ABSTRACT
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 Role of the AhR in TCDD Immunotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 Defects in Primary Immune Organs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Thymus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Bone Marrow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Defects in Adaptive Immune Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 B Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 T Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
CD4+ T cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 CD8+ T cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Antigen Presenting Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 Immunological Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Defects in Innate Immune Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Toxicity to the Developing Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 Is the Human Immune System Aff ected by Dioxin? . . . . . . . . . . . . . . . . . . . . . . 249 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
The immunotoxicity of the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been studied for many years. Based on studies in mice, TCDD is one of the most potent immune suppressive chemicals known. Exposure to a single dose of TCDD in the low μg/kg (i.e., ppb) range impairs host resistance to infectious agents, and suppresses lymphocyte responses to a variety of antigens. Although the immunosuppressive action of TCDD has been studied for almost 30 years, many unanswered questions remain regarding the mechanisms by which the immune system is affected. It is clear that the immunotoxic process is initiated by the binding of TCDD to the aryl hydrocarbon receptor (AhR), a cytoplasmic binding protein that, together with AhR nuclear translocator
(ARNT/HIF-1β), functions as a ligand-activated transcription factor. However, the molecular consequences of AhR activation within hematopoietic cells have not yet been elucidated. Understanding the mechanisms of AhR-mediated immunotoxicity is important because the AhR binds many other polyhalogenated aromatic hydrocarbons (PHAH) that are present in the environment as contaminants, including other polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and polybrominated and polychlorinated biphenyls (PBBs and PCBs, respectively). In a larger sense, it is also possible that understanding the mechanisms of AhR-mediated immune suppression will open new avenues for drug development that may aid in the treatment of many human diseases, including autoimmunity, allergy, or transplant rejection.
