Pigment Cell Research Suppl. 2: 237-241 (1992)
The Significance of Depigmentation JAMES J. NORDLUND University of Cincinnati College of Medicine, Department of Dermatology, Cincinnati, Ohio 45221 Supported in part by grants from the National Vitiligo Foundation, Tyler, Texas
Alterations in skin color, hyper- or hypopigmentation, are generally dismissed by most individuals, physicians, and even many dermatologists as insignificant nuisances. The prevailing misperception is that pigmentary changes are merely cosmetic aberrations. For the individual wi.th dark or white spots on the skin, the pain and anguish of disfigurement are a preeminent concern. But for dermatologists and pigment cell biologists, these should be biological problems of great significance. For this article we shall concern ourselves only with depigmentation. In thinking about the significance of depigmentation, it is important to recognize that acquired depigmentation is a widespread phenomenon which affects many species of vertebrates such as chickens, swine, horses, mice, dogs, cats, elephants, whales, as well as humans. We do not know whether the depigmentation occurs in non-vertebrate species. It seems l’ikely that acquired depigmentation is the clinical manifestation of numerous different disease processes. However, we call all types of idiopathic acquired depigmentation in humans vitiligo or vitiligo-like. The latter term is most commonly used to describe depigmentation in non-human species. The purpose of this article is to highlight the importance of depigmentation from three perspectives: that of the human patient; that of the dermatologist who is consulted for treatment; and that of the pigment cell biologist who seeks to establish the cause or the biological effects of the loss of melanocytes from the integument. PATIENT PERSPECTIVES
It La
caused by white spots usually present on the face, neck, hands or even by those on covered parts of the body such as the genitalia. The anguish spares no one regardless of age or sex (1). To the patient, vitiligo is not merely cosmetic but a form of disfigurement similar to a burn scar ( 2 ) . They are glad they do not have a fatal malignancy. Physicians and medical personnel might gain important insights into the patient’s concern and anxiety if, for a mere three days, they applied a white dye on their face and hands before they faced their public. Despite the emotional pain of vitiligo, a third of the patients cope with the problem quite well. Some become proactive and organize support groups or organize activities to raise funds for research. But two-thirds of patients with vitiligo do not cope well (1). The lives of one-third are significantly impaired by this disease, Many are sexually inhibited, whether married or not ( 3 ) . Those who have or desire a job requiring frequent contact with the public and a proper appearance, such as sales people, television personnel or corporate executives, have lost or been rejected from jobs. For one-third of the world’s five billion people, vitiligo carries additional cultural burdens. Especially in parts of the world such as the Middle East, the African continent, the Indian subcontinent and Asia, vitiligo carries social penalties. Affected individuals are not readily married and sometimes not employable. Even siblings can be ostracized, especially those living in rural areas in these countries. In the 1950’s Prime Minister Nehru of India noted that the cultural effects of vitiligo which made millions of individuals societal outcasts was a major hindrance to the development of India into a first class nation.
truism that nobody wishes t o have Paclcnts arc Launted by frlerids. relatives and physicians by statements such as
THE DERMATOLOGIST’S PERSPECTIVE
“It is only cosmetic” or, “You should be glad you do not have cancer”. The patients are painfully aware of their unattractive appearance
Depigmentation fs common. It has many known causes. Burns, thermal injuries and other forms
Q
o p o t t c d akin,
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J. J. Nordlund
of trauma are common causes for depigmentation. These are easily recognized. There are less obvious causes for partial or total pigment loss such as sarcoidosis, scleroderma, or genetic diseases like piebaldism. These forms of depigmentation usually differ in their clinical manifestations from vitiligo and the causes usually are apparent to the alert physician. Idiopathic vitiligo has no known cause by definition and typically, although not always, appears first on the hands and feet (60% of affected individuals) (unpublished data). It spreads to the arms, face, ventral trunk and legs. It is often much less severe or spares the dorsal surfaces such as the back and buttocks. The scalp, palms, soles and oral cavity are very commonly involved, although these areas are rarely examined and thus most physicians are unaware of these points. Chemical depigmentation clinically can be very similar or identical to idiopathic vitiligo. However, it is caused by exposure to specific types of chemicals. It is a misperception that phenol or hydroquinone can cause vitiligo-like depigmentation. There are anecdotes of patients using hydroquinone and acquiring vitiligo. Hydroquinone is available commercially over-the-counter in a 2% bleaching cream and is used by millions of individuals to lighten the skin or to remove unsightly dark splotches. Idiopathic vitiligo affects about 1% of the population or two million Americans. Statistically it is predictable that some people exposed to hydroquinone will also develop idiopathic vitiligo. There is no scientifically rigorous evidence that hydroquinone is a melanocytotoxin either in vivo or in vitro. In contrast to hydroquinone, chemicals such as monobenzyl ether of hydroquinone, paratertiary butyl catechol, paratertiary butyl phenol or 4-isopropyl catechol are rnelanocytotoxins. The mechanism of cytotoxicity of these agents is not obvious, but all are hydroquinone with an aliphatic or aromatic side chain. Application of 20% or even 40% monobenzone to the skin of patients with extensive vitiligo does not produce immediate melanocyte destruction. It often takes 1-2 years to achieve depigmentation and some patients even when using 40% cream applied twice daily under saran wrap occlusion do not achieve depigmentation. The question must be asked if monobenzone is a specific melanocyte poison, why topical preparations used under these conditions do not readily depigment all patients. The mechanism by which these complex derivatives of hydroquinone kill melanocytes is probably complex. Chemical leukoderma resembles but may not be identical to idiopathic vitiligo. There are several malignancies such as melanoma and cutaneous T cell lymphoma which are associated with vitiligo-like depigmentation. Until it has been shown that idiopathic vitiligo has the same cause as depigmentation associated with a malignancy, the term vitiligo-like seems preferable for the latter types of pigment loss.
About 20% of patients with metastatic melanoma develop depigmentation. These patients seem to survive longer than predicted from the thickness of their primary tumor or the stage of progression of their malignancy (4). Whether the mechanism which causes the destruction of normal melanocytes also retards the growth of the malignant melanocytes and therefore prolongs survival, or whether because the patient lives longer normal melanocytes are destroyed as innocent bystanders is a moot point. The Sinclair mini-pigs are an animal model which resemble humans with metastatic melanoma and vitiligolike depigmentation (5). The Sinclair miniswine exhibit depigmentation in association with metastatic melanoma. The tumors regress spontaneously. Many investigators have postulated that an immune mechanism is responsible both for the depigmentation and the regression of the tumor. Intensive searches for either cytotoxic antibodies ( 6 ) or lymphocytes (7,8) which cause the depigmentation or disappearance of the tumor have been unsuccessful. Several types of lymphoproliferative disorders have been associated with hypo- or depigmentation. Patients with Hodgkin's disease, multiple myeloma, chronic lymphocytic leukemia and cutaneous T cell lymphoma have been noted to develop a vitiligo-like condition (9). These associations could be chance occurrences. It seems enigmatic that lymphomas which are known to cause cellular or humoral immunodeficiency (for example, Hodgkin's disease and chronic lymphocytic leukemia) have preceded the development of vitiligo which is most popularly believed to be an autoimmune disease. Patients with AIDS have developed vitiligo (10). Probably the most common lymphoproliferative disorder associated with hypo- or depigmentation is cutaneous T-cell lymphoma. This cutaneous malignancy may first present as loss of pigment and only a biopsy will suggest the etiology. How or why these two disorders are associated is not known and may also only represent a chance occurrence. Vitiligo is said to be associated with a variety of endocrine disorders such as Hashimoto's thyroiditis, hyper- and hypothyroid, adrenal insufficiency, pernicious anemia or gonadal dysfunction. These are all considered to be autoimmune diseases. Thomas Addison in 1855 in his book Diseases of the Supra-Adrenal Gland noted that twelve patients had hyperpigmented skin and atrophic adrenal glands. Two of his patients also had a vitiligo-like depigmentation. Eleven of the twelve patients were autopsied and all had a scrofulous destruction of the adrenal glands. His twelfth patient who had both adrenal insufficiency and depigmentation was not autopsied. Of course, the diagnosis of tuberculosis of the adrenal gland could not be made by Addison until the discovery of mycobacteria by Robert Koch some years later. The findings of Thomas Addison probably should be distinguished from the Addison's disease extant today which is rarely of tuberculous origin. The reports of Addison have been cited as examples of an autoimmune cause of vitiligo, but this assumption should be reconsidered more carefully.
J. J. Nordlund
239
Pernicious anemia in patients with vitiligo seems to be extremely rare. Thyroiditis is known to affect somewhere between ten and thirty percent of the population at large. Whether there is a real association of thyroiditis in vitiligo is not definitively established.
The evidence for this is that vitiligo supposedly begins around the eyes, nose, mouth and other orifices. However, clinical studies suggest that this is a misperception and that it begins much more commonly on the hands and feet (unpublished data).
Alopecia areata is also said to be associated with vitiligo and many believe it to be of autoimmune origin. In studies of over 500 patients with vitiligo done at two institutions with strong interests in depigmentation, it was observed that only 1% of patients had both vitiligo and alopecia areata (unpublished data). The prevalence of alopecia areata is estimated to vary from 0.1-1% of the population at large. Whether patients with vitiligo develop alopecia areata more commonly than normal patients is not known. But one must question the significance of the association if 99% of patients with vitiligo do not have alopecia.
The autoimmune hypothesis is most popular and based mostly on circumstantial evidence. In the previous discussion it was noted that vitiligo is said to be associated with other autoimmune diseases such as adrenal insufficiency, pernicious anemia, thyroiditis (9,11), although the significance of these associations is not obvious. That vitiligo has been observed in patients with lymphoma or AIDS and other immunosuppressed states has been cited as evidence for an autoimmune origin. However, one should think that patients with immunodeficiency disorders would be spared from developing vitiligo. That patients with metastatic melanoma develop a vitiligo-like condition is considered to be some of the strongest evidence for an autoimmune pathogenesis. It is known that melanomas typically elicit an immune response to a variety of tumor associated antigens. These humoral or cytotoxic factors are said to be the cause of vitiligo in patients with melanoma. Attempts to document that the antibodies (12,13) or lymphocytes (14) are cytotoxic either to melanoma cells or normal human melanocytes have been unsuccessful.
There have been a number of patients with multiple endocrine failures such as thyroid, adrenal, gonadal insufficiency and pernicious anemia (11). They have also had vitiligo. These rare patients may be the best clinical example of autoimmune disease associated with vitiligo.
PERSPECTIVES OF THE PIGMENT CELL BIOLOGIST That depigmentation is observed widespread throughout the animal kingdom is an indication that some biological processes common to pigment cells in many species could be involved in melanocyte destruction. The most common theories for vitiligo and depigmentation are three-fold, namely the neural, autoimmune and autotoxic hypotheses (9). The neural theory is based on several facts:
1) that melanocytes have a common embryological origin as nerve cells, i.e., the neural crest; 2) that catechols structurally are similar to the melanin precursor dopa; 3) that nerves transmit catecholic agents which might affect melanocyte function, an idea documented only for dermal melanophores in lower vertebrates like amphibians; 4) that vitiligo can be segmental in distribution. Frequently segmental vitiligo is misconstrued to be dermatomal. Most segmental vitiligo does not follow dermatomal patterns. For example, it often will affect an entire leg from the inguinal fold on the ventral surface and the gluteal crease on the posterior surface and extend down to the tips of the toes. There are no hard data to support nor to refute the neural theory. The autotoxic theory is based on the concept that melanin precursors which are indoles and quinones can be cytotoxic for melanocytes. Addition of these various chemicals into cultures of melanocytes may cause their destruction. On the other hand, many of these compounds do not exist in the chemical forms which are drawn on paper, but form semiquinones and ether highly reactive molecules. Whether they undergo similar chemical changes i n v i v o is not known. It has also been stated that hyperpigmentation is associated with vitiligo.
One patient with mucocutaneous candidiasis and vitiligo was found by indirect immunofluorescence technique to have in a skin biopsy C3 deposited on melanocytes (15). The complement presumably was fixed by IgG. However, in the second study four of six patients with mucocutaneous candidiasis but without vitiligo were found to have similar antibodies which fixed C3 (16). Apparently the antibodies were not cytotoxic in four of the seven patients. More recently the serum of patients with vitiligo was found to have an antibody detected i n vitro by a lysis of either melanocytes or melanoma cells tagged by a lactoperoxidase method (17,18). The antibody appears to be polyclonal and to attack epitopes on several different molecules. It is assumed that the antigens are on the surface of the cell because the method of detection was a lactoperoxidase technique. However, it is known that lactoperoxidase does iodinate cytoplasmic contents. In addition, the only published data show that the antibodies attach to melanosomal proteins. Melanosomal proteins can also be found on the surfaces of normal melanocytes. In the initial studies the melanocytes were grown in media containing phorbol esters and cholera toxin. Fibroblasts were used as control cells and grown, in normal media. Fibroblasts in regular media showed minimal reactivity to the antibodies. However, if the fibroblasts were grown in phorbol esters and cholera toxin like the melanocytes, they exhibit very high levels of cross-reactivity, The histology of vitiligo in most patients is rather banal and shows only a small increase in mononuclear cells at the edge of the lesion.
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It is true that about 5% of patients will have one or more lesions which exhibit erythema at the edge and a more dense infiltrate in the dermis. The histology for most active vitiligo suggests that if an immune mechanism is involved, it might be an antibody dependent cellular cytotoxic reaction (19). This hypothesis has been tested in vitro. Approximately one-third of sera from vitiligo patients caused cytotoxicity of normal human melanocytes in conjunction with natural killer cells. Approximately another third of the sera cause monocyte destruction by a complement fixing cytotoxicity. That two-thirds of the sera do not cause cytotoxicity by an ADCC form of cytotoxicity is not strongly supportive of the histology of active spreading vitiligo or an autoimmune cause for vitiligo. In the Smyth chicken, vitiligo depigmentation begins as an intramelanocytic defect with an increased synthesis of the enzyme tyrosinase and mistranslocation of the enzyme both to melanosomes and to lysosomes. The excessive melanization causes death of melanocytes releasing cytoplasmic contents. The dying melanocytes elicit an immune response which accelerates the depigmentation. In the vit/vit mouse which exhibits a form of depigmentation which resembles in many ways that observed in humans, there have been numerous studies done looking for evidence of an autoimmune role. The data strongly suggest that there is no role for the immune system in depigmentation in this species. The strongest evidence is reciprocal transplants of skin from a young vit/vit mouse to the congenic parental strain, the C57BL/6 mouse, and reciprocal graft of the C57 skin to the vit/vit mouse (20). Results show that the vit/vit skin on the C57 mouse depigments, whereas the C57 skin on the vit/vit mouse retains its color. These data strongly suggest that the defect is intramelanocytic, not a systemic immune reaction. Recently conditions were discovered for the maintenance and culture of murine and adult human melanocytes in culture (21). Melanocytes from animals or normal humans or those with vitiligo can be maintained for over 1 year. By electron microscopy the cells were found to exhibit marked morphologic abnormalities. The most common feature noted was dilated rough endoplasmic reticulum. The morphology of the endoplasmic reticulum resembled that of several endoplasmic reticulum storage diseases such as Ehlers-Danlos type IV or homozygous ( z / z ) alpha1 antitrypsin deficiency (R. Boissy, personal communication). These abnormalities of the rough endoplasmic reticulum can be enhanced by the addition of Brefeldin A, a chemical obtained from a fungus. The chemical is known to block translocation of proteins from the endoplasmic reticulum into the Golgi apparatus. Normal human melanocytes from individuals without vitiligo can be made to resemble morphologically those from patients with vitiligo by the addition of Brefeldin A (R. Boissy, personal communication). The abnormalities either in vitiligo or normal melanocytes can be reversed by the addition of cycloheximide which blocks protein synthesis. These data suggest that in
mice and humans the depigmentation may begin as an intracellular defect. Possibly in humans like in the Smyth chicken the immune system may accelerate the depigmenting process. A most surprising and poorly known effect of depigmentation is that the white skin does not sensitize easily to applications of potent contact allergens such as dinitrofluorobenzene (22,23,24). In mice, the defect seems to be an afferent defect, in humans, an efferent defect. The abnormality is not due to deficient numbers or defective functions of Langerhans cells or lymphocytes. However, in both species the ability of the depigmented epidermis to express intracellular adhesion molecules (ICAM-1) in response to interferon-7 is highly muted although not completely absent (25). The suppressed expression of ICAM-1 cannot be attributed merely to the loss of melanocytes. Piebald W/Wv mice express apparently normal amounts of ICAM-1. Their response to contact allergens is intermediate between the vit/vit mice and normal C57 black mice. By some unknown mechanism, the vitiligo gene in mice and humans alters expression of ICAM and makes melanocytes susceptible to premature death. Melanocytes respond to and produce numerous immune/inflammatory cytokines (26) and are said to be immunocompetent cells by a number of investigators in the United States and Europe. Depigmentation is a unique opportunity for pigment cell biologists and immunologists to study the melanocyte and the regulation of immune/inflammatory responses within the epidermis. We conclude that all clinical phenomena, warts, acne, seborrheic keratosis,,skin tags and depigmentation, when studied will reveal a wealth of new knowledge about our skin and bodies. Such studies will open to our limited imaginations the phenomenal panorama of surprises and miracles that nature has devised to allow us to live happily in symbiosis with our environment. Depigmentation is an excellent example of how we can learn more about skin and melanocytes by studying disease processes in a systematic and careful way.
REFERENCES
1. Porter JR, Beuf AH, Lerner A, Nordlund JJ. The psychosocial effect of vitiligo: A comparison of vitiligo patients with "normal" controls, with psoriasis patients, and with patients with other pigmentary disorders. J Am Acad Dermatol 1986:15:220-224. 2. Porter J , Beuf A, Lerner AB, Nordlund JJ. Response to cosmetic disfigurement: Patients with vitiligo. Cutis 1987:39:493-494. 3. Porter JR, Beuf AH, Lerner AB, Nordlund JJ. The effect of vitiligo on sexual relationship. J Am Acad Dermatol 1990:22:221-222. 4. Nordlund JJ, Kirkwood J , Forget BM, Milton G , Lerner AB. Vitiligo in patients with metastatic melanoma: A good prognostic sign. J Am Acad Dermatol 1983:9:689-695.
J. J. Nordlund 5. Hook RR Jr, Berkelhammer J , Oxenhandler RW. Animal Model of Human Disease. Melanoma. Sinclair Swine Melanoma. Am J Pathol 1982:108:130-133. 6. Feeney-Burns L, Alspaugh M, Burns RP, Gao CL. Uveitis in melanomatous swine: Lack of evidence for humoral immune melanocyte destruction. Invest Ophthalmol Vis Sci 1985:26:551-560. 7. Oxenhandler RW, Berkelhammer J , Smith GD, Hook RR Jr. Growth and regression of cutaneous melanomas in Sinclair miniature swine. Am J Pathol 1982:109:259-269. 8. Aultman MD, Hook RR Jr. In vitro lymphocyte reactivity to soluble tumor extracts in Sinclair melanoma swine. Int J Cancer 1979:24:673-678. 9. Nordlund JJ, Lerner AB. Vitiligo: Its relationship to systemic disease. In: Moschella SL, ed. Dermatology Update. Reviews for Physicians. New York: Elsevier North Holland, Inc., 1979:411-432. 10. Duvic M, Rapini R, Hoots WK, Mansell PW. Human immunodeficiency virus-associated vitiligo: Expression of autoimmunity with immunodeficiency. J Am Acad Dermatol 1987~17~656-662. 11. McGregor BC, Katz HI, Doe RP. Vitiligo and multiple glandular insufficiencies. JAMA 1972:219:724-725. 12. Hudson L.D. The humoral immune system in melanoma, vitiligo, and halo nevus: A review of recent literature. J Assoc Military Dermatol 1979:5:15-18. 13. Howanitz M, Nordlund JJ, Lerner AB, Bystryn JC. Antibodies to melanocytes in patients with vitiligo. A;ch Deimatol 1981:117:705-708. 14. Mitchell M, Nordlund JJ, Lerner AB. Comparison of cell-mediated immunity to melanoma cells in patients with vitiligo, halo nevi and melanoma. J Invest Dermatol 1980:75:144-147. 15. Hertz KC, Gazze LA, Kirkpatrick CH, Katz SI. Autoimmune vitilino. Detection of antibodies to melanin produGing cells. N Engl J Med 1977~297~634-637. 16. Nordlund JJ, Howanitz N, Bystryn JC, Forget BM, Lerner AB. Anti-pigment cell factors and mucocutaneous candidiasis. Arch Dermatol 1981:117:210-212. 17. Naughton GK, Eisenger M, Bystryn JC. Antibodies to normal human melanocytes in vitiligo. J Exp Med 1983:158:246-251. 18. Naughton GK, Eisenger M, Bystryn JC. Detection of antibodies to melanocytes by specific immunoprecipitation. J Invest Dermatol 1983:81:540-542. 19. Norris DA, Capin L, Muglia JJ, et al. Enhanced susceptibility of melanocytes to different immunologic effector mechanisms in vitro: Potential mechanisms for postinflammatory hypopigmentation and vitiligo. Pigment Cell Res 1988:Suppl 1:113-123. 20. Amornsiripanitch S , Nordlund JJ, Barnes L, Trinkle L, Rheins LA. Immune studies in the depigmenting C57BL/Ler-vit/vit mice: An apparent isolated loss of contact hypersensitivity. J Immunol 1988:160:3438-3665. 21. Medrano EE, Nordlund JJ: Successful culture of melanocytes from human normal adults and J Invest Dermatol vitiligo donors. 1990:95:441-445.
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22. Nordlund JJ, Forget B, Kirkwood J , Lerner AB. Dermatitis produced by applications of monobenzone in patients with active vitiligo. Arch Dermatol 1985:121:1141-1145. 23. Rheins LA, Palkowski MR, Nordlund JJ. Alterations in cutaneous immune reactivity to dinitrofluorobenzene in graying C57BL/vi*vi mice. J Invest Dermatol 1986:86:539-542. 24. Van de Kerkhof PCM, Fokkink HJ. Irritancy of dithranol in normally pigmented and depigmented skin of patients with vitiligo. Acta Denn Venereol (Stockh) 1989:69:236-238. 25. Csato M, Nordlund JJ. Genetic deficiency of ICAM-1 in the depigmenting C57BL/Ler-vit/vit mice: The probable cause for associated loss of contact sensitization, J Invest Dermatol 1991:in press. 26. Swope VB, Abdel-Malek ZA, Kassem L, Nordlund JJ. Interleukins la and 6 and tumor necrosis factor-a are paracrine inhibitors of human melanocyte proliferation and melanogenesis. J Invest Dermatol 1991:96:180-185.
The Significance of Depigmentation JAMES J. NORDLUND University of Cincinnati College of Medicine, Department of Dermatology, Cincinnati, Ohio 45221 Supported in part by grants from the National Vitiligo Foundation, Tyler, Texas
Alterations in skin color, hyper- or hypopigmentation, are generally dismissed by most individuals, physicians, and even many dermatologists as insignificant nuisances. The prevailing misperception is that pigmentary changes are merely cosmetic aberrations. For the individual wi.th dark or white spots on the skin, the pain and anguish of disfigurement are a preeminent concern. But for dermatologists and pigment cell biologists, these should be biological problems of great significance. For this article we shall concern ourselves only with depigmentation. In thinking about the significance of depigmentation, it is important to recognize that acquired depigmentation is a widespread phenomenon which affects many species of vertebrates such as chickens, swine, horses, mice, dogs, cats, elephants, whales, as well as humans. We do not know whether the depigmentation occurs in non-vertebrate species. It seems l’ikely that acquired depigmentation is the clinical manifestation of numerous different disease processes. However, we call all types of idiopathic acquired depigmentation in humans vitiligo or vitiligo-like. The latter term is most commonly used to describe depigmentation in non-human species. The purpose of this article is to highlight the importance of depigmentation from three perspectives: that of the human patient; that of the dermatologist who is consulted for treatment; and that of the pigment cell biologist who seeks to establish the cause or the biological effects of the loss of melanocytes from the integument. PATIENT PERSPECTIVES
It La
caused by white spots usually present on the face, neck, hands or even by those on covered parts of the body such as the genitalia. The anguish spares no one regardless of age or sex (1). To the patient, vitiligo is not merely cosmetic but a form of disfigurement similar to a burn scar ( 2 ) . They are glad they do not have a fatal malignancy. Physicians and medical personnel might gain important insights into the patient’s concern and anxiety if, for a mere three days, they applied a white dye on their face and hands before they faced their public. Despite the emotional pain of vitiligo, a third of the patients cope with the problem quite well. Some become proactive and organize support groups or organize activities to raise funds for research. But two-thirds of patients with vitiligo do not cope well (1). The lives of one-third are significantly impaired by this disease, Many are sexually inhibited, whether married or not ( 3 ) . Those who have or desire a job requiring frequent contact with the public and a proper appearance, such as sales people, television personnel or corporate executives, have lost or been rejected from jobs. For one-third of the world’s five billion people, vitiligo carries additional cultural burdens. Especially in parts of the world such as the Middle East, the African continent, the Indian subcontinent and Asia, vitiligo carries social penalties. Affected individuals are not readily married and sometimes not employable. Even siblings can be ostracized, especially those living in rural areas in these countries. In the 1950’s Prime Minister Nehru of India noted that the cultural effects of vitiligo which made millions of individuals societal outcasts was a major hindrance to the development of India into a first class nation.
truism that nobody wishes t o have Paclcnts arc Launted by frlerids. relatives and physicians by statements such as
THE DERMATOLOGIST’S PERSPECTIVE
“It is only cosmetic” or, “You should be glad you do not have cancer”. The patients are painfully aware of their unattractive appearance
Depigmentation fs common. It has many known causes. Burns, thermal injuries and other forms
Q
o p o t t c d akin,
238
J. J. Nordlund
of trauma are common causes for depigmentation. These are easily recognized. There are less obvious causes for partial or total pigment loss such as sarcoidosis, scleroderma, or genetic diseases like piebaldism. These forms of depigmentation usually differ in their clinical manifestations from vitiligo and the causes usually are apparent to the alert physician. Idiopathic vitiligo has no known cause by definition and typically, although not always, appears first on the hands and feet (60% of affected individuals) (unpublished data). It spreads to the arms, face, ventral trunk and legs. It is often much less severe or spares the dorsal surfaces such as the back and buttocks. The scalp, palms, soles and oral cavity are very commonly involved, although these areas are rarely examined and thus most physicians are unaware of these points. Chemical depigmentation clinically can be very similar or identical to idiopathic vitiligo. However, it is caused by exposure to specific types of chemicals. It is a misperception that phenol or hydroquinone can cause vitiligo-like depigmentation. There are anecdotes of patients using hydroquinone and acquiring vitiligo. Hydroquinone is available commercially over-the-counter in a 2% bleaching cream and is used by millions of individuals to lighten the skin or to remove unsightly dark splotches. Idiopathic vitiligo affects about 1% of the population or two million Americans. Statistically it is predictable that some people exposed to hydroquinone will also develop idiopathic vitiligo. There is no scientifically rigorous evidence that hydroquinone is a melanocytotoxin either in vivo or in vitro. In contrast to hydroquinone, chemicals such as monobenzyl ether of hydroquinone, paratertiary butyl catechol, paratertiary butyl phenol or 4-isopropyl catechol are rnelanocytotoxins. The mechanism of cytotoxicity of these agents is not obvious, but all are hydroquinone with an aliphatic or aromatic side chain. Application of 20% or even 40% monobenzone to the skin of patients with extensive vitiligo does not produce immediate melanocyte destruction. It often takes 1-2 years to achieve depigmentation and some patients even when using 40% cream applied twice daily under saran wrap occlusion do not achieve depigmentation. The question must be asked if monobenzone is a specific melanocyte poison, why topical preparations used under these conditions do not readily depigment all patients. The mechanism by which these complex derivatives of hydroquinone kill melanocytes is probably complex. Chemical leukoderma resembles but may not be identical to idiopathic vitiligo. There are several malignancies such as melanoma and cutaneous T cell lymphoma which are associated with vitiligo-like depigmentation. Until it has been shown that idiopathic vitiligo has the same cause as depigmentation associated with a malignancy, the term vitiligo-like seems preferable for the latter types of pigment loss.
About 20% of patients with metastatic melanoma develop depigmentation. These patients seem to survive longer than predicted from the thickness of their primary tumor or the stage of progression of their malignancy (4). Whether the mechanism which causes the destruction of normal melanocytes also retards the growth of the malignant melanocytes and therefore prolongs survival, or whether because the patient lives longer normal melanocytes are destroyed as innocent bystanders is a moot point. The Sinclair mini-pigs are an animal model which resemble humans with metastatic melanoma and vitiligolike depigmentation (5). The Sinclair miniswine exhibit depigmentation in association with metastatic melanoma. The tumors regress spontaneously. Many investigators have postulated that an immune mechanism is responsible both for the depigmentation and the regression of the tumor. Intensive searches for either cytotoxic antibodies ( 6 ) or lymphocytes (7,8) which cause the depigmentation or disappearance of the tumor have been unsuccessful. Several types of lymphoproliferative disorders have been associated with hypo- or depigmentation. Patients with Hodgkin's disease, multiple myeloma, chronic lymphocytic leukemia and cutaneous T cell lymphoma have been noted to develop a vitiligo-like condition (9). These associations could be chance occurrences. It seems enigmatic that lymphomas which are known to cause cellular or humoral immunodeficiency (for example, Hodgkin's disease and chronic lymphocytic leukemia) have preceded the development of vitiligo which is most popularly believed to be an autoimmune disease. Patients with AIDS have developed vitiligo (10). Probably the most common lymphoproliferative disorder associated with hypo- or depigmentation is cutaneous T-cell lymphoma. This cutaneous malignancy may first present as loss of pigment and only a biopsy will suggest the etiology. How or why these two disorders are associated is not known and may also only represent a chance occurrence. Vitiligo is said to be associated with a variety of endocrine disorders such as Hashimoto's thyroiditis, hyper- and hypothyroid, adrenal insufficiency, pernicious anemia or gonadal dysfunction. These are all considered to be autoimmune diseases. Thomas Addison in 1855 in his book Diseases of the Supra-Adrenal Gland noted that twelve patients had hyperpigmented skin and atrophic adrenal glands. Two of his patients also had a vitiligo-like depigmentation. Eleven of the twelve patients were autopsied and all had a scrofulous destruction of the adrenal glands. His twelfth patient who had both adrenal insufficiency and depigmentation was not autopsied. Of course, the diagnosis of tuberculosis of the adrenal gland could not be made by Addison until the discovery of mycobacteria by Robert Koch some years later. The findings of Thomas Addison probably should be distinguished from the Addison's disease extant today which is rarely of tuberculous origin. The reports of Addison have been cited as examples of an autoimmune cause of vitiligo, but this assumption should be reconsidered more carefully.
J. J. Nordlund
239
Pernicious anemia in patients with vitiligo seems to be extremely rare. Thyroiditis is known to affect somewhere between ten and thirty percent of the population at large. Whether there is a real association of thyroiditis in vitiligo is not definitively established.
The evidence for this is that vitiligo supposedly begins around the eyes, nose, mouth and other orifices. However, clinical studies suggest that this is a misperception and that it begins much more commonly on the hands and feet (unpublished data).
Alopecia areata is also said to be associated with vitiligo and many believe it to be of autoimmune origin. In studies of over 500 patients with vitiligo done at two institutions with strong interests in depigmentation, it was observed that only 1% of patients had both vitiligo and alopecia areata (unpublished data). The prevalence of alopecia areata is estimated to vary from 0.1-1% of the population at large. Whether patients with vitiligo develop alopecia areata more commonly than normal patients is not known. But one must question the significance of the association if 99% of patients with vitiligo do not have alopecia.
The autoimmune hypothesis is most popular and based mostly on circumstantial evidence. In the previous discussion it was noted that vitiligo is said to be associated with other autoimmune diseases such as adrenal insufficiency, pernicious anemia, thyroiditis (9,11), although the significance of these associations is not obvious. That vitiligo has been observed in patients with lymphoma or AIDS and other immunosuppressed states has been cited as evidence for an autoimmune origin. However, one should think that patients with immunodeficiency disorders would be spared from developing vitiligo. That patients with metastatic melanoma develop a vitiligo-like condition is considered to be some of the strongest evidence for an autoimmune pathogenesis. It is known that melanomas typically elicit an immune response to a variety of tumor associated antigens. These humoral or cytotoxic factors are said to be the cause of vitiligo in patients with melanoma. Attempts to document that the antibodies (12,13) or lymphocytes (14) are cytotoxic either to melanoma cells or normal human melanocytes have been unsuccessful.
There have been a number of patients with multiple endocrine failures such as thyroid, adrenal, gonadal insufficiency and pernicious anemia (11). They have also had vitiligo. These rare patients may be the best clinical example of autoimmune disease associated with vitiligo.
PERSPECTIVES OF THE PIGMENT CELL BIOLOGIST That depigmentation is observed widespread throughout the animal kingdom is an indication that some biological processes common to pigment cells in many species could be involved in melanocyte destruction. The most common theories for vitiligo and depigmentation are three-fold, namely the neural, autoimmune and autotoxic hypotheses (9). The neural theory is based on several facts:
1) that melanocytes have a common embryological origin as nerve cells, i.e., the neural crest; 2) that catechols structurally are similar to the melanin precursor dopa; 3) that nerves transmit catecholic agents which might affect melanocyte function, an idea documented only for dermal melanophores in lower vertebrates like amphibians; 4) that vitiligo can be segmental in distribution. Frequently segmental vitiligo is misconstrued to be dermatomal. Most segmental vitiligo does not follow dermatomal patterns. For example, it often will affect an entire leg from the inguinal fold on the ventral surface and the gluteal crease on the posterior surface and extend down to the tips of the toes. There are no hard data to support nor to refute the neural theory. The autotoxic theory is based on the concept that melanin precursors which are indoles and quinones can be cytotoxic for melanocytes. Addition of these various chemicals into cultures of melanocytes may cause their destruction. On the other hand, many of these compounds do not exist in the chemical forms which are drawn on paper, but form semiquinones and ether highly reactive molecules. Whether they undergo similar chemical changes i n v i v o is not known. It has also been stated that hyperpigmentation is associated with vitiligo.
One patient with mucocutaneous candidiasis and vitiligo was found by indirect immunofluorescence technique to have in a skin biopsy C3 deposited on melanocytes (15). The complement presumably was fixed by IgG. However, in the second study four of six patients with mucocutaneous candidiasis but without vitiligo were found to have similar antibodies which fixed C3 (16). Apparently the antibodies were not cytotoxic in four of the seven patients. More recently the serum of patients with vitiligo was found to have an antibody detected i n vitro by a lysis of either melanocytes or melanoma cells tagged by a lactoperoxidase method (17,18). The antibody appears to be polyclonal and to attack epitopes on several different molecules. It is assumed that the antigens are on the surface of the cell because the method of detection was a lactoperoxidase technique. However, it is known that lactoperoxidase does iodinate cytoplasmic contents. In addition, the only published data show that the antibodies attach to melanosomal proteins. Melanosomal proteins can also be found on the surfaces of normal melanocytes. In the initial studies the melanocytes were grown in media containing phorbol esters and cholera toxin. Fibroblasts were used as control cells and grown, in normal media. Fibroblasts in regular media showed minimal reactivity to the antibodies. However, if the fibroblasts were grown in phorbol esters and cholera toxin like the melanocytes, they exhibit very high levels of cross-reactivity, The histology of vitiligo in most patients is rather banal and shows only a small increase in mononuclear cells at the edge of the lesion.
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It is true that about 5% of patients will have one or more lesions which exhibit erythema at the edge and a more dense infiltrate in the dermis. The histology for most active vitiligo suggests that if an immune mechanism is involved, it might be an antibody dependent cellular cytotoxic reaction (19). This hypothesis has been tested in vitro. Approximately one-third of sera from vitiligo patients caused cytotoxicity of normal human melanocytes in conjunction with natural killer cells. Approximately another third of the sera cause monocyte destruction by a complement fixing cytotoxicity. That two-thirds of the sera do not cause cytotoxicity by an ADCC form of cytotoxicity is not strongly supportive of the histology of active spreading vitiligo or an autoimmune cause for vitiligo. In the Smyth chicken, vitiligo depigmentation begins as an intramelanocytic defect with an increased synthesis of the enzyme tyrosinase and mistranslocation of the enzyme both to melanosomes and to lysosomes. The excessive melanization causes death of melanocytes releasing cytoplasmic contents. The dying melanocytes elicit an immune response which accelerates the depigmentation. In the vit/vit mouse which exhibits a form of depigmentation which resembles in many ways that observed in humans, there have been numerous studies done looking for evidence of an autoimmune role. The data strongly suggest that there is no role for the immune system in depigmentation in this species. The strongest evidence is reciprocal transplants of skin from a young vit/vit mouse to the congenic parental strain, the C57BL/6 mouse, and reciprocal graft of the C57 skin to the vit/vit mouse (20). Results show that the vit/vit skin on the C57 mouse depigments, whereas the C57 skin on the vit/vit mouse retains its color. These data strongly suggest that the defect is intramelanocytic, not a systemic immune reaction. Recently conditions were discovered for the maintenance and culture of murine and adult human melanocytes in culture (21). Melanocytes from animals or normal humans or those with vitiligo can be maintained for over 1 year. By electron microscopy the cells were found to exhibit marked morphologic abnormalities. The most common feature noted was dilated rough endoplasmic reticulum. The morphology of the endoplasmic reticulum resembled that of several endoplasmic reticulum storage diseases such as Ehlers-Danlos type IV or homozygous ( z / z ) alpha1 antitrypsin deficiency (R. Boissy, personal communication). These abnormalities of the rough endoplasmic reticulum can be enhanced by the addition of Brefeldin A, a chemical obtained from a fungus. The chemical is known to block translocation of proteins from the endoplasmic reticulum into the Golgi apparatus. Normal human melanocytes from individuals without vitiligo can be made to resemble morphologically those from patients with vitiligo by the addition of Brefeldin A (R. Boissy, personal communication). The abnormalities either in vitiligo or normal melanocytes can be reversed by the addition of cycloheximide which blocks protein synthesis. These data suggest that in
mice and humans the depigmentation may begin as an intracellular defect. Possibly in humans like in the Smyth chicken the immune system may accelerate the depigmenting process. A most surprising and poorly known effect of depigmentation is that the white skin does not sensitize easily to applications of potent contact allergens such as dinitrofluorobenzene (22,23,24). In mice, the defect seems to be an afferent defect, in humans, an efferent defect. The abnormality is not due to deficient numbers or defective functions of Langerhans cells or lymphocytes. However, in both species the ability of the depigmented epidermis to express intracellular adhesion molecules (ICAM-1) in response to interferon-7 is highly muted although not completely absent (25). The suppressed expression of ICAM-1 cannot be attributed merely to the loss of melanocytes. Piebald W/Wv mice express apparently normal amounts of ICAM-1. Their response to contact allergens is intermediate between the vit/vit mice and normal C57 black mice. By some unknown mechanism, the vitiligo gene in mice and humans alters expression of ICAM and makes melanocytes susceptible to premature death. Melanocytes respond to and produce numerous immune/inflammatory cytokines (26) and are said to be immunocompetent cells by a number of investigators in the United States and Europe. Depigmentation is a unique opportunity for pigment cell biologists and immunologists to study the melanocyte and the regulation of immune/inflammatory responses within the epidermis. We conclude that all clinical phenomena, warts, acne, seborrheic keratosis,,skin tags and depigmentation, when studied will reveal a wealth of new knowledge about our skin and bodies. Such studies will open to our limited imaginations the phenomenal panorama of surprises and miracles that nature has devised to allow us to live happily in symbiosis with our environment. Depigmentation is an excellent example of how we can learn more about skin and melanocytes by studying disease processes in a systematic and careful way.
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J. J. Nordlund 5. Hook RR Jr, Berkelhammer J , Oxenhandler RW. Animal Model of Human Disease. Melanoma. Sinclair Swine Melanoma. Am J Pathol 1982:108:130-133. 6. Feeney-Burns L, Alspaugh M, Burns RP, Gao CL. Uveitis in melanomatous swine: Lack of evidence for humoral immune melanocyte destruction. Invest Ophthalmol Vis Sci 1985:26:551-560. 7. Oxenhandler RW, Berkelhammer J , Smith GD, Hook RR Jr. Growth and regression of cutaneous melanomas in Sinclair miniature swine. Am J Pathol 1982:109:259-269. 8. Aultman MD, Hook RR Jr. In vitro lymphocyte reactivity to soluble tumor extracts in Sinclair melanoma swine. Int J Cancer 1979:24:673-678. 9. Nordlund JJ, Lerner AB. Vitiligo: Its relationship to systemic disease. In: Moschella SL, ed. Dermatology Update. Reviews for Physicians. New York: Elsevier North Holland, Inc., 1979:411-432. 10. Duvic M, Rapini R, Hoots WK, Mansell PW. Human immunodeficiency virus-associated vitiligo: Expression of autoimmunity with immunodeficiency. J Am Acad Dermatol 1987~17~656-662. 11. McGregor BC, Katz HI, Doe RP. Vitiligo and multiple glandular insufficiencies. JAMA 1972:219:724-725. 12. Hudson L.D. The humoral immune system in melanoma, vitiligo, and halo nevus: A review of recent literature. J Assoc Military Dermatol 1979:5:15-18. 13. Howanitz M, Nordlund JJ, Lerner AB, Bystryn JC. Antibodies to melanocytes in patients with vitiligo. A;ch Deimatol 1981:117:705-708. 14. Mitchell M, Nordlund JJ, Lerner AB. Comparison of cell-mediated immunity to melanoma cells in patients with vitiligo, halo nevi and melanoma. J Invest Dermatol 1980:75:144-147. 15. Hertz KC, Gazze LA, Kirkpatrick CH, Katz SI. Autoimmune vitilino. Detection of antibodies to melanin produGing cells. N Engl J Med 1977~297~634-637. 16. Nordlund JJ, Howanitz N, Bystryn JC, Forget BM, Lerner AB. Anti-pigment cell factors and mucocutaneous candidiasis. Arch Dermatol 1981:117:210-212. 17. Naughton GK, Eisenger M, Bystryn JC. Antibodies to normal human melanocytes in vitiligo. J Exp Med 1983:158:246-251. 18. Naughton GK, Eisenger M, Bystryn JC. Detection of antibodies to melanocytes by specific immunoprecipitation. J Invest Dermatol 1983:81:540-542. 19. Norris DA, Capin L, Muglia JJ, et al. Enhanced susceptibility of melanocytes to different immunologic effector mechanisms in vitro: Potential mechanisms for postinflammatory hypopigmentation and vitiligo. Pigment Cell Res 1988:Suppl 1:113-123. 20. Amornsiripanitch S , Nordlund JJ, Barnes L, Trinkle L, Rheins LA. Immune studies in the depigmenting C57BL/Ler-vit/vit mice: An apparent isolated loss of contact hypersensitivity. J Immunol 1988:160:3438-3665. 21. Medrano EE, Nordlund JJ: Successful culture of melanocytes from human normal adults and J Invest Dermatol vitiligo donors. 1990:95:441-445.
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22. Nordlund JJ, Forget B, Kirkwood J , Lerner AB. Dermatitis produced by applications of monobenzone in patients with active vitiligo. Arch Dermatol 1985:121:1141-1145. 23. Rheins LA, Palkowski MR, Nordlund JJ. Alterations in cutaneous immune reactivity to dinitrofluorobenzene in graying C57BL/vi*vi mice. J Invest Dermatol 1986:86:539-542. 24. Van de Kerkhof PCM, Fokkink HJ. Irritancy of dithranol in normally pigmented and depigmented skin of patients with vitiligo. Acta Denn Venereol (Stockh) 1989:69:236-238. 25. Csato M, Nordlund JJ. Genetic deficiency of ICAM-1 in the depigmenting C57BL/Ler-vit/vit mice: The probable cause for associated loss of contact sensitization, J Invest Dermatol 1991:in press. 26. Swope VB, Abdel-Malek ZA, Kassem L, Nordlund JJ. Interleukins la and 6 and tumor necrosis factor-a are paracrine inhibitors of human melanocyte proliferation and melanogenesis. J Invest Dermatol 1991:96:180-185.
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