Istituto San Gallicano
Via San Gallicano 25/a - 00153 Rome, Italy
An important part of the XV International Pigment Cell Conference was devoted to the new aspects of vitiligo.
David Norris has presented an excellent lecture on the possible pathogenetic mechanisms of the depigmentation and of the repigmentation of the vitiligo spots. He reviewed, according to the new researchers on the disease, the biochemical alterations in the vitiligo subjects, the alteration in the catecholamine metabolism and the dysfunction in the antioxidant defence mechanisms of the melanocytes. These events may produce an alteration of the antigenic pattern of the cells, the release of auto-antigens and the development of an auto-immune reactions towards pigment cells. He underlined that different factors which have been considered as precipitating causes of the disease may produce an oxidative injury of the melanocytes. In this category he included the high UV exposure, the physical trauma and the release of inflammatory mediators such as some cytokines. He presented interesting data on the possible mechanisms of re-pigmentation of the vitiligo spots spontaneously produced or following the PUVA therapy. He demonstrated that leukotriene C4 (a poster form his group has been presented at the meeting), which is known to be a growth and chemiokinetic factor for neonatal melanocytes, is also chemotactic for the melanocytes. In response to PUVA therapy, the increased intraepidermal concentration of LTC4 may act as a signal for melanocyte migration out of the outer root sheath of the hair follicle into the depigmented areas. Through the expression of integrin receptors on melanocytes, the cell can adhere to the basal membrane of the colonised epidermis.
The immunologist's view point on etiopathogenesis of vitiligo has been presented by P.K. Das and co-workers from Amsterdam. This group has shown that melanocytes, in addition to produce cytokines, are able to constitutively express MHC class II antigens and are able to phagocyte latex particles. Now they have reported that melanocytes are capable of phagocitizing Mycobacterium leprae, processing and presenting antigenic fragments to T-cells. Therefore melanocytes may be involved in the immune reaction of the skin and can became a "stand by target" for activated T-cells. According to their hypothesis, even if the presence of inflammatory infiltrate is not a common finding in vitiligo skin, melanocytes may act as a target for T-cells sensitised towards auto antigens which produce a damage to melanocytes and go away from the skin (Hit and Run phenomenon).
An interesting discussion was developed during the symposium on Vitiligo.
P. Grimes reviewed the immune dysfunction detected in vitiligo subjects.
The Amsterdam group presented the immunophenotyping of infiltrate in inflammatory vitiligo, underlying the presence of CD4+ cells and macrophages in the perilesional skin and the decrease in the number of Langerhans cells in lesional skin. These authors suggested the possibility to separate an entity of inflammatory vitiligo in which the immune mechanism may be involved.
Goudie and co-workers presented a study on the possible identification of a specific T-cell clone in the skin of patients with vitiligo. By the polymerase chain reaction this group tried to identify a T-cell receptor gamma gene rearrangement similar to that recovered in cutaneous T-cell lymphoma. The analysis performed in 32 patients was negative, and this group suggested that the site of melanocytes damage may be dependent on other factors such as the inappropriate adhesion molecule expression or MHC class II antigen expression.
The second part of the workshop was focused on the free radical hypothesis of vitiligo and the modification of the scavenger systems in experimental animals and in man.
B. Salzer and K. Schallreuter presented an investigation on the personality and on the possible triggering events in patients with vitiligo. The study, conducted in more than 100 subjects, showed no specific characteristic personality pattern for patients with vitiligo, but underlined that the major part of the patients associated the onset or the progression of the disease with traumatic situation or stressful events.
Bowers reported that in Barred Plymouth Rock (a spontaneous model of vitiligo in animals) the level of superoxide dismutase in melanocytes is decreased, whereas the level of catalase is normal. A working hypothesis was proposed by this group: a genetic defect may account for the alteration of SOD activity and consequently the premature death of melanocytes, which can be observed both in vivo and in vitro in barred feather, may be due to the increased levels of oxyradicals. The addition of the dominant white gene to these chicken constitute the leghoron chicken and may produce the reduction of another anti-oxidant or the generation of a toxic factor leading to an early damage of melanocytes. A similar radical damage combined with a possible genetic defect of anti-oxidant system may account for the melanocyte death in vitiligo.
The radical hypothesis on the pathogenesis of vitiligo was also proposed by S. Passi e co-workers. The Roman group reported that an increase of catecholamine metabolites, namely homovanillic and vanil mandelic acid, can be detected in the urine of subjects with early or active phase of the disease. This finding were irrespective to the clinical appearance of the disease, i.e. segmental, acrofacial or generalised. This group proposed that the increased release of catecholamine at the nerve endings can induce high level of catecholamines on the skin which can produce a cytotoxic effect trough two mechanisms: a direct one via the spontaneous oxidation of the catecholamines and the generation of free radicals; the second one via the vasoconstriction of dermal vessels, the subsequent ischaemia-hypoxia of the skin and the production of oxyradicals following the hypoxic damage of the cells. This hypothesis may account for the damage of epidermal cells other than melanocytes, such as keratinocytes and Langerhans cells, which has been described in the vitiligo lesions. These authors, according to their results, proposed the administration of a mixture of anti-oxidants, which include tocopherol acetate, selenium and selenium methionine as possible therapy in subjects with active vitiligo. The clinical pictures of some patients treated showed the stop of the progression of depigmentation and the repigmentation of some spots.
An interesting presentation has been done by Dr. K. Schallreuter. She has performed different experiments on the enzymatic activities on the skin vitiligo subjects. According to her results, the keratinocytes are able to synthesise epinephrine via biopterin dependent tyrosine hydroxylase pathway. In vitiligo subjects an alteration of this enzymatic pathway can be detected with an increase of tyrosine hydroxylase activity and the reduction of phenylethanolamine-N-methyl transferase and ultimately an increase of norepinephrine synthesis. As consequence of these enzymatic modifications, there is an increase of the skin content of tetrahydrobiopterin, a fluorescent substance which may be responsible for the appearance of the vitiligo skin under Wood light. In summary the author suggested that vitiligo may be a primarily defect in biopterin production leading to an upregulated catecholamine biosynthesis in epidermis of these patients, the production of elevated amount of toxic free radicals and the consequent damage of melanocytes which possess low antioxidant enzymatic activities.
At the moment we have not completely clarified all the aspects of the pathogenesis of vitiligo, but certainly we have made some new steps in the comprehension of the disease.