Mutant HSP70 reverses autoimmune depigmentation in vitiligo

Jeffrey A. Mosenson, Andrew Zloza, John D. Nieland, Elizabeth Garrett-Mayer, Jonathan M. Eby, Erica J. Huelsmann, Previn Kumar, Cecele J. Denman, Andrew T. Lacek, Frederick J. Kohlhapp, Ahmad Alamiri, Tasha Hughes, Steven D. Bines, Howard L. Kaufman, Andreas Overbeck, Shikhar Mehrotra, Claudia Hernandez, Michael I. Nishimura, Jose A. Guevara-Patino, I. Caroline Le Poole*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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. We report that modified inducible heat shock protein 70 (HSP70i) prevents T cell-mediated depigmentation. HSP70i is the molecular link between stress and the resultant immune response. We previously showed that HSP70i induces an inflammatory dendritic cell (DC) phenotype and is necessary for depigmentation in vitiligo mouse models. Here, we observed a similar DC inflammatory phenotype in vitiligo patients. In a mouse model of depigmentation, DNA vaccination with a melanocyte antigen and the carboxyl terminus of HSP70i was sufficient to drive autoimmunity. Mutational analysis of the HSP70i substratebinding domain established the peptide QPGVLIQVYEG as invaluable for DC activation, andmutant HSP70i could not induce depigmentation. Moreover, mutant HSP70iQ435A bound human DCs and reduced their activation, as well as induced a shift from inflammatory to tolerogenic DCs in mice. HSP70iQ435A-encoding DNA applied months before spontaneous depigmentation prevented vitiligo inmice expressing a transgenic, melanocyte-reactive T cell receptor. Furthermore, use of HSP70i Q435A therapeutically in a different, rapidly depigmentingmodel after loss of differentiated melanocytes resulted in 76% recovery of pigmentation. Treatment also prevented relevant T cells from populating mouse skin. In addition, ex vivo treatment of human skin averted the disease-related shift fromquiescent to effector T cell phenotype. Thus, HSP70iQ435A DNA delivery may offer potent treatment opportunities for vitiligo.

Original languageEnglish (US)
Article number174ra28
JournalScience translational medicine
Volume5
Issue number174
DOIs
StatePublished - Feb 27 2013

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Mutant HSP70 reverses autoimmune depigmentation in vitiligo'. Together they form a unique fingerprint.

Cite this