SCOR IN CELLULAR AND MOLECULAR MECHANISMS OF ASTHMA

Most cases of asthma begin during the first years of
life. This suggests that a significant proportion of the risk for the
development of asthma can be attributed to complex gene by environment
interactions occurring during these early years. Understanding the
developmental alterations of the immune system in early life that are
associated with the subsequent development of asthma, is essential to
designing a strategy for primary and secondary prevention of the disease. In
this SCOR proposal we will integrate molecular, immunologic, genetic, genomic,
and epidemiologic approaches to study the immune, genetic, and environmental
interactions that occur at the beginning of asthma. In Project 1 we explore
the gene by environment interactions that may be involved in the apparent
protective effect of an increased microbial burden in early life on the
development of early allergic sensitization and asthma. A population sample of
children living in rural areas of Europe and in whom exposure to indoor
endotoxin has been assessed will be studied. Known or newly discovered
polymorphisms in genes coding for the main components of the endotoxin
response system will be assessed and related to endotoxin exposure and
asthma-related outcomes. In Project 2, the genetic and immune factors that
explain the strong and independent relation between atopic dermatitis (eczema)
in early life and the subsequent development of asthma will be explored. It is
well known that most children who will go on to develop asthma show
Th2-deviated responses to local aeroallergens very early in life, but not all
children who do show such responses develop the disease. Project 3 will
explore the complex molecular mechanisms that determine if a Th2-deviated
response will result in the synthesis of IgG4, IgE or both in humans. Finally,
we have recently described five new polymorphisms in the promoter region of
the CD14 gene. We have shown that these polymorphisms are associated with
total serum IgE levels in school children. Project 4 will explore the biology
of novel proximal and distant regulatory elements of the CD14 gene and will
thus provide new insights on the mechanisms by which the innate immune
response may influence the susceptibility to early allergies and asthma.
Our SCOR offers a unique opportunity to study in a comprehensive manner the
way in which environmental factors and genetic background influence the
maturation of the immune system during the initial phases of the asthma
process.