Wiete Westerhof

Local immune response in skin of generalized vitiligo patients. Destruction of melanocytes is associated with the prominent presence of CLA+ T cells at the perilesional site.

In situ immune infiltrates in lesional, perilesional, and nonlesional skin biopsies from patients with vitiligo were analyzed by immunohistochemistry and compared with immune infiltrates found in the skin of normal healthy donors and relevant disease controls. An increased influx of activated skin-homing T cells and macrophages were seen in the perilesional biopsies. The overall percentages of cutaneous leukocyte-associated antigen-positive (CLA+) T cells were similar to those found in normal healthy donors. This is compatible with the similar expression of E-selectin. Most strikingly, however, the CLA+ T cells in perilesional skin were mainly clustered in the vicinity of disappearing melanocytes, and 60% to 66% of these interacting T cells expressed perforin and granzyme-B. The perforin+/granzyme-B+ cells were not seen in locations different from that of disappearing melanocytes. Interestingly, the majority of the infiltrating T cells were HLA-DR/CD8+. Another hallmark of the present study is the focal expression of intercellular adhesion molecule (ICAM)-1 and HLA-DR in the epidermis at the site of interaction between the immune infiltrates and the disappearing melanocytes. The data presented in this study are consistent with a major role for skin-homing T cells in the death of melanocytes seen in vitiligo.

Review of the etiopathomechanism of vitiligo: A convergence theory

Abstract Vitiligo is an acquired melanin pigmentary disorder manifesting itself by expanding depigmented lesions of the skin. To date, the etiopathomechanism of vitiligo has not been convincingly elucidated and a number of seemingly mutually opposed hypotheses with equal likelihood still coexist. Concurrent theories on vitiligo etiology, together with supportive evidence, are reviewed here. Due to the observed variation in clinical manifestations of the disease, it seems likely that the etiology of vitiligo may differ among patients. Therefore several theories on vitiligo etiopathogenesis have been combined to formulate a convergence theory for vitiligo. also presented in this article. This theory stales that stress, accumulation of toxic compounds, infection, autoimmunity. mutations, altered cellular environment and impaired melanocyte migration and or proliferation can all contribute to vitiligo etiopathogenesis in varying proportions.

Immunopolarization of CD4 + and CD8 + T Cells to Type-1–Like is Associated with Melanocyte Loss in Human Vitiligo

Vitiligo is an autoimmune condition characterized by loss of epidermal melanocytes. High frequencies of melanocyte-reactive cytotoxic T cells in the peripheral blood of vitiligo patients and the observed correlation between perilesional T-cell infiltration and melanocyte loss in situ suggest the important role of cellular autoimmunity in the pathogenesis of this disease. We isolated T cells from both perilesional and nonlesional skin biopsies obtained from five vitiligo patients, then cloned and analyzed their profile of cytokine production after short-term, nonspecific expansion in vitro. Perilesional T-cell clones (TCC) derived from patients with vitiligo exhibited a predominant Type-1–like cytokine secretion profile, whereas the degree of Type-1 polarization in uninvolved skin-derived TCC correlated with the process of microscopically observed melanocyte destruction in situ. Detailed analysis of broad spectrum of cytokines produced by perilesional- and nonlesional-derived CD4+ and CD8+ TCC confirmed polarization toward Type-1–like in both CD4 and CD8 compartments, which paralleled depigmentation process observed locally in the skin. Furthermore, CD8+ TCC derived from two patients also were analyzed for reactivity against autologous melanocytes. The antimelanocyte cytotoxic reactivity was observed among CD8+ TCC isolated from perilesional biopsies of two patients with vitiligo. Finally, in two of five patients, tetramer analysis revealed presence of high frequencies of Mart-1–specific CD8 T cells in T-cell lines derived from perilesional skin. Altogether our data support the role of cellular mechanisms playing a significant part in the destruction of melanocytes in human autoimmune vitiligo.

Vitiligo pathogenesis: autoimmune disease, genetic defect, excessive reactive oxygen species, calcium imbalance, or what else?

Abstract:  The pathobiology of vitiligo has been hotly disputed for as long as one remembers, and has been a magnet for endless speculation. Evidently, the different schools of thought – ranging, e.g. from the concept that vitiligo essentially is a free‐radical disorder to that of vitiligo being a primary autoimmune disease – imply very different consequences for the best therapeutic strategies that one should adopt. As a more effective therapy for this common, often disfiguring pigmentary disorder is direly needed, we must strive harder to settle the pathogenesis debate definitively – on the basis of sound experimental evidence, rather than by a war of dogmatic theories.

Extracellular matrix characterization during healing of full-thickness wounds treated with a collagen/elastin dermal substitute shows improved skin regeneration in pigs.

We investigated the architecture of the extracellular matrix (ECM) during healing of full-thickness wounds in the pig. Two different treatments, one based on epidermal transplantation (split skin mesh grafts, SP wounds) and one consisting of a combination of epidermal transplantation and a dermal matrix substitute (MA wounds) were compared. The dermal matrix consisted of native bovine collagen coated with elastin hydrolysate. The latter treatment reduced wound contraction and improved tissue regeneration. The expression patterns of fibronectin, von Willebrand factor, laminin, chondroitin sulfate, and elastin, detected by immunohistochemistry, were examined in time and indicated different stages of healing. During the early phase of healing the dermal matrix induced more granulation tissue, a different fibronectin expression pattern, and rapid vascular cell ingrowth (von Willebrand factor). Furthermore, in the MA wounds chondroitin sulfate was detected earlier in the basement membrane and fibronectin staining disappeared more rapidly. During later stages of healing, chondroitin sulfate expression was selective for areas in which ECM remodeling was active; in these specific areas elastin staining reappeared. ECM remodeling and elastin regeneration occurred both in the upper and lower dermis for the MA wounds but only in the upper dermis for the SP wounds. Electron microscopic evaluation of the wounds after 2 weeks showed many myofibroblasts in the SP wounds, whereas in the MA wounds cells associated with the dermal matrix had characteristics of normal fibroblasts. The results suggest that the biodegradable dermal matrix served as a template for dermal tissue regeneration, allowed faster regeneration, and improved the quality of healing in large full-thickness skin defects.

A global survey of the role of ultraviolet radiation and hormonal influences in the development of melasma.

Background It has been generally believed that the four main causes of melasma are pregnancy, hormonal contraception, family history and sun exposure; however, there are few published comprehensive studies that confirm these assertions. The Pigmentary Disorders Academy – an international group of experts in pigmentary disorders – designed and conducted a global survey of women to investigate the effect of these factors on onset and chronicity of melasma and the course of the disease in order to gain a better understanding of the causative factors associated with this disorder, with a particular focus on hormonal factors and UV exposure in females.

Production of catecholamines in the human epidermis.

Cell-free extracts from human full thickness skin (i.e., epidermis and dermis), suction blister roofs (i.e., epidermis) and from human keratinocytes express biopterin-dependent tyrosine hydroxylase a well as phenylethanolamine-N-methyl transferase, both representing key enzymes for the biosynthesis of epinephrine. These enzyme activities could not be detected in cell extracts from human melanocytes and human fibroblasts. Since keratinocytes in the human epidermis, and in cell cultures, express a high density of beta-2-adrenoceptors, and this signal transduction system regulates intracellular calcium homeostasis, it can be concluded that epinephrine production in the epidermis activates calcium transport via the beta-2-adrenoceptor system. Our results show for the first time that the human epidermis has the capacity to independently produce epinephrine.

Repigmentation in vitiligo vulgaris by autologous minigrafting: Results in nineteen patients

BACKGROUND Minigrafting is a successful therapy for localized vitiligo but has never been reported for vitiligo vulgaris. OBJECTIVE Our purpose was to evaluate the efficacy of minigrafting in vitiligo vulgaris. METHODS In 59 patients with stable vitiligo vulgaris, a minigraft test was done by implanting two minigrafts in the lesion to be grafted. Patients were selected for grafting when spread of pigment was observed within 3 months. The rate of repigmentation was evaluated by digital image analysis. RESULTS Twenty-three patients (36 lesions), of 24 with a positive minigraft test, were grafted. The results of 19 patients were analyzed, showing 80% to 99% repigmentation in 14 lesions, 50% to 80% repigmentation in 10 lesions, and zero to 50% repigmentation in 12 lesions. Time of observation varied from 3 to 12 months after grafting. Best results were observed after 9 to 12 months. In all patients with a positive Koebner phenomenon depigmentation of the minigrafts developed. CONCLUSION Autologous minigrafting is an effective therapy for stable vitiligo vulgaris in a selected group of patients.

Treatment of vitiligo vulgaris with narrow‐band UVB and oral Polypodium leucotomos extract: a randomized double‐blind placebo‐controlled study

Background  The first choice treatment for vitiligo vulgaris is narrow‐band UVB (NB‐UVB), but no satisfactory treatment exists.

Reduced wound contraction and scar formation in punch biopsy wounds. Native collagen dermal substitutes. A clinical study

In full‐thickness skin wounds dermal regeneration usually fails, resulting in scar formation and wound contraction. We studied dermal regeneration by implantation of collagenous matrices in a human punch biopsy wound model.