Developmental Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Induced and Exacerbated Autoimmunity in Adulthood

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dc.contributor.authorMustafa, Amjad Issaen
dc.contributor.committeechairGogal, Robert M. Jr.en
dc.contributor.committeememberAhmed, S. Ansaren
dc.contributor.committeememberReilly, Christopher M.en
dc.contributor.committeememberLi, Liwuen
dc.contributor.committeememberPrater, Mary R.en
dc.contributor.committeememberHolladay, Steven D.en
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.date.accessioned2014-03-14T20:05:23Zen
dc.date.adate2009-01-31en
dc.date.available2014-03-14T20:05:23Zen
dc.date.issued2008-12-18en
dc.date.rdate2012-06-22en
dc.date.sdate2009-01-01en
dc.description.abstractDevelopmental 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.en
dc.description.degreePh. D.en
dc.identifier.otheretd-01012009-150100en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-01012009-150100/en
dc.identifier.urihttp://hdl.handle.net/10919/25935en
dc.publisherVirginia Techen
dc.relation.haspartAMJAD.MUSTAFA.DISSERTATION.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectprenatal exposureen
dc.subjectTCDDen
dc.subjectSNF1mouseen
dc.subjectC57BL/6 mouseen
dc.subjectautoimmunityen
dc.titleDevelopmental Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Induced and Exacerbated Autoimmunity in Adulthooden
dc.typeDissertationen
thesis.degree.disciplineBiomedical Sciences and Pathobiologyen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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