The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease

Grant P Parnell; Prudence N Gatt; Malgorzata Krupa; Dorothee Nickles; Fiona C McKay; Stephen D Schibeci; Marcel Batten; Sergio Baranzini; Andrew Henderson; Michael Barnett; Mark Slee; Steve Vucic; Graeme J Stewart; David R Booth

doi:10.1016/j.clim.2014.01.003

The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease

Clin Immunol. 2014 Mar;151(1):16-24. doi: 10.1016/j.clim.2014.01.003. Epub 2014 Jan 15.

Affiliations

¹ Institute for Immunology and Allergy Research, Westmead Millennium Institute University of Sydney, Sydney, New South Wales 2145, Australia.
² School of Medicine, Flinders University of South Australia, South Australia 5042, Australia.
³ Department of Neurology, University of California at San Francisco, CA 94158, USA.
⁴ Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
⁵ Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2050 Australia.
⁶ Westmead Clinical School, University of Sydney, Westmead Hospital, Sydney, New South Wales 2145, Australia.
⁷ Institute for Immunology and Allergy Research, Westmead Millennium Institute University of Sydney, Sydney, New South Wales 2145, Australia. Electronic address: david.booth@sydney.edu.au.

PMID: 24495857
DOI: 10.1016/j.clim.2014.01.003

Abstract

We have identified a marked over-representation of transcription factors controlling differentiation of T, B, myeloid and NK cells among the 110 MS genes now known to be associated with multiple sclerosis (MS). To test if the expression of these genes might define molecular subtypes of MS, we interrogated their expression in blood in three independent cohorts of untreated MS (from Sydney and Adelaide) or clinically isolated syndrome (CIS, from San Francisco) patients. Expression of the transcription factors (TF) controlling T and NK cell differentiation, EOMES, TBX21 and other TFs was significantly lower in MS/CIS compared to healthy controls in all three cohorts. Expression was tightly correlated between these TFs, with other T/NK cell TFs, and to another downregulated gene, CCL5. Expression was stable over time, but did not predict disease phenotype. Optimal response to therapy might be indicated by normalization of expression of these genes in blood.

Keywords: EOMES; Gene expression; Multiple sclerosis; TBX21; Transcription factors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
B-Lymphocytes / pathology
Case-Control Studies
Cell Differentiation
Chemokine CCL5 / genetics
Chemokine CCL5 / immunology
Cohort Studies
Female
Gene Expression Profiling
Gene Expression Regulation
Humans
Killer Cells, Natural / immunology
Killer Cells, Natural / metabolism
Killer Cells, Natural / pathology
Male
Middle Aged
Multiple Sclerosis / diagnosis
Multiple Sclerosis / genetics*
Multiple Sclerosis / immunology
Multiple Sclerosis / pathology
Signal Transduction
T-Box Domain Proteins / genetics*
T-Box Domain Proteins / immunology
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
T-Lymphocytes / pathology

Substances

CCL5 protein, human
Chemokine CCL5
EOMES protein, human
T-Box Domain Proteins
T-box transcription factor TBX21