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Year:
2000
| Volume: 8
| Issue: 3
| Pages: 119-126
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Review Article |
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PATHOGENETIC MECHANISMS IN EPIDERMODYSPLASIA VERRUCIFORMIS
Marina A. JOVANOVIC, DJordjije KARADAGLIC |
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DOI:
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Abstract: |
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Epidermodysplasia verruciformis (EV) is a rare, lifelong disease, exclusively manifested on skin. Most freguently it starts in the early childhood. Plane wart- like lesions on the limbs are combined with pityriasis versicolor-like wart on the trunk, neck and face, and reddish or brownish plaques that undergo malignant transformation in more than 60% of patients. Tumors arising are seborrhoic and actinic keratoses, Bowen«s disease and squamous cell carcinomas (SCC). Carcinomas are confined mainly to the sun exposed areas. They appear in the fourth and fifth decades of life, and develop slowly, with low invasive and metastatic potential. EV is now considered as a genetically transmitted facilitation of skin infection by one or more EV specific types of human papillomavirus (EV HPV). It raised enormous interest since it is: 1) a widespread persistent infection of the skin with EV HPVs; 2) a precancerous genodermatosis, the first model of human viral cutaneous oncogenesis; 3)characterized by long duration and slow progression, the clinical manifestations of apoptosis, which is in EV associated with inflammation; 4) a model of local defence mechanisms in the progression of HPV-associated cancers, as a consequence of apoptosis arising from immune defect in EV HPV presentation, that leads to to specific immunotolerance. The interacting immunogenetic and environmental factors, especially UV irradiation, result in the inability of patients' immune system to reject EV HPV-harboring kerationocytes. A susceptibility locus for REV has been mapped to chromosome 17 qter, in a region flanked by D17S939 and D17S802 markers. Frequences of the HLA-DRB1/11, -DQA10501, -DQB10301 haplotypes were found to be significantly higher in EV patients, and could represent susceptibility allels, or a marker in the linkage disequilibrium with a gene predisposing to EV. This could provide a genetic basis determining specific defect of cell-mediated immune responses directed against EV HPVs. Upregulation of E6 and E7 gene transcription during the EV HPV-associated malignant progression is of the basic significance. The E2 protein is the most important viral factor, regulating the expression of E6 and E7 oncogenes. Acting as a transcription factor, E2 binds specific site within the viral long control region (LCR), and this results in activation of E6 and E7 transcription and viral DNS replication. Oncoproteins E6 and E7 of "high-oncogenic" EV HPV-s may directly inhibit antioncogene p53 induced transactivation of downstream genes. This results in the aberant overexpression of non-functional wild-type p53 protein, and enhance apoptosis in EV lesion. The overproduction of TNF-alpha, and TGF-beta is one of the main mediators of UVB induced local immunosuppression in EV. However, TNF-alpha and TGF-beta are the main cytokines capable of inhibiting HPV oncogene expression at the same time. This could be one of the possible explanations for a low invasive and metastatic potential of EV cancer. In spite of heavy immunosuppression due to an immunogenetic defect, patients with EV have some important defence mechansims. |
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Key words:
Genodermatosis; Human papillomavirus; Viral oncogenesis; Immunity; Epidermodysplasia verruciformis |
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