Influence of maternal atopy and innate and adaptive immune stimuli on cord blood hematopoietic progenitor cells

Abstract

<p>The recent and dramatic rise in allergic disease, coupled with the manifestation of the disease within the first years of life, suggests that <em>in utero</em> events are likely critically important to the inception of allergy. Epidemiological and experimental evidence suggest that both genetic predisposition and prenatal environmental exposures (e.g., <em>in utero</em> microbial exposures) play a role in modulating neonatal immunity and subsequent development of allergy. Of relevance to the work in this thesis, reports suggest that bacterial agents can directly alter myelopoiesis and, in connection to allergy, we have previously shown that cord blood (CB) progenitors from high-atopic risk infants demonstrate altered hematopoietic responses. However, whether CB progenitor cell hematopoietic responses are directly altered by microbial stimulation, and what effect maternal atopy has on these responses are unclear. Therefore, this thesis examines the influences of bacterial lipopolysaccharide (LPS) stimulation (innate immunity), maternal atopy, and adaptive immune stimuli (representative of an atopic milieu) on CB progenitor cell eosinophilopoiesis. We show that CB progenitors from healthy, pregnant women respond to LPS through increased eosinophil-basophil (Eo/B) colony forming units (CFU) via the mitogen-activated protein kinase (MAPK) signalling pathway (Chapter 2), whereas the presence of maternal atopy (as defined by skin prick test positivity) is associated with reduced CB CD34⁺ cell LPS-induced Eo/B CFU formation (Chapter 3). To investigate the potential mechanism of reduced eosinophilopoiesis in high-atopic risk infants, CB progenitors stimulated with IL-4 (a surrogate <em>ex vivo</em> for maternal atopy), but not IL-13, demonstrate reduced LPS-induced MAPK activation and Eo/B CFU formation (Chapter 4). This novel work provides insight into mechanisms relating to the influence of maternal atopy and/or potential intrauterine exposures (e.g., prenatal cytokines) on the responsiveness of CB progenitor cells to LPS, which may be of key importance for the development of atopic illnesses. These observations may help in the generation of novel biomarkers and therapeutic targets for childhood atopy.</p>