SEARCH

SEARCH BY CITATION

Keywords:

  • Allergy;
  • epigenetics;
  • fetal programming;
  • immune regulation;
  • microbial exposure

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Allergic March
  5. Reduced Microbial Stimulation and the Allergy Epidemic
  6. Epigenetic Regulation
  7. Epigenetic Regulation of Childhood Immune Development
  8. The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development
  9. Conclusion
  10. Acknowledgements
  11. References

Citation Jenmalm MC. Childhood Immune Maturation and Allergy Development: Regulation by Maternal Immunity and Microbial Exposure. Am J Reprod Immunol 2011; 66 (Suppl. 1): 75–80

Problem  The increasing allergy prevalence in affluent countries may be caused by reduced microbial stimulation, resulting in an abnormal post-natal immune maturation. Most studies investigating the underlying mechanisms have focused on post-natal microbial exposure. Also, the maternal microbial environment during pregnancy may program the immune development of the child, however.

Method of study  This review focuses on how maternal immunity and microbial exposures regulate childhood immune and allergy development.

Results  Prenatal environmental exposures may alter gene expression via epigenetic mechanisms, aiming to induce physiological adaptations to the anticipated post-natal environment, but potentially also increasing disease susceptibility in the offspring. Although the importance of fetal programming mostly has been studied in cardiovascular and metabolic disease, this hypothesis is also very attractive in the context of environmentally influenced immune-mediated diseases.

Conclusion  Efficacious preventive measures, required to combat the allergy epidemic, may be identified by determining how the immune interaction between mother and child is influenced by microbial factors.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Allergic March
  5. Reduced Microbial Stimulation and the Allergy Epidemic
  6. Epigenetic Regulation
  7. Epigenetic Regulation of Childhood Immune Development
  8. The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development
  9. Conclusion
  10. Acknowledgements
  11. References

Allergic diseases have become a major public health problem in affluent societies.1,2 Asthma is the most common chronic disease among children, with a major impact on both the physiological and psychological well-being of young children,3 as well as on socio-economic costs because of hospital admittance, treatment costs and parental sick leave.4 The allergy epidemic must be counteracted by research identifying successful preventive measures, which do not exist today.

The Allergic March

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Allergic March
  5. Reduced Microbial Stimulation and the Allergy Epidemic
  6. Epigenetic Regulation
  7. Epigenetic Regulation of Childhood Immune Development
  8. The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development
  9. Conclusion
  10. Acknowledgements
  11. References

Allergic diseases are characterized by inappropriate immune responses to innocuous foreign proteins, allergens. Atopy is defined as personal and/or familiar tendency to produce IgE antibodies to allergens, that is, become sensitized.5 The excessive Th2-like responses to allergens in atopic individuals include high production of IgE-inducing IL-4 and IL-13 and eosinophilia-enhancing IL-5 and IL-9.6,7 During the early phase of the IgE-mediated allergic reaction, allergen cross-linking of IgE antibodies on mast cells and basophils triggers release of inflammatory mediators.7 Cytotoxic mediators from eosinophils are important in the late-phase reaction and lead to chronic inflammation.7

Atopic eczema, bronchial asthma, allergic rhinoconjunctivitis and immediate types of urticaria and food allergy all belong to the allergic diseases. The allergic march typically begins with the development of IgE antibodies to food allergens accompanied with symptoms of atopic eczema and food allergy.8 After sensitization during infancy, most children develop tolerance to food allergens.8 Later in childhood, inhalant allergen sensitization develops together with asthmatic symptoms, while onset of allergic rhinoconjunctivitis is usually seen from early school age.8

Reduced Microbial Stimulation and the Allergy Epidemic

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Allergic March
  5. Reduced Microbial Stimulation and the Allergy Epidemic
  6. Epigenetic Regulation
  7. Epigenetic Regulation of Childhood Immune Development
  8. The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development
  9. Conclusion
  10. Acknowledgements
  11. References

As changes in the genotype cannot explain the rapid increase in the allergy prevalence, loss of protective factors or appearance of risk factors in the environment may contribute to the increased prevalence of these diseases since the middle of the last century. A reduced microbial pressure, resulting in insufficient induction of T cells with regulatory and/or Th1-like properties to counteract allergy-inducing Th2 response, may underlie the allergy epidemic.9–13 Most studies investigating the underlying mechanisms have focused on post-natal microbial exposure.14–18

An increasing body of evidence from studies of others and us suggests that the maternal microbial environment during pregnancy can program the immune development of the child, however.13,19,20 Thus, experimental murine models demonstrate that maternal treatment with lipopolysaccharide21–23 or the commensal Acinetobacter lwoffii24 during gestation attenuates allergic sensitization and airway inflammation in the offspring. Also, epidemiological studies indicate that maternal farm environment exposure during pregnancy protects against allergic sensitization and disease, whereas exposures during infancy alone have weaker or no effect at all.13,25,26 Continued enhanced post-natal microbial exposure may be required for optimal allergy protection, however.26 Furthermore, in human allergy intervention studies, probiotic supplementation to the mother during pregnancy, as well as to her baby post-natally, may be important for preventive effects.27,28 Thus, a preventive effect on atopic eczema has primarily been demonstrated in studies by us and others where probiotics were given both pre- and post-natally,19,29–33 whereas two studies with post-natal supplementation only failed to prevent allergic disease.34,35 Prenatal probiotic supplementation was not given until 36 weeks of gestation in any of the studies, however.19,29–33 If prenatal microbial exposure is vital for the preventive effect, starting supplementation already from the second trimester of pregnancy, when circulating fetal T cells have developed,36 may have a more powerful preventive effect on allergy development.

Epigenetic Regulation

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Allergic March
  5. Reduced Microbial Stimulation and the Allergy Epidemic
  6. Epigenetic Regulation
  7. Epigenetic Regulation of Childhood Immune Development
  8. The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development
  9. Conclusion
  10. Acknowledgements
  11. References

Regulation by epigenetic mechanisms, heritable changes in gene expression occurring without alterations in the DNA sequences,37 a kind of cellular memory, may play a major role in prenatal immune programming.38 Epigenetic modifications determine the degree of DNA compaction and accessibility for gene transcription, thus resulting in changes in gene expression that are subsequently passed to somatic daughter cells during mitosis.37 The main processes modulating DNA accessibility to establish epigenetic memory occur via post-translational histone modifications and methylation of DNA CpG dinucleotides.37 DNA methylation, associated with transcriptional repression, is more rigid than histone modifications, with DNA methyltransferases conferring covalent methyl modifications to evolutionary conserved regulatory gene elements, CpG islands.39 The methylation pattern is thus preserved with high fidelity through cell divisions, assuring preservation of cellular inheritance.39

Epigenetic Regulation of Childhood Immune Development

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Allergic March
  5. Reduced Microbial Stimulation and the Allergy Epidemic
  6. Epigenetic Regulation
  7. Epigenetic Regulation of Childhood Immune Development
  8. The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development
  9. Conclusion
  10. Acknowledgements
  11. References

Prenatal environmental exposures may alter gene expression via epigenetic mechanisms, aiming to induce physiological adaptations to the anticipated post-natal environment, but potentially also increasing disease susceptibility in the offspring.40 This ‘Developmental Origins of Health and Disease’ hypothesis40 was originally proposed by David Barker.41 Although the importance of fetal programming mostly has been studied in cardiovascular and metabolic disease,40 this hypothesis is also very attractive in the context of environmentally influenced immune-mediated diseases. The maternal microbial environment during pregnancy may program the immune development of the child,20 via epigenetic mechanisms, regulating appropriate maturation of innate immunity24,25 and T helper and regulatory responses.12,42 Th1, Th2 and Th17 differentiation is under epigenetic control,43–45 and human T regulatory cell commitment requires demethylation of the FOXP3 promoter.46

The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Allergic March
  5. Reduced Microbial Stimulation and the Allergy Epidemic
  6. Epigenetic Regulation
  7. Epigenetic Regulation of Childhood Immune Development
  8. The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development
  9. Conclusion
  10. Acknowledgements
  11. References

Epigenetically regulated childhood immune development by maternal microbial exposure is likely induced via changes in maternal immune regulation,22,24 as there is a close immunological interaction between the mother and her offspring during pregnancy.47,48 The placenta allows a cross talk between maternal stimuli, possibly induced via microbial stimulation of maternal toll-like receptors, and fetal responses.24 As fetal T cells have developed during the second trimester of gestation,36 maternal signals may then direct the immune cell lineage commitment of the offspring during a critical developmental period when the epigenetic program is highly susceptible to environmental influences.20 During pregnancy, the fetal–maternal interface is characterized by high levels of Th2-like cytokines49 and enrichment of T regulatory cells,50 most likely functioning to divert the maternal immune response away from damaging Th1-mediated immunity.51 The association of cord blood IgE levels and neonatal IFN-γ production with maternal but not paternal atopic heredity52,53 may depend on an even stronger Th2 deviation in atopic than non-atopic pregnant women.54,55 As the cytokine milieu shapes the T helper differentiation, particularly during naïve as compared to established responses,56 the neonatal immune system is Th2 skewed.57 The Th2 cytokine locus in murine neonatal CD4+ T cells is poised epigenetically for rapid and robust production of IL-4 and IL-13.58 We have shown an even more marked neonatal Th2 skewing in infants later developing allergic disease,48 possibly because of prenatal epigenetic effects via maternal immune regulation that may be possible to redress by enhanced microbial exposure, for example, via probiotic supplementation, during pregnancy. The Th2 bias of the newborn should then develop toward a more balanced immune phenotype, including maturation of Th1-like responses12 and appropriate development of regulatory T-cell responses.11 In farm studies, contact with multiple animal species during pregnancy is positively correlated to Treg cell function and IFN-γ production at birth and with innate immune receptor expression at birth and during childhood.13,25,42,59,60 A failure of Th2 silencing during maturation of the immune system may underlie development of Th2-mediated allergic disease.61 Appropriate microbial stimulation, both pre- and post-natally, may be required to avoid this pathophysiological process.26

In this respect, the gut microbiota is quantitatively the most important source of microbial stimulation and may provide a primary signal for the maturation of a balanced post-natal innate and adaptive immune system.62,63 It is likely that our immune system has evolved as much to manage and exploit beneficial microbes as to fend off pathogens.64,65 The gut microbiota differs during the first months of life in children who later do or do not develop allergic disease,66–68 and the diversity of the microbiota may play an important role in regulating allergy69,70 and mucosal immune development.63 To what extent the maternal gut microbiota composition influences that of her offspring is not yet fully clear. Differences in microbiota composition depending on delivery mode do indicate a mother–child transmission of microbiota during vaginal delivery.71,72 Because of the vast complexity of the gut microbiota, more detailed, basic microbial ecology studies, now made possible by advances in DNA sequencing technologies,73,74 in clinically and immunologically well-characterized children and their mothers are needed, however. Also, how the maternal gut microbiota impacts the development of the microbiota of the child, in addition to the effects on immune maturation during infancy, needs further investigation.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Allergic March
  5. Reduced Microbial Stimulation and the Allergy Epidemic
  6. Epigenetic Regulation
  7. Epigenetic Regulation of Childhood Immune Development
  8. The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development
  9. Conclusion
  10. Acknowledgements
  11. References

The maternal microbial environment during pregnancy may program the immune development of the child. Prenatal environmental exposures may alter gene expression via epigenetic mechanisms, aiming to induce physiological adaptations to the anticipated post-natal environment, but potentially also increasing disease susceptibility in the offspring. Efficacious preventive measures, required to combat the allergy epidemic, may be identified by determining how the immune interaction between mother and child is influenced by microbial factors.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Allergic March
  5. Reduced Microbial Stimulation and the Allergy Epidemic
  6. Epigenetic Regulation
  7. Epigenetic Regulation of Childhood Immune Development
  8. The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development
  9. Conclusion
  10. Acknowledgements
  11. References

This work was supported by the Swedish Research Council, the Ekhaga Foundation, the Research Council for the South-East Sweden, the Swedish Asthma and Allergy Association, the Olle Engkvist Foundation and the Vårdal Foundation – for Health Care Sciences and Allergy Research.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Allergic March
  5. Reduced Microbial Stimulation and the Allergy Epidemic
  6. Epigenetic Regulation
  7. Epigenetic Regulation of Childhood Immune Development
  8. The Role of Maternal Microbial Exposure and Immune Regulation in Childhood Allergy Development
  9. Conclusion
  10. Acknowledgements
  11. References
  • 1
    Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, Williams H: Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006; 368:733743.
  • 2
    Eder W, Ege MJ, von Mutius E: The asthma epidemic. N Engl J Med 2006; 355:22262235.
  • 3
    Rydström I, Dalheim-Englund AC, Holritz-Rasmussen B, Möller C, Sandman PO: Asthma – quality of life for Swedish children. J Clin Nurs 2005; 14:739749.
  • 4
    Jansson SA, Arnlind MH, Dahlén SE, Lundbäck B: [Costs of asthma and allergies to society unknown. Cost studies can give better planning of health care and research]. Läkartidningen 2007; 104:27922796.
  • 5
    Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, Ortega Martell JA, Platts-Mills TA, Ring J, Thien F, Van Cauwenberge P, Williams HC: Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 2004; 113:832836.
  • 6
    Jenmalm MC, Van Snick J, Cormont F, Salman B: Allergen-induced Th1 and Th2 cytokine secretion in relation to specific allergen sensitization and atopic symptoms in children. Clin Exp Allergy 2001; 31:15281535.
  • 7
    Kim HY, DeKruyff RH, Umetsu DT: The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol 2010; 11:577584.
  • 8
    Hattevig G, Kjellman B, Björkstén B: Appearance of IgE antibodies to ingested and inhaled allergens during the first 12 years of life in atopic and non-atopic children. Pediatr Allergy Immunol 1993; 4:182186.
  • 9
    Schaub B, Lauener R, von Mutius E: The many faces of the hygiene hypothesis. J Allergy Clin Immunol 2006; 117:969977.
  • 10
    Böttcher MF, Jenmalm MC, Voor T, Julge K, Holt PG, Björkstén B: Cytokine responses to allergens during the first 2 years of life in Estonian and Swedish children. Clin Exp Allergy 2006; 36:619628.
  • 11
    Lloyd CM, Hawrylowicz CM: Regulatory T cells in asthma. Immunity 2009; 31:438449.
  • 12
    Vuillermin PJ, Ponsonby AL, Saffery R, Tang ML, Ellis JA, Sly P, Holt P: Microbial exposure, interferon gamma gene demethylation in naive T-cells, and the risk of allergic disease. Allergy 2009; 64:348353.
  • 13
    von Mutius E, Vercelli D: Farm living: effects on childhood asthma and allergy. Nat Rev Immunol 2010; 10:861868.
  • 14
    Böttcher MF, Björkstén B, Gustafson S, Voor T, Jenmalm MC: Endotoxin levels in Estonian and Swedish house dust and atopy in infancy. Clin Exp Allergy 2003; 33:295300.
  • 15
    Bashir ME, Louie S, Shi HN, Nagler-Anderson C: Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J Immunol 2004; 172:69786987.
  • 16
    Foliaki S, Pearce N, Björkstén B, Mallol J, Montefort S, von Mutius E: Antibiotic use in infancy and symptoms of asthma, rhinoconjunctivitis, and eczema in children 6 and 7 years old: International Study of Asthma and Allergies in Childhood Phase III. J Allergy Clin Immunol 2009; 124:982989.
  • 17
    Kwon HK, Lee CG, So JS, Chae CS, Hwang JS, Sahoo A, Nam JH, Rhee JH, Hwang KC, Im SH: Generation of regulatory dendritic cells and CD4+ Foxp3+ T cells by probiotics administration suppresses immune disorders. Proc Natl Acad Sci U S A 2010; 107:21592164.
  • 18
    Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrlander C, Heederik D, Piarroux R, von Mutius E: Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011; 364:701709.
  • 19
    Abrahamsson TR, Jakobsson T, Böttcher MF, Fredrikson M, Jenmalm MC, Björkstén B, Oldaeus G: Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol 2007; 119:11741180.
  • 20
    Hawrylowicz C, Ryanna K: Asthma and allergy: the early beginnings. Nat Med 2010; 16:274275.
  • 21
    Blümer N, Herz U, Wegmann M, Renz H: Prenatal lipopolysaccharide-exposure prevents allergic sensitization and airway inflammation, but not airway responsiveness in a murine model of experimental asthma. Clin Exp Allergy 2005; 35:397402.
  • 22
    Gerhold K, Avagyan A, Seib C, Frei R, Steinle J, Ahrens B, Dittrich AM, Blumchen K, Lauener R, Hamelmann E: Prenatal initiation of endotoxin airway exposure prevents subsequent allergen-induced sensitization and airway inflammation in mice. J Allergy Clin Immunol 2006; 118:666673.
  • 23
    Cao L, Wang J, Zhu Y, Tseu I, Post M: Maternal endotoxin exposure attenuates allergic airway disease in infant rats. Am J Physiol Lung Cell Mol Physiol 2010; 298:L670677.
  • 24
    Conrad ML, Ferstl R, Teich R, Brand S, Blumer N, Yildirim AO, Patrascan CC, Hanuszkiewicz A, Akira S, Wagner H, Holst O, von Mutius E, Pfefferle PI, Kirschning CJ, Garn H, Renz H: Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J Exp Med 2009; 206:28692877.
  • 25
    Ege MJ, Bieli C, Frei R, van Strien RT, Riedler J, Ublagger E, Schram-Bijkerk D, Brunekreef B, van Hage M, Scheynius A, Pershagen G, Benz MR, Lauener R, von Mutius E, Braun-Fahrlander C: 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; 117:817823.
  • 26
    Douwes J, Cheng S, Travier N, Cohet C, Niesink A, McKenzie J, Cunningham C, Le Gros G, von Mutius E, Pearce N: Farm exposure in utero may protect against asthma, hay fever and eczema. Eur Respir J 2008; 32:603611.
  • 27
    Lee J, Seto D, Bielory L: Meta-analysis of clinical trials of probiotics for prevention and treatment of pediatric atopic dermatitis. J Allergy Clin Immunol 2008; 121:116121.
  • 28
    Tang ML, Lahtinen SJ, Boyle RJ: Probiotics and prebiotics: clinical effects in allergic disease. Curr Opin Pediatr 2010; 22:626634.
  • 29
    Kalliomäki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E: Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 2001; 357:10761079.
  • 30
    Kalliomäki M, Salminen S, Poussa T, Arvilommi H, Isolauri E: Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 2003; 361:18691871.
  • 31
    Kukkonen K, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, Tuure T, Kuitunen M: Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2007; 119:192198.
  • 32
    Wickens K, Black PN, Stanley TV, Mitchell E, Fitzharris P, Tannock GW, Purdie G, Crane J: A differential effect of 2 probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol 2008; 122:788794.
  • 33
    Kim JY, Kwon JH, Ahn SH, Lee SI, Han YS, Choi YO, Lee SY, Ahn KM, Ji GE: Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: a double-blind, randomized, placebo-controlled trial. Pediatr Allergy Immunol 2010; 21:e386e393.
  • 34
    Taylor AL, Dunstan JA, Prescott SL: Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. J Allergy Clin Immunol 2007; 119:184191.
  • 35
    Soh SE, Aw M, Gerez I, Chong YS, Rauff M, Ng YP, Wong HB, Pai N, Lee BW, Shek LP: Probiotic supplementation in the first 6 months of life in at risk Asian infants--effects on eczema and atopic sensitization at the age of 1 year. Clin Exp Allergy 2009; 39:571578.
  • 36
    Papiernik M: Correlation of lymphocyte transformation and morphology in the human fetal thymus. Blood 1970; 36:470479.
  • 37
    Jaenisch R, Bird A: Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003; 33(Suppl):245254.
  • 38
    Martino D, Prescott S: Epigenetics and prenatal influences on asthma and allergic airways disease. Chest 2011; 139:640647.
  • 39
    Kim JK, Samaranayake M, Pradhan S: Epigenetic mechanisms in mammals. Cell Mol Life Sci 2009; 66:596612.
  • 40
    Wadhwa PD, Buss C, Entringer S, Swanson JM: Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med 2009; 27:358368.
  • 41
    Barker DJ: The fetal and infant origins of adult disease. BMJ 1990; 301:1111.
  • 42
    Schaub B, Liu J, Hoppler S, Schleich I, Huehn J, Olek S, Wieczorek G, Illi S, von Mutius E: Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol 2009; 123:774782.
  • 43
    Wilson CB, Rowell E, Sekimata M: Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 2009; 9:91105.
  • 44
    Janson PC, Winerdal ME, Winqvist O: At the crossroads of T helper lineage commitment – epigenetics points the way. Biochim Biophys Acta 2009; 1790:906919.
  • 45
    Janson PC, Linton LB, Bergman EA, Marits P, Eberhardson M, Piehl F, Malmström V, Winqvist O: Profiling of CD4+ T cells with epigenetic immune lineage analysis. J Immunol 2011; 186:92102.
  • 46
    Janson PC, Winerdal ME, Marits P, Thorn M, Ohlsson R, Winqvist O: FOXP3 promoter demethylation reveals the committed Treg population in humans. PLoS ONE 2008; 3:e1612.
  • 47
    Jenmalm MC, Björkstén B: Cord blood levels of immunoglobulin G subclass antibodies to food and inhalant allergens in relation to maternal atopy and the development of atopic disease during the first 8 years of life. Clin Exp Allergy 2000; 30:3440.
  • 48
    Sandberg M, Frykman A, Ernerudh J, Berg G, Matthiesen L, Ekerfelt C, Nilsson LJ, Jenmalm MC: Cord blood cytokines and chemokines and development of allergic disease. Pediatr Allergy Immunol 2009; 20:519527.
  • 49
    Tsuda H, Michimata T, Hayakawa S, Tanebe K, Sakai M, Fujimura M, Matsushima K, Saito S: A Th2 chemokine, TARC, produced by trophoblasts and endometrial gland cells, regulates the infiltration of CCR4+ T lymphocytes into human decidua at early pregnancy. Am J Reprod Immunol 2002; 48:18.
  • 50
    Mjösberg J, Berg G, Jenmalm MC, Ernerudh J: FOXP3+ regulatory T cells and T helper 1, T helper 2, and T helper 17 cells in human early pregnancy decidua. Biol Reprod 2010; 82:698705.
  • 51
    Piccinni MP, Beloni L, Livi C, Maggi E, Scarselli G, Romagnani S: Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat Med 1998; 4:10201024.
  • 52
    Liu CA, Wang CL, Chuang H, Ou CY, Hsu TY, Yang KD: Prenatal prediction of infant atopy by maternal but not paternal total IgE levels. J Allergy Clin Immunol 2003; 112:899904.
  • 53
    Prescott SL, Holt PG, Jenmalm MC, Björkstén B: Effects of maternal allergen-specific IgG in cord blood on early postnatal development of allergen-specific T-cell immunity. Allergy 2000; 55:470475.
  • 54
    Sandberg M, Frykman A, Jonsson Y, Persson M, Ernerudh J, Berg G, Matthiesen L, Ekerfelt C, Jenmalm MC: Total and allergen-specific IgE levels during and after pregnancy in relation to maternal allergy. J Reprod Immunol 2009; 81:8288.
  • 55
    Prescott SL, Breckler LA, Witt CS, Smith L, Dunstan JA, Christiansen FT: Allergic women show reduced T helper type 1 alloresponses to fetal human leucocyte antigen mismatch during pregnancy. Clin Exp Immunol 2010; 159:6572.
  • 56
    Paul WE, Zhu J: How are Th2-type immune responses initiated and amplified? Nat Rev Immunol 2010; 10:225235.
  • 57
    Zaghouani H, Hoeman CM, Adkins B: Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells. Trends Immunol 2009; 30:585591.
  • 58
    Rose S, Lichtenheld M, Foote MR, Adkins B: Murine neonatal CD4+ cells are poised for rapid Th2 effector-like function. J Immunol 2007; 178:26672678.
  • 59
    Pfefferle PI, Buchele G, Blumer N, Roponen M, Ege MJ, Krauss-Etschmann S, Genuneit J, Hyvarinen A, Hirvonen MR, Lauener R, Pekkanen J, Riedler J, Dalphin JC, Brunekeef B, Braun-Fahrlander C, von Mutius E, Renz H: Cord blood cytokines are modulated by maternal farming activities and consumption of farm dairy products during pregnancy: the PASTURE Study. J Allergy Clin Immunol 2010; 125:108115.
  • 60
    Roduit C, Wohlgensinger J, Frei R, Bitter S, Bieli C, Loeliger S, Buchele G, Riedler J, Dalphin JC, Remes S, Roponen M, Pekkanen J, Kabesch M, Schaub B, von Mutius E, Braun-Fahrlander C, Lauener R: Prenatal animal contact and gene expression of innate immunity receptors at birth are associated with atopic dermatitis. J Allergy Clin Immunol 2011; 127:179185.
  • 61
    Böttcher MF, Jenmalm MC, Björkstén B: Immune responses to birch in young children during their first 7 years of life. Clin Exp Allergy 2002; 32:16901698.
  • 62
    Hooper LV, Macpherson AJ: Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol 2010; 10:159169.
  • 63
    Sjögren YM, Tomicic S, Lundberg A, Böttcher MF, Björkstén B, Sverremark-Ekstrom E, Jenmalm MC: Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses. Clin Exp Allergy 2009; 39:18421851.
  • 64
    Travis J: On the origin of the immune system. Science 2009; 324:580582.
  • 65
    Lee YK, Mazmanian SK: Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 2010; 330:17681773.
  • 66
    Björkstén B, Sepp E, Julge K, Voor T, Mikelsaar M: Allergy development and the intestinal microflora during the first year of life. J Allergy Clin Immunol 2001; 108:516520.
  • 67
    Kalliomäki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E: Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 2001; 107:129134.
  • 68
    Sjögren YM, Jenmalm MC, Böttcher MF, Björkstén B, Sverremark-Ekström E: Altered early infant gut microbiota in children developing allergy up to 5 years of age. Clin Exp Allergy 2009; 39:518526.
  • 69
    Wang M, Karlsson C, Olsson C, Adlerberth I, Wold AE, Strachan DP, Martricardi PM, Åberg N, Perkin MR, Tripodi S, Coates AR, Hesselmar B, Saalman R, Molin G, Ahrné S: Reduced diversity in the early fecal microbiota of infants with atopic eczema. J Allergy Clin Immunol 2008; 121:129134.
  • 70
    Forno E, Onderdonk AB, McCracken J, Litonjua AA, Laskey D, Delaney ML, Dubois AM, Gold DR, Ryan LM, Weiss ST, Celedon JC: Diversity of the gut microbiota and eczema in early life. Clin Mol Allergy 2008; 6:11.
  • 71
    Adlerberth I, Lindberg E, Aberg N, Hesselmar B, Saalman R, Strannegård IL, Wold AE: Reduced enterobacterial and increased staphylococcal colonization of the infantile bowel: an effect of hygienic lifestyle? Pediatr Res 2006; 59:96101.
  • 72
    Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R: Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 2010; 107:1197111975.
  • 73
    Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI: A core gut microbiome in obese and lean twins. Nature 2009; 457:480484.
  • 74
    Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Jian M, Zhou Y, Li Y, Zhang X, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Bork P, Ehrlich SD: A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464:5965.