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Lucas Casaca, Vera Isabel (2014): Role of Th1 and Th2 cell-specific polymorphisms and of Regulatory T cells modulated by farm exposure for the determination of childhood allergic diseases. Dissertation, LMU München: Medizinische Fakultät



Summary: Allergic diseases have exponentially increased during the last decades. The complexity of its aetiology is due to multifaceted interactions between genetic and environmental factors on the development of the immune system. While advances of technology have identified allergy susceptibility genes, functional assays are needed to better understand the underlying mechanisms. Epidemiological studies have consistently shown that rural/farm environments are protective for the development of allergic diseases, including asthma and atopic sensitization. Importantly, prenatal and early life exposures have been shown to confer the strongest protection effects. The mechanisms of how farming modulates the immune system are still not disentangled in detail but include regulation of innate receptors and Regulatory T cells. In the herewith presented thesis, the following main findings were achieved in the context of genetic and immunological influences on development of allergic disease in two different birth cohort studies: First, 200 neonates were assessed for genetic influence of polymorphisms on neonatal immune responses and development of allergic diseases in childhood. The present study suggested a role for polymorphisms in the Th2-pathway, particularly for STAT6 rs324011, on immune regulation at an early stage of immune maturation, namely significantly lower Treg-associated gene expression and Th1-polarization. Polymorphisms in the Th1-pathway, namely the transcription factors TBX21 and HLX1, were shown to be relevant in shaping early immune responses and mainly Th2 cytokines at birth. Th1 and Th2 genotype-related immune responses at birth were partially associated with development of allergic diseases and/or protection during early life. These children are currently followed until the age of 6 years to further investigate allergic and respiratory disease during age-related immune maturation. Secondly, almost 150 children were investigated at the age of 6 years to assess the role of regulatory T cells in relation to farm exposures and clinical outcomes of allergic diseases. Our data indicated an inverse association of farm exposures and the prevalence of asthma during childhood. Children exposed to hay, stable and farm milk had a lower prevalence of asthma. Regarding underlying immune mechanisms, we have detected that children with contact to hay have increased levels of Treg cells and that farm milk intake earlier during childhood can still be partially reflected on Treg cells levels at age 6 years. Assessing Treg functional mechanisms, changes in cytokine secretion were observed depending on the farming and asthmatic status of the children, however confirmation in a larger number of children is required In summary the present work indicated that Th1 and Th2 polymorphisms were associated with modulated immune responses already at birth and influenced allergic disease development during the first three years of life. Furthermore, farm exposures were associated with a lower prevalence of asthma and associated with modulation of regulatory T cell frequency in German children at age 6 years.