title: Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event.
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.
authors.affiliation: Departments of Neurology and Radiology, University of California, San Francisco, CA 94143-0435, USA.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.forename: Daniel
authors.initials: D
authors.lastname: Pelletier
authors.forename: Roland G
authors.initials: RG
authors.lastname: Henry
authors.forename: Stacy J
authors.initials: SJ
authors.lastname: Caillier
authors.forename: Joanne
authors.initials: J
authors.lastname: Wang
authors.forename: Derek
authors.initials: D
authors.lastname: Pappas
authors.forename: Simona
authors.initials: S
authors.lastname: Casazza
authors.forename: Darin T
authors.initials: DT
authors.lastname: Okuda
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
mesh_terms: D000328:Adult; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D012307:Risk Factors; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C098669:TOB1 protein, human; D025521:Tumor Suppressor Proteins