I. Caroline Le Poolea, Rosalie M. Luitenb
a Department of Pathology, Oncology Institute, Loyola University, Chicago, Ill., USA;
b The Netherlands Institute for Pigment Disorders, Department of Dermatology,
Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Abstract
Vitiligo is characterized by progressive skin depigmentation resulting from an autoimmune response targeting epidermal melanocytes. Melanocytes are particularly immunogenic by virtue of the contents of their melanosomes, generating the complex radical scavenging molecule melanin in a process that involves melanogenic enzymes and structural components, including tyrosinase, MART-1, gp100, TRP-2 and TRP-1. These molecules are also prime targets of the immune response in both vitiligo and melanoma. The immunogenicity of melanosomal proteins can partly be explained by the dual role of melanosomes, involved both in melanin synthesis and processing of exogenous antigens. Melanocytes are capable of presenting antigens in the context of MHC class II, providing HLA-DR melanocytes in
perilesional vitiligo skin the option of presenting melanosomal antigens in response to trauma and local inflammation. Type I cytokine-mediated immunity to melanocytes in vitiligo involves T cells reactive with melanosomal antigens, similar to T cells observed in melanoma. In vitiligo, however, T cell tuning allows T cells with higher affinity for melanocyte differentiation antigens to enter the circulation after escaping clonal deletion in primary lymphoid organs. The resulting efficacious and progressive autoimmune response to melanocytes provides a roadmap for melanoma therapy.
Introducing Autoimmune Vitiligo
Progressive depigmentation of the skin is considered the hallmark of vitiligo, an autoimmune disease that strikes approximately 1% of the global population.
An increased incidence of vitiligo is noted among select consanguineous communities. Responses to a vitiligo questionnaire support a female gender bias of approximately 1.25. This is in concordance with an increased general prevalence of autoimmune disease noted among women, a finding which has not been adequately explained to date. The mean age of onset for human vitiligo is 28, while the median age is 13 years, reflecting a proportion of patients that
develop late-onset vitiligo Early-onset vitiligo appears more clearly associated with hereditary factors, whereas environmental factors contribute particularly to late-onset vitiligo which displays a different distribution of the lesions . Vitiligo is generally classified according to the extent, type and distribution of the lesions, ranging from focal vitiligo to segmental, inflammatory and generalized vitiligo, and finally to universal vitiligo. Segmental vitiligo is exceptional because
of its asymmetric distribution and characteristically slow progression, suggestive of a separate, converging etiology.
Several factors may contribute to the pathogenesis of autoimmune vitiligo, including genetic predisposition, toxic metabolites interfering with melanin metabolism, neurochemical factors and specific autoimmunity against melanocytes . Interestingly, patients generally report itch immediately preceding depigmentation of the skin, suggesting a release of histamine and other inflammatory mediators by mast cells in active disease [unpubl. observation]. Furthermore, repigmentation therapies, such as steroids and UV irradiation, are immunosuppressive and the beneficial effect of such treatment indicates the involvement of autoimmunity in vitiligo [7]. Such an involvement of autoimmune reactivity in melanocyte destruction leading to vitiligo is further supported by an association between vitiligo and other autoimmune diseases (fig. 1), most notably Hashimoto’s thyroiditis. Among vitiligo patients, the incidence of Hashimoto’s thyroiditis is increased 2.5-fold compared to the general population. Other diseases reported to associate with vitiligo include diabetes, psoriasis and Raynaud’s disease.
Autoimmune reactivity in vitiligo was initially demonstrated by an increased prevalence of circulating autoantibodies to melanocytes in association with progressive disease [9]. Target antigens reported for the humoral response are primarily of intracellular, melanosomal origin. Antibodies have limited access to target antigens expressed within viable cells, and antibodies to intracellular antigens are likely generated in response to melanocyte damage. An important exception is the membrane receptor for melanin concentrating hormone (MCHR) [10]. Antibodies binding to membrane antigens expressed exclusively by melanocytes can contribute to melanocyte destruction by antibody-mediated cellular cytotoxicity. In this regard, reduced expression of the complement associated
factors decay-accelerating factor (DAF/CD55), CD59 and membrane cofactor protein (MCP/CD46] has been demonstrated in vitiligo skin,
suggesting that vitiligo melanocytes are increasingly sensitive to complement mediated cytotoxicity.
A contribution of cytotoxic T cells in melanocyte destruction was long overlooked. As melanocytes are dispersed throughout the basal layer of the epidermis,
few T cells are required to target only the perilesional area surrounding actively depigmenting lesions. Immune infiltrates contain CD8 T cells, macrophages and to a lesser extent CD4 T cells. This was first described for patients with overt inflammatory borders surrounding the lesions. Colocalization of disappearing melanocytes was found with CD8T cells that expressed the skin-homing marker, cutaneous leukocyte-associated antigen (CLA), and the T cell activation markers perforin and granzyme B.Infiltrating T cells were also shown to express the IL-2 receptor -chain, CD25. Now commonly associated with regulatory T cells, expression of CD25 is morelikely indicative of T cell activation in progressing vitiligo, where regulatory Tcells are infrequently found in the skin [unpubl. observation].
T cell infiltrates per se are commonly observed in progressive generalized vitiligo, constituting the majority of patients. Vitiligo patients carry increased numbers of peripheral T cells reactive with melanocyte differentiation antigens, tyrosinase, gp100 or MART-1, compared to healthy donors [14–17]. The finding of CLA expression by circulating MART-1-specific T cells in vitiligo patients supports the role of skin-homing autoreactive T cells in the pathogenesis of vitiligo [16].
Melanocyte-specific cytotoxic T cells are also found in the perilesional vitiligo skin during active disease, suggesting their involvement in the depigmentation
process.
As vitiligo is not restricted to humans, but also reported in horses, dogs and chickens, animal models are available to study the etiopathology of the disease
in more detail. In particular the Smyth line chicken has proven useful to establish the involvement of an autoimmune response to melanocytes. Several
observations made in the Smyth Line chicken are in concordance with human disease, including expression of a type I cytokine pattern, cytotoxic T cell
involvement and a contribution of stress as a precipitating factor .
Vitiligo and Melanoma
The contribution of effector T cells to progressive vitiligo provides an interesting link to effective antitumor immunity in melanoma, where the majority of tumor-infiltrating T cells were found to respond to the melanosomal differentiation antigens gp100 or MART-1 [19]. It has long been recognized that vitiligo can develop in melanoma patients with an active immune response to their tumor and visible development of autoimmunity is considered a positive
prognostic factor among melanoma patients . This was recently substantiated by a markedly increased survival rate observed among melanoma patients that developed autoimmunity in response to IFN- treatment.
Clonally expanded T cells as well as autoantibodies reactive with melanocyte differentiation antigens expressed by melanocytes and melanoma cells were found in the circulation of melanoma patients with leukoderma, as well as in autoimmune vitiligo skin. The same holds true for circulating autoantibodies [28]. The development of vitiligo has frequently been observed in response to melanoma immunotherapy by vaccination with melanoma antigens,
or by adoptive transfer of melanoma-specific T cells, suggesting that the anti melanoma immune response can also attack normal melanocytes. In the adoptive transfer studies, infused T cells were found to infiltrate the depigmented skin lesions, indicating that activated T cells can cause human vitiligo. Interestingly, vitiligo was also observed after lymphocyte infusion for relapsed leukemia [34]. The development of vitiligo following vaccination in combination with anti-CTLA-4 blockade or by lymphodepletion prior to adoptive transfer suggests that a decreased regulatory T cell function favors the induction of vitiligo. Taken together, these studies show that immune responses to common antigens present on melanoma cells and normal melanocytes following specific immunotherapy may lead to skin depigmentation and tumor rejection.
The frequency of MART-1-reactive T cells among melanoma patients is not significantly different from vitiligo patients. Similar numbers of anti-
MART-1 T cells from vitiligo patients, however, effectuate a higher avidity towards peptide-loaded target cells than T cells from melanoma patients, and a distinctly higher cytotoxicity of vitiligo T cells towards melanoma cells has been observed [35]. This difference in the avidity of the T cell response in vitiligo compared to melanoma may result from T cell tuning and activation mechanisms in vitiligo patients, as described below . This is of particular interest as we study the T cell receptor (TCR) genes expressed by vitiligo and melanoma lesional T cells. Similarity among particularly -chains of TCR reactive with MART-1 among both T cell populations has been reported. As suggested by Palermo et al. [35], affinity maturation characterized by restricted TCR repertoires and increased avidity may be initiated in either disease, but is not likely to progress in the immunosuppressive melanoma environment.In animals that develop spontaneously regressing melanomas, such as Lippizaner horses or the Sinclair swine, tumor regression is similarly associated with marked depigmentation [38]. Moreover, new antimelanoma vaccines tested in mice similarly support a link between immune reactivity to normal and transformed
melanocytes. In fact, vaccine-induced depigmentation serves as a model for autoimmune vitiligo. For example, after adoptive transfer of high-avidity T cells against tyrosinase derived from albino mice, recipient pigmented mice develop depigmentation with a distribution pattern strikingly similar to vitiligo. Vaccination of gp100-specific TCR transgenic mice bearing large subcutaneous B16 melanoma tumors with gp100 peptide and IL-2 induced T cell activation in vivo, leading to tumor regression as well as vitiligo. Moreover, another murine model of vaccination with GM-CSF-producing B16 melanoma cells demonstrated that the efficacy of antitumor therapy correlated with the frequency of tyrosinase-related protein-specific cytotoxic T cells in the periphery,as well as with the extent of autoimmune skin depigmentation.
The beneficial effect of a decreased regulatory T cell function either by anti-CTLA-4 blockade or by lymphodepletion prior to adoptive transfer on the development of
vitiligo and melanoma regression was also demonstrated in these murine models. Interestingly, progressive depigmentation can be observed in mice treated with anti melanoma vaccines in the absence of tumors, as first demonstrated by Overwijk et al. This principle is illustrated in figure 2. In the pathogenesis of vitiligo, T cells are adequately activated to exert effect or function in vivo. Therefore, the activated T cell response in vitiligo represents a clinically relevant example of an effector T cell population with proven in vivo efficacy, that can serve as an example for antimelanoma T cell responses.
Challenges to the Skin: The Elicitation Phase
Approximately 50% of vitiligo patients experience a Koebner phenomenon, exhibiting new and expanding lesions initiated from a site of previous
trauma, excessive sun exposure or contact with bleaching phenols . These data support the concept that stress to the skin can precipitate
the disease. Trauma to the skin can locally generate oxygen radicals, and a reduced ability of vitiligo melanocytes to detoxify highly reactive radicals has been proposed, supported by observations of reduced dihydrobiopterin synthesis, increased H2O2 stress and reduced catalase activity in vitiligo skin [43]. These findings have ultimately led to the development of pseudocatalase treatment for vitiligo to restore the redox balance. Interestingly, protein disulfide isomerase
(PDI) is an integral part of the major histocompatibility complex (MHC) class I loading complex, and the activity of this enzyme affects the oxidation status of
the disulfide bond in the groove of the HLA-A*0201 molecule, thereby determining its accessibility to peptides.
It can thus be hypothesized that an altered redox potential following stress influences the efficiency of peptides binding the groove of MHC class I and thereby affects the visibility of the cell to infiltrating effector T cells. Among patients not exhibiting the Koebner phenomenon, it is well possible that an emotionally traumatic event such as a recent death in the family can trigger the onset of disease. Emotional stress (anxiety) and physical stress (trauma) are generally associated with elevated plasma levels of proopiomelanocortin (POMC) the precursor molecule to melanocortin peptides, including ACTH, - and -melanocyte-stimulating hormones (MSH), and -endorphin. In the skin, keratinocytes and melanocytes can also produce these melanocortins
in response to UV radiation, which subsequently enhance the biosynthesis of eumelanin in melanocytes [45]. -MSH is not only known to stimulate melanogenesis and melanocyte proliferation, it can also suppress immune responses through its effects on melanocortin receptor-expressing cells. In this respect -MSH induces down regulation of cytokine production and the expression of costimulatory molecules on dendritic cells. Surprisingly, vitiligo patients display reduced plasma levels of -MSH, which suggests decreased POMC processing in vitiligo skin .
Vitiligo patients also accumulate H2O2 in the skin, which oxidizes -MSH and further decreases its availability.
Conversely, -MSH can protect melanocytes from oxidative damage by its antioxidant effect during melanin synthesis, and therefore the reduced availability
of -MSH in vitiligo skin may enhance oxidative stress in vitiligo skin. Reduced levels of -MSH in vitiligo may therefore facilitate a local immune
response against melanocytes . The situation of oxidative stress puts intracellular protein synthesis on hold in favor of heat shock protein (HSP) synthesis, offering epidermal cells protection from impending apoptosis. Among protein expression induced by stress, HSP70 is actively secreted by melanocytes and stimulates dendritic cells to cross-present chaperoned antigens, thereby initiating an immune response against melanocytes [49]. This is of particular relevance for forms of stress with a selective effect on melanocytes, such as exposure to bleaching phenols with a structural similarity to substrates of melanogenesis. In this respect, 4-tertiary butyl phenol (4-TBP), a causative agent in occupational vitiligo, appears to be metabolized by enzymes of the melanogenic pathway converting the compounds into cytotoxic compounds exclusively in melanocytes .
At lower concentrations, 4-TBP suppresses melanogenesis through competitive inhibition of tyrosinase, whereas at higher concentrations the compound is selectively cytotoxic towards melanocytes [50]. Similarly, monobenzyl ether of hydroquinone induces depigmentation upon topical application [51]. This depigmentation treatment has been used for vitiligo patients with extensive vitiligo.
Phenolic agents, UV and to some extent mechanical injury all increase local levels of reactive oxygen species. Among these reactive oxygen species, nitric oxide may enhance depigmentation by reducing the adhesive capacity of melanocytes . Nitric oxide is toxic to melanocytes and nitric oxide synthase is inhibited by MSH, suggesting that abundant nitric oxide contributes to vitiligo pathogenesis . Other eliciting factors in vitiligo include hormones, such as estrogens, and neural factors, such as catecholamines, of which increased levels were associated with active vitiligo. The contribution of this and other mechanisms may be elucidated by studying the mode of cell death in vitiligo melanocytes. The main mechanism of melanocyte death is likely apoptosis, although the sparcity of dying melanocytes in any given stretch of skin complicates capture apoptotic melanocytes in the skin in situ . This hypothesis is supported by the fact that melanocyte-specific T cells are frequently found in perilesional vitiligo skin and that T cells are known to kill target cells by apoptosis through the release of granzyme B. Moreover, increased expression of integrins and decreased apoptosis were shown to correlate with melanocyte retention in cultured skin substitutes .
Immune Activation
In response to 4-TBP exposure, we have found that melanocytes upregulate expression of HSP70 and a larger proportion of the HSP70 appears to be
secreted by vitiligo melanocytes than by control melanocytes. Since HSP70 is known to enhance immunity to associating proteins, as shown in melanoma vaccination studies of HSP70 bound to melanosomal proteins, it may also be involved in accelerating depigmentation in vivo [49]. In response to HSP70, dendritic cells upregulate expression of the TNF family member TRAIL, enabling dendritic cells to kill melanocytes with elevated expression of TRAILR1 and TRAILR2 in response to 4-TBP. An indication of the in vivo relevance of these findings is the altered, patchy expression of HSP70 in lesional epidermis (in 3 of 3 patients) compared to nonlesional skin (fig. 3).
HSP70 is known to induce dendritic cell activation by binding to HSP receptors on these cells [49]. CD91, a receptor for HSP70, was abundantly expressed among vitiligo-infiltrating dendritic cells (data not shown), indicating that HSP-mediated dendritic cell activation through receptors for HSP70 and other relevant immunogenic stress proteins may be involved in the pathogenesis of vitiligo. In the presence of HSP70, an increased number of melanocyte-reactive T
cells is recruited from skin-draining lymph nodes and upon arrival in the skin, the cytotoxic effector function of these T cells is enhanced. Moreover, extracellular
HSP70 can induce the expression of the costimulatory molecule ICAM-1 specifically in melanocytes among a culture of ICAM-1-negative keratinocytes
[unpubl. observation]. In line with the proposed involvement of HSP70 in vitiligo, ICAM-1 is also consistently upregulated in perilesional vitiligo skin .
As a costimulatory pathway, ICAM-1/LFA-1 interactions determine in part the interaction between a T cell and its target, and thus the avidity of the T cell
response. In this regard we have proposed that differential ICAM-1 expression by melanocytes in vitiligo can contribute to T cell-mediated depigmentation [57].
Costimulation is also determined by interaction of CD28 with either B7 molecules on the melanocyte cell surface or its alternative, immunomodulating ligand CTLA-4. Genetically determined CTLA-4 deficiencies in autoimmune disease (including vitiligo) may result in preferential binding of CD28 to B7, supporting effective costimulation rather than CTLA-4-mediated immunoregulation [58]. The cytokine microenvironment in perilesional vitiligo skin is also conducive for dendritic cell activation and T cell-mediated cytotoxicity. Macrophages and dendritic cells are abundantly present in depigmenting vitiligo skin. The activation state of macrophages and dendritic cells within vitiligo skin has not been described to date. Since Langerhans cells, dendritic cells and melanophages
may each be involved in phagocytosis, antigen processing and/or presentation of melanocyte-derived antigens in skin-draining lymph nodes, it is important to assess the physiology of these cell types within perilesional areas of actively depigmenting skin. In this respect it has been shown that Langerhans cells in
perilesional vitiligo skin express elevated levels of -1,6-branched N-glycans, which appears to be indicative of Langerhans cell activation in progressive disease
[Pawelek, pers. commun.]. Similar glycosylation patterns expressed by macrophages are considered a negative prognostic indicator in breast cancer and
melanoma.
The apparent discrepancy between -1,6-branched N-glycan expression in active vitiligo representing immune activation and its expression in tumors generally representing a lack of effective immunity is best understood realizing that the glycosylation pattern reflects the abundance of cells engaged in
phagocytosis, regardless of cell type, whereas tumor-infiltrating macrophages and vitiligo-derived Langerhans cells differ in their ability to activate a specific
immune response [60]. Considering that Langerhans cells are located in close proximity to melanocytes in the epidermis, that in vitiligo lesional skin Langerhans cells are predominantly located in the basal layer of the epidermis, and that reduced contact sensitization was noted for lesional vitiligo skin, it is
likely that Langerhans cells are involved in vitiligo etiology by processing and cross-presentation of melanocyte antigens.
A contribution of immune activation to progressive depigmentation is also supported by expression of MHC class II in perilesional epidermis. Perilesional
expression of HLA-DR is relevant, as melanocytes can present antigens in the context of MHC class II. Besides presenting endogenous melanosomal peptides
in the context of MHC class II, melanocytes are also capable of processing exogenous antigens and presenting them in the context of MHC class II. This is
likely relevant to explain the extraordinary link to depigmentation observed in tuberculoid leprosy if melanocytes are killed after processing and presenting
immunodominant antigens of Mycobacterium leprae, including hsp65. In support of this theory, we have demonstrated class II restricted killing of hsp65 presenting
melanocytes in vitro. Several data support an abundance of type 1 cytokines in perilesional skin, indicating a cell-mediated immune response to melanocytes.
The polarization of the T cell response towards a type 1 response during progression of depigmentation in vitiligo has been demonstrated in a study of vitiligo-infiltrating T cells that were isolated and cultured from vitiligo skin. In this study, T cell clones derived from vitiligo-infiltrating T cells skin predominantly
exhibited type 1-like cytokine secretion profiles. Interestingly, already in uninvolved skin of these vitiligo patients microdepigmentation was observed in situ,
correlating with the extent of type 1 polarization of local skin-derived T cells. The ratio of CD4 to CD8T cells is decreased in peripheral blood of vitiligo
patients regardless of disease status [62], signifying a relative increase in cytotoxic T cells. Immunohistochemical analysis of skin tissue sections similarly
revealed a decreased CD4 to CD8T cell ratio, indicating that the shift in the balance between CD4 and CD8 T cells cultured from vitiligo skin was not due to differences in the in vitro expansion capacity of these T cell subsets. Based on these findings, the cytokine profiles observed among cultured cells
are considered representative of those found in progressive vitiligo skin. Moreover, the type 1 cytokine secretion patterns of T cells in vitiligo were confirmed
in the prime animal model for vitiligo, the Smyth line chicken [18].
Cytotoxic T cells infiltrating the skin in patients with progressive vitiligo are found in close proximity to remaining melanocytes in the skin [11]. The
CD8 T cells derived from progressively depigmenting skin were cytotoxic towards autologous melanocytes in vitro. We have recently found that melanocyte-specific T cells can induce apoptosis of melanocytes in situ in nonlesional skin of vitiligo patients [unpubl. data], indicating that the effector phase of melanocyte destruction is mediated by cytotoxic T cells.
It should be noted that T cells reactive with melanocyte differentiation antigens can be found in the peripheral blood of healthy donors and their
presence per se can therefore not be considered evidence of autoimmune phenomena. For the MART-1 antigen, it was shown that a large pool of MART-1-
specific T cells are generated in the thymus, which circulate as naïve T cells in the peripheral blood of healthy individuals [64]. Tumor-antigen-driven activation
and expansion of this T cell pool is seen in melanoma patients and may also occur during vitiligo development, where activated MART-1-specific T cells
are found in the skin. In autoimmune disease, T cells expressing high-affinity TCR fail to be clonally deleted in primary lymphoid organs and as a result, high-avidity T cells recognizing self antigens enter the circulation T cells. This is observed in autoimmune polyendocrinopathy, where the development of vitiligo highlights
the severity of disease [65]. Negative selection is dependent at least in part on presentation of peripheral antigens in the thymus, allowing only T cells with
low avidity towards encountered antigens to enter the periphery . In this respect, autoimmune regulator-dependent presentation of the melanocyte differentiation
antigen gp100 has been demonstrated. It is possible that a particular autoimmune disease reflects a lack of presentation of a select antigen or set
of antigens in the thymus, however, additional mechanisms are likely to contribute to organ-specific autoimmunity. For example, selection against high affinity
TCR can be masked by T cell tuning [36]. Here high-avidity T cells with high-affinity TCR pass clonal selection criteria by downplaying their avidity in the thymus, for example by expression of CD5 to reduce TCR signaling, or by altering CD4 or CD8 expression levels during selection. Once tuned, T cells migrate to the site expressing their native antigens and these cells propagate and undergo limited affinity maturation to express higher-affinity TCR.
Although T cell tuning may explain how high-avidity T cells enter the circulation, it does not automatically explain autoimmunity. When tuned high-avidity
T cells enter the circulation, the hyporesponsive state must be overcome for autoimmunity to arise. This can occur when the target antigen is overexpressed as in melanoma. Alternatively, the danger model proposed by Matzinger suggests that any given antigen, self or nonself, evokes an immune response
when it is presented to the immune system in combination with a danger signal. This is reflected primarily in the state of activation of antigen-presenting cells, and dendritic cell activation signals thus constitute a turning point in the immune response. Mechanical injury, UV exposure and contact with bleaching phenols may thus precipitate vitiligo by inducing such danger signals leading to activation of dendritic cells. Depending on the activation signal, dendritic cells
induce type 1 T cell responses, corresponding to the type 1 cytokine expression patterns observed in progressive vitiligo.
Immune Regulation
Differential progression of the immune response among vitiligo and melanoma patients is also determined by regulatory T cells. Melanoma
immunotherapy studies have demonstrated that depletion or suppression of regulatory T cells improves the induction of antimelanoma immune responses.
Regulatory T cells apparently interfere with antitumor reactivity in melanoma patients, preventing a successful outcome of antitumor immunotherapy.
Indeed, melanoma tissue contains the immunosuppressive cytokines IL-10 and TGF-, indicative of immunoregulation taking place within the tumor
microenvironment.
Where melanocyte-specific T cells occasionally infiltrate the skin, local immune suppression by skin-resident regulatory T cells prohibits these autoreactive
T cells from exerting effector functions in healthy individuals. Regulatory/suppressor T cells expressing immunosuppressive cytokines including
IL-10 and TGF- are continuously present in the skin, keeping ongoing immune responses in check . The regulatory T cells thereby preserve skin
homeostasis, which can be overruled in inflammatory conditions. In melanoma tissue, however, the level of immune suppression is more pronounced and
impairs most of the effector function of antitumor immune responses. In addition, local immunosurveillance of the skin immune system against the outgrowth
of melanoma cells, which is present in healthy individuals, is actively suppressed in melanoma patients, allowing tumor outgrowth.
Vitiligo patients generally lack effective immunoregulation, which allows high-avidity T cells to attack melanocytes in the skin. The association observed
between vitiligo and other autoimmune diseases is indicative of this lack of immune regulation. In the microenvironment of the vitiligo skin, infiltrating T
cells may undergo a process analogous to affinity maturation among B cells, resulting in T cells with TCR of increasing affinity, which cause progressive
depigmentation. Recent data indicate that regulatory T cell function is altered in vitiligo, and in the absence of functional, skin-infiltrating regulatory T cells the
ongoing immune response is perpetuated [unpubl. data]. Such intrinsic defect may also explain the marked difference in distribution patterns of the lesions in
patients with autoimmune vitiligo in contrast to patients that develop progressive depigmentation secondary to their disease, as in melanoma.
Intervention
(Table 1)
A definitive cure for vitiligo has yet to be found. Currently, successful therapeutic measures require a situation of stable disease to repopulate lesional vitiligo skin with melanocytes by a variety of surgical skin grafting methods in combination with (narrow-band) UVB radiation. The problem remains that patients with a
propensity to develop vitiligo run the risk of recurrent disease, and curing vitiligo is clearly a two-tiered process consisting of halting progression of depigmentation
followed by repigmentation of lesional skin. Effective measures are available to repopulate stable vitiligo lesions by surgical transplantation measures in combination with UVB treatment to stimulate melanocyte migration, proliferation and melanization . The perceived inefficacy of available vitiligo treatments results
from a lack of focus on halting disease progression, most notably by interfering with autoimmune reactivity to melanocytes. Several principal steps can be taken
towards intervention, as summarized in table 1. In the end, a two-tiered approach is necessary to successfully treat vitiligo.
Acknowledgments
This work was supported in part by NIH/NCI grant RO1CA109536, NIH/NIAMS
grant RO3AR050137 and support from the National Vitiligo Foundation (USA) to C.L.P.
R.M.L. is supported by grants from the Netherlands Organisation for Scientific Research
(NWO-VIDI 016.056.337) and the Dutch Cancer Society (UVA2006-3606).
