RESUMEN
This paper presents the Italian guidelines for autoantibody testing in myasthenia gravis that have been developed following a consensus process built on questionnaire-based surveys, internet contacts and discussions during dedicated workshops of the sponsoring Italian Association of Neuroimmunology (AINI). Essential clinical information on myasthenic syndromes, indications and limits of antibody testing, instructions for result interpretation and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
Asunto(s)
Autoanticuerpos , Miastenia Gravis/diagnóstico , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores Colinérgicos/inmunología , Humanos , Miastenia Gravis/inmunologíaRESUMEN
BACKGROUND: The recent literature suggests that the incidence and prevalence of myasthenia gravis (MG) are changing. We performed a population-based study of MG in the province of Trentino (524,826 inhabitants) and compared the results with those collected 20 years ago. METHODS: Multiple sources of information (discharge diagnosis, antibody tests and anticholinesterase drugs) were analyzed. Incidence was calculated from 2005 to 2009. Prevalence was calculated on December 31, 2009. Comparison was made with descriptive statistics for 1981-1990 for the identical region. RESULTS: Incidence and prevalence greatly increased in comparison with 1981-1990 data. The prevalence rate increased from 82.9 (95% confidence interval, CI, 58.4-114.3) in 1990 to 129.6 (95% CI 100.6-164.3) per million population, whereas the average annual incidence increased from 7.4 (95% CI 5-10.4) per million person-years in 1981-1990 to 14.8 (95% CI 10.5-20.3) in 2005-2009. This increase was mainly due to male patients with late-onset MG. CONCLUSIONS: The study confirms the increase in incidence and prevalence of late-onset MG in the same region 20 years apart. So we should consider MG also as a disease of the elderly.
Asunto(s)
Miastenia Gravis/epidemiología , Adulto , Distribución por Edad , Anciano , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Distribución por Sexo , Análisis de Supervivencia , Tasa de SupervivenciaRESUMEN
Bone marrow mesenchymal stromal cells (BM-MSCs) may survive and proliferate in the presence of cycling neoplastic cells. Exogenously administered MSCs are actively incorporated in the tumor as stromal fibroblasts, thus competing with the local mesenchymal cell precursors. For this reason, MSCs have been suggested as a suitable carrier for gene therapy strategies, as they can be genetically engineered with genes encoding for biologically active molecules that can inhibit tumor cell proliferation and enhance the antitumor immune response. We used BM-MSCs engineered with the murine interferon-alpha (IFN-α) gene (BM-MSCs/IFN-α) to assess in a mouse plasmacytoma model the efficacy of this approach toward neoplastic plasma cells. We found that IFN-α can be efficiently produced and delivered inside the tumor microenvironment. Subcutaneous multiple administration of BM-MSCs/IFN-α significantly hampered the tumor growth in vivo and prolonged the overall survival of mice. The antitumor effect was associated with enhanced apoptosis of tumor cells, reduction in microvessel density, and ischemic necrosis. By contrast, intravenous administration of BM-MSCs/IFN-α did not significantly modify the survival of mice, mainly as a consequence of an excessive entrapment of injected cells in the pulmonary vessels. In conclusion, BM-MSCs/IFN-α are effective in inhibiting neoplastic plasma cell growth; however, systemic administration of engineered MSCs needs to be improved to make this approach potentially suitable for the treatment of multiple myeloma.
Asunto(s)
Interferón-alfa/metabolismo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Plasmacitoma/terapia , Animales , Apoptosis , Células de la Médula Ósea/citología , Línea Celular Tumoral , Supervivencia Celular , Técnicas de Cocultivo , Terapia Genética , Interferón-alfa/genética , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Neovascularización Patológica/terapia , Células Plasmáticas/patología , Plasmacitoma/irrigación sanguínea , Plasmacitoma/patología , Proteínas Recombinantes/metabolismo , Antígenos Thy-1/metabolismo , Trasplante Heterólogo , Carga TumoralRESUMEN
De novo expression of B7-1 impaired tumorigenicity of TRAMP-C2 mouse prostate adenocarcinoma (TRAMP-C2/B7), but it did not elicit a protective response against TRAMP-C2 parental tumor, unless after in vitro treatment with IFN-gamma. TRAMP-C2 cells secrete TGF-beta and show low MHC-I expression. Treatment with IFN-gamma increased MHC-I expression by induction of some APM components and antagonizing the immunosuppressant activity of TGF-beta. Thus, immunization with TRAMP-C2/B7 conferred protection against TRAMP-C2-derived tumors in function of the IFN-gamma-mediated fine-tuned modulation of either APM expression or TGF-beta signaling. To explore possible clinical translation, we delivered IFN-gamma to TRAMP-C2 tumor site by means of genetically engineered MSCs secreting IFN-gamma.
Asunto(s)
Adenocarcinoma/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Interferón gamma/inmunología , Neoplasias de la Próstata/inmunología , Adenocarcinoma/genética , Animales , Antígeno B7-1/genética , Antígeno B7-1/inmunología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Genes MHC Clase I , Antígenos de Histocompatibilidad Clase I/genética , Masculino , Células Madre Mesenquimatosas/inmunología , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Neoplasias de la Próstata/genética , Bazo/citología , Bazo/inmunología , Transfección , Factor de Crecimiento Transformador beta/inmunología , Regulación hacia ArribaRESUMEN
Myasthenia gravis (MG) is an autoimmune disease of neuromuscular junctions where thymus plays a pathogenetic role. Thymectomy benefits patients, and thymic hyperplasia, a lymphoid infiltration of perivascular spaces becoming site of autoantibody production, is recurrently observed. Cytokines and chemokines, produced by thymic epithelium and supporting survival and migration of T and B cells, are likely to be of great relevance in pathogenesis of thymic hyperplasia. In thymic epithelial cell (TEC) cultures derived "in vitro" from normal or hyperplastic age-matched MG thymuses, we demonstrate by gene profiling analysis that MG-TEC basally overexpress genes coding for p38 and ERK1/2 MAPKs and for components of their signaling pathways. Immunoblotting experiments confirmed that p38 and ERK1/2 proteins were overexpressed in MG-TEC and, in addition, constitutively activated. Pharmacological blockage with specific inhibitors confirmed their role in the control of IL-6 and RANTES gene expression. According to our results, IL-6 and RANTES levels were abnormally augmented in MG-TEC, either basally or upon induction by adhesion-related stimuli. The finding that IL-6 and RANTES modulate, respectively, survival and migration of peripheral lymphocytes of myasthenic patients point to MAPK transcriptional and posttranscriptional abnormalities of MG-TEC as a key step in the pathological remodelling of myasthenic thymus.
Asunto(s)
Linfocitos B/enzimología , Linfocitos B/inmunología , Quimiocina CCL5/biosíntesis , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Interleucina-6/biosíntesis , Miastenia Gravis/enzimología , Miastenia Gravis/inmunología , Linfocitos T/enzimología , Linfocitos T/inmunología , Adolescente , Adulto , Linfocitos B/patología , Estudios de Casos y Controles , Movimiento Celular , Supervivencia Celular , Niño , Activación Enzimática , Células Epiteliales/enzimología , Células Epiteliales/inmunología , Quinasas MAP Reguladas por Señal Extracelular/genética , Femenino , Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Miastenia Gravis/patología , Linfocitos T/patología , Timo/enzimología , Timo/inmunología , Timo/patología , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
A previously isolated and characterized IgM monoclonal antibody (mAb 1H6.2) specific to myelin basic protein (MBP) and to MBP epitopes expressed by nonneural cells was used to immunoprecipitate and investigate the expression of MBP epitopes by human T cells. Peripheral T lymphocytes secreted MBP epitopes, and secretion increased in time after mitogen stimulation. Conversely, thymocytes secreted these proteins independently on mitogen stimulation. Specific antibody reactivity (primarily due to IgG3) towards immunoprecipitated MBP epitopes was found in all tested sera from healthy donors and from multiple sclerosis patients as well as in sera from normal human cord blood. Collectively, these data provide insights into the immunological mechanisms leading to central and peripheral tolerance to MBP products.
Asunto(s)
Autoanticuerpos/sangre , Epítopos de Linfocito T/biosíntesis , Epítopos de Linfocito T/inmunología , Proteína Básica de Mielina/inmunología , Proteína Básica de Mielina/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Especificidad de Anticuerpos , Autoanticuerpos/biosíntesis , Sitios de Unión de Anticuerpos , Células Cultivadas , Preescolar , Humanos , Sueros Inmunes/biosíntesis , Sueros Inmunes/sangre , Inmunidad Celular , Inmunidad Innata , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/sangre , Inmunoglobulina G/clasificación , Gammopatía Monoclonal de Relevancia Indeterminada/sangre , Gammopatía Monoclonal de Relevancia Indeterminada/inmunología , Esclerosis Múltiple/sangre , Esclerosis Múltiple/inmunología , Proteína Básica de Mielina/biosíntesisRESUMEN
Bioactive molecules that can gain access to body tissues through the gastrointestinal tract may interact with immune regulatory circuits and effector functions. Among these are plant lectins, such as wheat germ (WG) agglutinin, which constitute common components of the human diet and target the immune system on a daily basis. Dietary bioactive molecules might be considered as immunomodulatory signals. To investigate the possible effects on the immune system of the long-term absence of such signals, two groups of rats were fed on a diet containing or deprived of WG. The WG-deprived diet induced a state of functional unresponsiveness in lymphocytes from primary and secondary lymphoid organs, as evaluated by in vitro stimulation with T cell mitogen phytohemoagglutinin (PHA) and B cell mitogen lypopolysaccarides (LPS). The unresponsive state of the immune cells could be reversed by injection of antigen emulsified in oil with inactivated mycobacteria (complete Freund's adjuvant, CFA) Dietary signals can thus interact with the immune system possibly influencing its shaping during ontogenesis.