Autoimmune Destruction of Skin Melanocytes by Perilesional T Cells from Vitiligo Patients

Abstract

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.

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

“…In the elicitation phase of vitiligo, triggers including physical trauma to the skin, emotional stresses, and imbalances of endogenous neural factors, metabolites or hormones lead to oxidative stress within melanocytes which then respond by actively secreting heat-shock protein 70 and chaperoned melanocyte antigens [6]. During the immune activation stage, -presenting dendritic cells with the subsequent activation and recruitment of anti-melanocyte autoreactive cytotoxic T lymphocytes to the skin [7] (Fig. 1).…”

“…In addition, several studies have identified a pivotal role for cytotoxic T cells in inducing melanocyte-specific destruction in vitiligo [7], including the findings that CD8 + T cells isolated from vitiligo skin are cytotoxic to melanocytes, recognise melanocyte-specific autoantigens [7], and induce autologous melanocyte apoptosis through IL-6 and IL-13 [9] (Fig. 1).…”

Epigallocatechin-3-gallate (EGCG) Suppresses the Trafficking of Lymphocytes to Epidermal Melanocytes <i>via</i> Inhibition of JAK2: Its Implication for Vitiligo Treatment

“…4,18,19) In vitiligo patients and animal models, IFN-γ level is significantly elevated in lesional skin. 4,20) IFN-γ signaling regulates the expression of cytokine as well as adhesion molecules facilitating the lymphocyte migration.…”

“…4,5) Moreover, immunosuppressive therapies targeting T-cell activation have been shown to be effective for vitiligo treatment.…”

“…2,3) Lesional CD8+ T cells specially induce melanocyte apoptosis in unaffected skin ex vivo, and the frequency of anti-melanocyte CD8+ T cells in both the blood and skin of vitiligo patients correlates with the severity of disease. 4,5) Moreover, immunosuppressive therapies targeting T-cell activation have been shown to be effective for vitiligo treatment. 6,7) These evidences all support a direct role for T lymphocytes in melanocyte destruction in human vitiligo.…”