Apoptosis Team.

Several members of the Sherr Laboratory team investigate how polycyclic aromatic hydrocarbons (PAH) induce cell suicide (apoptosis). Recent studies have demonstrated that a number of common environmental pollutants (e.g., aromatic hydrocarbons, dioxins, PCBs) compromise the immune system as well as induce cancer. Like immunosuppressive therapeutics (e.g., steroids), these compounds induce thymic atrophy, decrease resistance to infectious agents and tumors, impair B cell antibody responses, decrease cytotoxic T cell activity, inhibit natural killer activity and decrease cytokine production. Immunotoxicity mediated by extremely low concentrations of environmental pollutants is regulated by a cytoplasmic aryl hydrocarbon receptor (AhR), which, when bound by hydrocarbons, dioxins, or PCBs, translocates to the nucleus, binds specific gene promoter DNA sequences, and induces transcription of a number of genes including proto-oncogenes and cytokine genes. Members of the Sherr Laboratory have demonstrated that the developing immune system is particularly sensitive to AhR ligands. That is, low doses of PAH induce bone marrow stromal cells to elaborate a death factor which induces programmed cell death/apoptosis in neighboring pre-B lymphocytes. This observation implies that environmental chemicals can compromise immune system development and that the AhR may play a role in B lymphocyte development through apoptosis regulation.

Much of the “A” team has been unraveling the network of intracellular signals that occur within bone marrow B cells following exposure to PAH and resulting in cell suicide. Jessica Emberley, a pre-doctoral student in the Boston University Immunology Training Program, has developed elegant systems for mapping this pathway. Extending the work of Heui-Young Ryu, DSc, formerly of the Sherr Laboratory, Emberley has demonstrated that the B cell death pathway is not mediated by TNF receptor family-mediated signaling but likely begins with activation of several caspases. She also has demonstrated that multiple interacting apoptosis pathways involving caspases, mitochondria, and apoptosis-promoting genes contribute to environmental chemical-induced bone marrow B cell apoptosis. Some of this apoptosis work has been performed in collaboration with the laboratory of Dr. Jennifer Schlezinger, a Research Assistant Professor in the Department of Environmental Health who studies environmental phthaltes and other activators of a receptor called PPAR which induce rapid bone marrow B cell death. These studies represent an important step forward in the clarification of how environmental chemicals dysregulate pre-B cell development.

Several additional cell subsets within lymphoid organs are targeted by AhR-binding chemicals. For example, Lenka Pospisil Allan, a pre-doctoral student in the Boston University Immunology Training Program, has demonstrated that bone marrow stromal cells respond to PAH exposure by delivering apoptosis signals to bone marrow B cells and to other hematopoetic cells. Allan has employed protein chemistry techniques to partially characterize the “death factor” responsible for its production. She also has used AhR-defective mice and gene microarrays to define AhR-regulated stromal cell genes. In addition, Allan has recently demonstrated that mature human B cells may be particularly sensitive to environmental PAHs because of their propensity to up-regulate the AhR after immune activation.

The work of the “A” team is supported by grants from the National Institute of Environmental Health and the Superfund Basic Science Research Program.