Vitiligo: An Update on Pathophysiology and Treatment Options

Reinhart Speeckaert; Nanja van Geel


Am J Clin Dermatol. 2017;18(6):733-744. 

In This Article

Pathophysiology of Non-segmental Vitiligo

An extensive debate has been conducted in the literature regarding the mechanisms leading to vitiligo. Several hypotheses have been put forward including an autoimmune theory, melanocytorrhagy, oxidative stress, and neural mechanisms. Although different mechanisms may play a role, the autoimmune hypothesis is currently considered as the main pathway (Figure 1).

Figure 1.

Pathogenesis of non-segmental vitiligo: after minor injury, damage-associated molecular patterns are released (1) and oxidative stress is enhanced (2). Melanocytes lose their adhesion (3) and inflammasomes are activated (4). This proinflammatory signaling leads to antigen processing and dendritic cell presentation in the draining lymph nodes (5). Specific cytotoxic T cells are generated towards the skin (6). As a result of down-regulated regulatory T-cell activity (7), lymphocytes produce inflammatory cytokines (8) and autoantibodies (9). Cytokines and oxidative stress exert a reciprocal stimulation augmenting the immune response (10). A chemokine gradient is generated that preferentially recruits cytotoxic T cells towards the skin (11). This leads to the immune-based destruction of melanocytes (12). CXCL chemokine (C-X-C motif) ligand, IFN interferon, IL interleukin, TNF tumor necrosis factor

Innate Immunity

Koebner Phenomenon. Koebner phenomenon is considered as an initial trigger. This is clearly visible in clinical practice as patients often display depigmentations at sites of chronic friction (e.g., waist region) or after traumata. Koebner phenomenon may explain some differences in the distribution pattern according to age and sex. In children, the lower extremities are very frequently affected, while in adults, the upper extremities are more frequently affected.[21] In men, the beard area is particularly vulnerable, which can be attributed to shaving. The presence of depigmentations after trauma (friction or injury) is more frequent in patients with active disease.[22]

Danger-Associated Molecular Patterns. Given the importance of Koebner phenomenon, researchers have attempted to identify factors released during the stress response and damage of vitiligo melanocytes. Danger-associated molecular patterns (DAMP) are of particular interest as they may trigger the observed inflammatory response in the active stage of vitiligo. Heat shock proteins, especially heat shock protein (HSP) 70, have been found to be elevated in the skin of patients with vitiligo and correlated with active disease.[23] Inducible HSP70 is preferentially secreted by stressed melanocytes and mouse models demonstrated an essential role of HSP70 in the immune response, resulting in vitiligo.[23,24] HSP70 has been shown to enhance interferon (IFN)-α signaling in plasmacytoid dendritic cells. This may be one of the mechanisms that bridges innate with adaptive immunity as IFNα induces lymphocyte-attracting chemokines. MxA, an IFN-α inducible protein, shows strong expression in active perilesional vitiligo skin, suggesting a contributing effect of IFN-α in disease progression.[25] S100B is also a DAMP released by damaged melanocytes. S100B levels are increased in active vitiligo and may stimulate inflammatory responses.[26] High mobility group box 1, another DAMP that signals through RAGE, is increased in the blood of patients with vitiligo and induces melanocyte apoptosis.[27]

Deficient Melanocyte Adhesion. Another explanation of Koebner phenomenon may be found in intrinsic adhesion defects of melanocytes. Several research groups provided evidence that vitiligo melanocytes have decreased adhesive properties.[28] Altered E-cadherin expression levels in melanocytes have been found in vitiligo skin prior to the development of depigmentations. Deficient E-cadherin expression leads to the loss of epidermal melanocyte adhesion during oxidative or mechanical stress.[29] Loss of melanocytes from the epidermal layer could be an early phenomenon in vitiligo.

Oxidative Stress. A large amount of literature shows multiple elevated oxidative stress markers (superoxide dismutase, malondialdehyde, reactive oxygen species) and a collapse of antioxidative mechanisms (catalase, glutathione) in the skin and in the blood of patients with vitiligo. This is proposed to be an early factor leading to subsequent immune-mediated melanocyte destruction. Unfortunately, antioxidants have been used with limited success in vitiligo. Whether oxidative stress is pathogenic in vitiligo or a side effect of the inflammatory response remains to be elucidated. However, in-vitro vitiligo melanocytes display an increased sensitivity to oxidative stress, leading to cellular death.[30]

Inflammasomes. To date, the role of inflammasomes has been scarcely investigated in vitiligo. Inflammasomes are a component of the innate immune system resulting in the release of interleukin (IL)-1β and IL-18. Some interesting results have been found on NLRP1 with immunohistochemistry showing a significant association of NLRP1 with disease activity. Interestingly, marked NLRP1 staining was found in keratinocytes throughout the epidermal layer in perilesional vitiligo skin. NLRP1 staining even outperformed the simple presence of an inflammatory infiltrate to predict further disease progression.[31] Genetic research showed that NLRP1 haplotypes associated with vitiligo carry an increased capacity for IL-1β processing.[32]