Immunologic Research

, Volume 57, Issue 1–3, pp 246–257 | Cite as

Neonatal immunology: responses to pathogenic microorganisms and epigenetics reveal an “immunodiverse” developmental state

Immunology & Microbiology in Miami

Abstract

Neonatal animals have heightened susceptibility to infectious agents and are at increased risk for the development of allergic diseases, such as asthma. Experimental studies using animal models have been quite useful for beginning to identify the cellular and molecular mechanisms underlying these sensitivities. In particular, results from murine neonatal models indicate that developmental regulation of multiple immune cell types contributes to the typically poor responses of neonates to pathogenic microorganisms. Surprisingly, however, animal studies have also revealed that responses at mucosal surfaces in early life may be protective against primary or secondary disease. Our understanding of the molecular events underlying these processes is less well developed. Emerging evidence indicates that the functional properties of neonatal immune cells and the subsequent maturation of the immune system in ontogeny may be regulated by epigenetic phenomena. Here, we review recent findings from our group and others describing cellular responses to infection and developmentally regulated epigenetic processes in the newborn.

Keywords

Neonatal T helper cells Mucosal infection Epigenetics 

References

  1. 1.
    Rowe J, Macaubas C, Monger T, Holt BJ, Harvey J, Poolman JT, et al. Heterogeneity in diphtheria-tetanus-acellular pertussis vaccine-specific cellular immunity during infancy: relationship to variations in the kinetics of postnatal maturation of systemic th1 function. J Infect Dis. 2001;184(1):80–8. doi:10.1086/320996.PubMedCrossRefGoogle Scholar
  2. 2.
    Webster RB, Rodriguez Y, Klimecki WT, Vercelli D. The human IL-13 locus in neonatal CD4+ T cells is refractory to the acquisition of a repressive chromatin architecture. J Biol Chem. 2007;282(1):700–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Ribeiro-do-Couto LM, Boeije LC, Kroon JS, Hooibrink B, Breur-Vriesendorp BS, Aarden LA, et al. High IL-13 production by human neonatal T cells: neonate immune system regulator? Eur J Immunol. 2001;31(11):3394–402.PubMedCrossRefGoogle Scholar
  4. 4.
    Schaub B, Liu J, Schleich I, Hoppler S, Sattler C, von Mutius E. Impairment of T helper and T regulatory cell responses at birth. Allergy. 2008;63(11):1438–47.PubMedCrossRefGoogle Scholar
  5. 5.
    Prescott SL, Macaubas C, Holt BJ, Smallacombe TB, Loh R, Sly PD, et al. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol. 1998;160(10):4730–7.PubMedGoogle Scholar
  6. 6.
    Gans H, Yasukawa L, Rinki M, DeHovitz R, Forghani B, Beeler J, et al. Immune responses to measles and mumps vaccination of infants at 6, 9, and 12 months. J Infect Dis. 2001;184(7):817–26.PubMedCrossRefGoogle Scholar
  7. 7.
    Gans HA, Maldonado Y, Yasukawa LL, Beeler J, Audet S, Rinki MM, et al. IL-12, IFN-gamma, and T cell proliferation to measles in immunized infants. J Immunol. 1999;162(9):5569–75.PubMedGoogle Scholar
  8. 8.
    Gans HA, Arvin AM, Galinus J, Logan L, DeHovitz R, Maldonado Y. Deficiency of the humoral immune response to measles vaccine in infants immunized at age 6 months. JAMA. 1998;280(6):527–32. doi:10.1001/jama.280.6.527.PubMedCrossRefGoogle Scholar
  9. 9.
    Gans H, DeHovitz R, Forghani B, Beeler J, Maldonado Y, Arvin AM. Measles and mumps vaccination as a model to investigate the developing immune system: passive and active immunity during the first year of life. Vaccine. 2003;21(24):3398–405. doi:10.1016/S0264-410X(03)00341-4.PubMedCrossRefGoogle Scholar
  10. 10.
    White OJ, Rowe J, Richmond P, Marshall H, McIntyre P, Wood N, et al. Th2-polarisation of cellular immune memory to neonatal pertussis vaccination. Vaccine. 2010;28(14):2648–52. doi:10.1016/j.vaccine.2010.01.010.PubMedCrossRefGoogle Scholar
  11. 11.
    Mascart F, Hainaut M, Peltier A, Verscheure V, Levy J, Locht C. Modulation of the infant immune responses by the first pertussis vaccine administrations. Vaccine. 2007;25(2):391–8. doi:10.1016/j.vaccine.2006.06.046.PubMedCrossRefGoogle Scholar
  12. 12.
    Renz H, Brandtzaeg P, Hornef M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat Rev Immunol. 2011;12(1):9–23. doi:10.1038/nri3112.PubMedCrossRefGoogle Scholar
  13. 13.
    Cuenca AG, Wynn JL, Moldawer LL, Levy O. Role of innate immunity in neonatal infection. Am J Perinatol. 2013;30(2):105–12. doi:10.1055/s-0032-1333412.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Guilmot A, Hermann E, Braud VM, Carlier Y, Truyens C. Natural killer cell responses to infections in early life. J Innate Immun. 2011;3(3):280–8. doi:10.1159/000323934.PubMedCrossRefGoogle Scholar
  15. 15.
    Ygberg S, Nilsson A. The developing immune system—from foetus to toddler. Acta Paediatr. 2011;101(2):120–7. doi:10.1111/j.1651-2227.2011.02494.x.PubMedCrossRefGoogle Scholar
  16. 16.
    Siegrist CA, Aspinall R. B-cell responses to vaccination at the extremes of age. Nat Rev Immunol. 2009;9(3):185–94. doi:10.1038/nri2508.PubMedCrossRefGoogle Scholar
  17. 17.
    Willems F, Vollstedt S, Suter M. Phenotype and function of neonatal DC. Eur J Immunol. 2009;39(1):26–35.PubMedCrossRefGoogle Scholar
  18. 18.
    Mold JE, McCune JM. Immunological tolerance during fetal development: from mouse to man. Adv Immunol. 2012;115:73–111. doi:10.1016/B978-0-12-394299-9.00003-5.PubMedCrossRefGoogle Scholar
  19. 19.
    Kollmann TR, Levy O, Montgomery RR, Goriely S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity. 2012;37(5):771–83. doi:10.1016/j.immuni.2012.10.014.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Vekemans J, Amedei A, Ota MO, D’Elios MM, Goetghebuer T, Ismaili J, et al. Neonatal bacillus Calmette-Guerin vaccination induces adult-like IFN-gamma production by CD4+ T lymphocytes. Eur J Immunol. 2001;31(5):1531–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Ryan M, Murphy G, Ryan E, Nilsson L, Shackley F, Gothefors L, et al. Distinct T-cell subtypes induced with whole cell and acellular pertussis vaccines in children. Immunology. 1998;93(1):1–10.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Ausiello CM, Urbani F, la Sala A, Lande R, Cassone A. Vaccine- and antigen-dependent type 1 and type 2 cytokine induction after primary vaccination of infants with whole-cell or acellular pertussis. Infect Immun. 1997;65:2168–74.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Black A, Bhaumik S, Kirkman RL, Weaver CT, Randolph DA. Developmental regulation of Th17-cell capacity in human neonates. Eur J Immunol. 2012;42(2):311–9. doi:10.1002/eji.201141847.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Cosmi L, De Palma R, Santarlasci V, Maggi L, Capone M, Frosali F, et al. Human interleukin 17-producing cells originate from a CD161+ CD4+ T cell precursor. J Exp Med. 2008;205(8):1903–16. doi:10.1084/jem.20080397.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Echeverry A, Schesser K, Adkins B. Murine neonates are highly resistant to Yersinia enterocolitica following orogastric exposure. Infect Immun. 2007;75(5):2234–43.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Echeverry A, Saijo S, Schesser K, Adkins B. Yersinia enterocolitica promotes robust mucosal inflammatory T-cell immunity in murine neonates. Infect Immun. 2010;78(8):3595–608.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Glode MP, Sutton A, Moxon ER, Robbins JB. Pathogenesis of neonatal Escherichia coli meningitis: induction of bacteremia and meningitis in infant rats fed E. coli K1. Infect Immun. 1977;16(1):75–80.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Pluschke G, Mercer A, Kusecek B, Pohl A, Achtman M. Induction of bacteremia in newborn rats by Escherichia coli K1 is correlated with only certain O (lipopolysaccharide) antigen types. Infect Immun. 1983;39(2):599–608.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Mushtaq N, Redpath MB, Luzio JP, Taylor PW. Prevention and cure of systemic Escherichia coli K1 infection by modification of the bacterial phenotype. Antimicrob Agents Chemother. 2004;48(5):1503–8.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Mushtaq N, Redpath MB, Luzio JP, Taylor PW. Treatment of experimental Escherichia coli infection with recombinant bacteriophage-derived capsule depolymerase. J antimicrob chemother. 2005;56(1):160–5. doi:10.1093/jac/dki177.PubMedCrossRefGoogle Scholar
  31. 31.
    Martindale J, Stroud D, Moxon ER, Tang CM. Genetic analysis of Escherichia coli K1 gastrointestinal colonization. Mol Microbiol. 2000;37(6):1293–305.PubMedCrossRefGoogle Scholar
  32. 32.
    Zelmer A, Bowen M, Jokilammi A, Finne J, Luzio JP, Taylor PW. Differential expression of the polysialyl capsule during blood-to-brain transit of neuropathogenic Escherichia coli K1. Microbiology. 2008;154(Pt 8):2522–32. doi:10.1099/mic.0.2008/017988-0.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Zelmer A, Martin MJ, Gundogdu O, Birchenough G, Lever R, Wren BW, et al. Administration of capsule-selective endosialidase E minimizes upregulation of organ gene expression induced by experimental systemic infection with Escherichia coli K1. Microbiology. 2010;156(Pt 7):2205–15. doi:10.1099/mic.0.036145-0.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Birchenough GM, Johansson ME, Stabler RA, Dalgakiran F, Hansson GC, Wren BW, et al. Altered innate defenses in the neonatal gastrointestinal tract in response to colonization by neuropathogenic Escherichia coli. Infect Immun. 2013;81(9):3264–75. doi:10.1128/IAI.00268-13.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Fernandez MI, Thuizat A, Pedron T, Neutra M, Phalipon A, Sansonetti PJ. A newborn mouse model for the study of intestinal pathogenesis of shigellosis. Cell Microbiol. 2003;5(7):481–91.PubMedCrossRefGoogle Scholar
  36. 36.
    Fernandez MI, Regnault B, Mulet C, Tanguy M, Jay P, Sansonetti PJ, et al. Maturation of paneth cells induces the refractory state of newborn mice to Shigella infection. J Immunol. 2008;180(7):4924–30.PubMedCrossRefGoogle Scholar
  37. 37.
    Shim DH, Ryu S, Kweon MN. Defensins play a crucial role in protecting mice against oral Shigella flexneri infection. Biochem Biophys Res Commun. 2010;401(4):554–60. doi:10.1016/j.bbrc.2010.09.100.PubMedCrossRefGoogle Scholar
  38. 38.
    Bry L, Falk P, Huttner K, Ouellette A, Midtvedt T, Gordon JI. Paneth cell differentiation in the developing intestine of normal and transgenic mice. Proc Natl Acad Sci USA. 1994;91(22):10335–9.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Ganz T, Sherman MP, Selsted ME, Lehrer RI. Newborn rabbit alveolar macrophages are deficient in two microbicidal cationic peptides, MCP-1 and MCP-2. Am Rev Respir Dis. 1985;132(4):901–4.PubMedGoogle Scholar
  40. 40.
    Ouellette AJ, Greco RM, James M, Frederick D, Naftilan J, Fallon JT. Developmental regulation of cryptdin, a corticostatin/defensin precursor mRNA in mouse small intestinal crypt epithelium. J Cell Biol. 1989;108(5):1687–95.PubMedCrossRefGoogle Scholar
  41. 41.
    Huttner KM, Brezinski-Caliguri DJ, Mahoney MM, Diamond G. Antimicrobial peptide expression is developmentally regulated in the ovine gastrointestinal tract. J Nutr. 1998;128(2 Suppl):297S–9S.PubMedGoogle Scholar
  42. 42.
    Mallow EB, Harris A, Salzman N, Russell JP, DeBerardinis RJ, Ruchelli E, et al. Human enteric defensins. Gene structure and developmental expression. J Biol Chem. 1996;271(8):4038–45.PubMedCrossRefGoogle Scholar
  43. 43.
    Starner TD, Agerberth B, Gudmundsson GH, McCray PB Jr. Expression and activity of beta-defensins and LL-37 in the developing human lung. J Immunol. 2005;174(3):1608–15.PubMedCrossRefGoogle Scholar
  44. 44.
    Burger-van Paassen N, Loonen LM, Witte-Bouma J, Korteland-van Male AM, de Bruijn AC, van der Sluis M, et al. Mucin Muc2 deficiency and weaning influences the expression of the innate defense genes Reg3beta, Reg3gamma and angiogenin-4. PLoS ONE. 2012;7(6):e38798. doi:10.1371/journal.pone.0038798.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Cash HL, Whitham CV, Behrendt CL, Hooper LV. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science. 2006;313(5790):1126–30. doi:10.1126/science.1127119.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Levast B, Schulz S, Hurk S, Gerdts V. Animal models for neonatal diseases in humans. Vaccine. 2013;31(21):2489–99. doi:10.1016/j.vaccine.2012.11.089.PubMedCrossRefGoogle Scholar
  47. 47.
    Pott J, Stockinger S, Torow N, Smoczek A, Lindner C, McInerney G, et al. Age-dependent TLR3 expression of the intestinal epithelium contributes to rotavirus susceptibility. PLoS Pathog. 2012;8(5):e1002670. doi:10.1371/journal.ppat.1002670.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Lopez-Guerrero DV, Meza-Perez S, Ramirez-Pliego O, Santana-Calderon MA, Espino-Solis P, Gutierrez-Xicotencatl L, et al. Rotavirus infection activates dendritic cells from Peyer’s patches in adult mice. J Virol. 2010;84(4):1856–66. doi:10.1128/JVI.02640-08.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Weitkamp JH, Kallewaard N, Kusuhara K, Bures E, Williams JV, LaFleur B, et al. Infant and adult human B cell responses to rotavirus share common immunodominant variable gene repertoires. J Immunol. 2003;171(9):4680–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Blutt SE, Warfield KL, Lewis DE, Conner ME. Early response to rotavirus infection involves massive B cell activation. J Immunol. 2002;168(11):5716–21.PubMedCrossRefGoogle Scholar
  51. 51.
    Rollo EE, Kumar KP, Reich NC, Cohen J, Angel J, Greenberg HB, et al. The epithelial cell response to rotavirus infection. J Immunol. 1999;163(8):4442–52.PubMedGoogle Scholar
  52. 52.
    Ramig RF. The effects of host age, virus dose, and virus strain on heterologous rotavirus infection of suckling mice. Microb Pathog. 1988;4(3):189–202. doi:10.1016/0882-4010(88)90069-1.PubMedCrossRefGoogle Scholar
  53. 53.
    VanCott JL, Prada AE, McNeal MM, Stone SC, Basu M, Huffer B Jr, et al. Mice develop effective but delayed protective immune responses when immunized as neonates either intranasally with nonliving VP6/LT(R192G) or orally with live rhesus rotavirus vaccine candidates. J Virol. 2006;80(10):4949–61.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Arnold IC, Dehzad N, Reuter S, Martin H, Becher B, Taube C, et al. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J Clin Invest. 2011;121(8):3088–93. doi:10.1172/JCI45041.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Arnold IC, Lee JY, Amieva MR, Roers A, Flavell RA, Sparwasser T, et al. Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia. Gastroenterology. 2011;140(1):199–209. doi:10.1053/j.gastro.2010.06.047.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Oertli M, Sundquist M, Hitzler I, Engler DB, Arnold IC, Reuter S, et al. DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. J Clin Invest. 2012;122(3):1082–96. doi:10.1172/JCI61029.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Burns-Guydish SM, Olomu IN, Zhao H, Wong RJ, Stevenson DK, Contag CH. Monitoring age-related susceptibility of young mice to oral Salmonella enterica serovar Typhimurium infection using an in vivo murine model. Pediatr Res. 2005;58(1):153–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Rhee SJ, Walker WA, Cherayil BJ. Developmentally regulated intestinal expression of IFN-gamma and its target genes and the age-specific response to enteric Salmonella infection. J Immunol. 2005;175(2):1127–36.PubMedCrossRefGoogle Scholar
  59. 59.
    Garvy BA, Qureshi MH. Delayed inflammatory response to Pneumocystis carinii infection in neonatal mice is due to an inadequate lung environment. J Immunol. 2000;165(11):6480–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Empey KM, Hollifield M, Garvy BA. Exogenous heat-killed Escherichia coli improves alveolar macrophage activity and reduces Pneumocystis carinii lung burden in infant mice. Infect Immun. 2007;75(7):3382–93. doi:10.1128/IAI.00174-07.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Garvy BA, Harmsen AG. Susceptibility to Pneumocystis carinii infection: host responses of neonatal mice from immune or naive mothers and of immune or naive adults. Infect Immun. 1996;64(10):3987–92.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Qureshi MH, Garvy BA. Neonatal T cells in an adult lung environment are competent to resolve Pneumocystis carinii pneumonia. J Immunol. 2001;166(9):5704–11.PubMedCrossRefGoogle Scholar
  63. 63.
    Qureshi MH, Cook-Mills J, Doherty DE, Garvy BA. TNF-alpha-dependent ICAM-1- and VCAM-1-mediated inflammatory responses are delayed in neonatal mice infected with Pneumocystis carinii. J Immunol. 2003;171(9):4700–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Qureshi MH, Empey KM, Garvy BA. Modulation of proinflammatory responses to Pneumocystis carinii f. sp. muris in neonatal mice by granulocyte-macrophage colony-stimulating factor and IL-4: role of APCs. J Immunol. 2005;174(1):441–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Kurkjian C, Hollifield M, Lines JL, Rogosky A, Empey KM, Qureshi M, et al. Alveolar macrophages in neonatal mice are inherently unresponsive to Pneumocystis murina infection. Infect Immun. 2012;80(8):2835–46. doi:10.1128/IAI.05707-11.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Lines JL, Hoskins S, Hollifield M, Cauley LS, Garvy BA. The migration of T cells in response to influenza virus is altered in neonatal mice. J Immunol. 2010;185(5):2980–8. doi:10.4049/jimmunol.0903075.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Tregoning JS, Yamaguchi Y, Harker J, Wang B, Openshaw PJ. The role of T cells in the enhancement of respiratory syncytial virus infection severity during adult reinfection of neonatally sensitized mice. J Virol. 2008;82(8):4115–24. doi:10.1128/JVI.02313-07.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Bhattacharya S, Beal BT, Janowski AM, Shornick LP. Reduced inflammation and altered innate response in neonates during paramyxoviral infection. Virol J. 2011;8:549. doi:10.1186/1743-422X-8-549.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Bonville CA, Ptaschinski C, Percopo CM, Rosenberg HF, Domachowske JB. Inflammatory responses to acute pneumovirus infection in neonatal mice. Virol J. 2010;7:320. doi:10.1186/1743-422X-7-320.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Dakhama A, Park JW, Taube C, Joetham A, Balhorn A, Miyahara N, et al. The enhancement or prevention of airway hyper responsiveness during reinfection with respiratory syncytial virus is critically dependent on the age at first infection and IL-13 production. J Immunol. 2005;175(3):1876–83.PubMedCrossRefGoogle Scholar
  71. 71.
    Culley FJ, Pollott J, Openshaw PJ. Age at first viral infection determines the pattern of T cell-mediated disease during reinfection in adulthood. J Exp Med. 2002;196(10):1381–6.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Empey KM, Orend JG, Peebles RS Jr, Egana L, Norris KA, Oury TD, et al. Stimulation of immature lung macrophages with intranasal interferon gamma in a novel neonatal mouse model of respiratory syncytial virus infection. PLoS ONE. 2012;7(7):e40499. doi:10.1371/journal.pone.0040499.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Tasker L, Lindsay RW, Clarke BT, Cochrane DW, Hou S. Infection of mice with respiratory syncytial virus during neonatal life primes for enhanced antibody and T cell responses on secondary challenge. Clin Exp Immunol. 2008;153(2):277–88. doi:10.1111/j.1365-2249.2008.03591.x.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Han J, Dakhama A, Jia Y, Wang M, Zeng W, Takeda K et al. Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand. J Allergy Clin Immunol. 2012;130(5):1175-86 e9. doi:10.1016/j.jaci.2012.08.033.Google Scholar
  75. 75.
    Lee YM, Miyahara N, Takeda K, Prpich J, Oh A, Balhorn A, et al. IFN-gamma production during initial infection determines the outcome of reinfection with respiratory syncytial virus. Am J Respir Crit Care Med. 2008;177(2):208–18. doi:10.1164/rccm.200612-1890OC.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Ripple MJ, You D, Honnegowda S, Giaimo JD, Sewell AB, Becnel DM, et al. Immunomodulation with IL-4R alpha antisense oligonucleotide prevents respiratory syncytial virus-mediated pulmonary disease. J Immunol. 2010;185(8):4804–11. doi:10.4049/jimmunol.1000484.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    You D, Marr N, Saravia J, Shrestha B, Lee GI, Turvey SE, et al. IL-4Ralpha on CD4+ T cells plays a pathogenic role in respiratory syncytial virus reinfection in mice infected initially as neonates. J Leukoc Biol. 2013;93(6):933–42. doi:10.1189/jlb.1012498.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Horvat JC, Beagley KW, Wade MA, Preston JA, Hansbro NG, Hickey DK, et al. Neonatal chlamydial infection induces mixed T-cell responses that drive allergic airway disease. Am J Respir Crit Care Med. 2007;176(6):556–64.PubMedCrossRefGoogle Scholar
  79. 79.
    Jupelli M, Selby DM, Guentzel MN, Chambers JP, Forsthuber TG, Zhong G, et al. The contribution of interleukin-12/interferon-gamma axis in protection against neonatal pulmonary Chlamydia muridarum challenge. J Interferon Cytokine Res. 2010;30(6):407–15. doi:10.1089/jir 2009.0083.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Jupelli M, Guentzel MN, Meier PA, Zhong G, Murthy AK, Arulanandam BP. Endogenous IFN-gamma production is induced and required for protective immunity against pulmonary chlamydial infection in neonatal mice. J Immunol. 2008;180(6):4148–55.PubMedCrossRefGoogle Scholar
  81. 81.
    Beckett EL, Phipps S, Starkey MR, Horvat JC, Beagley KW, Foster PS, et al. TLR2, but not TLR4, is required for effective host defence against Chlamydia respiratory tract infection in early life. PLoS ONE. 2012;7(6):e39460. doi:10.1371/journal.pone.0039460.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Jupelli M, Murthy AK, Chaganty BK, Guentzel MN, Selby DM, Vasquez MM, et al. Neonatal chlamydial pneumonia induces altered respiratory structure and function lasting into adult life. Lab Invest. 2011;91(10):1530–9. doi:10.1038/labinvest.2011.103.PubMedCrossRefGoogle Scholar
  83. 83.
    Horvat JC, Starkey MR, Kim RY, Phipps S, Gibson PG, Beagley KW et al. Early-life chlamydial lung infection enhances allergic airways disease through age-dependent differences in immunopathology. J Allergy Clin Immunol. 2010;125(3):617–25, 25 e1–25 e6.Google Scholar
  84. 84.
    Principi N, Esposito S, Blasi F, Allegra L. Role of Mycoplasma pneumoniae and Chlamydia pneumoniae in children with community-acquired lower respiratory tract infections. Clin Infect Dis. 2001;32(9):1281–9. doi:10.1086/319981.PubMedCrossRefGoogle Scholar
  85. 85.
    Hansbro PM, Beagley KW, Horvat JC, Gibson PG. Role of atypical bacterial infection of the lung in predisposition/protection of asthma. Pharmacol Ther. 2004;101(3):193–210. doi:10.1016/j.pharmthera.2003.10.007.PubMedCrossRefGoogle Scholar
  86. 86.
    Webley WC, Salva PS, Andrzejewski C, Cirino F, West CA, Tilahun Y, et al. The bronchial lavage of pediatric patients with asthma contains infectious Chlamydia. Am J Respir Crit Care Med. 2005;171(10):1083–8. doi:10.1164/rccm.200407-917OC.PubMedCrossRefGoogle Scholar
  87. 87.
    Webley WC, Tilahun Y, Lay K, Patel K, Stuart ES, Andrzejewski C, et al. Occurrence of Chlamydia trachomatis and Chlamydia pneumoniae in paediatric respiratory infections. Eur Respir J. 2009;33(2):360–7. doi:10.1183/09031936.00019508.PubMedCrossRefGoogle Scholar
  88. 88.
    Procario MC, Levine RE, McCarthy MK, Kim E, Zhu L, Chang CH, et al. Susceptibility to acute mouse adenovirus type 1 respiratory infection and establishment of protective immunity in neonatal mice. J Virol. 2012;86(8):4194–203. doi:10.1128/JVI.06967-11.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2011;13(2):97–109. doi:10.1038/nrg3142.Google Scholar
  90. 90.
    Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23(7):781–3. doi:10.1101/gad.1787609.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693–705. doi:10.1016/j.cell.2007.02.005.PubMedCrossRefGoogle Scholar
  92. 92.
    Margueron R, Reinberg D. Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet. 2010;11(4):285–96. doi:10.1038/nrg2752.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Rose S, Lichtenheld M, Foote M, Adkins B. Murine neonatal CD4+ cells are poised for rapid Th2 effector-like function. J Immunol. 2007;178(5):2667–78.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Yoshimoto M, Yoder MC, Guevara P, Adkins B. The murine Th2 locus undergoes epigenetic modification in the thymus during fetal and postnatal ontogeny. PLoS ONE. 2013;8(1):e51587. doi:10.1371/journal.pone.0051587.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Schoenborn JR, Dorschner MO, Sekimata M, Santer DM, Shnyreva M, Fitzpatrick DR, et al. Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma. Nat Immunol. 2007;8(7):732–42.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Martino D, Maksimovic J, Joo JH, Prescott SL, Saffery R. Genome-scale profiling reveals a subset of genes regulated by DNA methylation that program somatic T-cell phenotypes in humans. Genes Immun. 2012;. doi:10.1038/gene.2012.7.PubMedGoogle Scholar
  97. 97.
    Martino DJ, Tulic MK, Gordon L, Hodder M, Richman TR, Metcalfe J, et al. Evidence for age-related and individual-specific changes in DNA methylation profile of mononuclear cells during early immune development in humans. Epigenetics. 2011;6(9):1085–94. doi:10.4161/epi.6.9.16401.PubMedCrossRefGoogle Scholar
  98. 98.
    White GP, Hollams EM, Yerkovich ST, Bosco A, Holt BJ, Bassami MR, et al. 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(8):557–64. doi:10.1111/j.1399-3038.2006.00465.x.PubMedCrossRefGoogle Scholar
  99. 99.
    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(6):2820–7.PubMedCrossRefGoogle Scholar
  100. 100.
    Kaminuma O, Kitamura F, Miyatake S, Yamaoka K, Miyoshi H, Inokuma S et al. T-box 21 transcription factor is responsible for distorted T(H)2 differentiation in human peripheral CD4+ T cells. J Allergy Clin Immunol. 2009;123(4):813-23 e3. doi:10.1016/j.jaci.2009.01.055.
  101. 101.
    Jacoby M, Gohrbandt S, Clausse V, Brons NH, Muller CP. Interindividual variability and co-regulation of DNA methylation differ among blood cell populations. Epigenetics. 2012;7(12):1421–34. doi:10.4161/epi.22845.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Luo C, Burgeon E, Carew JA, McCaffrey PG, Badalian TM, Lane WS, et al. Recombinant NFAT1 (NFATp) is regulated by calcineurin in T cells and mediates transcription of several cytokine genes. Mol Cell Biol. 1996;16(7):3955–66.PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Kiani A, Garcia-Cozar FJ, Habermann I, Laforsch S, Aebischer T, Ehninger G, et al. Regulation of interferon-gamma gene expression by nuclear factor of activated T cells. Blood. 2001;98(5):1480–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Chow CW, Rincon M, Davis RJ. Requirement for transcription factor NFAT in interleukin-2 expression. Mol Cell Biol. 1999;19(3):2300–7.PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Kadereit S, Mohammad SF, Miller RE, Woods KD, Listrom CD, McKinnon K, et al. Reduced NFAT1 protein expression in human umbilical cord blood T lymphocytes. Blood. 1999;94(9):3101–7.PubMedGoogle Scholar
  106. 106.
    Weitzel RP, Lesniewski ML, Haviernik P, Kadereit S, Leahy P, Greco NJ, et al. microRNA 184 regulates expression of NFAT1 in umbilical cord blood CD4+ T cells. Blood. 2009;113(26):6648–57. doi:10.1182/blood-2008-09-181156.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Lederhuber H, Baer K, Altiok I, Sadeghi K, Herkner KR, Kasper DC. MicroRNA-146: tiny player in neonatal innate immunity? Neonatology. 2011;99(1):51–6. doi:10.1159/000301938.PubMedCrossRefGoogle Scholar
  108. 108.
    Nahid MA, Pauley KM, Satoh M, Chan EK. miR-146a is critical for endotoxin-induced tolerance: implication in innate immunity. J Biol Chem. 2009;284(50):34590–9. doi:10.1074/jbc.M109.056317.PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Nahid MA, Satoh M, Chan EK. Mechanistic role of microRNA-146a in endotoxin-induced differential cross-regulation of TLR signaling. J Immunol. 2011;186(3):1723–34. doi:10.4049/jimmunol.1002311.PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Chassin C, Kocur M, Pott J, Duerr CU, Gutle D, Lotz M, et al. miR-146a mediates protective innate immune tolerance in the neonate intestine. Cell Host Microbe. 2010;8(4):358–68. doi:10.1016/j.chom.2010.09.005.PubMedCrossRefGoogle Scholar
  111. 111.
    Huang HC, Yu HR, Huang LT, Chen RF, Lin IC, Ou CY, et al. miRNA-125b regulates TNF-alpha production in CD14+ neonatal monocytes via post-transcriptional regulation. J Leukoc Biol. 2012;92(1):171–82. doi:10.1189/jlb.1211593.PubMedCrossRefGoogle Scholar
  112. 112.
    Palin AC, Ramachandran V, Acharya S, Lewis DB. Human neonatal naive CD4+ T cells have enhanced activation-dependent signaling regulated by the MicroRNA miR-181a. J Immunol. 2013;190(6):2682–91. doi:10.4049/jimmunol.1202534.PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Goriely S, Van Lint C, Dadkhah R, Libin M, De Wit D, Demonte D et al. A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells. J Exp Med. 2004;199(7):1011–6. doi:10.1084/jem.20031272.Google Scholar
  114. 114.
    Porras A, Kozar S, Russanova V, Salpea P, Hirai T, Sammons N, et al. Developmental and epigenetic regulation of the human TLR3 gene. Mol Immunol. 2008;46(1):27–36. doi:10.1016/j.molimm.2008.06.030.PubMedCrossRefGoogle Scholar
  115. 115.
    Yancopoulos GD, Desiderio SV, Paskind M, Kearney JF, Baltimore D, Alt FW. Preferential utilization of the most JH-proximal VH gene segments in pre-B-cell lines. Nature. 1984;311(5988):727–33.PubMedCrossRefGoogle Scholar
  116. 116.
    Perlmutter RM, Kearney JF, Chang SP, Hood LE. Developmentally controlled expression of immunoglobulin VH genes. Science. 1985;227(4694):1597–601.PubMedCrossRefGoogle Scholar
  117. 117.
    Xu CR, Schaffer L, Head SR, Feeney AJ. Reciprocal patterns of methylation of H3K36 and H3K27 on proximal vs. distal IgVH genes are modulated by IL-7 and Pax5. Proc Natl Acad Sci USA. 2008;105(25):8685–90.PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Garman RD, Doherty PJ, Raulet DH. Diversity, rearrangement, and expression of murine T cell gamma genes. Cell. 1986;45(5):733–42.PubMedCrossRefGoogle Scholar
  119. 119.
    Goldman JP, Spencer DM, Raulet DH. Ordered rearrangement of variable region genes of the T cell receptor gamma locus correlates with transcription of the unrearranged genes. J Exp Med. 1993;177(3):729–39.PubMedCrossRefGoogle Scholar
  120. 120.
    Heilig JS, Tonegawa S. Diversity of murine gamma genes and expression in fetal and adult T lymphocytes. Nature. 1986;322(6082):836–40.PubMedCrossRefGoogle Scholar
  121. 121.
    Agata Y, Katakai T, Ye SK, Sugai M, Gonda H, Honjo T, et al. Histone acetylation determines the developmentally regulated accessibility for T cell receptor gamma gene recombination. J Exp Med. 2001;193(7):873–80.PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Hao B, Krangel MS. Long-distance regulation of fetal V(delta) gene segment TRDV4 by the Tcrd enhancer. J Immunol. 2011;187(5):2484–91. doi:10.4049/jimmunol.1100468.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Martino D, Prescott S. Epigenetics and prenatal influences on asthma and allergic airways disease. Chest. 2011;139(3):640–7. doi:10.1378/chest.10-1800.PubMedCrossRefGoogle Scholar
  124. 124.
    Martino DJ, Prescott SL. Silent mysteries: epigenetic paradigms could hold the key to conquering the epidemic of allergy and immune disease. Allergy. 2009;65(1):7–15. doi:10.1111/j.1398-9995.2009.02186.x.PubMedCrossRefGoogle Scholar
  125. 125.
    Pfefferle PI, Pinkenburg O, Renz H. Fetal epigenetic mechanisms and innate immunity in asthma. Curr Allergy Asthma Rep. 2010;10(6):434–43. doi:10.1007/s11882-010-0147-6.PubMedCrossRefGoogle Scholar
  126. 126.
    North ML, Ellis AK. The role of epigenetics in the developmental origins of allergic disease. Ann Allergy Asthma Immunol. 2011;106(5):355-61; quiz 62. doi:10.1016/j.anai.2011.02.008.Google Scholar
  127. 127.
    Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med. 2009;180(5):462–7. doi:10.1164/rccm.200901-0135OC.PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    Bobetsis YA, Barros SP, Lin DM, Weidman JR, Dolinoy DC, Jirtle RL, et al. Bacterial infection promotes DNA hypermethylation. J Dent Res. 2007;86(2):169–74. doi:10.1177/154405910708600212.PubMedCrossRefGoogle Scholar
  129. 129.
    Hollingsworth JW, Maruoka S, Boon K, Garantziotis S, Li Z, Tomfohr J, et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest. 2008;118(10):3462–9. doi:10.1172/JCI34378.PubMedCentralPubMedGoogle Scholar
  130. 130.
    Schaub B, Liu J, Hoppler S, Schleich I, Huehn J, Olek S et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol. 2009;123(4):774-82 e5. doi:10.1016/j.jaci.2009.01.056.Google Scholar
  131. 131.
    Vuillermin PJ, Ponsonby AL, Saffery R, Tang ML, Ellis JA, Sly P, et al. Microbial exposure, interferon gamma gene demethylation in naive T-cells, and the risk of allergic disease. Allergy. 2009;64(3):348–53. doi:10.1111/j.1398-9995.2009.01970.x.PubMedCrossRefGoogle Scholar
  132. 132.
    Perera F, Tang WY, Herbstman J, Tang D, Levin L, Miller R, et al. 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(2):e4488. doi:10.1371/journal.pone.0004488.PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Tang WY, Levin L, Talaska G, Cheung YY, Herbstman J, Tang D, et al. Maternal exposure to polycyclic aromatic hydrocarbons and 5′-CpG methylation of interferon-gamma in cord white blood cells. Environ Health Perspect. 2012;120(8):1195–200. doi:10.1289/ehp.1103744.PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Haberg SE, London SJ, Stigum H, Nafstad P, Nystad W. Folic acid supplements in pregnancy and early childhood respiratory health. Arch Dis Child. 2009;94(3):180–4. doi:10.1136/adc.2008.142448.PubMedCentralPubMedCrossRefGoogle Scholar
  135. 135.
    Whitrow MJ, Moore VM, Rumbold AR, Davies MJ. Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol. 2009;170(12):1486–93. doi:10.1093/aje/kwp315.PubMedCrossRefGoogle Scholar
  136. 136.
    Fedulov AV, Kobzik L. Allergy risk is mediated by dendritic cells with congenital epigenetic changes. Am J Respir Cell Mol Biol. 2011;44(3):285–92. doi:10.1165/rcmb.2009-0400OC.PubMedCentralPubMedCrossRefGoogle Scholar
  137. 137.
    Brand S, Teich R, Dicke T, Harb H, Yildirim AO, Tost J et al. Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. J Allergy Clin Immunol. 2011;128(3):618-25 e1-7. doi:10.1016/j.jaci.2011.04.035.Google Scholar
  138. 138.
    Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grize L, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med. 2002;347(12):869–77. doi:10.1056/NEJMoa020057.PubMedCrossRefGoogle Scholar
  139. 139.
    Ege MJ, Bieli C, Frei R, van Strien RT, Riedler J, Ublagger E, et al. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J Allergy Clin Immunol. 2006;117(4):817–23. doi:10.1016/j.jaci.2005.12.1307.PubMedCrossRefGoogle Scholar
  140. 140.
    Douwes J, Cheng S, Travier N, Cohet C, Niesink A, McKenzie J, et al. Farm exposure in utero may protect against asthma, hay fever and eczema. Eur Respir J. 2008;32(3):603–11. doi:10.1183/09031936.00033707.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyUniversity of Miami Miller School of MedicineMiamiUSA

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