Seminar addresses developmental origins of immune disease
By Heather King
Biochemist Paige Lawrence, Ph.D., delivered a guest lecture April 26 at NIEHS, hosted by NIEHS Health Scientist Administrator Mike Humble, Ph.D. Her talk, “Developmental exposures, epigenetics, and the immune system” addressed the relationship between environmental agents and defects in the immune system that she has identified in the course of her NIEHS-funded (http://projectreporter.nih.gov/project_info_description.cfm?aid=8204752&icde=12406577&ddparam=&ddvalue=&ddsub=&cr=2&csb=default&cs=ASC) research.
Lawrence is a professor at the University of Rochester Medical Center School of Medicine and Dentistry where she holds appointments in both Environmental Medicine, and Microbiology and Immunology. The research Lawrence (http://lifesciences.envmed.rochester.edu/test/index.html) presented focused on how maternal dioxin exposure during pregnancy can alter the immune response of a developing fetus or newborn and lead to increased rates of respiratory infection. Dioxins are found in cigarette smoke and are a common environmental pollutant, and understanding the biological mechanisms behind their adverse effects on human health is a major NIEHS initiative.
A focus on dioxins
While Lawrence has also studied the immune effects of other environmental agents, such as bisphenol A (BPA) and neonatal oxygen supplementation, her talk focused on dioxins and other molecules that bind the aryl hydrocarbon receptor (AhR). The AhR is a biological sensor that binds toxins and, in response, stimulates the expression of various proteins, including toxin-metabolizing enzymes and cytokines, which regulate the immune system.
By treating mice with the classic dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at low, environmentally relevant doses, Lawrence’s group has been able to observe an altered immune response while maintaining a functional, intact immune system.
Increased susceptibility to influenza
After treating pregnant mice with TCDD, researchers exposed the offspring to mouse-adapted influenza A virus. Compared to the offspring of unexposed mice, the dioxin-exposed mice produced fewer virus-targeting cells and had an overall weakened immune response.
The timing of maternal exposure was also relevant, with dioxin exposure during the later stages of pregnancy and the early postnatal period causing a more significant reduction in immune response.
Effects on offspring follow bone marrow graft
Notably, the dioxin-altered immune response Lawrence observes can be transferred from animal to animal, by transplanting the immune precursor cells found in bone marrow. Her research group demonstrated this by performing bone marrow transplantation between exposed and unexposed mouse pups. The dioxin-induced immune defects follow the grafts, showing that biological changes in the basic immune cells are the source of the defective response.
Evidence for epigenetic changes in immune cells
Though epigenetic regulation of the immune system is not well studied, Lawrence decided to investigate the possibility that such changes, which include DNA methylation and histone modifications, are factors in the immune response to maternal dioxin exposure. To properly evaluate epigenetic changes, researchers in her group had to first sort specific types of immune cells, from the lymph nodes of exposed and unexposed mice, into groups. This labor-intensive project paid off, by showing that significant changes in DNA methylation go along with the dioxin-induced immune changes she has observed.
Lawrence found that a specific type of immune cell, the CD8+ T cell, shows interesting changes in the levels of a key DNA methyltransferase. Preliminary results also show differences in global DNA methylation patterns between the offspring of dioxin exposed versus unexposed mice. To perform global studies of DNA methylation changes, Lawrence is working in collaboration with professor Lee Kraus, Ph.D., of the University of Texas Southwestern Medical Center. Together, they are studying epigenetic changes across the genome in CD8+ T cells, and other immune cells, following maternal dioxin exposure. These studies and others in Lawrence’s laboratory promise to bring new attention to epigenetic changes that play a role in the immune response, especially changes resulting from environmental exposures.
The Keystone Science Lecture Seminar Series gives NIEHS-supported investigators, such as Lawrence, the opportunity to present findings about environmental exposures that affect human health.
(Heather King, Ph.D., is an Intramural Research Training Award fellow in the NIEHS Laboratory of Structural Biology Protein Expression Core.)
Mutants show the AhR receptor is key, not nurturing behaviors
To connect the impaired immune response in mouse pups to dioxin exposure, researchers in the Lawrence laboratory repeated their experiments with pups lacking the dioxin receptor, AhR.
They found offspring that do not produce dioxin receptor, do not exhibit immune defects with maternal dioxin exposure, establishing the critical role of AhR in the altered immune function and the specific AhR-based pathway of impaired immunity. The experiments also show changes in maternal nurturing behaviors that could result from exposure are not a factor, because exposed mothers produce pups without immune defects when those pups lack AhR.