17: Autocytotoxic Hypothesis for the Destruction of Melanocytes as the Cause of Vitiligo
SEUNG-KYUNG H A N N A N D W O O - H Y U N G C H U N
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individuals with certain genes that he labelled vitiligo genes, that is, suscep- tibility genes. Excessive quantities of toxic by-products generated either in the epidermis or upper dermis damaged the melanocyte that seems to have a limited ability to proliferate and replace dying or dead cells.
Genetic protective mechanisms
Lerner (1971) postulated that melanocytes have a genetically based protec- tive mechanism that eliminates any toxic precursors or by-products (such as dopa, DOPAchrome, 5,6-dihydroxyindole) produced during the synthesis of melanin. In individuals of kinships sharing certain genes, these genetic protective mechanisms are deficient. There is an accumulation of melanocy- totoxic products causing the death of pigment cells. The end result clinically is depigmentation.
Membrane permeability
Wick (1977) noted that the outer membranes of melanosomes are normally responsible for retarding or blocking the diffusion of the toxic intermediary products of melanin synthesis into the cytoplasm and nucleus where they might cause irreversible damage and death to the cell. Defects either inher- ited or acquired in the membranes of melanosomes probably would result in the demise of the melanocytes.
Peroxidation of membrane lipids
Riley (1970) suggested that depigmentation produced by infusions of hydroxyanisole is brought about by the formation of semiquinone free radi- cals. He suggested the hydroxyanisole is taken up like tyrosine into the melanosome where it is oxidized by the enzyme tyrosinase. It can only be partially oxidized and forms a semiquinone. These compounds diffuse out of the melanosomes to initiate the chain of peroxidation of lipids in the mem- branes of mitochondria or the cell itself. The peroxidation causes damage to critical cellular organelles and ultimately the selective destruction of melanocytes. However, neither semiquinone free radicals nor increased levels of the two tyrosine derivatives described by Brun (1972) have been found in vitiliginous skin. These four ways by which phenolic derivatives might kill melanocytes are not mutually incompatible nor all inclusive.
Chemical leukoderma
There are many in uitro observations that suggest or confirm a toxic role for tyrosine-like molecules, melanin precursors or by-products. Chemicals with structures similar to melanin intermediates have been added to cul- tures of melanocytes or melanoma cells. The cells undergo cytolysis (Wick 1987; Prezioso et al. 1990). Most of the chemicals that have a cytotoxic poten-
tial are phenols and quinones. Brun (1972) suggested that vitiligo might be due to the inhibitory action on the tyrosine-tyrosinase system by a phenolic derivative which may be a degradative product of a normally occurring component in melanin synthesis. Such a chemical disrupts melanogenesis, possibly by competitive inhibition for tyrosinase and leads to melanocyte death. Graham et al. (1978) have shown that dopachrome produced during melanin synthesis is a highly toxic metabolite specifically for melanocytes.
Derivatives of hydroquinone (monobenzyl ether of hydroquinone), cat- echols or phenol applied to the skin of humans, or some animals, may induce vitiligo-like cutaneous depigmentation. Frenk (1969) reported the ultrastructure of chemically induced depigmentation to be similar to that of vitiligo. (See Chapter 32 for a detailed presentation about topical melanocy- totoxic chemicals.) Many depigmenting agents show striking structural similarity to tyrosine or dopa. Brun (1972) observed two tyrosine deriva- tives, p-hydroxycinnamic acid and p-hydroxyphenylpyruvic acid to be strong inhibitors of melanogenesis. Tyrosine, dopa, and tryptophan (a second amino acid that also can be incorporated into the synthesis of melanin) show a selective cytotoxicity towards melanin-producing cells.
Treatment of cells with phenylthiourea, a selective inhibitor of tyrosinase activity and melanin formation, completely protects the cells from the toxicity of the melanin precursors.
Melatonin and the melatonin receptor
Other investigators have suggested that melanin synthesis is disrupted by abnormalities of the melatonin receptor. Melatonin is derived from the pineal gland, the retina, cells in the gastrointestinal tract and, perhaps, other extrapineal sites. In amphibians and some mammals it is responsible for rapid decrease in colour and down-regulation of melanin formation (Slominski et al. 1989). That is, melatonin is a naturally occurring inhibitor and modulator of melanin synthesis (Logan & Weatherhead 1980). It exerts its regulatory role by an interaction with a specific receptor and is a product of the multistep conversion of L-tryptophan to serotonin and subsequently melatonin. The synthesis and secretion of melatonin are stimulated by cate- cholamines (Ebadi & Govitrapong 1986). Melatonin exhibits a host of activi- ties including immunomodulatory and antitumour activities.
A defective receptor might result in the uncontrolled production of melanin with the release of free radicals and toxic products of melanogene- sis. This process damages melanocytes by a build up of toxic products and free radicals generated during melanogenesis without a parallel increase in the production of the scavenger melanin. In addition, keratinocytes are damaged by toxic products released from melanocytes or by transport of metabolically active melanosomes into keratinocytes. Release of cellular proteins could provoke a secondary autoimmune response against intracel- lular or altered cell surface antigens on the melanocytes and increase the propensity of melanocytes to undergo malignant transformation. Other 139
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scavenger systems may also be defective and render the patient more vul- nerable to toxic products generated. As a consequence, the melanocyte damage is magnified by a vicious cycle: decrease or loss of melanocyte support by keratinocytes within a functional pigmentary unit (Nordlund 1985).
Melatonin and the autoimmune hypothesis
A secondary autoimmune response to altered cell surface proteins on the damaged melanocytes and keratinocytes, as well as to intracellular antigens sharing homology with surface antigens, leads to an irreversible loss of melanocytes (’point of no return’).
The melatonin receptor could be subject to abnormal activation by several mechanisms that include:
1 an increased concentration of melatonin in the skin caused by excessive production of melatonin in the pineal gland or in peripheral production sites (perhaps the skin) initiated by an increased release of catecholamines and other neurotransmitters;
2 a hereditary tendency toward expression of an increased number of melatonin receptors; and
3 a dysfunction of the melatonin receptor caused by an intrinsic activation without binding of ligand, activation by binding of a ligand other than melatonin or via stimulating autoantibodies against the melatonin receptor.
The latter speculation is suggested by the association of vitiligo with Grave‘s disease, which displays stimulatory autoantibodies against thyroid-stimulating hormone (TSH) receptors. The immunomodulatory properties of melatonin could further contribute to the autoimmune phe- nomena associated with vitiligo.
The melatonin hypothesis emphasizes the pivotal role of a hyperactive melatonin receptor in the initial phase of vitiligo pathogenesis, and stresses the interdependence of the different systems affected. All the experimental and clinical findings about vitiligo and depigmentation can be explained within the confines of the melatonin hypothesis, including the association with other autoimmune diseases, neurologic/psychiatric disorders and stress, melanoma, hereditary factors and Koebner’s phenomenon. Sponta- neous or therapeutically induced repigmentation of vitiligo skin lesions would be possible before the ‘point of no return’ has been reached. It has been suggested (but there are no data yet to confirm) that there is a higher incidence of vitiligo in patients with Addison’s disease. If this supposition were true, the phenomenon could be explained by the stimulatory effect of melanocyte-stimulating hormone (MSH) and ACTH on the generation of toxic products and free radicals of melanogenesis.
Although the melatonin hypothesis is consistent with the many clinical observations about vitiligo, the theory is without any substantial experi- mental basis. For example, it is still necessary to establish that human melanocytes actually have functional melatonin receptors and that activa-
tion of these receptors can lead to a build up of toxic products of melanogen- esis. There is no clinical evidence that melatonin has any role in the regula- tion of melanin production in humans. The recently reported finding that 5-methoxypsoralen actually increased melatonin serum levels in 11 normal volunteers awaits explanation (Souetre et al. 1987). In vitiligo, serum mela- tonin levels may be of minor relevance, as opposed to melatonin concentra- tion in the skin and degree of receptor activation of the target cells.
Conclusion
The clinical and laboratory observations noted here provide some basis for the autocytotoxic theory for melanocyte destruction but much more work needs to be done before this hypothesis is confirmed. In the meantime, the pathogenesis of vitiligo remains a mystery.
References
Bleehen, S.S., Pathak, M.A., Hori, Y. & Fitzpatrick, T.B. (1968) Depigmentation of skin with 4-isopropy1catecho1, mercaptoamines, and other compounds. Journal oflnvestiga- tive Dermatology 50,103-117.
Brun, R. (1972) Apropos de l'etiologie du vitiligo. Dermatologica 145,169-174.
Ebadi, M. & Govitrapong, P. (1986) Neural pathways and neurotransmitters affecting melatonin synthesis. Journal of Neural Transmission 21 (Suppl.), 125-155.
Frenk, E. (1969) Experimentelle Depigmentierung der Meerschweinchenhaut durch selektiv toxische Wirkung von Hydrochinon-monoathylather auf die Melanocyten.
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Graham, D.G., Tiffany, S.M. & Vogel, F.S. (1978) The toxicity of melanin precursors.
Lerner, A.B. (1971) On the etiology of vitiligo and gray hair. American Journal ofMedicine Lerner, A.B. & Nordlund, J.J. (1978) Vitiligo: loss of pigment in skin, hair and eyes.
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Logan, A. & Weatherhead, 8. (1980) Post-tyrosinase inhibition of eumelanogenesis by melatonin in hair follicles in vitro. Journal oflnvestigative Dermatology 74,47-50.
Nordlund, J.J. (1985) The pigmentary system: new interpretations of old data. Journal of Dermatology 12,105-116.
Prezioso, J.A., Fitzgerald, G.B. &Wick, M.M. (1990) Effects of tyrosinase activity on the cytotoxicity of 3,4dihydroxybenzylamine and buthionine sulfoximine in human melanoma cells. Pigment Cell Research 3,49-54.
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Souetre, E., Salvati, E., Belugou, J.L. et al. (1987) 5-Methoxypsolaren increases the plasma Weatherhead, B. & Logan, A. (1981) Interaction of a-melanocyte stimulating hormone,
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melatonin, cyclic AMP and cyclic GMP in the control of melanogenesis in hair follicle melanocytes in vitro. journal of Endocrinology 90,89-96.
Wick, M.M. (1977) 1-Dopa methyl ester as a new antitumour agent. Nature 269,512-513.
Wick, M.M. (1987) Inhibition of transformation by levodopa-carbodopa in lymphocytes derived from patients with melanoma. Journal oflnvestigative Dermatology 88,532-534.
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18: Neural Pathogenesis
GIOVANNI E . ORECCHIA Dedication: To my wife Laura
One commonly accepted theory for the pathogenesis of vitiligo is the neural hypothesis. The neural theory is supported by clinical, physiolog- ical, microscopic, ultrastructural, immunohistochemical and biochemical findings.