In patients with vitiligo the epidermis contains increased levels of ROS, mainly H
2O
2 and peroxynitrite, as well as inadequate antioxidant defenses [
68]. This ROS increase originates from several sources, both exogenous (ultraviolet radiations, trauma, stress, infections, malignancies, certain drugs) and endogenous. First, there is an elevated activity of NADPH oxidase and NOS, with secondary increase production of ROS and reactive nitrogen species [
69] (Fig.
1). Then, there is an accumulation of tetra-hydro-biopterin, an essential cofactor for the aromatic amino acid hydroxylases and NOS. Increased biopterin levels boost the formation of H
2O
2 and inhibit the function of phenylalanine and tyrosine hydroxylases, thus impairing melanin production in melanocytes and inducing norepinephrine accumulation in keratinocytes [
70]. Finally, there is an increased activity of MAO-A, which leads to the accumulation of toxic levels of H
2O
2 [
71], and a largely impaired mitochondrial function [
72]. Low levels of antioxidants, such as catalase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, superoxide dismutase, and vitamins C and E have been reported in the epidermis and serum of vitiligo patients [
73‐
75]. Recently, Jian and colleagues have shown that the anti-oxidant response element nuclear factor E2 protects melanocytes from H
2O
2 damage through the induction of antioxidant genes, such as heme oxygenase-1, and that this pathway is functionally deficient in vitiligo melanocytes, rendering them more susceptible to oxidative stress [
76,
77].
Increased skin content of ROS not only directly damages the melanocytes but also induces an autoimmune response against them. In fact, ROS modify the structure of key vitiligo autoantigens such as melan A and tyrosinase, leading to the formation of novel epitopes which then trigger autoreactivity. During the early stages of vitiligo, lipid peroxidation levels, a marker of oxidative stress, have been reported to be increased, whereas melanocyte antibodies appear in later disease stages [
72], suggesting that ROS play a role in initiating vitiligo and amplifying the loss of melanocytes.