What triggers the proliferation of the ORS-inactive melanocytes in vitiligo is not known. Identification of the stimuli, however, will be the key to the development of any specific new treatment for vitiligo. Melanocytes have the ability to proliferate under certain circumstances, such as UVL exposure or injury to the epidermis (Starrico 1961; Bessou et al. 1995). But the effects of different stimuli on melanocytes are usually mediated by the produc- tion of some molecules that can modify the behaviour of melanocytes.
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Many factors are shown to stimulate melanocytes to proliferate and to migrate under different conditions. UVL exposure, endothelins, granulo- cyte/macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) are just a few of the molecules that enhance the growth of melanocytes. Endothelins are a powerful stimulus to melanocytes and are found to enhance the proliferation and melanogenesis of human melanocytes in vitro (Hara et al. 1995; Lahav et al. 1996; Reid et al. 1996). After ultraviolet irradiation, synthesis and secretion of endothelin-1 by kera- tinocytes are up-regulated, which, along with several other growth factors, produced by keratinocytes, stimulate melanocyte to proliferate, to migrate, and to form dendrites (Hara et al. 1995). It is believed that the effects of endothelins on melanocytes are mediated by protein kinase C and tyrosine kinase pathways (Imokawa et al. 1996a). GM-CSF, another intrinsic keratinocyte-derived growth factor after UVL irradiation, binds to the spe- cific binding sites on human melanocytes and stimulates DNA synthesis and melanization (Imokawa et al. 1996b), which may play an essential role in the maintenance of melanocyte proliferation and UVL-induced pigmen- tation in the epidermis. SCF, also known as mast cell growth factor and kit ligand, has been shown markedly to promote human melanocytes to prolif- erate and to melanize in vivo (Costa et al. 1996). SCF, acting through the tyro- sine kinase receptor c-kit on melanocytes, regulates integrin protein expression in vitro and induces a rapid increase in actin stress fibre forma- tion, thereby enhances melanocyte adhesion and migration on fibronectin (Scott et al. 1996). Interestingly, the expression of the c-kit receptor by epi- dermal melanocytes was found to be reduced in vitiligo, which may con- tribute to the defective growth and survival of melanocytes in vitiligo (Norris et al. 1996). However, it may also be a consequence of melanocyte damage of unknown aetiology.
When proliferating, melanocytes undergo dramatic morphological changes to speed the process: dendrites are drawn back into the cell body;
cells become spherical and detach from their support; and cell division takes place while the cell is suspended (Kippenberger et al. 1997). These changes are mediated by the selective expression of adhesion molecules, such as integrins, ICAM-I, E-cadherin, and CD44, etc. Danen et al. (1996) demonstrated that nonproliferating melanocytes have an increased surface expression of alpha 2 beta 1 and alpha 6 beta 1 integrins which induce cell adhesion to basement membrane collagen and laminin. On the other hand, focal contact proteins, the transmembrane proteins that link the extracellu- lar matrix to the actin cytoskeleton of cells and play a key role in the control of melanocyte migration (Scott et al. 1995), may also be modified to enhance the mobility of melanocytes. After exposure to therapeutic agents, espe- cially UVL exposure, it is believed that keratinocytes as well as other inflam- matory cells in vitiligo lesions may release different melanocyte growth factors to stimulate the inactive melanocyte reservoir in the ORS of hair fol- licles. Some of the factors may be able to modify the expression of adhesion molecules and focal contact proteins on the surface of melanocytes and 165
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CHAPTER 20
The Melanocyte Reservoir
keratinocytes and to prepare the melanocytes for proliferation and migra- tion. The newly proliferated melanocyte population, attracted by higher concentrations of growth factors in the epidermis, gradually migrates into the nearby epidermis and further differentiates to produce melanin.
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The Melanocyte Reservoir
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21 : PUVA Therapy
WARWICK L. MORISON
Photochemotherapy with psoralen compounds and subsequent exposure to UVA (320400nm) radiation is commonly termed PUVA therapy. This treatment has been used in the management of vitiligo for over 2500 years and is still the main treatment available for achieving repigmentation in this condition. PUVA therapy for vitiligo is tedious and prolonged, usually requiring 100-300 exposures to achieve maximal repigmentation and even then only a few patients achieve total repigmentation. These features deter many physicians from offering the treatment to their patients but this is unfortunate since careful selection of patients can produce quite satisfac- tory results. Furthermore, use of combination treatments can considerably improve results.