RESUMO
BACKGROUND: Many patients with multiple sclerosis do not respond to interferon beta, which is widely used as an immunomodulatory treatment in this disease. We aimed to assess the functional relevance of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), which is upregulated on incubation with interferon beta, for clinical treatment response. METHODS: We quantified gene expression longitudinally by realtime-PCR of the peripheral immune cells of 82 patients with multiple sclerosis. In a first cohort of 62 patients, 20 were classified as first-year responders since they did not have relapses during treatment with interferon beta 1a; 19 were classified as first-year non-responders; and 23 developed neutralising antibodies to interferon beta. A second cohort, also characterised by MRI, consisted of 11 patients on interferon beta 1a and nine patients who were not treated. Concentrations of soluble TRAIL were determined by ELISA in serum samples of nine non-treated patients, 49 patients before treatment (29 responders, 20 non-responders), as well as longitudinally in a subset of 23 patients. FINDINGS: In both patient cohorts, drug-responders could be distinguished from non-responders by early and sustained induction of TRAIL (p<0.0001, each). In the presence of neutralising antibodies, initial upregulation of TRAIL expression was subsequently abrogated. Raised concentrations of soluble TRAIL in patients' serum samples before the start of treatment allowed prediction of the treatment response in the first year (ROC analysis with area under the curve 0.879 [0.785-0.974]). INTERPRETATION: Our data suggest that TRAIL expression is a candidate for pretreatment assessment and might thus be used as a prognostic marker of treatment response to interferon beta in multiple sclerosis. Furthermore, our observations have implications for the development of future immunoregulatory strategies in multiple sclerosis therapy.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Glicoproteínas de Membrana/sangue , Esclerose Múltipla/tratamento farmacológico , Adolescente , Adulto , Proteínas Reguladoras de Apoptose , Biomarcadores/sangue , Feminino , Regulação da Expressão Gênica , Humanos , Ligantes , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Ligante Indutor de Apoptose Relacionado a TNF , Fator de Necrose Tumoral alfa/genética , Regulação para CimaRESUMO
TNF-related apoptosis-inducing ligand (TRAIL) is not only involved in cell death but also in other immunoregulatory mechanisms. So far, the regulation of the TRAIL pathway in physiologic and pathologic conditions remains unclear. Due to the implication in brain damage and the elevated expression in peripheral immune cells of patients with multiple sclerosis (MS), an autoimmune disease of the central nervous system, TRAIL might play a central role in the pathology of this disease. Here, we have identified a highly polymorphic region in the TRAIL promoter. Using single-strand conformation polymorphism analysis, we found four single nucleotide polymorphisms (SNPs) within 111 base pairs. One of these SNPs is located in a binding site for the transcription factor AP-1. However, the RNA and protein expression of TRAIL revealed no obvious differences in relation to the genotypes. Furthermore, investigating samples from both MS patients and healthy controls we could not detect any association of these newly described polymorphisms to the clinical disease pattern. Thus, the TRAIL promoter contains a highly polymorphic area which has, however, no impact on molecule expression, and is neither directly related to increased risk of developing MS nor associated with a certain course of this heterogeneous disease in our population.
Assuntos
Glicoproteínas de Membrana/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/genética , Adulto , Proteínas Reguladoras de Apoptose , Clonagem Molecular/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Genótipo , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Glicoproteínas de Membrana/fisiologia , Pessoa de Meia-Idade , Muromonab-CD3/fisiologia , Fenótipo , Polimorfismo Conformacional de Fita Simples , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Análise de Sequência de DNA/métodos , Estatísticas não Paramétricas , Ligante Indutor de Apoptose Relacionado a TNF , Fatores de Tempo , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
Both tau and beta-amyloid 42 (Abeta42) have been implicated in Alzheimer's disease (AD) and tau alone in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). These proteins can be measured in the cerebrospinal fluid (CSF); differences from normal CSF levels may reflect pathophysiological mechanisms. Using ELISAs, we investigated the levels of total CSF-tau (here referred to as tau), phosphorylated CSF-tau (phosphotau), and Abeta42 in patients with AD (n = 19), FTD (n = 14), ALS (n = 11) and Parkinson's disease (PD; n = 15) and in age-matched controls (n = 17). Both CSF-tau and CSF-phosphotau were increased in AD compared with FTD (p < 0.001), ALS (p < 0.001), PD (p < 0.001) and controls (p < 0.001). CSF-Abeta42 was markedly decreased in AD and ALS (both p < 0.001) and slightly decreased in FTD (p < 0.01) and PD (p < 0.05) compared with controls. Using CSF-phosphotau may improve the differentiation of AD from FTD and ALS in clinical praxis. Furthermore, decreased CSF-Abeta42 levels may be common in neurodegenerative disorders possibly reflecting changes in the metabolism of beta-amyloid or axonal degeneration.