Pathogenic Mechanisms of Autoimmunity in Vitiligo
The ability of vitiligo-associated antibodies to destroy melanocytes has been demonstrated in vitro by both complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity [131, 133, 140].
In vivo , the administration of IgG from vitiligo patients into human skin grafted onto nude mice has been shown to induce melanocyte destruction [132]. In a reconstructed epidermis model, sera from 9/13 (69%) vitiligo patients induced the detachment of melanocytes, although this was not related to disease extent or activity [141]. Vitiligo patient antibodies against MCHR1 were demonstrated to block the function of the receptor [133]. However, it is not known if or how this activity could affect the melanocyte function [133]. Moreover, IgG anti-melanocyte antibodies are able to induce the expression of HLA-DR and ICAM-1 on melanocytes and the release of IL-8 from melanocytes [134]. By enhancing the antigen-presenting activity of melanocytes in this way, they become targets for cytotoxic T cells. Presently, it has not been determined if melanocytes are a primary or secondary target of the humoral immune response in vitiligo. They might arise from a genetic susceptibility to immune dysregulation at the T or B lymphocyte level, leading to lack of tolerance to pigment cell antigens [142]. Alternatively, vitiligo antibodies might originate from an immune response against melanocytes damaged by some other mechanism [142].
Interestingly, the normally intracellular melanocyte antigens TYRP1 and PMEL can be expressed on the cell surface and so can be accessible by antibodies [143, 144]. In addition, pigment cell antibodies in vitiligo might be secondary to destruction of the melanocyte from another immune cause such as T-cells, but that once triggered the antibodies are themselves destructive to melanocytes. While the potential for cytotoxic CD8+ T cells to eliminate melanocytes in both vitiligo and melanoma immunotherapy is clear, the exact mechanism that these cells use is not fully understood. Several cytotoxic effector proteins such as perforin, granzyme, Fas ligand and cytokines can be used to destroy target cells [145]. It is believed that cytotoxic T cells mainly use perforin and granzyne as fast-acting method of destroying cancer cells or virus-infected cells, whereas Fas ligand-driven killing mechanism may act as slower-acting alternative process [146]. In fact, several intracellular signaling pathways promote cytotoxic T cell killing via perforin, granzyme and F as ligand, and therefore it is currently unclear how these pathways are selectively used by T cells and how they communicate [145]. Additionally, T cell-mediated killing mechanism in autoimmune vitiligo may differ from that of cancer or viral-infected cells. Therefore, how melanocyte in vitiligo are eliminated is not yet clear, and this requires further studies in order to unveil the exact mechanism involved in details. Melanocytes from perilesional skin of vitiligo patients demonstrates physiological and histological abnormalities which may induce autoimmune reaction against melanocytes. Genes that are implicated in antigen presentation confer a significant risk for the development of vitiligo [147]. One hypothesis suggests that modified proteins called neo-antigen can be extremely immunogenic stimulating an immune response against them, since thymic epithelial cells responsible for T cell education do not synthesise such proteins [148]. This leads to the formation of highly self-reactive T cells with high-affinity receptors that target neo-antigens [148]. Melanoma is immunogenic owing to somatic DNA mutation that result in neo-antigen generation [149]. However, self-reactive T cells are unlikely to target mutated proteins in vitiligo, since untransformed melanocytes do not have the ability to mutate their DNA [39]. Several biochemical processes have been involved in neo-antigen formation as well such as deamidation, carbanylation, citrullination, oxidation and alternative mRNA splicing [38]. These processes are implicated in generating neo-antigen in untransformed beta islet cells [38].