The long-term objective of this study is to address the complex interactions between environmental factors and genetic background in determining the onset of asthma in early life. To accomplish this objective we propose to establish the major molecular mechanisms and assess the impact on immune development in early life of a frequent polymorphism that we have recently identified in the promoter region of the CD14 gene. CD14 is the main receptor for lipopolysaccharide and other bacterial """"""""danger"""""""" signals. These signals may play a crucial role in deviating primary immune responses towards a mature, Th-l-like phenotype by enhancing IL-12 production by antigen presenting cells. We found that one genotype of the CD14 polymorphism was associated with increased levels of circulating soluble CD14 and with increased interferon-gamma responses and decreased IL-4 responses to mitogens by peripheral blood mononuclear cells. The same CD14 genotype was also associated with decreased total serum IgE levels in atopic Caucasian children. We hypothesize that subjects who are genetically predisposed to having higher CD14 expression will be more responsive to bacterial """"""""danger"""""""" signals that deviate their immune reactions towards a Th-1 like phenotype at the time of the first encounters with an antigen. We thus propose to assess longitudinally the development of Th-0/Th-1/Th-2 responses in infants with different CD14 genotypes who will be enrolled at birth. We will also assess the maturation of IL-12 responses by antigen presenting cells and the molecular basis of immaturity of IL-12 expression. CD14 genotypes will be assessed for influence on IgE production and allergic sensitization occurring during the first three years of life. Finally, we will use electrophoretic mobility shift assays and promoter reporter constructs to determine the nature of the alterations in promoter function induced by the newly discovered CD14 polymorphism. A better understanding of the gene-by-environment interactions in the development of the immune responses in early life may allow us to design more powerful primary prevention strategies for asthma and allergies at or before the time in which these two phenotypes are first established.
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