Title page for ETD etd-01012009-150100


Type of Document Dissertation
Author Mustafa, Amjad Issa
Author's Email Address amustafa@vt.edu
URN etd-01012009-150100
Title Developmental Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Induced and Exacerbated Autoimmunity in Adulthood
Degree PhD
Department Biomedical Sciences and Pathobiology
Advisory Committee
Advisor Name Title
Gogal, Robert M. Jr. Committee Chair
Ahmed, S. Ansar Committee Member
Holladay, Steven D. Committee Member
Li, Liwu Committee Member
Prater, Mary Renee Committee Member
Reilly, Christopher M. Committee Member
Keywords
  • prenatal exposure
  • TCDD
  • SNF1mouse
  • C57BL/6 mouse
  • autoimmunity
Date of Defense 2008-12-18
Availability unrestricted
Abstract
Developmental 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure can permanently alter immune system ontogeny, resulting in the dysregulation of a number of vital immune pathways. We hypothesized that developmental exposure to TCDD may also impair the establishment of self-tolerance, resulting in an increased risk of autoimmunity. For example, we observed that a single prenatal TCDD exposure given to non-autoimmune-prone high affinity aryl hydrocarbon receptor (AhR) C57BL/6 mice resulted in an immune complex-mediated autoimmune disease during the adult stage. Further using a similar TCDD exposure protocol, autoimmune-prone low affinity AhR SNF1 mice exhibited acceleration and exacerbation of lupus-like nephritis in adulthood. Examination of these mice showed that perinatal TCDD exposure adversely affected both primary immune organs of the adaptive immune system. In the thymic compartment, prenatal TCDD affected thymocyte cellularity, differentiation and maturation as well as central tolerance as indicated by high levels of autoreactive Vβ TCR T cells in the periphery. Prenatal TCDD also altered bone marrow B lymphopoiesis and B cell maturation and differentiation in the spleen. Functionally, these B cell changes resulted in high serum autoantibodies titers to dsDNA, ssDNA and cardiolipin suggesting a loss in central B cell tolerance. The functional assessment of T cells, via cytokine production showed that prenatal TCDD mice altered Th1/Th2 levels. As a result, significant changes were detected in the kidney characterized by increased immune complex deposition in the glomeruli, lymphocytic infiltration and general pathologic changes. This would suggest that multiple immune pathways are affected by prenatal TCDD and work either independently or synergistically to display immune-mediated disease during aging. Importantly, this study has also shown that the sex of an individual appears to influence both the type of immune pathways affected by TCDD as well as the progression and severity of the autoimmunity. In summary, these studies clearly demonstrate that postnatal immune system impairment due to prenatal TCDD exposure is not limited to immunosuppression but also can include inappropriate immune activation manifested as a hypersensitivity that can lead to the onset of autoimmune disease.
Files
  Filename       Size       Approximate Download Time (Hours:Minutes:Seconds) 
 
 28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access 
  AMJAD.MUSTAFA.DISSERTATION.pdf 5.03 Mb 00:23:16 00:11:58 00:10:28 00:05:14 00:00:26

Browse All Available ETDs by ( Author | Department )

dla home
etds imagebase journals news ereserve special collections
virgnia tech home contact dla university libraries

If you have questions or technical problems, please Contact DLA.