Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

Vitiligo is an autoimmune disease characterized by destruction of melanocytes, leaving 0.5% of the population with progressive depigmentation. Current treatments offer limited efficacy. Observations that heat shock proteins (HSPs) can serve as adjuvants in antitumor vaccines first suggested to us a link between HSPs and stress-induced vitiligo. Such proteins are marvelously well conserved throughout evolution, which has placed them in the spotlight for helping to understand the intriguing relationship between infection and immunity. Intracellularly, inducible heat shock protein 70 (HSP70i) is upregulated by stress and helps protect cells from undergoing apoptosis. In times of stress, melanocytes will secrete antigen bound HSP70i to act as an alarm signal in activating dendritic cells (DCs), invoking a targeted response towards melanocytes. Thus HSPs are candidate molecules mediating the transition between causative stress and the autoimmune response to follow. We hypothesized that HSP70i is important for inducing an autoimmune response in vitiligo through presentation of melanocyte antigens and activation of dendritic cells and , and that blocking its dendritic cell activating region will halt depigmentation. Data in this dissertation reveal 1) Vitiliginous melanocytes (e.g., melanocytes harvested from vitiligo patient nonlesional skin) secrete higher levels of HSP70i, 2) HSP70i colocalizes with melanocyte antigens, 3) HSP70i is required to induce vitiligo, 4) The sequence QPGVLIQVYEG located in the C-terminus is required for immune activity leading to depigmentation, 5) Vaccination with mutant HSP70iQ435A prevents and treats vitiligo by altering antigen presenting cell and T cell profiles. Together these findings suggest that the autoimmune response is funneled through HSP70i, and provide compelling experimental evidence that exposure to inducible heat shock protein 70 (HSP70i) carrying a single amino acid modification offers potent prophylactic and therapeutic opportunities in vitiligo.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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