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].