M. Marquina

An imbalance in Akt/mTOR is involved in the apoptotic and acantholytic processes in a mouse model of pemphigus vulgaris

Abstract:  Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by the presence of IgG autoantibodies against Dsg3. 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.

Ear, nose and throat manifestations in pemphigus vulgaris

Background  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.

The role of nitric oxide synthases in pemphigus vulgaris in a mouse model

Background  Pemphigus vulgaris (PV) is a blistering autoimmune disease characterized by IgG autoantibodies against desmoglein 3. Nitric oxide synthases (NOS) may contribute to the increase of inflammation in tissues by the generation of nitrotyrosine residues (NTR).

Repigmentation of Gray Hair After Thyroid Hormone Treatment

BACKGROUND AND OBJECTIVES Darkening of gray and white hairs occurred in 2 patients with increased exogenous triiodothyronine (T3) due to treatment of myxedema coma in one case and iatrogenic hyperthyroidism in the other. We hypothesized that thyroid hormone may affect the homeostasis of hair follicles. To test our hypothesis and investigate the influence of thyroid hormone on the hair cycle, we used an in vivo murine model and an in vitro model based on culture of follicular units. METHODS We used the standard C57BL/6 murine model of the hair cycle. T3 (0.5 microg) dissolved in ethanol was applied topically once daily for 10 days to a depilated area in the telogen phase on the backs of the mice. Follicular units, obtained from hair transplant interventions, were cultured in vitro with different concentrations of T3. RESULTS On day 5, all T3-treated mice entered the anagen phase, whereas the anagen phase started spontaneously in control mice on day 9, and not until day 15 had all controls entered this phase. In the in vitro experiment, follicular units treated with 100 nmol/L T3 grew significantly larger compared to the control group. CONCLUSIONS These data suggest that follicles in the telogen phase can be induced to enter the anagen phase by the topical application of T3. This thyroid hormone may reverse graying of the terminal hair. In the in vitro experiments, T3 stimulated hair shaft growth. Follicular melanocytes may be the target cell for these actions.

Remisión clínica completa prolongada en pacientes con pénfigo vulgar grave después del tratamiento con ciclos intravenosos de ciclofosfamida

Background. Corticosteroids are the systemic treatment of choice in patients with pemphigus vulgaris, but chronic administration is associated with side effects. Intravenous treatment with cyclophosphamide can improve the clinical signs of pemphigus vulgaris. Material and methods. We prospectively studied 8 patients diagnosed with pemphigus vulgaris. Six of these had mucocutaneous pemphigus vulgaris and 2 had mucosal pemphigus vulgaris. Treatment consisted of 10 cycles of cyclophosphamide at a dose of 10-15 mg/kg separated by 15 days, while maintaining the initial corticosteroid and immunosuppressant dose. Clinical efficacy was assessed and the anti-epidermal intercellular substance (EIS) and anti-desmoglein (DSG) 3 and 1 antibody titers were monitored (by indirect immunofluorescence and enzyme-linked immunosorbent assay, respectively). Results. All patients with pemphigus vulgaris responded excellently to treatment. Five of the 8 patients achieved complete remission of pemphigus lesions after 10 cycles of cyclophosphamide. In the other 3 patients, the skin lesions disappeared a few weeks after the last cycle of cyclo- phosphamide. A substantial reduction in immuno suppres- sant dose was possible in all patients. Furthermore, an improved immunologic response was observed in all cases

Prolonged Complete Clinical Remission in Patients With Severe Pemphigus Vulgaris After Cycles of Intravenous Cyclophosphamide

BACKGROUND Corticosteroids are the systemic treatment of choice in patients with pemphigus vulgaris, but chronic administration is associated with side effects. Intravenous treatment with cyclophosphamide can improve the clinical signs of pemphigus vulgaris. MATERIAL AND METHODS We prospectively studied 8 patients diagnosed with pemphigus vulgaris. Six of these had mucocutaneous pemphigus vulgaris and 2 had mucosal pemphigus vulgaris. Treatment consisted of 10 cycles of cyclophosphamide at a dose of 10-15 mg/kg separated by 15 days, while maintaining the initial corticosteroid and immunosuppressant dose. Clinical efficacy was assessed and the anti-epidermal intercellular substance (EIS) and anti-desmoglein (DSG) 3 and 1 antibody titers were monitored (by indirect immunofluorescence and enzyme-linked immunosorbent assay, respectively). RESULTS All patients with pemphigus vulgaris responded excellently to treatment. Five of the 8 patients achieved complete remission of pemphigus lesions after 10 cycles of cyclophosphamide. In the other 3 patients, the skin lesions disappeared a few weeks after the last cycle of cyclophosphamide. A substantial reduction in immuno suppressant dose was possible in all patients. Furthermore, an improved immunologic response was observed in all cases after cyclophosphamide treatment, with decreased anti-DSG1 and anti-DSG3 antibody titers and well as decreased circulating anti-EIS antibody titers. During the mean 15.1 month follow-up (range, 1-25 months), no new lesions appeared and no side effects of cyclophosphamide therapy were reported. CONCLUSIONS Fortnightly cycles of intravenous cyclophosphamide may be a useful therapeutic option in patients with severe pemphigus vulgaris. A reduction of corticosteroid dose was possible with this therapeutic approach and the cumulative cyclophosphamide dose was lower than with daily oral administration. Our findings also show that the therapeutic approach induces clinical and immunologic remission in most patients.

Penfigoide de mucosas : manifestaciones clínicas y tratamiento con corticoides, dapsona y ciclofosfamida en cinco pacientes

Resumen Introduccion El penfigoide cicatrizal incluye varios procesos que se caracterizan por la presencia de ampollas subepidermicas, y que afectan las mucosas y mas raramente a la piel. En la actualidad es mas aceptado el termino de penfigoide de mucosas (PM) que otros nombres utilizados anteriormente, ya que no definen con claridad el espectro tan amplio que presenta esta enfermedad. El PM puede producir disfunciones importantes, principalmente en las mucosas. Por lo tanto, es necesario realizar un diagnostico de la enfermedad lo antes posible, con el fin de instaurar pronto el tratamiento inmunosupresor sistemico. Material y metodos Presentamos nuestra experiencia en 5 pacientes con PM. Analizamos las manifestaciones clinicas y la respuesta al tratamiento inmunosupresor durante su curso evolutivo. Resultados La edad de los pacientes estuvo comprendida entre 41 y 69 anos. La localizacion mas frecuente de las lesions fue la mucosa oral (80 %) y la mucosa ocular (80 %), seguido de mucosa faringea (60 %), mucosa laringea (40 %), piel (40 %), mucosa anal (20 %) y mucosa genital (20 %). Tres pacientes recibieron corticoides sistemicos, dapsona y ciclofosfamida y, en uno, ademas se asociaron varias sesiones de plasmaferesis; un paciente se controlo con corticoides topicos y dapsona. Conclusiones Muchos de los pacientes con PM pueden presentar complicaciones secundarias graves. Por este motivo, es necesario confirmar pronto el diagnostico e instaurar el tratamiento adecuado lo antes posible. La asociacion de corticoides, dapsona y ciclofosfamida es una combinacion que ofrece muy buenos resultados.

Penfigoide de mucosas: anticuerpos IgG e IgA contra el antígeno BP180

Resumen Introduccion El penfigoide de mucosas (PM) es un grupo de enfermedades ampollosas autoinmunes, mediada por autoanticuerpos dirigidos contra diferentes proteinas de la union dermoepidermica, entre otras el antigeno BP180. Pacientes, materiales y metodos Se incluyen en este estudio 5 pacientes con PM. Estudiamos la presencia de autoanticuerpos circulantes frente al antigeno BP180 y frente a fragmentos extracelulares recombinantes de esta proteina. Resultados En todos los pacientes se detecto la presencia de anticuerpos circulantes frente a BP180. Los estudios de inmunofluorescencia indirecta (IFI) fueron positivos en 2 pacientes (20 %), asi como en tambien en 2 pacientes mediante la tecnica salt-split. En 3 pacientes se encontro reactividad frente al fragmento extracelular del BP180 (LAD-1), dos de ellos mediante IgA y uno con IgG. Solamente el suero de 2 pacientes reconocio el fragmento NC16A, y 4 de los 5 pacientes presentaron anticuerpos frente al dominio carboxiterminal BP180 4575. Conclusiones Las tecnicas de biologia molecular son de gran importancia para complementar el diagnostico de PM, en especial cuando los estudios de hematoxilina-eosina o de IF no ofrecen unos resultados satisfactorios para realizar un diagnostico de PM.

Asymptomatic digital angioleiomyoma

Angioleiomyomas that present with no symptoms are extremely rare, except when located on the head and neck. 1 Three cutaneous variants of this tumor have been described: piloleiomyoma, which originates in the erector pili muscle; angioleiomyoma, which originates in the smooth muscle of blood vessel walls; and genital leiomyoma, which originates in the smooth muscle of the scrotum, vulva, or nipple. An 18-year-old man presented with a mass from 7 years earlier, located on the third finger of his left hand. The lesion was supple, flesh-colored, and nodular, with an approximate diameter of 1.5 cm (Figure 1A). The skin surface was smooth and the tumor was not attached to deep tissues. Under local anesthesia, the lesion was removed and the tumor-feeding vessels were ligated (Figure 1B). A histopathological study with hematoxylin-eosin showed that the lesion was a regular, well-delimited neoplasm. It was well vascularized with thick vascular walls and bundles of intervascular smooth muscle fibers (Figure 2). The cells in smooth muscle bundles had an elongated nucleus, of rounded, cigar-shaped borders and abundant eosinophilic cytoplasm. All findings were consistent with the diagnosis of angioleiomyoma. Vascular leiomyomas are solitary benign tumors originating in the smooth muscle layer of the vessel walls. 5 However, some authors believe this entity could be a type of hamartoma, vascular malformation, or a stage within the continuous process of smooth muscle proliferation in the context of transformation of the hemangiomas to leiomyomas. 6-8 On occasions, special stains for smooth muscle cells (Masson trichrome and immunohistochemical techniques for smooth muscle vimentin, desmin, and actin) may be needed to 292 differentiate angioleiomyomas from other tumors. Hachisuga et al 7 have classified angioleiomyomas into 3 histological types: solid, in which the muscle bundles surround numerous small vascular lumens; cavernous, with dilated vascular channels, in which the vascular walls are difficult to distinguish from the intervascular smooth muscle; and venous, with thick vascular walls, readily distinguishable from intervascular smooth muscle. Angioleiomyomas are more common between the third and fifth decade of life and are twice as common among women as men. 9 Our patients lesion is atypical because there were no symptoms and because of its location (proximal phalanx of the third finger on the left hand). This type of lesion appears predominantly on the limbs, particularly the legs, but may also be found on any other part of the body such as the arms, trunk, head, and neck. 10 …

S130 – Otolaryngologic Manifestations in Penphigus Vulgaris

Objectives Pemphigus vulgaris is an autoimmune disease characterized by mucocutaneous intraepithelial blisters and pathogenic autoantibodies against desmoglein 3. There are 2 clinical forms: mucosal and mucocutaneous. The frequency of ear, nose and throat involvement in pemphigus vulgaris is not clearly defined. Only a few individual cases have been reported. The objective of this study was to determine the incidence of otolaryngologic involvement in patients with pemphigus. Methods We have studied prospectively all 18 patients diagnosed with PV and treated by Otolaryngology and Dermatology departments of the University Hospital of Navarra between 2001 and 2007. They were 10 cases of mucosal pemphigus and 8 cases of mucocutaneous pemphigus. All patients were evaluated by endoscopic examination. Results 15 patients presented with throat symptoms (83%), 13 pharyngeal (72%), and 8 laryngeal symptoms (44%). 16 patients (88%) had active pemphigus vulgaris lesions localized in pharyngeal and laryngeal mucosa. Laryngeal lesions were most commonly present in mucocutaneous patients. The frequency of nasal symptoms (38%) was lower than active pemphigus vulgaris lesions (63%). Oral symptoms and oral active lesions were the most frequent findings (94%). Only in 3 patients were sown erosions on the external auditory canal. Conclusions Endoscopic evaluation in patients affected by pemphigus vulgaris allows to study more extensive areas of mucosa. By obtaining more complete information concerning the extent of the disease, a more accurate diagnosis can be made, better choice of drug and dose may be decided, and ultimately, response to treatment may be improved.