Emerging experimental and observational data suggest that the immune system is susceptible to the influence of early life exposure to exogenous factors. The immune system begins to develop in utero, and continues to undergo tightly regulated developmental processes through adolescence and early adulthood. However, knowledge remains scant regarding how environmental exposures earlier in life modify susceptibility of immune cells to functional deficits throughout childhood and into adolescence, especially for the human immune system. Current evidence that environmental exposures perturb human immune function during early life is primarily limited to infants and young children. Presently, there is almost no information about how these observations relate to immune function during other critical developmental stages, such as adolescence. The objective of this project is to define how exposure to a specific category of environmental agents, polychlorinated biphenyls (PCBs), during key developmental periods, affects immune functions throughout childhood and into adolescence. The proposed work builds directly on findings that higher infant PCB levels are strongly associated with lower vaccine responses and greater respiratory morbidity in a birth cohort in eastern Slovakia. The proposed work will examine adaptive immune function and infection in 400 adolescents from this cohort. Building on our finding that 6-month PCB levels were inversely associated with anti-BCG specific antibody levels, our first aim will determine IgG- and IgA-specific anti-BCG and -MMR levels at 45 months, and 7 and 16 years of age. Leveraging extensive pre- and postnatal exposure data, this will allow the estimation of age-specific PCB- antibody associations, as well as permit the estimation of vaccine response trajectory over time.
This aim i s particularly important since vaccines administered in infancy are intended to create durable responses that contribute to protection as children age.
Our second aim examines PCB exposure in relation to functionality of distinct B cell and T cell subsets. Higher PCB concentrations are associated with lower antibody levels to vaccination in several studies. However, the mechanism is not known, and specific lymphocyte sub-types and functional capacity remain poorly characterized: data from this aim will help fill this knowledge gap. In the third aim, we will use PCR-based methods to measure the frequency of 22 common respiratory pathogens over a 1- year period of follow-up, including asymptomatic and symptomatic collections. We will also abstract physician- diagnosed lower respiratory tract infections (LRTIs) from birth through 16 years. With these measured endpoints, associations between pre- and postnatal PCB concentrations and symptomatic and asymptomatic respiratory infection will be assessed. By extending research with this established cohort from birth to adolescence, we will obtain new information about how this category of common pollutants impacts the human immune system.
This project addresses an issue of direct public health relevance, the findings of which will be broadly applicable to populations around the world. Altered immune function, leading to decreased vaccine responses or increased respiratory infection, is a serious global public health concern. This project will advance our understanding of how ubiquitous environmental exposures, such as polychlorinated biphenyls, affect these outcomes, moving us closer to effective primary prevention strategies to further reduce the burden of infectious disease.