Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event

Jean Christophe Corvol, Daniel Pelletier, Roland G. Henry, Stacy J. Caillier, Joanne Wang, Derek Pappas, Simona Casazza, Darin T. Okuda, Stephen L. Hauser, Jorge R. Oksenberg, Sergio E. Baranzini

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11839-11844
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number33
DOIs
StatePublished - Aug 19 2008

Keywords

  • Clinically isolated syndrome
  • Gene expression

ASJC Scopus subject areas

  • General

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    Corvol, J. C., Pelletier, D., Henry, R. G., Caillier, S. J., Wang, J., Pappas, D., Casazza, S., Okuda, D. T., Hauser, S. L., Oksenberg, J. R., & Baranzini, S. E. (2008). Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event. Proceedings of the National Academy of Sciences of the United States of America, 105(33), 11839-11844. https://doi.org/10.1073/pnas.0805065105