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.