Jo Lambert

The Quest for the Mechanism of Melanin Transfer

Skin pigmentation is accomplished by production of melanin in specialized membrane‐bound organelles termed melanosomes and by transfer of these organelles from melanocytes to surrounding keratinocytes. The mechanism by which these cells transfer melanin is yet unknown. A central role has been established for the protease‐activated receptor‐2 of the keratinocyte which effectuates melanin transfer via phagocytosis. What exactly is being phagocytosed – naked melanin, melanosomes or melanocytic cell parts – remains to be defined. Analogy of melanocytes to neuronal cells and cells of the haemopoietic lineage suggests exocytosis of melanosomes and subsequent phagocytosis of naked melanin. Otherwise, microscopy studies demonstrate cytophagocytosis of melanocytic dendrites. Other plausible mechanisms are transfer via melanosome‐containing vesicles shed by the melanocyte or transfer via fusion of keratinocyte and melanocyte plasma membranes with formation of tunnelling nanotubes. Molecules involved in transfer are being identified. Transfer is influenced by the interactions of lectins and glycoproteins and, probably, by the action of E‐cadherin, SNAREs, Rab and Rho GTPases. Further clues as to what mechanism and molecular machinery will arise with the identification of the function of specific genes which are mutated in diseases that affect transfer.

Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells

Squamous cell carcinomas (SCCs) of the skin are sun-induced skin cancers that are particularly numerous in patients on T cell immunosuppression. We found that blood vessels in SCCs did not express E-selectin, and tumors contained few cutaneous lymphocyte antigen (CLA)+ T cells, the cell type thought to provide cutaneous immunosurveillance. Tumors treated with the Toll-like receptor (TLR)7 agonist imiquimod before excision showed induction of E-selectin on tumor vessels, recruitment of CLA+ CD8+ T cells, and histological evidence of tumor regression. SCCs treated in vitro with imiquimod also expressed vascular E-selectin. Approximately 50% of the T cells infiltrating untreated SCCs were FOXP3+ regulatory T (T reg) cells. Imiquimod-treated tumors contained a decreased percentage of T reg cells, and these cells produced less FOXP3, interleukin (IL)-10, and transforming growth factor (TGF)-β. Treatment of T reg cells in vitro with imiquimod inhibited their suppressive activity and reduced FOXP3, CD39, CD73, IL-10, and TGF-β by indirect mechanisms. In vivo and in vitro treatment with imiquimod also induced IL-6 production by effector T cells. In summary, we find that SCCs evade the immune response at least in part by down-regulating vascular E-selectin and recruiting T reg cells. TLR7 agonists neutralized both of these strategies, supporting their use in SCCs and other tumors with similar immune defects.

Immune reactions in benign and malignant melanocytic lesions: lessons for immunotherapy

Spontaneous regression of benign and malignant melanocytic lesions can be a visible sign of immunosurveillance. In this review, we discuss different immune reactions against melanocytic lesions: halo nevus, Meyerson’s nevus, regression in melanoma and melanoma‐associated depigmentation. These entities present with particular clinical aspects, histology and evolution. In all entities, a melanocyte‐specific T‐cell reaction has been assumed but a different degree of melanocyte destruction is present. A focus on the immune responses in melanocytic lesions reveals several aspects of an adequate skin immunity and may help to identify the key points in the immune destruction of melanocytes. These insights can add to the knowledge of how to optimize immunotherapeutic strategies in melanoma.

New insights in segmental vitiligo: case report and review of theories

Segmental vitiligo and generalized vitiligo are in general considered to be separate entities. The aetiopathogenesis of segmental vitiligo remains unclear, although several hypotheses have been put forward including mainly neuronal mechanisms. The typical association with other autoimmune diseases, as seen in generalized vitiligo, seems to be significantly less in segmental vitiligo, although recent insights point towards a possible immune‐mediated overlap between the two subtypes. In this article, we describe a case with simultaneous presence of segmental vitiligo, alopecia areata, psoriasis and a halo naevus. To our knowledge, this is the first case with this exceptional combination. This concomitant presence could support the involvement of a shared autoimmune‐mediated process, and may provide new insights into the pathogenesis of segmental vitiligo and direct future research. In the light of this remarkable case, different possible aetiopathogenetic mechanisms leading to the clinical presentation of segmental vitiligo are discussed and a new three‐step theory is proposed.

In vivo vitiligo induction and therapy model: double-blind, randomized clinical trial.

In this study, we developed an in vivo vitiligo induction model to explore the underlying mechanisms leading to Koebner’s phenomenon and to evaluate the efficacy of therapeutic strategies. The model consisted of 12 pigmented test regions on the back of generalized vitiligo patients that were exposed to three Koebner induction methods: cryotherapy, 755u2003nm laser therapy, and epidermal abrasion. In addition, four cream treatments (pimecrolimus, tacrolimus, steroid and placebo) were randomly applied. Koebnerization was efficiently induced by all three induction methods. In general, cryotherapy was the best method of Koebner induction, followed by 755u2003nm laser therapy and epidermal abrasion. Reproducible results were obtained, which showed enhanced depigmented surface areas and higher amounts of T lymphocytes in placebo‐treated test zones compared to active treated areas. Tacrolimus and local steroids were better inhibitors of Koebner’s process (Pu2003<u20030.05) compared to pimecrolimus. Our in vivo vitiligo induction model is very informative to investigate vitiligo induction and to determine the efficacy of topical treatments in vitiligo. This proof of concept confirms the efficient comparison of head‐to‐head therapeutic strategies intra‐individually in a standardized, specific and better timed way.

Different phenotypes of segmental vitiligo based on a clinical observational study.

Backgroundu2002 Segmental vitiligo and generalized vitiligo are in general considered separate entities. However, clinico‐epidemiological data on segmental vitiligo are scarce compared with those of generalized vitiligo.

The biology of hyperpigmentation syndromes

Hyperpigmentation is a key feature in a variety of inherited and acquired syndromes. Nonetheless, determining the exact diagnosis only on the clinical phenotype can be challenging, and a detailed search for associated symptoms is often of crucial importance. As pigmentation pathways are regulated by complex signaling transduction cascades (e.g. MSH/cAMP, KIT signaling pathways), the underlying defects leading to elevated melanin production are numerous. With regard to treatment, limited therapeutic options exist, each with specific side effects. In acquired hyperpigmentation, the melanin deposition may, however, be reversible after adequate therapy of the underlying disorder or even disappear spontaneously. In this review, we provide an overview of the biology of hyperpigmentation syndromes classified according to the main underlying defect that deregulates physiological melanogenesis. The identification of novel genes or key players involved in hyperpigmentary disorders is becoming increasingly important in view of the development of safer and more efficient treatments.

Prognostic value and clinical significance of halo naevi regarding vitiligo

Backgroundu2002 Vitiligo and halo naevi can present together or separately. Whether they are different entities remains unclear.

Halo naevi with associated vitiligo-like depigmentations: pathogenetic hypothesis.

Backgroundu2002 In analogy with melanoma‐associated leucoderma, halo naevi may trigger in some patients the development of additional depigmentations which are in distribution, extent and prognosis not in accordance with classic vitiligo.

Immune mediated mechanisms of melanocyte destruction: Paving the way for efficient immunotherapeutic strategies against melanoma

Insights into immune reactions against benign and malignant melanocytes may help the development of more efficient immunotherapeutic treatments for melanoma. The interplay between an active systemic antitumor immunity and a responsive local tumor environment is crucial to achieve effective clinical responses. Increasing evidence confirms this strategy can lead to an adequate and durable immunosurveillance of melanocytes.