Vitiligo: An Update on Pathophysiology and Treatment Options

Reinhart Speeckaert; Nanja van Geel

Disclosures

Am J Clin Dermatol. 2017;18(6):733-744. 

In This Article

Adaptive Immunity

Development of a Melanocyte-Specific Response

The resulting inflammation in predisposed skin may lead to antigen presentation of melanocyte peptides by dendritic cells in the draining lymph nodes. This results in the generation of melanocyte-specific cytotoxic T cells and the production of melanocyte-specific autoantibodies by lymphocytes. Different subsets of cytotoxic T cells have been found in patients with vitiligo directed against melanocyte differentiation antigens (e.g., Mart-1, gp100). In-vitro experiments demonstrate that these cells carry the capacity to eliminate epidermal melanocytes in pigmented vitiligo skin.[33] This phenomenon is considered the main pathway of melanocyte destruction in vitiligo.

Regulatory T Cells. Nonetheless, the presence of melanocyte-specific immune cells is not sufficient to develop vitiligo. It has been shown that anti-melanocyte T cells can be found in healthy individuals. However, these self-reactive T cells display in healthy persons an anergic phenotype.[34] This indicates that a delicate balance between proinflammatory and antiinflammatory signaling exists, which becomes deregulated in vitiligo. Regulatory T cells are an important subclass of T cells responsible for attenuating immunity. The total number of Tregs in patients with vitiligo appears to be decreased compared with healthy controls and an association with disease activity has been observed. It is generally agreed that the total suppressive effect of Tregs is abrogated in patients with vitiligo.[35]

Cytokines and Chemokines. CD8 cytotoxic lymphocytes of patients with vitiligo produce predominantly IFN-γ, TNF-α, and IL-17 upon exposure to melanocyte differentiation peptides.[33] Interferonc appears to be a crucial cytokine in the final steps leading to melanocyte destruction. Other cytokines such as IL-1β, IL-2, IL-17, IL-22, IL-23, and IL-33 have also been shown to be elevated in the skin and/or blood of patients with vitiligo or vitiligo mice models.[36–39] Multiple reports have shown enhanced IL-17 levels, which might play a role in activating the inflammasome.[40,41]

Interferon-γ-related chemokines CXCL9 and CXCL10 were clearly elevated in human vitiligo skin and in a mouse model of vitiligo. In a vitiligo mouse model, inhibition of CXCL10 by a neutralizing antibody was capable of preventing vitiligo with signs of repigmentation.[42] Increasing evidence documents that CXCL9 and CXCL10 are linked to disease activity in vitiligo. Melanocytederived CXCL12 and CCL5 may play a role in the recruitment of antigen-presenting cells and T cells in vitiligo skin, and serum CXCL12 has been linked to vitiligo activity.[43,44] Additionally, oxidative stress may induce the secretion of particular chemokines such as CXCL16.[45]

Autoantibodies. Autoantibodies were observed decades ago in vitiligo; however, their pathogenic role has not been confirmed. Conflicting data exist on the association of the level of autoantibodies and vitiligo activity.[46,47] This resulted in a decline of research interest in these autoantibodies. However, a small pilot trial with rituximab showed some promising results, which suggests that the role of B lymphocytes in the pathogenesis of vitiligo might be underestimated.[48]

Proliferation, Migration, and Differentiation of Melanocytes

Besides immunological factors explaining the development of vitiligo, the difficulties related to repigmenting vitiligo skin are still a challenging research topic. The factors influencing successful differentiation, proliferation, and migration of melanocytes in vitiligo skin are poorly understood. Depletion of the melanocyte reservoir may explain some individual differences, although other factors are likely to play a role. Recently, a decrease in Wnt pathway signaling induced by oxidative stress has been found in vitiligo skin. The Wnt pathway is involved in melanocyte differentiation. Activating this pathway may promote the differentiation of melanoblasts and stimulate repigmentation.[49] Furthermore, UVB-induced Wnt expression triggers the differentiation of melanocyte stem cells through β-catenin activation. Targeting this pathway could therefore be a promising approach to induce repigmentation.[50]

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