The role of epigenetics in the developmental origins of allergic disease. Ann Allergy Asthma Immunol. 2011;106:355–61.

    PubMed  Article  CAS  Google Scholar 

  15. Bell C, Finer S, Lindgren C, Wilson G. Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS ONE. 2010;5:1–12.

    Article  Google Scholar 

  16. Trowbridge JJ, Snow JW, Kim J, Orkin SH. DNA Methyltransferase 1 Is Essential for and Uniquely Regulates Hematopoietic Stem and Progenitor Cells. Cell Stem Cell. 2009;5:442–9.

    PubMed  Article  CAS  Google Scholar 

  17. Sen GL, Reuter JA, Webster DE, Zhu L, Khavari PA. DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature. 2010;463:563–7.

    PubMed  Article  CAS  Google Scholar 

  18. Broeske A-M, Vockentanz L, Kharazi S, et al. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet. 2009;41:1207–U69.

    Article  CAS  Google Scholar 

  19. White GP, Watt PM, Holt BJ, Holt PG. 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 CD45RO- T cells. J Immunol. 2002;168:2820–7.

    PubMed  CAS  Google Scholar 

  20. White GP, Hollams EM, Yerkovich ST, Bosco A, Holt BJ, Bassami MR, Kusel M, Sly PD, Holt PG. CpG methylation patterns in the IFN gamma; promoter in naive T cells: Variations during Th1 and Th2 differentiation and between atopics and non-atopics. Pediatr Allergy Immunol. 2006;17:557–64.

    PubMed  Article  Google Scholar 

  21. Porrás A, Kozar S, Russanova V, et al. Developmental and epigenetic regulation of the human TLR3 gene. Mol Immunol. 2008;46:27–36.

    PubMed  Article  Google Scholar 

  22. Goriely S, Van Lint C, Dadkhah R, Libin M, De Wit D, Demonte D, Willems F, Goldman M. A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells. J Exp Med. 2004;199:1011–6.

    PubMed  Article  CAS  Google Scholar 

  23. Kim SY, Romero R, Tarca AL, et al. Methylome of Fetal and Maternal Monocytes and Macrophages at the Feto-Maternal Interface. Am J Reprod Immunol. 2012. doi:10.1111/j.1600-0897.2012.01108.x.

  24. Susan L Prescott, Annett Osei-Kumah, Tara Richman, Megan Hodder, David Martino, Janet A Dunstan, Meri Tulic, Boris Novakovic, Safferry R, Clifton VL Differential placental FOXP3 and Th2 gene expression with sex-specific differences in infant allergy. 2011, 128: 886–7

  25. Slaats GGG, Reinius LE, Alm J, Kere J, Scheynius A, Joerink M. DNA methylation levels within the CD14 promoter region are lower in placentas of mothers living on a farm. Allergy. 2012;67:895–903.

    PubMed  Article  CAS  Google Scholar 

  26. Smith M, Tourigny MR, Noakes P, Thornton CA, Tulic MK, Prescott SL. Children with egg allergy have evidence of reduced neonatal CD4 + CD25 + CD127lo/- regulatory T cell function. Journal of allergy and clinical immunology. 2008;121:1460–6.

    PubMed  Article  CAS  Google Scholar 

  27. Prescott SL, Noakes P, Chow BWY, Breckler L, Thornton CA, Hollams EM, Ali M, van den Biggelaar AHJ, Tulic MK. Presymptomatic differences in Toll-like receptor function in infants who have allergy. J Allergy Clin Immunol. 2008;122:391–9. 399.e1–5.

    PubMed  Article  CAS  Google Scholar 

  28. • Hinz D, Bauer M, Roder S, et al. Cord blood Tregs with stable FOXP3 expression are influenced by prenatal environment and associated with atopic dermatitis at the age of one year. Allergy. 2012;67:380–9. Of importance: This study demonstrates the utility of DNA methylation marks as surrogate markers of Treg cell numbers. The authors use a unique methodology to report an association between prenatal exposures, variations in Treg DNA methylation and allergic outcomes in infancy.

    PubMed  Article  CAS  Google Scholar 

  29. Janson PCJ, Winerdal ME, Winqvist O. At the crossroads of T helper lineage commitment-Epigenetics points the way. Bba-Gen Subjects. 2009;1790:906–19.

    Article  CAS  Google Scholar 

  30. Wei G, Wei L, Zhu J, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009;30:155–67.

    PubMed  Article  Google Scholar 

  31. Upadhyaya B, Yin Y, Hill BJ, Douek DC, Prussin C. Hierarchical IL-5 expression defines a subpopulation of highly differentiated human Th2 cells. J Immunol. 2011;187:3111–20.

    PubMed  Article  CAS  Google Scholar 

  32. Cohen CJ, Crome SQ, Macdonald KG, Dai EL, Mager DL, Levings MK. Human Th1 and th17 cells exhibit epigenetic stability at signature cytokine and transcription factor Loci. J Immunol. 2011;187:5615–26.

    PubMed  Article  CAS  Google Scholar 

  33. Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, Evans JG, Cimaz R, Bajaj-Elliott M, Wedderburn LR. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A. 2010;107:14751–6.

    PubMed  Article  CAS  Google Scholar 

  34. • Swamy RS, Reshamwala N, Hunter T, Vissamsetti S, Santos CB, Baroody FM, Hwang PH, Hoyte EG, Garcia MA, Nadeau KC. Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy. J Allergy Clin Immunol. 2012;130:215–24. Of importance. This study demonstrates some clear epigenetic changes in key immune cell populations in response to allergen therapy. These epigenetic events are clearly associated with altered immune outcomes.

    PubMed  Article  CAS  Google Scholar 

  35. Brand S, Kesper DA, Teich R, Kilic-Niebergall E, Pinkenburg O, Bothur E, Lohoff M, Garn H, Pfefferle PI, Renz H. DNA methylation of T(H)1/T(H)2 cytokine genes affects sensitization and progress of experimental asthma. J Allergy Clin Immunol. 2012. doi:10.1016/j.jaci.2011.12.963.

  36. Allan RS, Zueva E, Cammas F, et al. An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature. 2012. doi:10.1038/nature11173.

  37. Niedzwiecki M, Zhu H, Corson L, Grunig G, Factor PH, Chu S, Jiang H, Miller RL. Prenatal exposure to allergen, DNA methylation, and allergy in grandoffspring mice. Allergy. 2012. doi:10.1111/j.1398-9995.2012.02841.x.

  38. Xue X, Feng T, Yao S, Wolf KJ, Liu C-G, Liu X, Elson CO, Cong Y. Microbiota Downregulates Dendritic Cell Expression of miR-10a, Which Targets IL-12/IL-23p40. J Immunol. 2011;187:5879–86.

    PubMed  Article  CAS  Google Scholar 

  39. Mullins RJ, Camargo CA. Latitude, sunlight, vitamin D, and childhood food allergy/anaphylaxis. Curr Allergy Asthma Rep. 2012;12:64–71.

    PubMed  Article  CAS  Google Scholar 

  40. Vassallo MF, Camargo CA. Potential mechanisms for the hypothesized link between sunshine, vitamin D, and food allergy in children. J Allergy Clin Immunol. 2010;126:217–22.

    PubMed  Article  CAS  Google Scholar 

  41. Keet CA, Matsui EC, Savage JH. Potential mechanisms for the association between fall birth and food allergy. Allergy. 2012;67:777–82.

    Article  Google Scholar 

  42. Haussler MR, Haussler CA, Bartik L, Whitfield GK, Hsieh J-C, Slater S, Jurutka PW. Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutr Rev. 2008;66:S98–112.

    PubMed  Article  Google Scholar 

  43. Gynther PP, Toropainen SS, Matilainen JMJ, Seuter SS, Carlberg CC, Väisänen SS. Mechanism of 1α,25-dihydroxyvitamin D(3)-dependent repression of interleukin-12B. ACTA-BIOENERG. 2011;1813:810–8.

    Article  CAS  Google Scholar 

  44. Mahon B, Wittke A, Weaver V, Cantorna M. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J Cell Biochem. 2003;89:922–32.

    PubMed  Article  CAS  Google Scholar 

  45. Bailey LB, Berry RJ. Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. Am J Clin Nutr. 2005;81:1213S–7.

    PubMed  CAS  Google Scholar 

  46. Matsui EC, Matsui W. Higher serum folate levels are associated with a lower risk of atopy and wheeze. J Allergy Clin Immunol. 2009;123:1253–9. e2.

    PubMed  Article  CAS  Google Scholar 

  47. Dunstan JA, West C, McCarthy S, Metcalfe J, Meldrum S, Oddy WH, Tulic MK, D'Vaz N, Prescott SL. The relationship between maternal folate status in pregnancy, cord blood folate levels, and allergic outcomes in early childhood. Allergy. 2011. doi:10.1111/j.1398-9995.2011.02714.x.

  48. Hollingsworth JW, Maruoka S, Boon K, et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest. 2008;118:3462–9.

    PubMed  CAS  Google Scholar 

  49. Steegers-Theunissen RP, Obermann-Borst SA, Kremer D, Lindemans J, Siebel C, Steegers EA, Slagboom PE, Heijmans BT. Periconceptional Maternal Folic Acid Use of 400 μg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child. PLoS ONE. 2009;4:e7845.

    PubMed  Article  Google Scholar 

  50. Ulrich CM, Toriola AT, Koepl LM, Sandifer T, Poole EM, Duggan C, McTiernan A, Issa J-PJ. Metabolic, hormonal and immunological associations with global DNA methylation among postmenopausal women. Epigenetics. 2012;7:1–9.

    Article  Google Scholar 

  51. Cooper WN, Khulan B, Owens S, et al. DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: results of a pilot randomized controlled trial. FASEB J. 2012;26:1782–90.

    PubMed  Article  CAS  Google Scholar 

  52. Boeke CE, Baccarelli A, Kleinman KP, Burris HH, Litonjua AA, Rifas-Shiman SL, Tarantini L, Gillman MW. Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood Prospective results from a folate-replete population. Epigenetics. 2012;7:253–60.

    PubMed  Article  CAS  Google Scholar 

  53. Zhang FF, Morabia A, Carroll J, Gonzalez K, Fulda K, Kaur M, Vishwanatha JK, Santella RM, Cardarelli R. Dietary patterns are associated with levels of global genomic DNA methylation in a cancer-free population. J Nutr. 2011;141:1165–71.

    PubMed  Article  CAS  Google Scholar 

  54. Perera F, Tang W-Y, Herbstman J, Tang D, Levin L, Miller R. Ho S-M Relation of DNA Methylation of 5'-CpG Island of ACSL3 to Transplacental Exposure to Airborne Polycyclic Aromatic Hydrocarbons and Childhood Asthma. PLoS ONE. 2009;4:e4488.

    PubMed  Article  Google Scholar 

  55. Liu J, Ballaney M, Al-alem U, Quan C, Jin X, Perera F, Chen L-C. Miller RL Combined Inhaled Diesel Exhaust Particles and Allergen Exposure Alter Methylation of T Helper Genes and IgE Production In Vivo. Toxicol Sci. 2008;102:76–81.

    PubMed  Article  CAS  Google Scholar 

  56. Nadeau K, McDonald-Hyman C, Noth EM, Pratt B, Hammond SK, Balmes J, Tager I. Ambient air pollution impairs regulatory T-cell function in asthma. J Allergy Clin Immunol. 2010;126:845–52. e10.

    PubMed  Article  CAS  Google Scholar 

  57. Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Adcock IM. Expression and activity of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med. 2002;166:392–6.

    PubMed  Article  Google Scholar 

  58. Cosio BG, Mann B, Ito K, Jazrawi E, Barnes PJ, Chung KF, Adcock IM. Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma. Am J Resp Crit Care. 2004;170:141–7.

    Article  Google Scholar 

  59. • Liang Y, Wang P, Zhao M, Liang G, Yin H, Zhang G, Wen H, Lu Q. Demethylation of the FCER1G promoter leads to FcεRI overexpression on monocytes of patients with atopic dermatitis. Allergy. 2012;67:424–30. Of importance. A key methylation event associated with the IgE pathway is described by the authors. They use a luciferase reporter assay to demonstrate the functional effects on gene expression.

    PubMed  Article  CAS  Google Scholar 

  60. Han J, Park S-G, Bae J-B, Choi J, Lyu J-M, Park SH, Kim HS, Kim Y-J, Kim S, Kim T-Y. The characteristics of genome-wide DNA methylation in naive CD4+ T cells of patients with psoriasis or atopic dermatitis. Biochem Bioph Res Co. 2012;422:157–63.

    Article  CAS  Google Scholar 

  61. Isidoro-Garcia M, Davila-Gonzalez I. Interactions between genes and the environment. Epigenetics in allergy. Allergol Immunopathol (Madr). 2007;35:254–8.

    Article  CAS  Google Scholar 

  62. Toperoff G, Aran D, Kark JD, et al. Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. Hum Mol Genet. 2012;21:371–83.

    PubMed  Article  CAS  Google Scholar 

Download references

Disclosure

Dr. Prescott has received grant support from the National Health and Medical Research Council and Ilhan Foundation and served on boards for Nestle, Danone, and ALK-Abello.

Dr. Martino reported no potential conflicts of interest relevant to this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David J. Martino.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Martino, D.J., Prescott, S.L. Progress in Understanding the Epigenetic Basis for Immune Development, Immune Function, and the Rising Incidence of Allergic Disease. Curr Allergy Asthma Rep 13, 85–92 (2013). https://doi.org/10.1007/s11882-012-0312-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-012-0312-1

Keywords

  • Epigenetics
  • Allergic disease
  • Anaphylaxis
  • Immune development
  • Sensitization
  • IgE
  • DNA methylation
  • Histone acetylation
  • Gene–environment interactions
  • Epigenetic regulation