A Mouse Model of Vitiligo with Focused Epidermal Depigmentation Requires IFN-γ for Autoreactive CD8+ T-Cell Accumulation in the Skin

Harris, John E.; Harris, Tajie H.; Weninger, Wolfgang; Wherry, E. John; Hunter, Christopher A.; Turka, Laurence A.

doi:10.1038/jid.2011.463

Cited by 320 publications

(325 citation statements)

References 23 publications

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“…Notably, periorbital and tail vitiligo ( Figure 4C) was observed in Aire GW/+ TRP-1 TCR Tg mice treated with aCTLA-4 antibody, reminiscent of epidermal vitiligo described in ref. 27. These findings provide evidence that Aire deficiency and CTLA-4 blockade also have additive effects in autoimmune destruction of melanocytes.…”

Section: Aire Deficiency Enhances Antimelanoma Effects Of Ctla-4 Blocsupporting

confidence: 51%

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Bakhru¹,

Zhu²,

Wang³

et al. 2017

JCI Insight

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Section: Aire Deficiency Enhances Antimelanoma Effects Of Ctla-4 Blocsupporting

confidence: 51%

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Bakhru¹,

Zhu²,

Wang³

et al. 2017

JCI Insight

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“…Existing mouse models of vitiligo are generally established through specifically expressing exogenic protein in skin melanocytes, leading to the destruction of the melanocytes by CD8 + CTL targeting the exogenic antigen (9)(10)(11)(12). As a consequence, these vitiligo models do not authentically represent the activation mechanism of autoimmune CD8 + T cells in human vitiligo.…”

Section: Discussionmentioning

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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“…Microbial stimulation of PBMCs from healthy subjects carrying the high-risk haplotype consistently resulted in increased production of IFN-γ and IL-1β, both of which have been implicated in the pathogenesis of several autoimmune diseases, including vitiligo (27)(28)(29). Further studies are needed to evaluate whether IL-1 blocking agents, which are used in the treatment of a broad spectrum of conditions characterized by IL-1-mediated inflammation (29), could represent a useful treatment approach to vitiligo.…”

Section: Discussionmentioning

confidence: 99%

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

Cavalli

Hayashi

Jin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genomewide association study of 2,853 Caucasian vitiligo patients. The superenhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5-and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an "adjuvant" during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.A utoimmune diseases are a group of over 80 disorders that together affect 3-5% of the United States population (1, 2). Many autoimmune diseases are associated with genetic variation in the HLA class I and class II gene regions of the major histocompatibility complex (MHC) on chromosome 6p21.3. HLA class I molecules present peptide antigens on the surface of almost all cells, whereas HLA class II molecules present antigens on the surface of antigen-presenting cells, such as dendritic cells, mononuclear phagocytes, and B cells. Contributions of HLA molecules to autoimmunity have almost exclusively focused on antigenic diversity and specificity. Although polymorphisms in intergenic regions of the MHC might additionally affect the complex transcriptional regulation of HLA genes, the potential role of these noncoding regions in the pathogenesis of autoimmune diseases has received much less attention.Vitiligo is an autoimmune disease in which white spots of skin and overlying hair result from progressive destruction of melanocytes by autoreactive T cells (3). In previous genome-wide association studies of autoimmune vitiligo in European-derived Caucasian (EUR) populations, we have identified association with 27 different loci (4-6), most strongly with MHC class II r...

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A Mouse Model of Vitiligo with Focused Epidermal Depigmentation Requires IFN-γ for Autoreactive CD8+ T-Cell Accumulation in the Skin

Cited by 320 publications

References 23 publications

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

A mouse model of vitiligo induced by monobenzone

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

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