In vitiligo, skin depigmentation is associated with focal infiltrates of CD8+ cytotoxic lymphocytes reactive, at least in part, with melanocyte differentiation antigens. In melanoma, a similar T cell mediated immune response targeting melanocyte differentiation antigens is observed where breaking of tolerance to self antigens can be explained by the increasing abundance of target antigens. In vitiligo however, a qualitative difference involving HSP70 appears to be crucial for breaking of tolerance to melanocyte differentiation antigens. HSP70 is abundantly released by vitiligo melanocytes under stress and will activate dendritic cells, leading to enhanced processing and presentation of antigens chaperoned by the stress protein. HSP70 also enhances T cell cytotoxicity to perpetuate an ongoing autoimmune response to melanocytes. We hypothesize that eliminating HSP70 as a key player in precipitating and perpetuating the autoimmune response to melanocytes will halt the spread of vitiligo. We propose to further demonstrate a crucial role for HSP70 in vitiligo and to test the efficacy of HSP70-binding antibodies potentially suitable for treatment of progressive disease according to the following specific aims [1] The role of HSP70 in fine tuning accessibility and processing of model melanosomal target antigen TRP1 by DC will be identified, [2] The depigmentation enhancing activity of HSP70 will be defined in our newly established in vivo mouse model of autoimmune vitiligo, and [3] HSP70 blocking antibodies will be tested for functional activity and the ability to interfere with progressive vitiligo. Lay abstract: Research in the laboratory of Dr. Le Poole is focused on the etiopathology of autoimmune vitiligo. Patients with vitiligo present with progressive depigmentation of the skin due to the loss of pigment forming melanocytes from the basal layer of the epidermis. This leaves patients with disfiguring skin lesions, ostracizing them for approximately 55 years of their life. There are few treatments of limited efficacy available for this devastating condition. The research proposed in our current project application will serve to support the development of a novel treatment modality for vitiligo, based on the novel concept that HSP70 plays a crucial role in the loss of skin color.

Public Health Relevance

In vitiligo, patients generally experience stress to the skin preceding depigmentation, compromising melanocyte physiology. HSP70, released from stressed melanocytes and chaperoning melanocyte specific antigens, can activate DC and elicit a progressive T cell mediated immune response to melanocytes. Here we propose to explore the mechanism and the merit of blocking HSP70 from activating an immune response in order to halt disease progression in our newly established model of autoimmune vitiligo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054749-05
Application #
8323929
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2008-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$314,566
Indirect Cost
$65,519
Name
Loyola University Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Mosenson, Jeffrey A; Flood, Kelsey; Klarquist, Jared et al. (2014) Preferential secretion of inducible HSP70 by vitiligo melanocytes under stress. Pigment Cell Melanoma Res 27:209-20
Mosenson, Jeffrey A; Eby, Jonathan M; Hernandez, Claudia et al. (2013) A central role for inducible heat-shock protein 70 in autoimmune vitiligo. Exp Dermatol 22:566-9
Mosenson, Jeffrey A; Zloza, Andrew; Nieland, John D et al. (2013) Mutant HSP70 reverses autoimmune depigmentation in vitiligo. Sci Transl Med 5:174ra28
Mosenson, Jeffrey A; Zloza, Andrew; Klarquist, Jared et al. (2012) HSP70i is a critical component of the immune response leading to vitiligo. Pigment Cell Melanoma Res 25:88-98
Elassiuty, Yasser E; Klarquist, Jared; Speiser, Jodi et al. (2011) Heme oxygenase-1 expression protects melanocytes from stress-induced cell death: implications for vitiligo. Exp Dermatol 20:496-501
Klarquist, Jared; Barfuss, Allison; Kandala, Sridhar et al. (2009) Melanoma-associated antigen expression in lymphangioleiomyomatosis renders tumor cells susceptible to cytotoxic T cells. Am J Pathol 175:2463-72