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The Immunological Basis of the Hygiene Hypothesis

  • Petra Ina Pfefferle
  • René Teich
  • Harald Renz
Part of the Allergy Frontiers book series (ALLERGY, volume 1)

The hygiene hypothesis has gained much attention as an explanatory model for increases in the incidence of allergic diseases. Since epidemiological evidence mainly comes from cross-sectional studies, which are not able to elucidate cause— effect relationships, this concept is still in conflict with opposite results. The role of microbial compounds as important exogenous triggers of immuno-programming is central to the hygiene hypothesis. Several prototypical components from both gram-positive and gram-negative bacteria have been investigated under experimental and clinical conditions. These approaches clearly demonstrate that the route of exposure, the time of exposure, and the dose are critical variables, which determine the outcome of downstream immune responses. The innate immune system plays a central role in the initiation of effector responses, by signaling through pattern recognition receptors, particularly toll-like receptors (TLRs) and balancing the type of T-cell effector response, including TH-1, TH-2, and regulatory T cells. Recent studies focus on the role of microbiota and the commensal gut and skin flora as immuno-modulators. Most recently, Acinetobacter lwoffii and Lactococcus lactis have been identified in the environment of traditional farms further supporting the concept that environmental components play a decisive role in programming early immune responses.

Keywords

Atopic Dermatitis Allergic Disease Allergy Clin Immunol Allergic Disorder Allergic Airway Inflammation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Wuthrich B (1989) Epidemiology of the allergic diseases: are they really on the increase? Int Arch Allergy Appl Immunol 90(suppl 1):3–10PubMedGoogle Scholar
  2. 2.
    Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911–920PubMedGoogle Scholar
  3. 3.
    Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299:1259–1260PubMedGoogle Scholar
  4. 4.
    Sheikh A, Strachan DP (2004) The hygiene theory: fact or fiction? Curr Opin Otolaryngol Head Neck Surg 12:232–236PubMedGoogle Scholar
  5. 5.
    Wills-Karp M, Santeliz J, Karp CL (2001) The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 1:69–75PubMedGoogle Scholar
  6. 6.
    Bach JF (2005) Six questions about the hygiene hypothesis. Cell Immunol 233(2):158–61PubMedGoogle Scholar
  7. 7.
    Guarner F, Bourdet-Sicard R, Brandtzaeg P, et al. (2006) Mechanisms of disease: the hygiene hypothesis revisited. Nat Clin Pract Gastroenterol Hepatol 3:275–284PubMedGoogle Scholar
  8. 8.
    Yazdanbakhsh M, Kremsner PG, van Ree R (2002) Allergy, parasites, and the hygiene hypothesis. Science 296:490–494PubMedGoogle Scholar
  9. 9.
    Moncayo AL, Cooper PJ (2006) Geohelminth infections: impact on allergic diseases. Int J Biochem Cell Biol 38:1031–1035PubMedGoogle Scholar
  10. 10.
    Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299:1259–1260PubMedGoogle Scholar
  11. 11.
    Lemanske RF Jr (2002) The childhood origins of asthma (COAST) study. Pediatr Allergy Immunol 13(suppl 15):38–43PubMedGoogle Scholar
  12. 12.
    Celedon JC, Wright RJ, Litonjua AA, et al. (2003) Day care attendance in early life, maternal history of asthma, and asthma at the age of 6 years. Am J Respir Crit Care Med 167:1239–1243PubMedGoogle Scholar
  13. 13.
    Hoffjan S, Nicolae D, Ostrovnaya I, et al. (2005) Gene—environment interaction effects on the development of immune responses in the 1st year of life. Am J Hum Genet 76:696–704PubMedGoogle Scholar
  14. 14.
    Kinra S, Davey SG, Jeffreys M, et al. (2006) Association between sibship size and allergic diseases in the Glasgow Alumni Study. Thorax 61:48–53PubMedGoogle Scholar
  15. 15.
    Bernsen RM, de Jongste JC, van der Wouden JC (2003) Birth order and sibship size as independent risk factors for asthma, allergy, and eczema. Pediatr Allergy Immunol 14:464–469PubMedGoogle Scholar
  16. 16.
    Nowak D, Heinrich J, Jorres R, et al. (1996) Prevalence of respiratory symptoms, bronchial hyperresponsiveness and atopy among adults: west and east Germany. Eur Respir J 9:2541–2552PubMedGoogle Scholar
  17. 17.
    Heinrich J, Hoelscher B, Frye C, et al. (2002) Trends in prevalence of atopic diseases and allergic sensitization in children in Eastern Germany. Eur Respir J 19:1040–1046PubMedGoogle Scholar
  18. 18.
    Waser M, von Mutius E, Riedler J, et al. (2005) Exposure to pets, and the association with hay fever, asthma, and atopic sensitization in rural children. Allergy 60:177–184PubMedGoogle Scholar
  19. 19.
    Giovannangelo M, Nordling E, Gehring U, et al. (2007) Variation of biocontaminant levels within and between homes: the AIRALLERG study. J Expo Sci Environ Epidemiol 17:134–140PubMedGoogle Scholar
  20. 20.
    Giovannangelo M, Gehring U, Nordling E, et al. (2006) Childhood cat allergen exposure in three European countries: the AIRALLERG study. Sci Total Environ 369:82–90PubMedGoogle Scholar
  21. 21.
    Wamboldt FS, Ho J, Milgrom H, et al. (2002) Prevalence and correlates of household exposures to tobacco smoke and pets in children with asthma. J Pediatr 141:109–115PubMedGoogle Scholar
  22. 22.
    Sandin A, Bjorksten B, Braback L (2004) Development of atopy and wheezing symptoms in relation to heredity and early pet keeping in a Swedish birth cohort. Pediatr Allergy Immunol 15:316–322PubMedGoogle Scholar
  23. 23.
    de Marco R, Pattaro C, Locatelli F, et al. (2004) Influence of early life exposures on incidence and remission of asthma throughout life. J Allergy Clin Immunol 113:845–852PubMedGoogle Scholar
  24. 24.
    Lau S, Illi S, Platts-Mills TA, et al. (2005) Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-specific IgG and development of asthma in childhood: report of the German Multicentre Allergy Study (MAS 90). Allergy 60:766–773PubMedGoogle Scholar
  25. 25.
    Kummeling I, Stelma FF, Dagnelie PC, et al. (2007) Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study. Pediatrics 119:e225–e231PubMedGoogle Scholar
  26. 26.
    Floistrup H, Swartz J, Bergstrom A, et al. (2006) Allergic disease and sensitization in Steiner school children. J Allergy Clin Immunol 117:59–66PubMedGoogle Scholar
  27. 27.
    Alm JS, Swartz J, Lilja G, et al. (1999) Atopy in children of families with an anthroposophic lifestyle. Lancet 353:1485–1488PubMedGoogle Scholar
  28. 28.
    Braun-Fahrlander C (2000) Allergic diseases in farmers' children. Pediatr Allergy Immunol 11(suppl 13):19–22PubMedGoogle Scholar
  29. 29.
    Zucker BA, Muller W (2000) Investigations on airborne microorganisms in animal stables: 3. Relationship between inhalable endotoxin, inhalable dust and airborne bacteria in a hen house. Berl Munch Tierarztl Wochenschr 113:279–283PubMedGoogle Scholar
  30. 30.
    Lee SA, Adhikari A, Grinshpun SA, et al. (2006) Personal exposure to airborne dust and microorganisms in agricultural environments. J Occup Environ Hyg 3:118–130PubMedGoogle Scholar
  31. 31.
    Braun-Fahrlander C, Gassner M, Grize L, et al. (1999) Prevalence of hay fever and allergic sensitization in farmer's children and their peers living in the same rural community. SCARPOL team. Swiss Study on Childhood Allergy and Respiratory Symptoms with Respect to Air Pollution. Clin Exp Allergy 29:28–34PubMedGoogle Scholar
  32. 32.
    Dimich-Ward H, Chow Y, Chung J, et al. (2006) Contact with livestock: a protective effect against allergies and asthma? Clin Exp Allergy 36:1122–1129PubMedGoogle Scholar
  33. 33.
    Braback L, Hjern A, Rasmussen F (2004) Trends in asthma, allergic rhinitis and eczema among Swedish conscripts from farming and non-farming environments: a nationwide study over three decades. Clin Exp Allergy 34:38–43PubMedGoogle Scholar
  34. 34.
    Portengen L, Sigsgaard T, Omland O, et al. (2002) Low prevalence of atopy in young Danish farmers and farming students born and raised on a farm. Clin Exp Allergy 32:247–253PubMedGoogle Scholar
  35. 35.
    Eduard W, Omenaas E, Bakke PS, et al. (2004) Atopic and non-atopic asthma in a farming and a general population. Am J Ind Med 46:396–399PubMedGoogle Scholar
  36. 36.
    Von Ehrenstein OS, von Mutius E, Illi S, et al. (2000) Reduced risk of hay fever and asthma among children of farmers. Clin Exp Allergy 30:187–193Google Scholar
  37. 37.
    Ege MJ, Bieli C, Frei R, et al. (2006) 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 117:817–823PubMedGoogle Scholar
  38. 38.
    Riedler J, Braun-Fahrlander C, Eder W, et al. (2001) Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 358:1129–1133PubMedGoogle Scholar
  39. 39.
    Ege MJ, Bieli C, Frei R, et al. (2006) 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 117:817–823PubMedGoogle Scholar
  40. 40.
    Alfven T, Braun-Fahrlander C, Brunekreef B, et al. (2006) Allergic diseases and atopic sensi-tization in children related to farming and anthroposophic lifestyle: the PARSIFAL study. Allergy 61:414–421PubMedGoogle Scholar
  41. 41.
    Waser M, Michels KB, Bieli C, et al. (2007) Inverse association of farm milk consumption with asthma and allergy in rural and suburban populations across Europe. Clin Exp Allergy 37:661–670PubMedGoogle Scholar
  42. 42.
    Perkin MR, Strachan DP (2006) Which aspects of the farming lifestyle explain the inverse association with childhood allergy? J Allergy Clin Immunol 117:1374–1381PubMedGoogle Scholar
  43. 43.
    Smit LA, Zuurbier M, Doekes G, et al. (2007) Hay fever and asthma symptoms in conventional and organic farmers in the Netherlands. Occup Environ Med 64:101–107PubMedGoogle Scholar
  44. 44.
    Leynaert B, Neukirch C, Jarvis D, et al. (2001) Does living on a farm during childhood protect against asthma, allergic rhinitis, and atopy in adulthood? Am J Respir Crit Care Med 164:1829–1834PubMedGoogle Scholar
  45. 45.
    Koskela HO, Happonen KK, Remes ST, et al. (2005) Effect of farming environment on sen-sitisation to allergens continues after childhood. Occup Environ Med 62:607–611PubMedGoogle Scholar
  46. 46.
    Radon K, Ehrenstein V, Praml G, et al. (2004) Childhood visits to animal buildings and atopic diseases in adulthood: an age-dependent relationship. Am J Ind Med 46:349–356PubMedGoogle Scholar
  47. 47.
    Byrd RS, Joad JP (2006) Urban asthma. Curr Opin Pulm Med 12:68–74PubMedGoogle Scholar
  48. 48.
    Simons E, Curtin-Brosnan J, Buckley T, et al. (2007) Indoor environmental differences between inner city and suburban homes of children with asthma. J Urban Health 84:577–590PubMedGoogle Scholar
  49. 49.
    Matsui EC, Eggleston PA, Buckley TJ, et al. (2006) Household mouse allergen exposure and asthma morbidity in inner-city preschool children. Ann Allergy Asthma Immunol 97:514–520PubMedGoogle Scholar
  50. 50.
    Turyk M, Curtis L, Scheff P, et al. (2006) Environmental allergens and asthma morbidity in low-income children. J Asthma 43:453–457PubMedGoogle Scholar
  51. 51.
    Matricardi PM, Bouygue GR, Tripodi S (2002) Inner-city asthma and the hygiene hypothesis. Ann Allergy Asthma Immunol 89:69–74PubMedGoogle Scholar
  52. 52.
    Ege MJ, Frei R, Bieli C, et al. (2007) Not all farming environments protect against the development of asthma and wheeze in children. J Allergy Clin Immunol 119:1140–1147PubMedGoogle Scholar
  53. 53.
    von Mutius E, Braun-Fahrlander C, Schierl R, et al. (2000) Exposure to endotoxin or other bacterial components might protect against the development of atopy. Clin Exp Allergy 30:1230–1234Google Scholar
  54. 54.
    Waser M, Schierl R, von Mutius E, et al. (2004) Determinants of endotoxin levels in living environments of farmers' children and their peers from rural areas. Clin Exp Allergy 34:389–397PubMedGoogle Scholar
  55. 55.
    Lauener RP, Birchler T, Adamski J, et al. (2002) Expression of CD14 and toll-like receptor 2 in farmers' and non-farmers' children. Lancet 360:465–466PubMedGoogle Scholar
  56. 56.
    Gereda JE, Leung DY, Thatayatikom A, et al. (2000) Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. Lancet 355:1680–1683PubMedGoogle Scholar
  57. 57.
    Kips JC, Anderson GP, Fredberg JJ, et al. (2003) Murine models of asthma. Eur Respir J 22:374–382PubMedGoogle Scholar
  58. 58.
    Gerhold K, Blumchen K, Bock A, et al. (2002) Endotoxins and allergy: lessons from the murine model. Pathobiology 70:255–259PubMedGoogle Scholar
  59. 59.
    Gerhold K, Blumchen K, Bock A, et al. (2002) Endotoxins prevent murine IgE production, T(H)2 immune responses, and development of airway eosinophilia but not airway hyperreac-tivity. J Allergy Clin Immunol 110:110–116PubMedGoogle Scholar
  60. 60.
    Delayre-Orthez C, de Blay F, Frossard N, et al. (2004) Dose-dependent effects of endotoxins on allergen sensitization and challenge in the mouse. Clin Exp Allergy 34:1789–1795PubMedGoogle Scholar
  61. 61.
    Tulic MK, Wale JL, Holt PG, et al. (2000) Modification of the inflammatory response to allergen challenge after exposure to bacterial lipopolysaccharide. Am J Respir Cell Mol Biol 22:604–612PubMedGoogle Scholar
  62. 62.
    Blümer N, Herz U, Wegmann M, et al. (2005) Prenatal lipopolysaccharide-exposure prevents allergic sensitization and airway inflammation, but not airway responsiveness in a murine model of experimental asthma. Clin Exp Allergy 35:397–402PubMedGoogle Scholar
  63. 63.
    Gerhold K, Avagyan A, Seib C, et al. (2006) Prenatal initiation of endotoxin airway exposure prevents subsequent allergen-induced sensitization and airway inflammation in mice. J Allergy Clin Immunol 118:666–673PubMedGoogle Scholar
  64. 64.
    Vercelli D (2003) Learning from discrepancies: CD14 polymorphisms, atopy and the endo-toxin switch. Clin Exp Allergy 33:153–155PubMedGoogle Scholar
  65. 65.
    van Strien RT, Engel R, Holst O, et al. (2004) Microbial exposure of rural school children, as assessed by levels of N-acetyl-muramic acid in mattress dust, and its association with respiratory health. J Allergy Clin Immunol 113:860–867PubMedGoogle Scholar
  66. 66.
    Peters M, Kauth M, Schwarze J, et al. (2006) Inhalation of stable dust extract prevents allergen induced airway inflammation and hyperresponsiveness. Thorax 61:134–139PubMedGoogle Scholar
  67. 67.
    Debarry J, Garn H, Hanuszkiewicz A, et al. (2007) Acinetobacter lwoffii and Lactococcus lactis strains isolated from farm cowsheds possess strong allergy-protective properties. J Allergy Clin Immunol 119:1514–1521PubMedGoogle Scholar
  68. 68.
    Romagnani S (2007) Coming back to a missing immune deviation as the main explanatory mechanism for the hygiene hypothesis. J Allergy Clin Immunol 119:1511–1513PubMedGoogle Scholar
  69. 69.
    Cross ML (2002) Microbes versus microbes: immune signals generated by probiotic lactoba-cilli and their role in protection against microbial pathogens. FEMS Immunol Med Microbiol 34:245–253PubMedGoogle Scholar
  70. 70.
    Ouwehand AC (2007) Antiallergic effects of probiotics. J Nutr 137:794S–797SGoogle Scholar
  71. 71.
    von der Weid T, Bulliard C, Schiffrin EJ (2001) Induction by a lactic acid bacterium of a population of CD4(+) T cells with low proliferative capacity that produce transforming growth factor beta and interleukin-10. Clin Diagn Lab Immunol 8:695–701PubMedGoogle Scholar
  72. 72.
    Hart AL, Lammers K, Brigidi P, et al. (2004) Modulation of human dendritic cell phenotype and function by probiotic bacteria. Gut 53:1602–1609PubMedGoogle Scholar
  73. 73.
    Sepp E, Julge K, Mikelsaar M, et al. (2005) Intestinal microbiota and immunoglobulin E responses in 5-year-old Estonian children. Clin Exp Allergy 35:1141–1146PubMedGoogle Scholar
  74. 74.
    Kalliomäki M, Kirjavainen P, Eerola E, et al. (2001) Distinct patterns of neonatal gut micro-flora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 107:129–134PubMedGoogle Scholar
  75. 75.
    Ouwehand AC, Isolauri E, He F, et al. (2001) Differences in Bifidobacterium flora composition in allergic and healthy infants. J Allergy Clin Immunol 108:144–145Google Scholar
  76. 76.
    Murray CS, Simpson B, Kerry G, et al. (2006) Dietary intake in sensitized children with recurrent wheeze and healthy controls: a nested case—control study. Allergy 61:438–442PubMedGoogle Scholar
  77. 77.
    Furrie E (2005) Probiotics and allergy. Proc Nutr Soc 64:465–469PubMedGoogle Scholar
  78. 78.
    Kalliomäki M, Salminen S, Arvilommi H, et al. (2001) Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357:1076–1079PubMedGoogle Scholar
  79. 79.
    Kalliomäki M, Salminen S, Poussa T, et al. (2003) Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 361:1869–1871PubMedGoogle Scholar
  80. 80.
    Kalliomäki M, Salminen S, Poussa T, et al. (2007) Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial. J Allergy Clin Immunol 119:1019–1021PubMedGoogle Scholar
  81. 81.
    Taylor AL, Dunstan JA, Prescott SL (2007) Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitiza-tion in high-risk children: a randomized controlled trial. J Allergy Clin Immunol 119:184–191PubMedGoogle Scholar
  82. 82.
    Taylor AL, Hale J, Hales BJ, et al. (2007) FOXP3 mRNA expression at 6 months of age is higher in infants who develop atopic dermatitis, but is not affected by giving probiotics from birth. Pediatr Allergy Immunol 18:10–19PubMedGoogle Scholar
  83. 83.
    Taylor A, Hale J, Wiltschut J, et al. (2006) Evaluation of the effects of probiotic supplementation from the neonatal period on innate immune development in infancy. Clin Exp Allergy 36:1218–1226PubMedGoogle Scholar
  84. 84.
    Kukkonen K, Savilahti E, Haahtela T, et al. (2007) Probiotics and prebiotic galacto-oligosac-charides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 119:192–198PubMedGoogle Scholar
  85. 85.
    Moro G, Arslanoglu S, Stahl B, et al. (2006) A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age. Arch Dis Child 91:814–819PubMedGoogle Scholar
  86. 86.
    Vaarala O (2003) Immunological effects of probiotics with special reference to lactobacilli. Clin Exp Allergy 33:1634–1640PubMedGoogle Scholar
  87. 87.
    Feleszko W, Jaworska J, Rha RD, et al. (2007) Probiotic-induced suppression of allergic sensitization and airway inflammation is associated with an increase of T regulatory-dependent mechanisms in a murine model of asthma. Clin Exp Allergy 37:498–505PubMedGoogle Scholar
  88. 88.
    Forsythe P, Inman MD, Bienenstock J (2007) Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice. Am J Respir Crit Care Med 175:561–569PubMedGoogle Scholar
  89. 89.
    Ogawa T, Hashikawa S, Asai Y, et al. (2006) A new synbiotic, Lactobacillus casei subsp. casei together with dextran, reduces murine and human allergic reaction. FEMS Immunol Med Microbiol 46:400–409PubMedGoogle Scholar
  90. 90.
    Daniel C, Repa A, Wild C, et al. (2006) Modulation of allergic immune responses by mucosal application of recombinant lactic acid bacteria producing the major birch pollen allergen Bet v 1. Allergy 61:812–819PubMedGoogle Scholar
  91. 91.
    Sashihara T, Sueki N, Ikegami S (2006) An analysis of the effectiveness of heat-killed lactic acid bacteria in alleviating allergic diseases. J Dairy Sci 89:2846–2855PubMedGoogle Scholar
  92. 92.
    Noverr MC, Huffnagle GB (2005) The ‘microflora hypothesis’ of allergic diseases. Clin Exp Allergy 35:1511–1520PubMedGoogle Scholar
  93. 93.
    Lambrecht BN, Hammad H (2003) Taking our breath away: dendritic cells in the pathogenesis of asthma. Nat Rev Immunol 3:994–1003PubMedGoogle Scholar
  94. 94.
    van Rijt LS, Jung S, Kleinjan A, et al. (2005) In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J Exp Med 201:981–991PubMedGoogle Scholar
  95. 95.
    de Heer HJ, Hammad H, Soullie T, et al. (2004) Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J Exp Med 200:89–98PubMedGoogle Scholar
  96. 96.
    Akbari O, Umetsu DT (2005) Role of regulatory dendritic cells in allergy and asthma. Curr Allergy Asthma Rep 5:56–61PubMedGoogle Scholar
  97. 97.
    Vandenbulcke L, Bachert C, Van Cauwenberge P, et al. (2006) The innate immune system and its role in allergic disorders. Int Arch Allergy Immunol 139:159–165PubMedGoogle Scholar
  98. 98.
    Schroder NW, Maurer M (2007) The role of innate immunity in asthma: leads and lessons from mouse models. Allergy 62:579–590PubMedGoogle Scholar
  99. 99.
    Bauer S, Hangel D, Yu P (2007) Immunobiology of toll-like receptors in allergic disease. Immunobiology 212:521–533PubMedGoogle Scholar
  100. 100.
    Duez C, Gosset P, Tonnel AB (2006) Dendritic cells and toll-like receptors in allergy and asthma. Eur J Dermatol 16:12–16PubMedGoogle Scholar
  101. 101.
    Sabroe I, Read RC, Whyte MK, et al. (2003) Toll-like receptors in health and disease: complex questions remain. J Immunol 171:1630–1635PubMedGoogle Scholar
  102. 102.
    Bauer S, Kirschning CJ, Hacker H, et al. (2001) Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci USA 98:9237–9242PubMedGoogle Scholar
  103. 103.
    Schnare M, Barton GM, Holt AC, et al. (2001) Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2:947–950PubMedGoogle Scholar
  104. 104.
    Chaudhuri N, Whyte MK, Sabroe I (2007) Reducing the toll of inflammatory lung disease. Chest 131:1550–1556PubMedGoogle Scholar
  105. 105.
    Vercelli D (2006) Mechanisms of the hygiene hypothesis: molecular and otherwise. Curr Opin Immunol 18:733–737PubMedGoogle Scholar
  106. 106.
    Nigo YI, Yamashita M, Hirahara K, et al. (2006) Regulation of allergic airway inflammation through toll-like receptor 4-mediated modification of mast cell function. Proc Natl Acad Sci USA 103:2286–2291PubMedGoogle Scholar
  107. 107.
    Murakami D, Yamada H, Yajima T, et al. (2007) Lipopolysaccharide inhalation exacerbates allergic airway inflammation by activating mast cells and promoting Th2 responses. Clin Exp Allergy 37:339–347PubMedGoogle Scholar
  108. 108.
    Rodriguez D, Keller AC, Faquim-Mauro EL, et al. (2003) Bacterial lipopolysaccharide signaling through toll-like receptor 4 suppresses asthma-like responses via nitric oxide synthase 2 activity. J Immunol 171:1001–1008PubMedGoogle Scholar
  109. 109.
    Cochran JR, Khan AM, Elidemir O, et al. (2002) Influence of lipopolysaccharide exposure on airway function and allergic responses in developing mice. Pediatr Pulmonol 34:267–277PubMedGoogle Scholar
  110. 110.
    Eisenbarth SC, Piggott DA, Huleatt JW, et al. (2002) Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 196:1645–1651PubMedGoogle Scholar
  111. 111.
    Eisenbarth SC, Piggott DA, Huleatt JW, et al. (2002) Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 196:1645–1651PubMedGoogle Scholar
  112. 112.
    Pulendran B, Kumar P, Cutler CW, et al. (2001) Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. J Immunol 167:5067–5076PubMedGoogle Scholar
  113. 113.
    Lauener RP, Birchler T, Adamski J, et al. (2002) Expression of CD14 and toll-like receptor 2 in farmers' and non-farmers' children. Lancet 360:465–466PubMedGoogle Scholar
  114. 114.
    Kitagaki K, Businga TR, Kline JN (2006) Oral administration of CpG-ODNs suppresses antigen-induced asthma in mice. Clin Exp Immunol 143:249–259PubMedGoogle Scholar
  115. 115.
    Sel S, Wegmann M, Sel S, et al. (2007) Immunomodulatory effects of viral TLR ligands on experimental asthma depend on the additive effects of IL-12 and IL-10. J Immunol 178:7805–7813PubMedGoogle Scholar
  116. 116.
    Yang IA, Barton SJ, Rorke S, et al. (2004) Toll-like receptor 4 polymorphism and severity of atopy in asthmatics. Genes Immun 5:41–45PubMedGoogle Scholar
  117. 117.
    Eder W, Klimecki W, Yu L, et al. (2004) Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 113:482–488PubMedGoogle Scholar
  118. 118.
    Ahmad-Nejad P, Mrabet-Dahbi S, Breuer K, et al. (2004) The toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe pheno-type. J Allergy Clin Immunol 113:565–567Google Scholar
  119. 119.
    Fageras BM, Hmani-Aifa M, Lindstrom A, et al. (2004) A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J Allergy Clin Immunol 114:561–567Google Scholar
  120. 120.
    Busse WW, Rosenwasser LJ (2003) Mechanisms of asthma. J Allergy Clin Immunol 111:S799–S804PubMedGoogle Scholar
  121. 121.
    Nakajima H, Takatsu K (2007) Role of cytokines in allergic airway inflammation. Int Arch Allergy Immunol 142:265–273PubMedGoogle Scholar
  122. 122.
    Romagnani S (2004) Immunologic influences on allergy and the TH1/TH2 balance. J Allergy Clin Immunol 113:395–400PubMedGoogle Scholar
  123. 123.
    Kearley J, McMillan SJ, Lloyd CM (2007) Th2-driven, allergen-induced airway inflammation is reduced after treatment with anti-Tim-3 antibody in vivo. J Exp Med 204:1289–1294PubMedGoogle Scholar
  124. 124.
    Qu Y, Zhao Y (2007) Regulatory CD4(+)CD25(+) T-cells are controlled by multiple pathways at multiple levels. Int Rev Immunol 26:145–160PubMedGoogle Scholar
  125. 125.
    Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336PubMedGoogle Scholar
  126. 126.
    O'Garra A, Vieira P (2004) Regulatory T cells and mechanisms of immune system control. Nat Med 10:801–805PubMedGoogle Scholar
  127. 127.
    Stock P, DeKruyff RH, Umetsu DT (2006) Inhibition of the allergic response by regulatory T cells. Curr Opin Allergy Clin Immunol 6:12–16PubMedGoogle Scholar
  128. 128.
    Xystrakis E, Boswell SE, Hawrylowicz CM (2006) T regulatory cells and the control of allergic disease. Expert Opin Biol Ther 6:121–133PubMedGoogle Scholar
  129. 129.
    Kearley J, Barker JE, Robinson DS, et al. (2005) Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med 202:1539–1547PubMedGoogle Scholar
  130. 130.
    Lapa e Silva JR, Possebon dS, Lefort J, et al. (2000) Endotoxins, asthma, and allergic immune responses. Toxicology 152:31–35PubMedGoogle Scholar
  131. 131.
    Baldini M, Lohman IC, Halonen M, et al. (1999) A polymorphism* in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 20:976–983PubMedGoogle Scholar
  132. 132.
    Koppelman GH, Reijmerink NE, Colin SO, et al. (2001) Association of a promoter polymorphism of the CD14 gene and atopy. Am J Respir Crit Care Med 163:965–969PubMedGoogle Scholar
  133. 133.
    Ober C, Tsalenko A, Parry R, et al. (2000) A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am J Hum Genet 67:1154–1562PubMedGoogle Scholar
  134. 134.
    Kabesch M, Hasemann K, Schickinger V, et al. (2004) A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases. Allergy 59:520–525PubMedGoogle Scholar
  135. 135.
    Blumer N, Sel S, Virna S, et al. (2007) Perinatal maternal application of Lactobacillus rham-nosus GG suppresses allergic airway inflammation in mouse offspring. Clin Exp Allergy 37:348–357PubMedGoogle Scholar
  136. 136.
    von Mutius E, Schmid S (2006) The PASTURE project: EU support for the improvement of knowledge about risk factors and preventive factors for atopy in Europe. Allergy 61:407–413Google Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Petra Ina Pfefferle
    • 1
  • René Teich
    • 1
  • Harald Renz
    • 1
  1. 1.Department of Clinical Chemistry and Molecular DiagnosticsPhilipps-University of MarburgMarburgGermany

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