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Project 2: Mechanisms of Polycyclic Aromatic Hydrocarbon-Linked Immunopathogene


Our overall objective is to determine the molecular mechanisms by which immune dysregulation leads to human disease, specifically the atopic diseases of food allergy, allergic rhinitis, allergic conjunctivitis and allergic asthma in the children exposed to high levels of PAHs (polycyclic aromatic hydrocarbons). We previously published work on an important link between PAH exposure in AAP and changes at the DNA level in immune cells that led to their impaired function. This decrease in cell function was directly associated with increases in Th2 cytokines, IL-4 and IL-13, and subsequent clinical outcomes of allergy and asthma, including decreased lung function, in the same pediatric subjects. However, the effect of these cellular changes on allergic disorders was not evaluated at the time; therefore, we will focus on the effects of PAH and will determine whether PAH exposure is associated with systemic immune dysregulation, leading to atopic diseases (food allergy, allergic rhinitis, allergic conjunctivitis, and allergic asthma). T cells are key mediators of the adaptive immune system and play critical roles in modulating inflammation (specifically regulatory T cells or Treg) and inducing allergy (i.e., Th2 effector cells which can lead to isotype switching of B cells to synthesize IgE, a molecule associated with allergies). <p/>To date, we have focused our studies on isolated T cell subsets; and, in this proposal, we will conduct studies on Th subsets to be able to elucidate the full mechanisms of how PAHs modulate the immune system. To do this, our approach is to perform a cross-sectional analysis in a well defined 'piece-wise' continuum of all pediatric ages in immune development for whom detailed information will be collected on human disease outcomes and for whom blood, saliva, and urine samples will be collected at repeated time points. We plan to use novel and innovative immunological studies including epigenetic pyrosequencing studies on single cells and massspectrometry based flow cytometry for detection of 38 simultaneous immune cell parameters. In this way, we will be able to determine key time points of sensitivity of the immune system to PAH exposure by defining the molecular mechanisms that play a role in immune system impairment during immune development.

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PUBLIC HEALTH RELEVANCE: By understanding the exact molecular links between PAH exposure and human disease at different stages in immune development in childhood, we can be better informed i) to make public policy changes that reduce or prevent exposures at critical ages in children, ii) to target monitoring of exposures, iii) to determine the extent to which the changes induced by PAH exposures on the immune system could lead to allergic disorders.

Nadeau, Kari C
University of California - Berkeley
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