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    The Role of Interferon Gamma in Melanocyte Clearance During Vitiligo

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    Authors
    Strassner, James P.
    Faculty Advisor
    John E. Harris
    Academic Program
    MD/PhD
    UMass Chan Affiliations
    Dermatology
    Document Type
    Doctoral Dissertation
    Publication Date
    2019-04-07
    Keywords
    Vitiligo
    autoimmunity
    biomarker
    single-cell RNA-sequencing
    T cell
    melanocyte
    T-cell effector functions
    Bioinformatics
    Dermatology
    Immune System Diseases
    Immunity
    Skin and Connective Tissue Diseases
    Translational Medical Research
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    Abstract
    Vitiligo is an autoimmune disease in which CD8+ T cells selectively destroy melanocytes, leading to a patchy, disfiguring depigmentation of the skin. Our group and others have highlighted the central role of IFN-γ-dependent chemokines in the progression of disease; however, IFN-γ is also reported to have pleiotropic effects on melanocyte biology. We examined whether IFN-γ has a direct role in melanocyte killing. We tested the T-cell effector functions IFN-γ, Fas ligand and perforin by deleting them from autoreactive T cells used to induce vitiligo in mice. We found that disease incidence, disease severity and T cell accumulation in the skin was reduced in mice receiving adoptive transfer of either IFN-γ deficient or Fas ligand deficient gp100-specific T cells; however, perforin was dispensable and led to increased disease scores and T cell accumulation. To determine how melanocytes are affected by IFN-γ signaling during vitiligo, we performed single-cell RNA-sequencing on suction blister biopsies obtained from vitiligo and healthy subjects. We discovered that integrin expression and TGFb2 signaling was decreased only in lesional melanocyte transcriptomes. Moreover, melanocytes appear to participate in their own demise by increasing HLA expression and recruiting effector cells through the chemotactic ligand CCL18. The loss of melanocyte retention factors may explain their clean disappearance from the skin during keratinocyte turnover. Taken together, we believe IFN-γ production by autoreactive T cells in the skin leads to clean loss of melanocytes by downregulation of melanocyte retention factors and by increasing their potential to be detected by effector cells during vitiligo.
    DOI
    10.13028/1swp-p534
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31242
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/1swp-p534
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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