RESUMO
Exposure to stressors can result in changes in immune function. Although there is increasing information concerning the peripheral hormonal and neural mediators of stress-induced changes in immune function, there is little information concerning the central nervous system mechanisms that lead to the peripheral changes. The following experiments examined the possible involvement of the benzodiazepine-GABAA-chloride complex in modulation of the in vivo antibody response. Rats were given either peripheral or intracerebroventricular injections of methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), a drug that has been shown to act at the benzodiazepine-GABAA complex and produces a behavioral state similar to anxiety. Rats were then immunized with keyhole limpet hemocyanin (KLH) and serum levels of KLH-specific antibody were measured for 2 weeks after immunization. Both peripheral and central administration of DMCM modulated the in vivo antibody response. The dose-response relationship of DMCM and changes in antibody levels was nonmonotonic, with high doses resulting in an increase in serum antibody levels and moderate doses resulting in a decrease in serum antibody levels. A possible role of the benzodiazepine-GABAA system in stress-induced immunomodulation is discussed.
Assuntos
Formação de Anticorpos/efeitos dos fármacos , Nível de Alerta/efeitos dos fármacos , Carbolinas/farmacologia , Convulsivantes/farmacologia , Animais , Formação de Anticorpos/imunologia , Nível de Alerta/fisiologia , Relação Dose-Resposta a Droga , Hemocianinas/imunologia , Imunoglobulina G/análise , Imunoglobulina M/análise , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Ratos , Ratos Sprague-DawleyAssuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 11 , Proteínas de Ligação a DNA/genética , Saúde da Família , Genes Supressores , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Proteína BRCA1/genética , Proteína BRCA2 , Suscetibilidade a Doenças , Complexos Endossomais de Distribuição Requeridos para Transporte , Feminino , Humanos , Proteínas de Neoplasias/genéticaRESUMO
Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. The gene mutated in AT, designated the ATM gene, encodes a large protein kinase with a PI-3 kinase-related domain. In this study, we investigated the mutational spectrum of the ATM gene in a cohort of AT patients living in Germany. We amplified and sequenced all 66 exons and the flanking untranslated regions from genomic DNA of 66 unrelated AT patients. We identified 46 different ATM mutations and 26 sequence polymorphisms and variants scattered throughout the gene. A total of 34 mutations have not been described in other populations. Seven mutations occurred in more than one family, but none of these accounted for more than five alleles in our patient group. The majority of the mutations were truncating, confirming that the absence of full-length ATM protein is the most common molecular basis of AT. Transcript analyses demonstrated single exon skipping as the consequence of most splice site substitutions, but a more complex pattern was observed for two mutations. Immunoblot studies of cell lines carrying ATM missense substitutions or in-frame deletions detected residual ATM protein in four cases. One of these mutations, a valine deletion proximal to the kinase domain, resulted in ATM protein levels >20% of normal in an AT lymphoblastoid cell line. In summary, our results survey and characterize a plethora of variations in the ATM gene identified by exon scanning sequencing and indicate a high diversity of mutations giving rise to AT in a non-isolated population.