Skin-Depigmenting Agent Monobenzone Induces Potent T-Cell Autoimmunity toward Pigmented Cells by Tyrosinase Haptenation and Melanosome Autophagy

Boorn, Jasper G. van den; Picavet, Daisy I.; Swieten, Paul F. van; Veen, Henk A. van; Konijnenberg, Debby; Veelen, Peter A. van; Capel, Toni van; Jong, Esther C. de; Reits, Eric; Drijfhout, Jan W.; Bos, Jan D.; Melief, Cornelis J.M.; Luiten, Rosalie M.

doi:10.1038/jid.2011.16

Cited by 135 publications

(101 citation statements)

References 49 publications

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“…While our studies investigate CD8 T cell-mediated vitiligo induced by melanoma, in the future it would be interesting to determine if these findings extend to other models of melanocyte destruction (e.g. vitiligo initiated by melanocytoxic chemicals (26, 27), monoclonal antibodies (28), or pathogenic CD4 T cells(29)).…”

Section: Discussionmentioning

confidence: 92%

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

Byrne

Zhang

Steinberg

et al. 2014

The Journal of Immunology

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Vitiligo is a CD8 T cell-mediated autoimmune disease that has been shown to promote the longevity of memory T cell responses to melanoma. However mechanisms whereby melanocyte/melanoma antigen-specific T cell responses are perpetuated in the context of vitiligo are not well understood. The present studies investigate the possible phenomenon of naïve T cell priming in hosts with melanoma-initiated, self-perpetuating, autoimmune vitiligo. Using naïve pmel (gp10025-33-specific) transgenic CD8 T cells, we demonstrate that autoimmune melanocyte destruction induces naive T cell proliferation in skin-draining lymph nodes, in an antigen-dependent fashion. These pmel T cells upregulate expression of CD44, P-selectin ligand, and granzyme B. However, they do not downregulate CD62L, nor do they acquire the ability to produce IFN-γ, indicating a lack of functional priming. Accordingly, adult thymectomized mice exhibit no reduction in the severity or kinetics of depigmentation or long-lived protection against melanoma, indicating that the continual priming of naïve T cells is not required for vitiligo or its associated anti-tumor immunity. Despite this, depletion of CD4 T cells during the course of vitiligo rescues the priming of naïve pmel T cells that are capable of producing IFN-γ and persisting as memory, suggesting an ongoing and dominant mechanism of suppression by regulatory T cells. This work reveals the complex regulation of self-reactive CD8 T cells in vitiligo, and demonstrates the overall poorly immunogenic nature of this autoimmune disease setting.

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Section: Discussionmentioning

confidence: 92%

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

Byrne

Zhang

Steinberg

et al. 2014

The Journal of Immunology

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“…Monobenzone can form quinone-haptens to the tyrosinase which in turn increase melanocyte cell immunogenicity (14). In addition, monobenzone may trigger autoimmunity to unaltered melanocytes by promoting the processing of melanocyte differentiation antigens via melanosome autophagy induction and tyrosinase ubiquitination enhancement (6,15).…”

Section: Discussionmentioning

confidence: 99%

“…Monobenzone-induced depigmentation was indistinguishable from vitiligo (3)(4)(5). Evidence suggests that monobenzone provokes systemic immune reaction and that its function depends on melanocytes (6,7). Therefore, inducing vitiligo-like depigmentation in mice with monobenzone might lead to the development of a new mouse model of vitiligo.…”

Section: Introductionmentioning

confidence: 99%

A mouse model of vitiligo induced by monobenzone

Zhu

Wang

2013

Experimental Dermatology

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The paucity of vitiligo animal models limits the understanding of vitiligo pathogenesis and the development of therapies for the skin disorder. In this study, we developed a new mouse model of vitiligo by topically applying the skindepigmenting agent monobenzone on mice. We demonstrated that monobenzone-induced skin depigmentation on the nonexposed sites and that the severity of lesions depended on drug dosage. The result of the histological examination of the depigmented skin indicated loss of epidermal melanocytes and perilesional accumulation of CD8 + T cells. Furthermore, the monobenzone-induced depigmentation of the Rag1 gene knockout did not appear on the non-exposed sites, supporting the involvement of infiltrating CD8 + T cells in melanocyte destruction. Resemblance in histological characteristics and pathogenesis between monobenzone-induced depigmentation and active human vitiligo suggests good potential of our mouse model for use in vitiligo research.

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“…Transmission electron microscopy analysis additionally revealed a massive cell vacuolization and organelles within some vesicles, seemingly autophagy suggesting images 41, 42, 43. Through autophagy, proteins and organelles are sequestered into double membrane vesicles (autophagosomes) and are subsequently delivered to the lysosomes for degradation 44.…”

Section: Discussionmentioning

confidence: 99%

AC‐1001 H3 CDR peptide induces apoptosis and signs of autophagy in vitro and exhibits antimetastatic activity in a syngeneic melanoma model

et al. 2016

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Antibody‐derived peptides modulate functions of the immune system and are a source of anti‐infective and antitumor substances. Recent studies have shown that they comprise amino acid sequences of immunoglobulin complementarity‐determining regions, but also fragments of constant regions. VH CDR3 of murine mAb AC‐1001 displays antimetastatic activities using B16F10‐Nex2 murine melanoma cells in a syngeneic model. The peptide was cytotoxic in vitro in murine and human melanoma cells inducing reactive oxygen species (ROS) and apoptosis by the intrinsic pathway. Signs of autophagy were also suggested by the increased expression of LC3/LC3II and Beclin 1 and by ultrastructural evidence. AC‐1001 H3 bound to both G‐ and F‐actin and inhibited tumor cell migration. These results are important evidence of the antitumor activity of Ig CDR‐derived peptides.

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Skin-Depigmenting Agent Monobenzone Induces Potent T-Cell Autoimmunity toward Pigmented Cells by Tyrosinase Haptenation and Melanosome Autophagy

Cited by 135 publications

References 49 publications

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

A mouse model of vitiligo induced by monobenzone

AC‐1001 H3 CDR peptide induces apoptosis and signs of autophagy in vitro and exhibits antimetastatic activity in a syngeneic melanoma model

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