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

70 Citations (Scopus)

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

Fingerprint

Multiple Sclerosis
T-Lymphocytes
Gene Expression
Autoimmune Experimental Encephalomyelitis
Down-Regulation
Biomarkers
Cell Proliferation
RNA
Genes
Proteins

Keywords

  • Clinically isolated syndrome
  • Gene expression

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event. / Corvol, Jean Christophe; Pelletier, Daniel; Henry, Roland G.; Caillier, Stacy J.; Wang, Joanne; Pappas, Derek; Casazza, Simona; Okuda, Darin T.; Hauser, Stephen L.; Oksenberg, Jorge R.; Baranzini, Sergio E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 33, 19.08.2008, p. 11839-11844.

Research output: Contribution to journalArticle

Corvol, JC, Pelletier, D, Henry, RG, Caillier, SJ, Wang, J, Pappas, D, Casazza, S, Okuda, DT, Hauser, SL, Oksenberg, JR & Baranzini, SE 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, vol. 105, no. 33, pp. 11839-11844. https://doi.org/10.1073/pnas.0805065105
Corvol, Jean Christophe ; Pelletier, Daniel ; Henry, Roland G. ; Caillier, Stacy J. ; Wang, Joanne ; Pappas, Derek ; Casazza, Simona ; Okuda, Darin T. ; Hauser, Stephen L. ; Oksenberg, Jorge R. ; Baranzini, Sergio E. / Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 33. pp. 11839-11844.
@article{bde40ad7a9274590ace55b76fdcdd26f,
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 na{\"i}ve 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.",
keywords = "Clinically isolated syndrome, Gene expression",
author = "Corvol, {Jean Christophe} and Daniel Pelletier and Henry, {Roland G.} and Caillier, {Stacy J.} and Joanne Wang and Derek Pappas and Simona Casazza and Okuda, {Darin T.} and Hauser, {Stephen L.} and Oksenberg, {Jorge R.} and Baranzini, {Sergio E.}",
year = "2008",
month = "8",
day = "19",
doi = "10.1073/pnas.0805065105",
language = "English (US)",
volume = "105",
pages = "11839--11844",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "33",

}

TY - JOUR

T1 - Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event

AU - Corvol, Jean Christophe

AU - Pelletier, Daniel

AU - Henry, Roland G.

AU - Caillier, Stacy J.

AU - Wang, Joanne

AU - Pappas, Derek

AU - Casazza, Simona

AU - Okuda, Darin T.

AU - Hauser, Stephen L.

AU - Oksenberg, Jorge R.

AU - Baranzini, Sergio E.

PY - 2008/8/19

Y1 - 2008/8/19

N2 - 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.

AB - 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.

KW - Clinically isolated syndrome

KW - Gene expression

UR - http://www.scopus.com/inward/record.url?scp=50149102578&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=50149102578&partnerID=8YFLogxK

U2 - 10.1073/pnas.0805065105

DO - 10.1073/pnas.0805065105

M3 - Article

C2 - 18689680

AN - SCOPUS:50149102578

VL - 105

SP - 11839

EP - 11844

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 33

ER -