Responses to Stress in Vitiligo
Melanocytes in the epidermis are regularly exposed to various
environmental stressors e.g., ultraviolet (UV) radiation, pollution,
microorganisms and oxidising chemicals, which can stimulate reactive
oxygen species production [32].
Reactive oxygen species consist of a number of oxygen-based free
radicals such as superoxide and hydrogen peroxide, formed during
multiple physiological and pathological processes [33]. Such free
radicals are constantly scavenged by antioxidants such as superoxide
dismutase, catalase, vitamin C, and vitamin E. As mentioned above, in
vitiligo patients, high levels of superoxide dismutase and low levels of
catalase have been observed in their skin [34]. Hydrogen peroxide
created from superoxide anion can easily cross melanocyte membranes
causing cellular damage [33]. Even though melanin present in the
skin protects melanocytes as well as adjacent keratinocytes through its
ability to absorb UV radiation, its synthesis likewise results in higher
amount of intracellular reactive oxygen species, causing to be
melanocytes more vulnerable to oxidative stress [35, 36]. In
addition, a decrease in the stability of tyrosinase-related protein-1
(TYRP1), which is required for melanin synthesis, has been observed in
vitiligo melanocytes, allowing accumulation of melanin intermediates
[37]. The build-up of intermediate products increases the risk of
protein misfolding, hence activating the unfolded protein response. This
in turn induces the restoration of endoplasmic reticulum homeostasis
through the halting of protein translation, inducing misfolded protein
degradation and promoting the synthesis of chaperons to facilitate
protein folding, sustained activation of which leads to apoptosis
[2].
Intrinsic defects may also render vitiligo melanocytes vulnerable to
oxidative stress. Observed anomalies include a dilated endoplasmic
reticulum, mitochondrial dysfunction, and an abnormal melanosome
structure, all of which suggests that these pigment cells are less
capable of dealing with such stressors than those from healthy
individuals [32]. ROS-mediated stress has been directly linked with
generation of neoantigenic epitopes within beta islet cells [38],
and likewise melanocyte stress may generate neoantigens. Elevated ROS in
melanocytes of vitiligo subjects has been correlated with peroxidation,
and thus it is likely that ROS generates melanocyte neoantigens via
protein carbonylation and oxidation [39].
Cellular stress has been found to develop in healthy melanocytes exposed
to phenolic derivatives such as 4-tertiary butylphenol and monobenzyl
ether of hydroquinone[40]. Once melanocytes become stressed, they
promote the secretion of inducible heat shock protein 70 (iHSP70), which
has been detected in vitiligo melanocytes and seen to correlate with
active disease [41]. Pathogens or damage-associated molecular
patterns (DAMP), which can evoke inflammation via pattern recognition
receptors (PRRs) including Toll-like receptors and nucleotide
oligomerization domain (NOD)-like receptors (NLRs). Indeed, NLRP1 has
been linked with vitiligo in a linkage study [42]. Innate immunity
is activated by the release of DAMPs from stressed cells. DAMPs are
likely to be constantly released from stressed melanocytes resulting in
skin inflammation in patients with vitiligo [43]. In agreement with
this, uninvolved skin of vitiligo patients shows increased numbers of
lymphocytes in comparison with healthy controls [44]. In addition,
increased iHSP70 expression in the skin of vitiligo patients causes
melanocytes loss [45]. Mice lacking expression of iHSP70 will not
develop experimental depigmentation, suggesting a role for iHSP70 in
vitiligo [46]. iHSP70 has been found to have potent adjuvant and
chaperone properties [47]. Under conditions of oxidative stress,
genetically compromised melanocytes secrete melanosomal
peptides-chaperoned iHSP70 that can activate dendritic cells and release
the inflammatory signal that initiates the immune response in vitiligo
[46]. Secreted iHSP70 from stressed vitiligo melanocytes was
reported to induce dendritic cells to elevate the expression of
coactivation markers CD80 and CD86, stimulating immune responses to
melanocytes [48, 49]. Therefore, it is likely that melanocyte stress
can contribute to instigation of autoimmunity through both neoantigen
generation and activation of innate immunity [39]. iHSP70 is thus a
link between oxidative stress as a trigger and the onset of the
autoimmune reaction in vitiligo.