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MIA Protein and Vitiligo

The Role of  Protein MIA (melanoma inhibitory activity) in the Development of Vitiligo

 

From: Bordignon M et al. Role of alpha5beta1 and MIA (melanoma inhibitory activity) in the pathogenesis of vitiligo. Journal of Dermatological Science 2013 (link to the article). We report only a brief summary of the work. For full detalis, please consult the original paper.

 

Vitiligo, also named as common generalized vitiligo, is an acquired pigmentary disorder of the skin and mucous membranes, and it is characterized by circumscribed depigmented macules and patches. Vitiligo is a progressive disorder in which some or all of the melanocytes in the affected skin seem to be selectively destroyed. Vitiligo affects 0.5-2% of the world population, and the average age of onset is 20 years.

 

Non-segmental vitiligo is the most common sub-type of vitiligo. Non-segmental vitiligo is an acquired chronic pigmentation disorder characterized by white patches, often symmetrical, which usually increase in size with time, corresponding to a substantial loss of functioning epidermal and sometimes hair follicle melanocytes.

 

Despite many studies performed on vitiligo skin, the exact pathogenesis of this dermatosis is still to be clarified and several pathogenetical mechanisms have been proposed during years, involving autoimmunity, cytotoxic metabolites, neural and genetic components; no convincing model describing the interplay of all these contributing factors has been formulated.

 

So far, two main features can be unequivocally ascribed to vitiligo: histologically there is lack of inflammation and clinically there is association with other autoimmune disorders. Recently, it has been suggested that the major and possible primary predisposing factor in vitiligo development could be a defective adhesion of melanocytes and that, based on in vivo and in vitro observations mechanical trauma and various chemical stressors could represent the main precipitating events. This theory considers vitiligo as a disease caused by the chronic detachment and named melanocytorrhagy the trans-epidermal loss of melanocytes which would be the silent manner by which the vitiliginous skin eliminates its pigment away.

 

Interactions between melanocytes and the basement membrane are mediated by integrins and a particular subgroup of integrins, named alpha5beta1, seems to be involved in melanocyte adhesion.

 

"Active detachment" and alpha5beta1 integrins are very interesting features also in another and more severe melanocytic disorder such as malignant melanoma. Malignant melanoma is the most severe skin cancer and its metastatic form is associated with the poorest prognosis. Recently, it seems that the metastatic dissemination of malignant melanoma (a melanocyte-derived tumor) could be mediated by an active detachment of tumor cells and that this detachment can be caused by a small protein secreted from malignant melanoma cells called melanoma inhibitory activity – MIA. It has been demonstrated that MIA interacts with integrin alpha5beta1.

 

So, it seems that the interactions between a malignant melanocytes self-produced protein (MIA) and a self-melanocyte adhesion molecule (alpha5beta1 integrin) would be responsible of an active detachment of neoplastic melanocyte cells in malignant melanoma.

 

In order to further clarify the pathogenesis of vitiligo, we investigated the expression of MIA in vitiliginous skin and its relationship with alpha5beta1 integrin.

 

Ten tissue samples of skin affected by vitiligo were included in our study. These samples were collected from the edge of vitiligoid patches, including both normopigmented and depigmented skin. All tissue samples had been obtained for diagnostic purposes. Five tissue samples of macroscopically normal pigmented skins were chosen for the experiments as sample controls. At the time of biopsies, all the patients have a negative history of melanoma, they were screened with skin exams for absence of this cutaneous neoplasia and they were not following any treatment for vitiligo.

 

Nine out of the ten bioptic samples were positive for MIA. The only MIA-negative sample derived from a patient suffering from segmental vitiligo, whereas the MIA-positive samples were obtained from patients suffering from NSV. All skin control samples were negative for the presence of MIA. The anti-alpha5beta1 antibody perfectly co-localized with anti-MIA antibody and that this feature were present also in melanocyte already detached from basal membrane and found in the upper epidermis. Our data show that 100% of non-segmental vitiligo suffering patients were positive for the presence of MIA.

 

The pathogenesis of vitiligo is still debated and none of the proposed model could explain properly the disease’s biology. The autoimmune hypothesis is the most accepted theory; however, this theory does not explain the lack of clinical signs consistent with inflammation in vitiligoid lesions and the prevalence of vitiligoid lesions in well-defined anatomic sites (such as face and acral regions). According to a non-immunological hypothesis for vitiligo pathogenesis, we focused on the role of MIA and integrins. The presence of MIA in non-malignant melanocytes was unexpected, as normal melanocytes do not express this molecule.

 

On the basis of our findings, we indicate a novel pathogenetic mechanism for non segmental vitiligo.

 

The normal attachment of melanocytes to the basal membrane mediated by alpha5beta1 integrins is perturbed by MIA. This first pathogenetic step is mandatory for disease development (the “priming factor”) and subsequently secondary pathogenetic stimuli, such as physical trauma, oxidative stress or autoantibodies, may lead to exfoliation of pigmented cells. This model may explain the lack of clinical signs of inflammation in vitiligoid lesions and the prevalence of vitiligoid lesions in well-defined anatomic sites. According to our hypothesis, melanocytes are not destroyed by the immune system, but they simply leave the scene silently. Melanocytes detach from the basal membrane towards the stratum corneum and exfoliate together with the surrounding keratinocytes. This process is consistent with the absence of an inflammatory response.

 

In conclusion, these studies demonstrate that the MIA protein is present in the skin affected by non-segmental vitiligo and that can cause the detachment of melanocytes, leading to the formation of the achromic patches in response to various stimuli and  without promoting any inflammatory process. As already observed in malignant melanoma, even in vitiligo the target of MIA is represented by the alpha5beta1 integrin, thus causing breakage and / or the weakening of connections between the melanocytes and the basal membrane. All these observations help to clarify the intricate puzzle of vitiligo and open the door to new therapeutic hope, since MIA is surely a potential target molecule for the development of specific therapies for the treatment of non-segmental vitiligo.

 

 - Research For Vitiligo
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