TRENDSin Immunology Vol.22 No.3 March 2001 http://immunology.trends.com 1471-4906/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(00)01844-5 130 Opinion Opinion Human epidermal melanocytes (MCs) function as a pivotal protective barrier against ultraviolet (UV) radiation and oxidative stress by generating the radical-scavenging pigment melanin 1 . In addition, they function in local immune reactivity as antigen- processing and antigen-presenting cells (APCs) 2 . In the disfiguring and psychologically debilitating disease vitiligo, MCs are eliminated from the lesional skin 3 in association with T-cell infiltrates 4,5 (Fig. 1). Recent data suggest that the destruction of MCs in vitiligo is mediated by skin-homing autoreactive T cells 6,7 and by additional specific and nonspecific immune components, including antibodies, complement factors and nitric oxide (NO), aided by melanogenic metabolites such as toxic ortho-quinones 1,8,9 . Studies on host melanoma immunity show that similar factors to those in vitiligo operate in the destruction of malignantly transformed MCs. In particular, the prevalence of antibodies and reactive T cells against the differentiation antigens of MCs in both vitiligo and melanoma patients demonstrates a clear parallel between autoimmunity and tumour immunity 1,10 . In vitiligo, natural immune tolerance is over-ridden such that the host immune surveillance system can orchestrate MC destruction, whereas in melanoma, an immune effector function of potential benefit to the host does not occur. Although much information is available on the mechanism of melanoma immunity, the pathomechanism of vitiligo, in the context of immunobiology of MCs, has received little attention to date. This article presents the viewpoint that autoimmunity and tumour immunity are two sides of the same coin; by elucidating the molecular pathogenesis of vitiligo, new therapeutic strategies for either disease might be revealed. MCs in normal human skin Melanogenesis and pigmentation MCs contribute to the prevention of skin cancer by generating melanin within compartments called melanosomes. Melanin-containing melanosomes are a specialized lysosome of MCs, and are distributed among surrounding keratinocytes (KCs) by a process that involves transfer of complete melanosomal organelles via dendrite-like processes that extend from a melanocyte to neighbouring KCs. Compounds specifically expressed in the melanosomal compartment of the cell and involved in the melanogenic pathway 1 are shown in Fig. 2. Briefly, melanogenesis involves multiple catalytic conversions starting from the amino acid tyrosine, leading to the formation of either pheomelanin (yellow/red melanin) or eumelanin (brown/black melanin), depending on the composition of the melanosome. Most of these melanosome-specific compounds, except the P-protein, have been described in recent years as target antigens in tumour immunity and autoimmunity 11,12 . MCs and the skin immune response Apart from responding to environmental growth factors and cytokines, MCs (like KCs) generate cytokines themselves. These cytokines assist in the maturation and migration of professional APCs such as Langerhans cells (LCs), and in the recruitment of immune infiltrates into the skin 13 . Indeed, such cytokine production, combined with the strategic position and dendritic morphology of melanocytes, has led to the suggestion that MCs, in conjunction with KCs and LCs, are active participants within the skin immune response 14 (Box 1). In this regard, it was demonstrated that melanocytes are capable of phagocytosis, and can process and present antigens to MHC class II- restricted T cells 2 . The processing of external antigens appears to involve fusion of phagosomes with melanosomes (Ref. 14), rather than with lysosomes, because melanosomes take over all lysosomal functions within the MC (Ref. 15). The presentation of antigens to CD4 + T cells is supported by the expression of several costimulatory molecules 2 , such as intercellular adhesion molecule 1 (ICAM-1) and leukocyte A symbiotic concept of autoimmunity and tumour immunity: lessons from vitiligo Pranab K. Das, René M.J.G.J. van den Wijngaard, Anna Wankowicz-Kalinska and I. Caroline Le Poole Vitiligo is a skin disease in which melanocytes (MCs) are eradicated from lesional epidermis, resulting in disfiguring loss of pigment. MCs are destroyed by M C-reactive T cells, as well as other non-immune and immune components. Similarities exist between the autoimmunity observed in vitiligo and the tumour immunity observed in melanoma immuno-surveillance. An analysis of these mechanisms might lead to the development of new therapies for both vitiligo and melanoma. Pranab K. Das* Dept of Pathology René M.J.G.J. van den Wijngaard Dept of Gastroenterology Anna Wankowicz- Kalinska Dept of Pathology, Academic Medical Centre, Amsterdam University, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. * e-mail: p.k.das@ amc.uva.nl I. Caroline Le Poole Skin Disease Research Laboratories, Cardinal Bernardin Cancer Center, Loyola University, Maywood, IL 60153, USA. ‘Studies on host melanoma immunity show that similar factors to those in vitiligo operate in the destruction of malignantly transformed MCs.’