Vitiligo pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]: Associate Editor(s)-in-Chief: Guillermo Rodriguez Nava, M.D. [2]

Overview[edit | edit source]

Vitiligo is caused by a loss of skin melanocytes. Although the exact mechanism is not known, at least in some cases, an autoimmune process may play a role. ^[1][2] The fact that vitiligo is more prevalent in patients with certain autoimmune disorders, such as Addison's disease, hyperthyroidism, alopecia areata and pernicious anemia supports this hypothesis,^[3][4][5] but it should also be recognized that the majority of patients with vitiligo do not have any autoimmune disorder.

Immune Mechanisms[edit | edit source]

• Both cellular immunity and humoral immunity have been linked to the pathogenesis of vitiligo.^[6]
  • A predominance of CD8+ T Lymphocytes and Th1 CD4+ T lymphocytes has been found in the perilesional areas^[7][8] exhibiting cytotoxical activity against melanocytes.^[9]
  • Vitiligo patients have circulating IgG and IgA autoantibodies to melanocytes proteins as tyrosinase, TYRP 1 and 2; the melanosomal matrix protein gp100 (Pmel17) and Melan A/MART 1.^[10][11] Passive immunization with monoclonal autoantibodies against the melanocyte membrane protein gp75 (TYRP1) in an animal model induced vitiligo-like lesions.^[12]

Non-immune Mechanisms[edit | edit source]

• A genetic predisposition to an alteration of the pathway of biopterins and catechols has been observed.
• The high production of toxic metabolites, mainly 6- and 7-BH₄ and noradrenaline, in combination with a redox unbalance lead to melanocyte damage.^[13][14][15]
• Following melanocyte damage, these are eliminated by three possible mechanisms:^[16]
  • Necrosis
  • Apoptosis^[17]
  • Detachment, so-called "melanocytorrhagy"^[18][19]
• Unified theory: the alterations in the membrane of the melanocytes and the liberation of antigens due to apoptosis and necrosis could sensitize the immune cells leading to an autoimmune process.^[20]

Genetics[edit | edit source]

Among 656 people with and without vitiligo in 114 families, several mutations (single-nucleotide polymorphisms) were identified in the NALP1 gene.^[21][22] The NALP1 gene, which is on chromosome 17 located at 17p13, is on a cascade that regulates inflammation and cell death, including myeloid and lymphoid cells. NALP1 is expressed at high levels in T cells and Langerhan's cells, white cells that are involved in skin autoimmunity. Among the inflammatory products of NALP1 are caspase 1 and caspase 5, which activate the inflammatory cytokine interleukin-1β. Interleukin-1β is expressed at high levels in patients with vitiligo.

Of the 656 people, 219 had vitiligo only, 70 had vitiligo with autoimmune thyroid disease, and 60 had vitiligo and other autoimmune diseases. Addison's disease (typically an autoimmune destruction of the adrenal glands) may be associated with vitiligo as well.

In one of the mutations, the amino acid leucine in the NALP1 protein was replaced by histidine (Leu155->His). The original protein and sequence is highly conserved in evolution, and found in humans, chimpanzee, rhesus monkey, and the bush baby, which means that it's an important protein and an alteration is likely to be harmful.

The following is the normal DNA and protein sequence in the NALP1 gene:

In some cases of vitiligo the first leucine is altered to histidine, by a Leu155→His mutation:

(Leucine is nonpolar and hydrophobic; histidine is positively charged and hydrophilic, so it is unlikely to serve the same function.^{[23] [24]})

The normal sequence of the DNA code for NALP1 of TCACTCCTCTACCAA is replaced in some of these vitiligo families by the sequence TCACACCTCTACCAA,^[25] which respectively code for the amino acid sequence of the normal NALP1 protein SLLYQ being replaced by SHLYQ.^[26]

Microscopic Pathology[edit | edit source]

Histological examination typically shows an absence of melanocytes in the affected areas of the skin. However, it is possible to sometimes identify degenerating melanocytes at the borders of the affected areas. In these patients, normal melanocytes may be found in normal skin areas yet, even in these regions, changes such as abnormal keratinocytes may be found, showing evidence of vacuolated cytoplasm in the basal layers of cells as well as granular extracellular materials.^[27] In certain situations it is possible to identify lymphocytic infiltrates on the margin of the lesions, which is consistent with the underlying immunological mechanism, responsible for the destruction of the melanocytes.^[28]

References[edit | edit source]

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