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Update on Pathogenesis of Vitiligo

Analyzing vitiligo’s complex pathways and exploring the convergence theory

By Jenny She [1], Stephen Moore [1], Harrison P. Nguyen, MD, MBA, MPH [1,2] | August 15, 2023

Historically, areas of trauma prompt an autoimmune reaction against melanocytes. Many of the factors, including metabolic abnormalities, oxidative stress, inflammation, and autoimmunity, unsurprisingly contribute toward melanocyte loss.1 The more recently described convergence theory combines all the existing theories into a comprehensive one, where several different mechanisms all reduce the viability of melanocytes. These primary pathogenic mechanisms include genetics, autoimmunity, oxidative stress, and neural hypothesis. However, vitiligo’s relationship with the environment, psychological stress, comorbidities, and individual genetic factors are difficult to integrate in terms of its pathogenesis.2 


A few genome-wide association studies have been performed in European subjects and have found 23 new loci and 7 possible loci which may provide a framework for vitiligo’s genetic architecture and pathobiology.3 Many of these genes encode immune and apoptotic regulators, autoimmune diseases, and melanocyte regulators. Another study found that TYR, TYRP1, DCT, and LARP7 were all related biomarkers of vitiligo while the immune cells CD4 T cell, CD8 T cell, Tregs, NK cells, dendritic cells, and macrophages are related to vitiligo occurrence.4 


Autoimmunity is closely related to genetics, with around 85% of the vitiligo susceptibility genes related to innate and adaptive immunity and apoptosis.1,2 In addition, vitiligo is often associated with other autoimmune disorders and other immune modulating drugs. Melanocytes use exosomes, miRNAs, melanocyte-specific antigens, and damage-associated molecular patterns to communicate stress to the innate immune system and dendritic cells to function as antigen-presenting cells. CD8+ T cells produce interferon-γ (IFN-γ), which after binding causes the recruitment of Janus kinase-1 to transcribe IFN-γ genes. Also, many patients with vitiligo have an impairment of T regulatory cells that help suppress the proliferation of activation of CD8+ autoreactive effectors. In addition to the CD8+ cells, a case study found that unstable vitiligo may be associated with autoimmune thyroiditis due to elevated thyroglobulin antibodies (TgAb) levels despite normal thyroid stimulating hormone and free thyroxine. Thyroid abnormalities and elevated TgAb may provide a useful and more widely available biomarker for vitiligo.5 

Oxidative stress 

After exposure to UV radiation and other chemicals, cutaneous melanocytes are more susceptible to excessive reactive oxygen species (ROS) production. These ROS are both endogenously and exogenously triggered through melanogenesis, the activation of the unfolded protein response, environmental factors, medications, and other internal disorders. During oxidative stress, ROS induces autophagy through the Nrf2 antioxidant pathway. However, excessive activation of Nrf2 antioxidant pathway actually inactivates autophagy.6 The Koebner phenomenon also implicates ROS because chronic friction increases inflammation and further increases the ROS. Oxidative stress also contributes to the loss of melanocyte dendrites. 

Neural hypothesis 

The neural or stress hypothesis asserts the neurochemical mediators secreted by cutaneous nerves are responsible for the cytotoxicity towards melanocytes.7 This hypothesis is supported by severe emotional stress or trauma, which may trigger or exacerbate vitiligo. A 2018 examination found some neural and endocrine markers that play a pivotal role in pathogenesis and/or consequences of vitiligo, including decreased free triiodothyronine and free thyroxine serum levels, an increase in cortisol serum levels, and a decrease in ACTH serum levels.8 

  1. Diotallevi F, Gioacchini H, De Simoni E, et al. Vitiligo, from pathogenesis to therapeutic advances: state of the art. Int J Mol Sci. 2023;24(5):4910. doi:10.3390/ijms24054910 
  2. Marchioro HZ, Silva de Castro CC, Fava VM, Sakiyama PH, Dellatorre G, Miot HA. Update on the pathogenesis of vitiligo. An Bras Dermatol. 2022;97(4):478-490. doi:10.1016/j.abd.2021.09.008 
  3. Jin Y, Andersen G, Yorgov D, et al. Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat Genet. 2016;48(11):1418-1424. doi:10.1038/ng.3680 
  4. Zhang J, Yu R, Guo X, et al. Identification of TYR, TYRP1, DCT and LARP7 as related biomarkers and immune infiltration characteristics of vitiligo via comprehensive strategies. Bioengineered. 2021;12(1):2214-2227. doi:10.1080/21655979.2021.1933743 
  5. Moore AY, Cepica T, Maberry S. Amelioration of unstable vitiligo and normalization of thryroglobulin antibodies with oral tofacitinib. JAAD Case Rep. 2022;23:64-66. doi:10.1016/j.jdcr.2022.02.025 
  6. Xuan Y, Yang Y, Xiang L, Zhang C. The role of oxidative stress in the pathogenesis of vitiligo: a culprit for melanocyte death. Oxid Med Cell Longev. 2022;2022:8498472. doi:10.1155/2022/8498472 
  7. Mohammed GF, Gomaa AH, Al-Dhubaibi MS. Highlights in pathogenesis of vitiligo. World J Clin Cases WJCC. 2015;3(3):221-230. doi:10.12998/wjcc.v3.i3.221 
  8. Kotb El-Sayed MI, Abd El-Ghany AA, Mohamed RR. Neural and Endocrinal Pathobiochemistry of Vitiligo: Comparative Study for a Hypothesized Mechanism. Front Endocrinol. 2018;9:197. doi:10.3389/fendo.2018.00197
1. Center for Clinical Studies, Houston, TX, USA; 2. Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA

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