Faculty Bibliography

Oculocutaneous albinism (OCA) is an inherited condition characterised by significantly reduced pigment in skin, hair and eyes, visual defects and an increased risk of skin cancer. In the South African black population, 1 in 4 000 people is affected. Quality of life in children with albinism is influenced not only by health problems, but also by stigmatisation, rejection and cultural issues. This review aims to explore the latest literature available on the epidemiology, genetics, clinical characteristics, psychosocial issues and possible management strategies, focusing on affected children. The knowledge provided here is required of health professionals if a more fully informed service is to be offered to these children and their families.

Vitiligo, an acquired depigmentation disorder, results from autoimmune targeting of melanocytes. Vitiligo can be triggered following exposure to phenols such as monobenzone (MBEH) and 4-tertiary butyl phenol (4-TBP). Melanocytes from individuals with idiopathic vitiligo (trigger is not known) are more sensitive to MBEH and 4-TBP. We hypothesized that stress response pathways activated following exposure to vitiligo triggers may be dysregulated in individuals who develop the disorder. We delineated the response of melanocytes from normally pigmented individuals (NMs) to challenge with MBEH and 4-TBP and identified two key survival pathways activated following exposure: the NRF2-regulated antioxidant response and the unfolded protein stress response (UPR). NRF2 knockdown sensitized NMs to MBEH (p < 0.0001), while NRF2 activation by knockdown of its repressor KEAP significantly decreased sensitivity (p < 0.0001). Similarly, inhibition of the PERK-eIF2alpha arm of the UPR with the chemical inhibitor GSK2606414 increased sensitivity to MBEH (cleaved PARP observed at 250 muM MBEH with GSK2606414 and 400 muM without). Activation of NRF2-regulated antioxidant responses and PERK-mediated phosphorylation of eIF2alpha following MBEH exposure was impaired in melanocytes from individuals who developed vitiligo. We have thus identified two stress response pathways that may be dysfunctional in vitiligo and contribute to the onset of depigmentation

Interfollicular epidermal melanocytes are continually subjected to environmental challenges and activate protective stress responses for survival. Dysregulation of these responses may increase susceptibility to depigmentation typical of chemical leukoderma (depigmentation limited to site of exposure) and vitiligo (progressive depigmentation due to an autoimmune response). We delineated the response of melanocytes from normally pigmented individuals (NMs) to challenge with the chemotoxins monobenzone (MBEH) and 4-tertiary butyl phenol (4-TBP) and determined that the unfolded protein stress response (UPR) was activated following exposure. The UPR, a key survival pathway, is activated when the homeostasis of the Endoplasmic Reticulum (ER) is disrupted, for example by cellular oxidative stress induced by chemotoxin exposure. The UPR, which consists of three signal transduction pathways initiated by PERK, IRE1 or ATF6 respectively, promotes restoration of ER homeostasis and survival. In this study, we assessed the cytoprotective effect of the PERK arm of the UPR. PERK phosphorylates a number of proteins including the eukaryotic translation initiation factor, eIF2alpha. We treated melanocytes with the PERK kinase inhibitor GSK2606414 and confirmed efficacy by monitoring eIF2alpha phosphorylation, which was reduced after treatment. Melanocytes were then dosed with MBEH in the presence or absence of GSK2606414. The inhibitor sensitized melanocytes to MBEH (Cleaved/c-PARP observed with 250 muM MBEH + GSK2606414, compared to 400 muM MBEH + vehicle). To further investigate the role of PERK in melanocytes, we used a gene silencing (shRNA) approach to knockdown expression. An 88% decrease in viability (p < 0.0001) was observed 3 days post-infection (shPERK versus scrambled/shNT). Cultures were maintained for 14 days when viability was found to be improved (40% decrease in viability, p < 0.0001). Melanocytes that survived prolonged PERK downregulation adapted and could be maintained in culture (shPERKLT). Survival correlated with a paradoxical increase in phospho-eIF2alpha and reduced sensitivity to MBEH (c-PARP observed with 500 muM MBEH in shPERKLT versus 400 muM MBEH in shNT cells). Intriguingly, while eIF2alpha is not typically phosphorylated in unstressed cells, a fraction of eIF2alpha was phosphorylated in melanocytes at baseline. Thus PERK may play a role in determining melanocyte viability and sensitivity to chemotoxins

In this perspective, we identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology. Significantly, this document encapsulates important advances in melanocyte and melanoma research including emerging frontiers in melanoma immunotherapy, medical and surgical oncology, dermatology, vitiligo, albinism, genomics and systems biology, epidemiology, pigment biophysics and chemistry, and evolution.

The International Federation of Pigment Cell Societies (IFPCS) held its XXIII triennial International Pigment Cell Conference (IPCC) in Denver, Colorado in August 2017. The goal of the summit was to provide a venue promoting a vibrant interchange among leading basic and clinical researchers working on leading-edge aspects of melanocyte biology and disease. The philosophy of the meeting, entitled Breakthroughs in Pigment Cell and Melanoma Research, was to deliver a comprehensive program in an inclusive environment fostering scientific exchange and building new academic bridges. This document provides an outlook on the history, accomplishments, and sustainability of the pigment cell and melanoma research community. Shared progress in the understanding of cellular homeostasis of pigment cells but also clinical successes and hurdles in the treatment of melanoma and dermatological disorders continue to drive future research activities. A sustainable direction of the societies creates an international forum identifying key areas of imminent needs in laboratory research and clinical care and ensures the future of this vibrant, diverse and unique research community at the same time. Important advances showcase wealth and breadth of the field in melanocyte and melanoma research and include emerging frontiers in melanoma immunotherapy, medical and surgical oncology, dermatology, vitiligo, albinism, genomics and systems biology, precision bench-to-bedside approaches, epidemiology, pigment biophysics and chemistry, and evolution. This report recapitulates highlights of the federate meeting agenda designed to advance clinical and basic research frontiers from melanoma and dermatological sciences followed by a historical perspective of the associated societies and conferences.