Mutant HSP70 Reverses Autoimmune Depigmentation in Vitiligo

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

doi:10.1126/scitranslmed.3005127

Cited by 107 publications

(121 citation statements)

References 47 publications

(83 reference statements)

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“…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].…”

Section: Autoimmunity In Vitiligomentioning

confidence: 99%

Understanding autoimmunity of vitiligo and alopecia areata

Rork

Rashighi²,

Harris³

2016

Current Opinion in Pediatrics

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Purpose of review Vitiligo and alopecia areata are common, disfiguring skin diseases. Treatment options are limited and include non-targeted approaches such as corticosteroids, topical calcineurin inhibitors, narrow band UVB phototherapy, and other immune-modifying agents. The purpose of this article is to review shared, novel mechanisms between vitiligo and alopecia areata, as well as discuss how they inform the development of future targeted treatments. Recent findings Vitiligo and alopecia areata are both autoimmune diseases, and striking similarities in pathogenesis have been identified at the level of both the innate and adaptive immune system. Increased reactive oxygen species and high cellular stress level have been suggested as the initiating trigger of the innate immune system in both diseases, and genome-wide association studies have implicated risk alleles that influence both innate and adaptive immunity. Most importantly, mechanistic studies in mouse models of vitiligo and alopecia areata have specifically implicated an IFN-γ-driven immune response, including IFN-γ, IFN-γ-induced chemokines, and cytotoxic CD8+ T cells as the main drivers of disease pathogenesis. These recent discoveries may reveal an effective strategy to develop new treatments, and several proof-of-concept clinical studies support this hypothesis. Summary The identification of IFN-γ-driven immune signaling pathways has enabled discoveries of potential new treatments for vitiligo and alopecia areata, and supports initiation of larger clinical trials.

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Section: Autoimmunity In Vitiligomentioning

confidence: 99%

Understanding autoimmunity of vitiligo and alopecia areata

Rork

Rashighi²,

Harris³

2016

Current Opinion in Pediatrics

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“…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].…”

Section: Cross Talk Between Oxidative Stress Er Stress and Immune Symentioning

confidence: 78%

“…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.…”

Section: Cross Talk Between Oxidative Stress Er Stress and Immune Symentioning

confidence: 97%

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

Mansuri¹

2014

Pigmentary Disorders

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“…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.…”

Section: The Roles Of Other Cell Types Involved Are Poorly Definedmentioning

confidence: 99%

Understanding mechanisms of autoimmunity through translational research in vitiligo

Strassner

Harris

2016

Current Opinion in Immunology

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Vitiligo is an autoimmune disease of the skin that leads to life-altering depigmentation and remains difficult to treat. However, clinical observations and translational studies over 30-40 years have led to the development of an insightful working model of disease pathogenesis: Genetic risk spanning both immune and melanocyte functions is pushed over a threshold by known and suspected environmental factors to initiate autoimmune T cell-mediated killing of melanocytes. While under cellular stress, melanocytes appear to signal innate immunity to activate T cells. Once the autoimmune T cell response is established, the IFN-γ-STAT1-CXCL10 signaling axis becomes the primary inflammatory pathway driving both progression and maintenance of vitiligo. This pathway is a tempting target for both existing and developing pharmaceuticals, but further detailing how melanocytes signal their own demise may also lead to new therapeutic targets. Research in vitiligo may be the future key to understand the pathogenesis of organ-specific autoimmunity, as vitiligo is common, reversible, progresses over the life of the individual, has been relatively well-defined, and is quite easy to study using translational and clinical approaches. What is revealed in these studies can lead to innovative treatments and also help elucidate the principles that underlie similar organ-specific autoimmune diseases, especially in cases where the target organ is less accessible.

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Mutant HSP70 Reverses Autoimmune Depigmentation in Vitiligo

Cited by 107 publications

References 47 publications

Understanding autoimmunity of vitiligo and alopecia areata

Understanding autoimmunity of vitiligo and alopecia areata

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

Understanding mechanisms of autoimmunity through translational research in vitiligo

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