RESUMO
Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells. At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (p<0.001). Low NK cell activity in both groups did not correlate with percentage and absolute number of CD16(+)/CD56(+) cells. When the NK cytotoxic activity was expressed based on activity/100 CD16(+)/CD56(+) cells, several patients who had displayed NK cell activity below 15 LU exhibited normal NK cell activity. Overall, after this correction factor, 45% of the children with autism still exhibited low NK cell activity, correlating with the intracellular level of glutathione. Finally, we cultured lymphocytes of patients with low or high NK cell activity/cell with or without glutathione, IL-2 and IL-15. The induction of NK cell activity by IL-2, IL-15 and glutathione was more pronounced in a subgroup with very low NK cell activity. We conclude that that 45% of a subgroup of children with autism suffers from low NK cell activity, and that low intracellular levels of glutathione, IL-2 and IL-15 may be responsible.
Assuntos
Transtorno Autístico/imunologia , Citotoxicidade Imunológica/fisiologia , Glutationa/fisiologia , Interleucina-15/fisiologia , Interleucina-2/fisiologia , Células Matadoras Naturais/imunologia , Adolescente , Análise de Variância , Transtorno Autístico/sangue , Transtorno Autístico/patologia , Estudos de Casos e Controles , Contagem de Células , Criança , Pré-Escolar , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Glutationa/farmacologia , Humanos , Interleucina-15/farmacologia , Interleucina-2/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , MasculinoRESUMO
Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.
Assuntos
Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Metionina/sangue , Estresse Oxidativo/genética , Adolescente , Transtorno Autístico/sangue , Catecol O-Metiltransferase/genética , Criança , Pré-Escolar , Primers do DNA , Feminino , Frequência do Gene , Glutationa Transferase/genética , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Metionina/metabolismo , Metilação , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Proteína Carregadora de Folato Reduzido , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/sangue , Transcobalaminas/genéticaRESUMO
This report, completed in November 2003, is intended to serve as a resource for physicians, public health officials and organizations involved in the evaluation and treatment of Lyme disease.
