Role of Th1 and Th2 cell-specific polymorphisms and of Regulatory T cells modulated by farm exposure for the determination of childhood allergic diseases

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.