Prenatal animal contact and gene expression of innate immunity receptors at birth are associated with atopic dermatitis

Published:November 29, 2010DOI:


      Cross-sectional studies have suggested that prenatal farm exposures might protect against allergic disease and increase the expression of receptors of the innate immune system. However, epidemiologic evidence supporting the association with atopic dermatitis remains inconsistent.


      To study the association between prenatal farm-related exposures and atopic dermatitis in a prospective study. We further analyzed the association between the expression of innate immune genes at birth and atopic dermatitis.


      A total of 1063 children who participated in a birth cohort study, Protection against Allergy-Study in Rural Environments, were included in this study. Doctor diagnosis of atopic dermatitis was reported by the parents from 1 to 2 years of age by questionnaire. Gene expression of Toll-like receptors (TLRs) and CD14 was assessed in cord blood leukocytes by quantitative PCR.


      Maternal contact with farm animals and cats during pregnancy had a significantly protective effect on atopic dermatitis in the first 2 years of life. The risk of atopic dermatitis was reduced by more than half among children with mothers having contact with 3 or more farm animal species during pregnancy compared with children with mothers without contact (adjusted odds ratio, 0.43; 95% CI, 0.19-0.97). Elevated expression of TLR5 and TLR9 in cord blood was associated with decreased doctor diagnosis of atopic dermatitis. A significant interaction between polymorphism in TLR2 and prenatal cat exposure was observed in atopic dermatitis.


      Maternal contact with farm animals and cats during pregnancy has a protective effect on the development of atopic dermatitis in early life, which is associated with a lower expression of innate immune receptors at birth.

      Key words

      Abbreviations used:

      EFRAIM (Mechanism of Early Protective Exposures on Allergy Development), GEE (General estimating equation), GMR (Geometric mean ratio), ISAAC (International Study of Asthma and Allergies in Childhood), OR (Odds ratio), PASTURE (Protection against Allergy-Study in Rural Environments), SNP (Single nucleotide polymorphism), TLR (Toll-like receptor)
      To read this article in full you will need to make a payment


      Subscribe to Journal of Allergy and Clinical Immunology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee.
        Lancet. 1998; 351: 1225-1232
        • Luoma R.
        • Koivikko A.
        • Viander M.
        Development of asthma, allergic rhinitis and atopic dermatitis by the age of five years: a prospective study of 543 newborns.
        Allergy. 1983; 38: 339-346
        • Riedler J.
        • Braun-Fahrlander C.
        • Eder W.
        • Schreuer M.
        • Waser M.
        • Maisch S.
        • et al.
        Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey.
        Lancet. 2001; 358: 1129-1133
        • Von Ehrenstein O.S.
        • Von Mutius E.
        • Illi S.
        • Baumann L.
        • Bohm O.
        • von Kries R.
        Reduced risk of hay fever and asthma among children of farmers.
        Clin Exp Allergy. 2000; 30: 187-193
        • Alfven T.
        • Braun-Fahrlander C.
        • Brunekreef B.
        • von Mutius E.
        • Riedler J.
        • Scheynius A.
        • et al.
        Allergic diseases and atopic sensitization in children related to farming and anthroposophic lifestyle—the PARSIFAL study.
        Allergy. 2006; 61: 414-421
        • Strachan D.P.
        Hay fever, hygiene, and household size.
        BMJ. 1989; 299: 1259-1260
        • Gibbs S.
        • Surridge H.
        • Adamson R.
        • Cohen B.
        • Bentham G.
        • Reading R.
        Atopic dermatitis and the hygiene hypothesis: a case-control study.
        Int J Epidemiol. 2004; 33: 199-207
        • Flohr C.
        • Pascoe D.
        • Williams H.C.
        Atopic dermatitis and the "hygiene hypothesis": too clean to be true?.
        Br J Dermatol. 2005; 152: 202-216
        • Ege M.J.
        • Bieli C.
        • Frei R.
        • van Strien R.T.
        • 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: 817-823
        • 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: 603-611
        • Lauener R.P.
        • Birchler T.
        • Adamski J.
        • Braun-Fahrlander C.
        • Bufe A.
        • Herz U.
        • et al.
        Expression of CD14 and Toll-like receptor 2 in farmers' and non-farmers' children.
        Lancet. 2002; 360: 465-466
        • Eder W.
        • Klimecki W.
        • Yu L.
        • von Mutius E.
        • Riedler J.
        • Braun-Fahrlander C.
        • et al.
        Toll-like receptor 2 as a major gene for asthma in children of European farmers.
        J Allergy Clin Immunol. 2004; 113: 482-488
        • Fageras Bottcher M.
        • Hmani-Aifa M.
        • Lindstrom A.
        • Jenmalm M.C.
        • Mai X.M.
        • Nilsson L.
        • et al.
        A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children.
        J Allergy Clin Immunol. 2004; 114: 561-567
        • Smit L.A.
        • Siroux V.
        • Bouzigon E.
        • Oryszczyn M.P.
        • Lathrop M.
        • Demenais F.
        • et al.
        CD14 and toll-like receptor gene polymorphisms, country living, and asthma in adults.
        Am J Respir Crit Care Med. 2009; 179: 363-368
        • Werner M.
        • Topp R.
        • Wimmer K.
        • Richter K.
        • Bischof W.
        • Wjst M.
        • et al.
        TLR4 gene variants modify endotoxin effects on asthma.
        J Allergy Clin Immunol. 2003; 112: 323-330
        • Novak N.
        • Yu C.F.
        • Bussmann C.
        • Maintz L.
        • Peng W.M.
        • Hart J.
        • et al.
        Putative association of a TLR9 promoter polymorphism with atopic eczema.
        Allergy. 2007; 62: 766-772
        • von Mutius E.
        • Schmid S.
        The PASTURE project: EU support for the improvement of knowledge about risk factors and preventive factors for atopy in Europe.
        Allergy. 2006; 61: 407-413
        • Asher M.I.
        • Keil U.
        • Anderson H.R.
        • Beasley R.
        • Crane J.
        • Martinez F.
        • et al.
        International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods.
        Eur Respir J. 1995; 8: 483-491
        • Bieli C.
        • Frei R.
        • Schickinger V.
        • Steinle J.
        • Bommer C.
        • Loeliger S.
        • et al.
        Gene expression measurements in the context of epidemiological studies.
        Allergy. 2008; 63: 1633-1636
        • Kormann M.S.
        • Carr D.
        • Klopp N.
        • Illig T.
        • Leupold W.
        • Fritzsch C.
        • et al.
        G-Protein-coupled receptor polymorphisms are associated with asthma in a large German population.
        Am J Respir Crit Care Med. 2005; 171: 1358-1362
        • Kormann M.S.
        • Depner M.
        • Hartl D.
        • Klopp N.
        • Illig T.
        • Adamski J.
        • et al.
        Toll-like receptor heterodimer variants protect from childhood asthma.
        J Allergy Clin Immunol. 2008; 122 (e1-8): 86-92
        • Benjamini Y.
        Controlling the false discovery rate: a practical and powerful approach to multiple testing.
        J R Stat Soc Series B Stat Methodol. 1995; 57: 289-300
        • Conrad M.L.
        • Ferstl R.
        • Teich R.
        • Brand S.
        • Blumer N.
        • Yildirim A.O.
        • et al.
        Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78.
        J Exp Med. 2009; 206: 2869-2877
        • 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: 869-877
        • Riedler J.
        • Eder W.
        • Oberfeld G.
        • Schreuer M.
        Austrian children living on a farm have less hay fever, asthma and allergic sensitization.
        Clin Exp Allergy. 2000; 30: 194-200
        • Braun-Fahrlander C.
        • Gassner M.
        • Grize L.
        • Neu U.
        • Sennhauser F.H.
        • Varonier H.S.
        • et al.
        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. 1999; 29: 28-34
        • Braback L.
        • Hjern A.
        • Rasmussen F.
        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. 2004; 34: 38-43
        • Ege M.J.
        • Frei R.
        • Bieli C.
        • Schram-Bijkerk D.
        • Waser M.
        • Benz M.R.
        • et al.
        Not all farming environments protect against the development of asthma and wheeze in children.
        J Allergy Clin Immunol. 2007; 119: 1140-1147
        • Krauss-Etschmann S.
        • Hartl D.
        • Heinrich J.
        • Thaqi A.
        • Prell C.
        • Campoy C.
        • et al.
        Association between levels of Toll-like receptors 2 and 4 and CD14 mRNA and allergy in pregnant women and their offspring.
        Clin Immunol. 2006; 118: 292-299
        • Halkjaer L.B.
        • Loland L.
        • Buchvald F.F.
        • Agner T.
        • Skov L.
        • Strand M.
        • et al.
        Development of atopic dermatitis during the first 3 years of life: the Copenhagen prospective study on asthma in childhood cohort study in high-risk children.
        Arch Dermatol. 2006; 142: 561-566
        • Hayashi F.
        • Smith K.D.
        • Ozinsky A.
        • Hawn T.R.
        • Yi E.C.
        • Goodlett D.R.
        • et al.
        The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5.
        Nature. 2001; 410: 1099-1103
        • Hemmi H.
        • Takeuchi O.
        • Kawai T.
        • Kaisho T.
        • Sato S.
        • Sanjo H.
        • et al.
        A Toll-like receptor recognizes bacterial DNA.
        Nature. 2000; 408: 740-745
        • Vicente-Suarez I.
        • Brayer J.
        • Villagra A.
        • Cheng F.
        • Sotomayor E.M.
        TLR5 ligation by flagellin converts tolerogenic dendritic cells into activating antigen-presenting cells that preferentially induce T-helper 1 responses.
        Immunol Lett. 2009; 125: 114-118
        • Martin-Orozco E.
        • Kobayashi H.
        • Van Uden J.
        • Nguyen M.D.
        • Kornbluth R.S.
        • Raz E.
        Enhancement of antigen-presenting cell surface molecules involved in cognate interactions by immunostimulatory DNA sequences.
        Int Immunol. 1999; 11: 1111-1118
        • Ahmad-Nejad P.
        • Mrabet-Dahbi S.
        • Breuer K.
        • Klotz M.
        • Werfel T.
        • Herz U.
        • et al.
        The toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype.
        J Allergy Clin Immunol. 2004; 113: 565-567