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

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.

Imiquimod enhances the systemic immunity attained by local cryosurgery destruction of melanoma lesions.

Melanoma lesions can be frozen in vivo, resulting in necrotic death of malignant cells and in tumor antigen release suitable for cross-presentation by professional antigen-presenting cells. Imiquimod is a small molecule with adjuvant pro-inflammatory effects that can be topically delivered as a cream. Local cryosurgery of B16/ovalbumin (OVA)-derived subcutaneous tumor nodules leads to curative destruction of the lesions. If imiquimod is repeatedly applied on the cryo-treated lesion, a conspicuous, leukocyte-rich inflammatory infiltrate appears during the days following treatment. Mice treated by cryosurgery plus imiquimod rejected rechallenges of B16/OVA in 90% of the cases, whereas cryosurgery alone failed to prevent tumor grafting in 70% of the cases. The combination treatment of B16/OVA tumors was also able to protect 60% of the mice against outgrowth of a lethal dose of non-transfected B16 tumor cells. Addition of imiquimod to cryosurgery results in increases of the cellular immune response against tumor antigens as measured by in vitro IFN-gamma production and T-cell proliferation in response to OVA. The potent memory response is not only directed against the OVA epitope, but also toward a broader range of B16 antigens. Our data indicate that these combined treatments turn the treated tumor lesion into an autologous tumor vaccine, which is even able to cause vitiligo in several cases. These preclinical data and the simplicity of the procedures warrant the design of a pilot clinical trial.

Penfigoide de mucosas: manifestaciones clínicas y tratamiento con corticoides, dapsona y ciclofosfamida en cinco pacientes / Mucous membrane pemphigoid: Clinical manifestations and treatment with corticosteroids, dapsone and cyclophosphamide in 5 patients

Introducción. El penfigoide cicatrizal incluye varios procesos que se caracterizan por la presencia de ampollas subepidérmicas, y que afectan las mucosas y más raramente a la piel. En la actualidad es más aceptado el término 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 diagnóstico de la enfermedad lo antes posible, con el fin de instaurar pronto el tratamiento inmunosupresor sistémico. Material y métodos. Presentamos nuestra experiencia en 5 pacientes con PM. Analizamos las manifestaciones clínicas y la respuesta al tratamiento inmunosupresor durante su curso evolutivo. Resultados. La edad de los pacientes estuvo comprendida entre 41 y 69 años. La localización más frecuente de las lesiones fue la mucosa oral (80 %) y la mucosa ocular (80 %), seguido de mucosa faríngea (60 %), mucosa laríngea (40 %), piel (40 %), mucosa anal (20 %) y mucosa genital (20 %). Tres pacientes recibieron corticoides sistémicos, dapsona y ciclofosfamida y, en uno, además se asociaron varias sesiones de plasmaféresis; un paciente se controló con corticoides tópicos y dapsona. Conclusiones. Muchos de los pacientes con PM pueden presentar complicaciones secundarias graves. Por este motivo, es necesario confirmar pronto el diagnóstico e instaurar el tratamiento adecuado lo antes posible. La asociación de corticoides, dapsona y ciclofosfamida es una combinación que ofrece muy buenos resultados

Introduction. Cicatricial pemphigoid includes several processes which are characterized by the presence of subepidermal bullae, and which affect the mucous membranes and, more rarely, the skin. At present, the term mucous membrane pemphigoid (MMP) is more accepted than other names used in the past, as they do not clearly define the broad spectrum presented by this disease. MMP can cause significant dysfunctions, primarily in the mucous membranes. Therefore, it is necessary to diagnose the disease as soon as possible, in order to quickly initiate systemic immunosuppressive treatment. Material and methods. We present our experience with 5 patients with MMP. We analyze the clinical manifestations and the response to immunosuppressive treatment during the evolution of the disease. Results. The patients were aged 41 to 69 years. The most frequent location of the lesions was the oral mucosa (80 %) and the ocular mucosa (80 %), followed by the pharyngeal mucosa (60 %), laryngeal mucosa (40 %), skin, anal mucosa (20 %) and genital mucosa (20 %). Three patients received systemic corticosteroids, dapsone and cyclophosphamide, and several sessions of plasmapheresis were also associated in one patient. One patient was controlled with topical corticosteroids and dapsone. Conclusions. Many patients with MMP can present with severe secondary complications. For this reason, the diagnosis must be confirmed quickly and the appropriate treatment started as soon as possible. The association of corticosteroids, dapsone and cyclophosphamide is a combination that gives very good results

Penfigoide de mucosas: anticuerpos IgG e IgA contra el antígeno BP180 / Mucous membrane pemphigoid: IgG and IgA antibodies against the BP180 antigen

Introducción. El penfigoide de mucosas (PM) es un grupo de enfermedades ampollosas autoinmunes, mediada por autoanticuerpos dirigidos contra diferentes proteínas de la unión dermoepidérmica, entre otras el antígeno BP180. Pacientes, materiales y métodos. Se incluyen en este estudio 5 pacientes con PM. Estudiamos la presencia de autoanticuerpos circulantes frente al antígeno BP180 y frente a fragmentos extracelulares recombinantes de esta proteína. Resultados. En todos los pacientes se detectó la presencia de anticuerpos circulantes frente a BP180. Los estudios de inmunofluorescencia indirecta (IFI) fueron positivos en 2 pacientes (20 %), así como en también en 2 pacientes mediante la técnica salt-split. En 3 pacientes se encontró reactividad frente al fragmento extracelular del BP180 (LAD-1), dos de ellos mediante IgA y uno con IgG. Solamente el suero de 2 pacientes reconoció el fragmento NC16A, y 4 de los 5 pacientes presentaron anticuerpos frente al dominio carboxiterminal BP180 4575. Conclusiones. Las técnicas de biología molecular son de gran importancia para complementar el diagnóstico de PM, en especial cuando los estudios de hematoxilina-eosina o de IF no ofrecen unos resultados satisfactorios para realizar un diagnóstico de PM

Introduction. Mucous membrane pemphigoid is a group of autoimmune bullous diseases, mediated by autoantibodies directed against different proteins in the dermoepidermal junction, including the BP180 antigen. Patients, material and methods. We included five patients with MMP in this study. We studied the presence of circulating autoantibodies against the BP180 antigen and against recombinant extracellular fragments of this protein. Results. We detected the presence of circulating antibodies against BP180 in all of the patients. Indirect immunofluorescence (IIF) studies were positive in 2 patients (20 %), as well as in 2 patients via salt-split studies. We found reactivity to the extracellular fragment of BP180 (LAD-1) in 3 patients, 2 of them via IgA and 1 with IgG. The serum of only 2 patients recognized the NC16A fragment, and 4 of the 5 patients had antibodies against the carboxy-terminal domain BP180 4575. Conclusions. Molecular biology techniques are very important to complement the diagnosis of MMP, especially when the results of hematoxylin-eosin or IF studies are not satisfactory for a diagnosis of MMP

[Mucous membrane pemphigoid: clinical manifestations and treatment with corticosteroids, dapsone and cyclophosphamide in 5 patients]. / Penfigoide de mucosas: manifestaciones clínicas y tratamiento con corticoides, dapsona y ciclofosfamida en cinco pacientes.

INTRODUCTION: Cicatricial pemphigoid includes several processes which are characterized by the presence of subepidermal bullae, and which affect the mucous membranes and, more rarely, the skin. At present, the term mucous membrane pemphigoid (MMP) is more accepted than other names used in the past, as they do not clearly define the broad spectrum presented by this disease. MMP can cause significant dysfunctions, primarily in the mucous membranes. Therefore, it is necessary to diagnose the disease as soon as possible, in order to quickly initiate systemic immunosuppressive treatment. MATERIAL AND METHODS: We present our experience with 5 patients with MMP. We analyze the clinical manifestations and the response to immunosuppressive treatment during the evolution of the disease. RESULTS: The patients were aged 41 to 69 years. The most frequent location of the lesions was the oral mucosa (80 %) and the ocular mucosa (80 %), followed by the pharyngeal mucosa (60 %), laryngeal mucosa (40 %), skin, anal mucosa (20 %) and genital mucosa (20 %). Three patients received systemic corticosteroids, dapsone and cyclophosphamide, and several sessions of plasmapheresis were also associated in one patient. One patient was controlled with topical corticosteroids and dapsone. CONCLUSIONS: Many patients with MMP can present with severe secondary complications. For this reason, the diagnosis must be confirmed quickly and the appropriate treatment started as soon as possible. The association of corticosteroids, dapsone and cyclophosphamide is a combination that gives very good results.

[Mucous membrane pemphigoid: IgG and IgA antibodies against the BP180 antigen]. / Penfigoide de mucosas: anticuerpos IgG e IgA contra el antígeno BP180.

INTRODUCTION: Mucous membrane pemphigoid is a group of autoimmune bullous diseases, mediated by autoantibodies directed against different proteins in the dermoepidermal junction, including the BP180 antigen. PATIENTS, MATERIAL AND METHODS: We included five patients with MMP in this study. We studied the presence of circulating autoantibodies against the BP180 antigen and against recombinant extracellular fragments of this protein. RESULTS: We detected the presence of circulating antibodies against BP180 in all of the patients. Indirect immunofluorescence (IIF) studies were positive in 2 patients (20 %), as well as in 2 patients via salt-split studies. We found reactivity to the extracellular fragment of BP180 (LAD-1) in 3 patients, 2 of them via IgA and 1 with IgG. The serum of only 2 patients recognized the NC16A fragment, and 4 of the 5 patients had antibodies against the carboxy-terminal domain BP180 4575. CONCLUSIONS: Molecular biology techniques are very important to complement the diagnosis of MMP, especially when the results of hematoxylin-eosin or IF studies are not satisfactory for a diagnosis of MMP.