PLoS One. 2014 Mar 6;9(3):e91097.
Expression of genes related to anti-inflammatory pathways are modified among farmers’ children.
Remo Frei and Caroline Roduit et al.
BACKGROUND: The hygiene hypothesis states that children exposed to higher loads of microbes such as farmers’ children suffer less from allergies later in life. Several immunological mechanisms underpinning the hygiene hypothesis have been proposed such as a shift in T helper cell balance, T regulatory cell activity, or immune regulatory mechanisms induced by the innate immunity.
OBJECTIVE: To investigate whether the proposed immunological mechanisms for the hygiene hypotheses are found in farmers’ children.
METHODS: We assessed gene expression levels of 64 essential markers of the innate and adaptive immunity by quantitative real-time PCR in white blood cells in 316 Swiss children of the PARSIFAL study to compare farmers’ to non-farmers’ expressions and to associate them to the prevalence of asthma and rhinoconjunctivitis, total and allergen-specific IgE in serum, and expression of Cε germ-line transcripts.
RESULTS: We found enhanced expression of genes of the innate immunity such as IRAK-4 and RIPK1 and enhanced expression of regulatory molecules such as IL-10, TGF-β, SOCS4, and IRAK-2 in farmers’ children. Furthermore, farmers’ children expressed less of the TH1 associated cytokine IFN-γ while TH2 associated transcription factor GATA3 was enhanced. No significant associations between the assessed immunological markers and allergic diseases or sensitization to allergens were observed.
CONCLUSION:Farmers’ children express multiple increased innate immune response and immune regulatory molecules, which may contribute to the mechanisms of action of the hygiene hypothesis.
A global rise in the prevalence of allergic diseases has been observed over the past decades with a higher prevalence of the diseases in Western countries than in developing countries. Nowadays, until 30% of children are affected by an allergic disease.
The epidemiologist David Strachan observed in 1989 that children suffered less from allergic rhinitis and atopic dermatitis with increasing numbers of siblings. The protective effect was attributed to more frequent infections during childhood.1 This observation led him formulate of the so-called hygiene hypothesis: a lack of infection in early childhood increases the risk of allergic diseases later in life.2
Since then the concept of the hygiene hypothesis has been extended to other immune-mediated diseases, such as type 1 diabetes and inflammatory bowel disease.3 Additionally, the spectrum of protective exposures was extended. So, environmental exposures with high levels of microbial components not causing infection, such as farming, have been suggested as one of the major preventive factors for allergy development.4
Several immune mechanisms underpinning the hygiene hypothesis have been described, mostly based on in vitro experiments or mouse models. The aim of our study was to reproduce these mechanisms in the context of the epidemiological PARSIFAL ((Prevention of Allergy Risk factors for Sensitization In children related to Farming and Anthroposophic Lifestyle). This study aimed to investigate factors making farm-life that protective.5 Therefore, we measured the expression levels of a whole bunch of immunological markers in white blood cells of the participating children. We then assessed whether these gene expression levels were regulated by farm-life on the one hand and whether they were associated with allergic health outcomes on the other hand.
Our results indicate that regulatory mechanisms induced by the innate immunity and less by T helper cells were induced in farm-children compared to children also living in rural areas but not on a farm. Regulatory molecules of the innate immunity and regulatory cytokines, such as IL-10 and TGF-β seemed to be critical.
The innate immune system constitutes the first line of defense to foreign molecules, such as microbes, and directs the adaptive immune response by T helper cell activation. The activation of the innate immunity is a tightly regulated process. It is already known that over activation might induce chronic inflammation leading to diseases such as allergies, colitis, or autoimmunity. Our data emphasize that growing up on a farm tunes the regulation of the innate immunity and thereby protects the children from the outbreak of an allergic disease.
- Bach, J.F. The effect of infections on susceptibility to autoimmune and allergic diseases. The New England journal of medicine 347, 911-920 (2002).
- Strachan, D.P. Hay fever, hygiene, and household size. BMJ (Clinical research ed 299, 1259-1260 (1989).
- Brown, E.M., Arrieta, M.C. & Finlay, B.B. A fresh look at the hygiene hypothesis: how intestinal microbial exposure drives immune effector responses in atopic disease. Seminars in immunology 25, 378-387 (2013).
- Braun-Fahrlander, C., 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 29, 28-34 (1999).
- Alfven, T., et al. Allergic diseases and atopic sensitization in children related to farming and anthroposophic lifestyle–the PARSIFAL study. Allergy 61, 414-421 (2006).