Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by the presence of IgG autoantibodies againstDsg3. Our aim was to investigate the molecular events implicated in the development and localization of apoptosis and acantholysis in PV. We used a passive transfer mouse model together with immunohistochemical (IHC) techniques and the TUNEL assay, with quantification analysis in the basal layer of the epidermis. The activated signalling molecules analysed and apoptotic cells detected showed an identical localization. Herein, we found for the first time in vivo an increased expression of activated HER receptor isoforms in the basal layer in PV lesions. Besides, we observed the almost total lack of activated Akt compared with a higher level of activated mTOR within the basal cells of the epidermis. Our observations strongly support that the restriction of acantholysis to the basal layer may be due, at least in part, to the selective and increased presence of activated HER receptor isoforms in these cells. After phosphorylation of HER receptor isoforms, intracellular signalling pathways are activated in the basal layer. In addition, the imbalance in Akt⁄mTOR that takes place in the basal cells may provide intracellular signals necessary for the development of apoptosis and acantholysis.

SUMMARYClassic polyarteritis nodosa (PAN) is a segmentary leucocytoclastic vasculitis that affects small-and medium-sized arteries. In 1931, Lindberg described the existence of a cutaneous variant of PAN, without visceral involvement and with a more favourable prognosis. We present four patients diagnosed with cutaneous PAN in our hospital between 1987 and 1998. The study group was composed of three women and one child, whose ages ranged from 11 to 70 years old. The follow-up period was between 2 and 13 years. Each patient was submitted for an initial clinical, histological and laboratory evaluation and subsequent follow-up. The presence of nodules was the most frequent cutaneous lesion, preferentially located in the lower limbs. The erythrocyte sedimentation rate was the only parameter that was altered in all patients. Cutaneous biopsies from all patients showed a segmentary leucocytoclastic vasculitis in the arteries of the deep dermis and⁄or hypodermis. Direct immunofluorescence was positive in just one patient. No visceral involvement was found in any patient. There is confusion about the correct definition of cutaneous PAN. Some clinical findings, such as nodules or livedo reticularis, typical of cutaneous PAN suggest a good prognosis; however, we consider that it is necessary to evaluate these patients for systemic involvement for the possibility of arteritis in other organs as the term polyarteritis suggests.

These observations strongly support the role of intracellular signalling cascades in the molecular mechanism of PV IgG-induced acantholysis.

SUMMARYBackground: Pemphigus vulgaris (PV) is an autoimmune disease characterized by mucocutaneous intraepithelial blisters and pathogenic autoantibodies against desmoglein 3. There are two clinical forms: mucosal (MPV) and mucocutaneous (MCPV). The frequency of ear, nose and throat (ENT) involvement in PV is not clearly defined. Only a few isolated individual cases have been reported.

Nonmelanoma skin cancer (NMSC) is a frequent complication after liver transplantation, but the risk factors of posttransplant NMSC have not been well defined. In a prospectively followed series of 170 liver transplant recipients, we assessed the incidence of NMSC, compared it with the expected incidence in the general population, and investigated which risk factors were related to NMSC. N onmelanoma skin cancer (NMSC) is the most frequently diagnosed malignancy after liver and other solid organ transplantations. 1 Its incidence may be higher than 80% 20 years after transplantation in countries with high sun exposure. 2 In most cases, these tumors are diagnosed sufficiently early to allow curative treatment, but squamous-cell carcinomas appear to be more aggressive in transplant recipients than in the general population. They may recur, metastasize, and be the cause of death. 1 So, aggressive preventive measures and frequent dermatologic assessment have been recommended. 3 The identification of those patients with a higher risk of development of NMSC may be useful to reinforce preventive measures and develop a tailored schedule of dermatologic follow-up in patients with higher risk of NMSC. Furthermore, if specific immunosuppressive regimens are found to be related to a higher risk of NMSC, these regimens should be avoided in patients with other risk factors of NMSC. Therefore, we have analyzed a cohort of prospectively followed liver transplantation (LT) recipients to determine which risk factors are independently associated with the development of NMSC.

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increase in protein expression level. This suggested that UV irradiation promotes both activation and expression levels of the Rfp-Ret kinase. Rfp-Ret kinase is constitutively active due to its oncogenic mutation (Takahashi et al, 1985). Thus, UV-mediated superactivation of the mutant Ret kinase, which was originally demonstrated in vitro (Kato et al, 2000), probably occurred also in vivo. The signal triggered through superactivation of Rfp-Ret kinase by UV might have promoted the production of Rfp-Ret together with ERK and c-Jun, although alternative mechanisms remain to be excluded. Whatever the underlying mechanism is, our data suggest that UV-induced full activation of a single oncogene and its product is included in the mechanism of malignant melanocytic tumor promotion, in addition to previously reported stepwise recruitment of multiple oncogene activations (Ziegler et al, 1994) and defects in the host defense mechanism (Kripke, 1979). This may stimulate new experiments for fully understanding the general mechanism of malignant tumor promotion following initiation.We thank K. Ban, Y. Umeda, Y. Kato, H. Saeki, and K. Uchiyama for their technical assistance.

Pemphigus vulgaris (PV) is an autoimmune blistering skin disease characterized by suprabasal acantholysis and by autoantibodies against desmoglein 3 localized on desmosomes. In addition, caspases also seem to participate in this blistering disease. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in cytoskeleton remodelling and formation and disassembly of cell adhesion structures. We have previously demonstrated that HER (human epidermal growth factor receptor related) isoforms, Src (Rous sarcoma) and mammalian target of rapamycin (mTOR), three molecules implicated in signalling processes, take part in suprabasal acantholysis and apoptosis induced by PV-IgG in a mouse model. Our aim was to investigate whether upregulation of FAK is implicated in the development of PV lesions. Herein, using a mouse model, PV-IgG administration showed an increased level of FAK phosphorylated on 397 and 925 tyrosine residues in the basal layer of epidermis.When mice were pretreated with a FAK inhibitor (FI), the acantholysis of the basal layer of epidermis was absent. More interestingly, we observed that phosphorylated FAK (Y397⁄925) decreased when HER isoforms, Src, mTOR and pan-caspases inhibitors were employed before PV-IgG administration. In addition, pretreatment with the FI before PV-IgG injection prevented the changes in both Bax and Bcl-2 expression and caspase-9 and caspase-3 activities induced by PV-IgG. Finally, FI reduced the expression of phosphorylated Src and mTOR in the basal cells of epidermis. In conclusion, our data reveal a novel role of phosphorylated FAK (Y397⁄925) in PV development involving HER isoforms, Src and mTOR kinases.