Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event
Open Access
- 19 August 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (33), 11839-11844
- https://doi.org/10.1073/pnas.0805065105
Abstract
Clinically isolated syndrome (CIS) refers to the earliest clinical manifestation of multiple sclerosis (MS). Currently there are no prognostic biological markers that accurately predict conversion of CIS to clinically definite MS (CDMS). Furthermore, the earliest molecular events in MS are still unknown. We used microarrays to study gene expression in naïve CD4+ T cells from 37 CIS patients at time of diagnosis and after 1 year. Supervised machine-learning methods were used to build predictive models of disease conversion. We identified 975 genes whose expression segregated CIS patients into four distinct subgroups. A subset of 108 genes further discriminated patients in one of these (group 1) from other CIS patients. Remarkably, 92% of patients in group 1 converted to CDMS within 9 months. Consistent down-regulation of TOB1, a critical regulator of cell proliferation, was characteristic of group 1 patients. Decreased TOB1 expression at the RNA and protein levels also was confirmed in experimental autoimmune encephalomyelitis. Finally, a genetic association was observed between TOB1 variation and MS progression in an independent cohort. These results indicate that CIS patients at high risk of conversion have impaired regulation of T cell quiescence, possibly resulting in earlier activation of pathogenic CD4+ cells.This publication has 48 references indexed in Scilit:
- RNA-Seq: a revolutionary tool for transcriptomicsNature Reviews Genetics, 2009
- Gene Expression and Isoform Variation Analysis using Affymetrix Exon ArraysBMC Genomics, 2008
- Expression of 24,426 human alternative splicing events and predicted cis regulation in 48 tissues and cell linesNature Genetics, 2008
- FIRMA: a method for detection of alternative splicing from exon array dataBioinformatics, 2008
- RNA-seq: An assessment of technical reproducibility and comparison with gene expression arraysGenome Research, 2008
- Global analysis of aberrant pre-mRNA splicing in glioblastoma using exon expression arraysBMC Genomics, 2008
- Genome-wide analysis of transcript isoform variation in humansNature Genetics, 2008
- The UCSC Genome Browser Database: 2008 updateNucleic Acids Research, 2007
- Heritability of alternative splicing in the human genomeGenome Research, 2007
- Discovery of tissue-specific exons using comprehensive human exon microarraysGenome Biology, 2007