Date of Graduation

5-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Cell & Molecular Biology (PhD)

Degree Level

Graduate

Department

Biological Sciences

Advisor/Mentor

Gisela F. Erf

Committee Member

Byung-Whi Kong

Second Committee Member

Julie A. Stenken

Third Committee Member

Yuchun Du

Keywords

Biological sciences, Health and environmental sciences, Autoimmune vitiligo, Environmental components, Hvt, Smyth line chicken, Tbp, Vitiligo

Abstract

The Smyth line (SL) of chickens is a well-established animal model for the study of spontaneous autoimmune vitiligo, displaying all the characteristics of human vitiligo. In humans, phenolic derivative 4-tertiary butyl phenol (4-TBP) has been shown to trigger vitiligo in susceptible individuals. In vitiligo-prone SL-chickens, live turkey herpesvirus (HVT) infection at hatch was identified as the most effective trigger of SL-vitiligo expression. This dissertation examined the role of the environmental factors 4-TBP and HVT in the etiology of SL-vitiligo. Specifically, the generation of reactive-oxygen-species by melanocyte-containing feather tissue (MC-FT) and cultured melanocytes in response to 4-TBP exposure in vitro (Study I) was examined. In vivo leukocyte infiltration, morphology of melanocytes, and gene-expression post 4-TBP injection into the feather pulp were also monitored (Study II). Results showed that independent of HVT administration at hatch and age of chicken, in vitro 4-TBP exposure induced more oxidative stress (P < 0.05) in cultured MC-FT and melanocytes from SL- than control-chickens. Alterations in melanocyte morphology and gene-expression of melanogenesis-, apoptosis- and stress-related proteins were observed in in vivo 4-TBP-treated SL compared to control feathers. These data support a heightened sensitivity of melanocytes to 4-TBP in SL-chickens. The reduction in MITF and increase in HSP70 and BCL2 observed in control- but not in SL-feathers may be an effective protective response to 4-TBP-induced cellular stress. In Study III, the relationship between HVT and SL-vitiligo expression was further examined. The observed progressive reduction (90 to 0%) in HVT's ability to trigger SL-vitiligo during the first 10 weeks of age suggests that HVT exerts its effect on vitiligo expression when adaptive immunity is not fully developed. The observation of elevated cytokine expression (IL-8, IL-10, IFN-ã and IL-21) during active SL-vitiligo which was preceded by increased levels of HVT at 1 to 0.5 weeks before SL-vitiligo onset, strengthens the association of HVT-infection and development of the melanocyte-specific autoimmune response. With the translocation of HVT to the feather, its presence and resulting immune activity may cause cellular stress in the inherently defective SL-melanocyte. Stress-associated melanocyte alterations may lead to immune recognition of SL-melanocytes and development of melanocyte-specific autoimmune disease.

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