Although multiple hypotheses have been suggested as potential triggers that cause vitiligo, studies strongly imply that changes in the
immune system are responsible for the condition. Vitiligo has been proposed to be a
multifactorial disease with genetic susceptibility and environmental factors both thought to play a role. Susceptibility to vitiligo may be affected by regional environmental risk factors, especially early in life. An event like a
sunburn, exposure to a chemical, stress or
emotional distress can trigger or exacerbate the condition. Skin depigmentation can occur at the site of physical trauma, an example of the
Koebner phenomenon; unlike in other skin diseases, this can be caused by daily activities, especially chronic friction on particular areas of the body. The phenomenon occurs in a third of patients with nonsegmental vitiligo (NSV) but is rarely seen in segmental vitiligo (SV). A genome-wide association study found approximately 36 independent susceptibility
loci for generalized vitiligo. One of them is the
TYR gene that encodes the protein
tyrosinase, which is an enzyme of the melanocytes that catalyzes
melanin biosynthesis, and a major
autoantigen in generalized vitiligo. The disorder has occurred in recipients of
bone marrow and
lymphocytes from donors with vitiligo.
Autoimmune associations Vitiligo is sometimes associated with
autoimmune and
inflammatory diseases such as
Hashimoto's thyroiditis,
scleroderma,
rheumatoid arthritis,
type 1 diabetes mellitus,
psoriasis,
Addison's disease,
pernicious anemia,
alopecia areata,
systemic lupus erythematosus, and
celiac disease. Among the inflammatory products of
NLRP1 are
caspase 1 and
caspase 7, which activate the inflammatory
cytokine interleukin-1β. Interleukin-1β and
interleukin-18 are expressed at high levels in people with vitiligo. In one of the mutations, the
amino acid leucine in the NALP1 protein was replaced by
histidine (Leu155 → His). The original protein and sequence are highly
conserved in evolution, and are found in humans,
chimpanzees,
rhesus monkeys, and
bush babies.
Addison's disease (typically an autoimmune destruction of the
adrenal glands) may also be seen in individuals with vitiligo.
Oxidative stress Numerous whole-exome sequencing studies have demonstrated that vitiligo is associated with polymorphisms in genes involved in the response to
oxidative stress, such as CAT, SOD1, SOD2, SOD3, NFE2L2, HMOX1, GST-M1, or GST-T1, supporting the association of elevated levels of reactive oxygen species in melanocytes with the induction of an autoimmune response. Thus, diseases presenting with altered mitochondrial function such as MELAS, Vogt-Koyanagi-Harada syndrome and Kabuki syndrome are associated with increased risk of vitiligo. In line with these observations, genetic alterations in mitochondrial DNA (mtDNA) of melanocytes associated with altered mitochondrial function lead to a release of mtDNA that can be detected in the skin of vitiligo patients. This mtDNA can be sensed by the cGAS-STING pathway, resulting in pro-inflammatory cytokine and chemokine production promoting the recruitment of cytotoxic CD8+ T cells. Mitochondrial antioxidants, NRF2 inhibitors, and TBK1 inhibitors are emerging as potential therapeutic options to block this cascade of events. == Diagnosis ==