Lymphoid Stress Surveillance Response Contributes to Vitiligo Pathogenesis

Abstract

Vitiligo is a chronic multifactorial depigmentation disorder characterized by the destruction and functional loss of melanocytes. Although a direct cytotoxic T cell attack is thought to be responsible for melanocyte damage, the events leading to the loss of self-tolerance toward melanocytic antigens are not understood. This research aimed to identify novel cellular and molecular factors that participate in vitiligo pathogenesis through the application of gene expression and immunofluorescence analysis of skin biopsy samples along with immunophenotyping of circulating cells. Our study provides insights into the mechanisms involved in melanocyte destruction. The upregulation of stress-ligand MICA/MICB, recognized by activating receptors on innate and innate-like T cells, imply involvement of lymphoid stress surveillance responses in vitiligo lesions. A simultaneous increase in the expression of transcription factor EOMES that is characteristic for innate-like virtual memory T cells, suggest a similar scenario. Local lymphoid stress surveillance has been previously associated with the amplification of systemic humoral responses that were mirrored in our study by increased T follicular helper cells and switched memory B cell proportions in patients with active vitiligo. In addition, microtubule-associated protein light chain 3 staining was compatible with the activation of autophagy in keratinocytes and in the remaining melanocytes of vitiligo lesional skin.

Increased Serum Levels of IFN-γ, IL-1β, and IL-6 in Patients with Alopecia Areata and Nonsegmental Vitiligo

“…Damaged cells upregulate stress ligands and IFN production. IFNs induce CXCL10 secretion from keratinocytes, which then attracts CXCR3-positive T cells [ 25 ]. Besides, TNF- α , IL-1 β , and IFN- γ can induce another cytotoxic effector molecule, inducible nitric oxide synthase (iNOS) [ 26 ].…”

The fate of melanocyte: Mechanisms of cell death in vitiligo

“…The glutamate/cysteine antiporter (System Xc‐) deficiency has also been claimed to cause cell death through activating ER stress and autophagic process in MCs (Zheng et al., 2016). Moreover, one study reported that keratinocytes and the scarce remaining MCs in vitiligo lesions had significantly more autophagic vacuoles, in comparison with control and non‐lesional skin (Raam et al., 2018). However, although autophagic process is frequently induced in a vast number of pathophysiologic settings, autophagic cell death rather than cell death with autophagy is another condition (Kroemer & Levine, 2008).…”

Myron Gordon Award paper: Microbes, T‐cell diversity and pigmentation

“…In melanocytes, upregulation of stress‐related MICA/MICB expression will activate innate immune cells (Raam et al., 2018), and increasing numbers of IFN‐γ–secreting LC1 and NK cells are found in blood and non‐lesional vitiligo skin (Tulic et al., 2019). Involvement of heat‐shock proteins is also indicated by demethylation of the HIF1α promoter in vitiligo CD8+ T cells (Deng et al., 2019).…”

“…Involvement of heat‐shock proteins is also indicated by demethylation of the HIF1α promoter in vitiligo CD8+ T cells (Deng et al., 2019). The latter can show prominent expression of EOMES, accompanied by “virtual” innate memory cell development (Raam et al., 2018). Interestingly, we found increased EOMES:Tbet expression in response to modified HSP70i (Mosenson et al., 2013).…”