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Cited by 94melanin and skin pigmentationHair Growth and DisordersMelanoma and MAPK Pathways

Patho-immunological mechanisms of vitiligo: The role of the innate and adaptive immunities and environmental stress factors

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Faraj, Safa, Kemp, Elizabeth Helen, Gawkrodger, David John·2022·Clinical and Experimental Immunology
DOI 10.1093/cei/uxab002PMC PMC8802175
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Abstract

Epidermal melanocyte loss in vitiligo, triggered by stresses ranging from trauma to emotional stress, chemical exposure or metabolite imbalance, to the unknown, can stimulate oxidative stress in pigment cells, which secrete damage-associated molecular patterns that then initiate innate immune responses. Antigen presentation to melanocytes leads to stimulation of autoreactive T-cell responses, with further targeting of pigment cells. Studies show a pathogenic basis for cellular stress, innate immune responses and adaptive immunity in vitiligo. Improved understanding of the aetiological mechanisms in vitiligo has already resulted in successful use of the Jak inhibitors in vitiligo. In this review, we outline the current understanding of the pathological mechanisms in vitiligo and locate loci to which therapeutic attack might be directed.

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Crossref · 10.1093/cei/uxab002

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  • A central pathogenic axis in vitiligo involves interferon-γ-mediated signaling through the JAK-STAT pathway, inducing chemokines such as CXCL9 and CXCL10 that recruit additional cytotoxic T cells to the skin.

    “A central pathogenic axis involves interferon-γ–mediated signaling through the JAK-STAT pathway, inducing chemokines such as CXCL9 and CXCL10 that recruit additional cytotoxic T cells to the skin.”

    From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [51]

    The Adaptive immunity section describes IFN-γ stimulating keratinocytes to produce CXCL9 and CXCL10, which recruit more T cells to vitiligo skin. It also identifies JAK1/2 as part of IFN-γ signaling, but our copy does not identify the downstream pathway as JAK-STAT; that specific part of the claim is unsupported. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Oxidative stress is a key initiating factor in vitiligo, leading to melanocyte damage, mitochondrial dysfunction, and release of danger-associated molecular patterns that activate innate immunity.

    “Oxidative stress is considered a key initiating factor, leading to melanocyte damage, mitochondrial dysfunction, and the release of danger-associated molecular patterns (DAMPs), which activate innate immunity.”

    From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [51]

    The Responses to stress in vitiligo and Innate immunity sections describe oxidative stress damaging melanocytes and triggering release of DAMPs that activate innate immunity. But the former lists mitochondrial dysfunction as an intrinsic anomaly that may make melanocytes vulnerable to oxidative stress, not as a consequence of it. The Histopathological features section also cautions that dysregulated redox balance might be a consequence rather than a cause of vitiligo. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Non-immune mechanisms including defective melanocyte adhesion, endoplasmic reticulum stress, and altered cellular metabolism increase melanocyte susceptibility to immune-mediated destruction in vitiligo.

    “Non-immune mechanisms also play a role, including defective melanocyte adhesion (melanocytorrhagy), endoplasmic reticulum stress, and altered cellular metabolism, all of which increase melanocyte susceptibility to immune-mediated destruction [50,51,52].”

    From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [51]

    The “Responses to stress in vitiligo” section links endoplasmic-reticulum abnormalities and the unfolded protein response to melanocyte stress and possible autoimmune activation. The convergence-theory section also proposes that metabolite imbalances can contribute to a sequence ending in immune-mediated melanocyte destruction. The paper does not establish defective melanocyte adhesion as one of these non-immune mechanisms; its discussion of melanocyte detachment concerns patient antibodies, and it presents the stress-to-autoimmunity link as a proposed mechanism rather than a demonstrated effect of all three factors. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In vitiligo, histopathological features such as loss of melanocytes and interface dermatitis correspond to autoimmune-mediated melanocyte destruction driven by cytotoxic T cells and interferon signaling.

    “In vitiligo, histopathological features such as loss of melanocytes and interface dermatitis correspond to autoimmune-mediated melanocyte destruction, driven by cytotoxic T cells and interferon signaling.”

    From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [51]

    The ‘Histopathological features of vitiligo and melanocyte degeneration’ section reports melanocyte loss, and the ‘Infiltrating T cells’ and ‘IFN-γ signalling pathway’ sections support a role for cytotoxic CD8+ T cells and interferon signaling in melanocyte destruction. The copy does not identify interface dermatitis as a histopathological feature, and it says the relative roles of degeneration and autoimmunity in melanocyte loss remain unclear. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 2

  1. [132]Xie P, Geoghegan W, Jordon R. Vitiligo autoantibodies. Studies of subclass distribution and complement activation. J Invest Dermatol 1991, 96, 627.
  2. [133]Aronson PJ, Hashimoto K. Association of IgA anti-melanoma antibodies in the sera of vitiligo patients with active disease. J Invest Dermatol 1987, 88, 475.

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Authors
Faraj, S., Kemp, E. H., & Gawkrodger, D. J.
Affiliations
University of Sheffield (GB)
Corresponding author
  • Faraj, Safa
  • Gawkrodger, David John
ORCID
Venue
Clinical and Experimental Immunology
Publisher
Oxford University Press (OUP)
Published
2021-12-05
Volume
207
Issue
1
Pages
27-43
ISSN
  • 0009-9104 (ISSN-L)
  • 1365-2249
DOI
10.1093/cei/uxab002
PMC
PMC8802175
OpenAlex
W4206804045
Semantic Scholar
a74ae06d13b8d5c5206101d823c680f623fae8b8
Cited by
94
References
238
Citations by year
2026: 15 · 2025: 32 · 2024: 12 · 2023: 29 · 2022: 5 · 2021: 1
FWCI
1.48
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Clinical & Experimental Immunology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Funders
Ministry of Education, Libya
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Health Sciences › Medicine › Urology › Hair Growth and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
vitiligo, melanocyte loss, oxidative stress, damage-associated molecular patterns, innate immunity, adaptive immunity, autoreactive T cells, antigen presentation, environmental stressors, trauma (physical injury), emotional stress, chemical exposure, JAK inhibitors, therapeutic target
MeSH terms
Humans, Immunity, Innate, Melanocytes, Vitiligo, Oxidative Stress, Adaptive Immunity

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