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      Transcriptome Analysis Reveals Markers of Aberrantly Activated Innate Immunity in Vitiligo Lesional and Non-Lesional Skin

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          Abstract

          Background

          Vitiligo is characterized by the death of melanocytes in the skin. This is associated with the presence of T cell infiltrates in the lesional borders. However, at present, there is no detailed and systematic characterization on whether additional cellular or molecular changes are present inside vitiligo lesions. Further, it is unknown if the normal appearing non-lesional skin of vitiligo patients is in fact normal. The purpose of this study is to systematically characterize the molecular and cellular characteristics of the lesional and non-lesional skin of vitiligo patients.

          Methods and Materials

          Paired lesional and non-lesional skin biopsies from twenty-three vitiligo patients and normal skin biopsies from sixteen healthy volunteers were obtained with informed consent. The following aspects were analyzed: (1) transcriptome changes present in vitiligo skin using DNA microarrays and qRT-PCR; (2) abnormal cellular infiltrates in vitiligo skin explant cultures using flow cytometry; and (3) distribution of the abnormal cellular infiltrates in vitiligo skin using immunofluorescence microscopy.

          Results

          Compared with normal skin, vitiligo lesional skin contained 17 genes (mostly melanocyte-specific genes) whose expression was decreased or absent. In contrast, the relative expression of 13 genes was up-regulated. The up-regulated genes point to aberrant activity of the innate immune system, especially natural killer cells in vitiligo. Strikingly, the markers of heightened innate immune responses were also found to be up-regulated in the non-lesional skin of vitiligo patients.

          Conclusions and Clinical Implications

          As the first systematic transcriptome characterization of the skin in vitiligo patients, this study revealed previously unknown molecular markers that strongly suggest aberrant innate immune activation in the microenvironment of vitiligo skin. Since these changes involve both lesional and non-lesional skin, our results suggest that therapies targeting the entire skin surface may improve treatment outcomes. Finally, this study revealed novel mediators that may facilitate future development of vitiligo therapies.

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          Most cited references72

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          NALP1 in vitiligo-associated multiple autoimmune disease.

          Christina Mailloux, Sheri L. Riccardi, Greggory LaBerge … (2007)
          Autoimmune and autoinflammatory diseases involve interactions between genetic risk factors and environmental triggers. We searched for a gene on chromosome 17p13 that contributes to a group of epidemiologically associated autoimmune and autoinflammatory diseases. The group includes various combinations of generalized vitiligo, autoimmune thyroid disease, latent autoimmune diabetes in adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus, and Addison's disease. We tested 177 single-nucleotide polymorphisms (SNPs) spanning the 17p13 linkage peak for association with disease and identified a strong candidate gene. We then sequenced DNA in and around the gene to identify additional SNPs. We carried out a second round of tests of association using some of these additional SNPs, thus elucidating the association with disease in the gene and its extended promoter region in fine detail. Association analyses resulted in our identifying as a candidate gene NALP1, which encodes NACHT leucine-rich-repeat protein 1, a regulator of the innate immune system. Fine-scale association mapping with the use of DNA from affected families and additional SNPs in and around NALP1 showed an association of specific variants with vitiligo alone, with an extended autoimmune and autoinflammatory disease phenotype, or with both. Conditional logistic-regression analysis of NALP1 SNPs indicated that at least two variants contribute independently to the risk of disease. DNA sequence variants in the NALP1 region are associated with the risk of several epidemiologically associated autoimmune and autoinflammatory diseases, implicating the innate immune system in the pathogenesis of these disorders. Copyright 2007 Massachusetts Medical Society.
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            Autoimmune destruction of skin melanocytes by perilesional T cells from vitiligo patients.

            Rosalie Luiten, Cornelis Melief, Debby Konijnenberg … (2009)
            In vitiligo, cytotoxic T cells infiltrating the perilesional margin are suspected to be involved in the pathogenesis of the disease. However, it remains to be elucidated whether these T cells are a cause or a consequence of the depigmentation process. T cells we obtained from perilesional skin biopsies, were significantly enriched for melanocyte antigen recognition, compared with healthy skin-infiltrating T cells, and were reactive to melanocyte antigen-specific stimulation. Using a skin explant model, we were able to dissect the in situ activities of perilesional T cells in the effector phase of depigmentation. We show that these T cells could infiltrate autologous normally pigmented skin explants and efficiently kill melanocytes within this microenvironment. Interestingly, melanocyte apoptosis was accompanied by suprabasal keratinocyte apoptosis. Perilesional T cells did, however, not induce apoptosis in lesional skin, which is devoid of melanocytes, indicating the melanocyte-specific cytotoxic activity of these cells. Melanocyte killing correlated to local infiltration of perilesional T cells. Our data show that perilesional cytotoxic T cells eradicate pigment cells, the characteristic hallmark of vitiligo, thereby providing evidence of T cells being able to mediate targeted autoimmune tissue destruction.
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              Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.

              Stanca A. Birlea, A Jian-Amadi, David J Gawkrodger … (2010)
              Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05x10(-23)) and class II molecules (P=4.50x10(-34)), PTPN22 (P=1.31x10(-7)), LPP (P=1.01x10(-11)), IL2RA (P=2.78x10(-9)), UBASH3A (P=1.26x10(-9)), and C1QTNF6 (P=2.21x10(-16)). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase. We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma. 2010 Massachusetts Medical Society
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                Author and article information

                Contributors
                Benjamin Edward Rich: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 10 December 2012
                Volume: 7
                Issue: 12
                Electronic Location Identifier: e51040
                Affiliations
                [1 ]Institute of Dermatology, Anhui Medical University, Hefei, China
                [2 ]Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada
                [3 ]Department of Medicine, University of British Columbia, Vancouver, Canada
                [4 ]Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
                [5 ]Department of Dermatology, The Third People's Hospital, Hangzhou, China
                [6 ]Skin Tumor Group, British Columbia Cancer Agency, Vancouver, Canada
                Dana-Farber Cancer Institute, United States of America
                Author notes

                Competing Interests: This work was in part supported by funding from Astellas Pharma Research Competition, Canada. However, this does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: RY YZ MS XZ. Performed the experiments: RY RB JY SW SZ MS. Analyzed the data: MS RY YH YW MG YZ. Contributed reagents/materials/analysis tools: RB ML JD XZ YZ AX. Wrote the paper: RY YZ.

                Article
                Publisher ID: PONE-D-12-11454
                DOI: 10.1371/journal.pone.0051040
                PMC ID: 3519491
                PubMed ID: 23251420
                SO-VID: b664741d-ed51-4200-8ae8-3b57218e72cb
                Copyright statement: Copyright @ 2012
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 20 April 2012
                Date accepted : 31 October 2012
                Page count
                Pages: 12
                Funding
                This work was supported by grants from National Natural Sciences Foundation of China (No. 30628021), Canadian Institutes of Health Research, Canadian Dermatology Foundation, and Astellas Pharma Research Competition, Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Computational Biology
                Subject: Genomics
                Subject: Genome Analysis Tools
                Subject: Transcriptomes
                Subject: Microarrays
                Subject: Genomics
                Subject: Genome Analysis Tools
                Subject: Transcriptomes
                Subject: Immunology
                Subject: Immune Cells
                Subject: NK cells
                Subject: Immunologic Techniques
                Subject: Immunofluorescence
                Subject: Autoimmunity
                Subject: Molecular Cell Biology
                Subject: Cytometry
                Subject: Cytometric Techniques
                Subject: Flow Cytometry
                Subject: Gene Expression
                Subject: DNA transcription
                Subject: Medicine
                Subject: Dermatology
                Subject: Dermatologic Pathology
                Subject: Inflammatory Diseases
                Subject: Pigmentary Disorders

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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