Mutant HSP70 Reverses Autoimmune Depigmentation in Vitiligo

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 substrate-binding domain established the peptide QPGVLIQVYEG as invaluable for DC activation, and mutant 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 in mice expressing a transgenic, melanocyte-reactive T cell receptor. Furthermore, use of HSP70iQ435A therapeutically in a different, rapidly depigmenting model 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 from quiescent to effector T cell phenotype. Thus, HSP70iQ435A DNA delivery may offer potent treatment opportunities for vitiligo.

Understanding autoimmunity of vitiligo and alopecia areata

“…These innate immune responses activate dendritic cells, which carry and present melanocyte-specific antigens to T cells [10*, 15]. In addition, cytokines secreted by innate immune cells likely act as the initial signal to help T cells locate stressed melanocytes [10*, 16, 17].…”

Could ER Stress Be A Major Link Between Oxidative Stress And Autoimmunity In Vitiligo?

“…Interestingly, mutant HSP70iQ435A has been shown to prevent and reverse the depigmentation in different mouse models prone to vitiligo. These findings indicate a vital role of HSP70 in precipitation of vitiligo and targeting HSP70i might be a promising approach towards the treatment of vitiligo [242][243][244].…”

“…Mosenson et al [242] reported that modified HSP70i prevents T cell-mediated depigmentation. In addition, they have also shown HSP70i induces an inflammatory DC phenotype in both vitiligo mouse models as well as in vitiligo patients, which is necessary for depigmentation [242,243]. Interestingly, mutant HSP70iQ435A has been shown to prevent and reverse the depigmentation in different mouse models prone to vitiligo.…”

Understanding mechanisms of autoimmunity through translational research in vitiligo

“…NK, CD11b + CD11c + cells, and macrophages infiltrate vitiligo lesions (37,38,56,57). Transcriptome and flow analysis of human skin revealed an infiltration of NK cells in lesional and non-lesional skin (56) which, in light of the recent discovery of NK-mediated killing of stressed melanocytes (36), could allow for a larger role in pathogenesis than previously thought.…”