The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

Fiona C McKay; Prudence N Gatt; Nicole Fewings; Grant P Parnell; Stephen D Schibeci; Monica A I Basuki; Joseph E Powell; Anita Goldinger; Marzena J Fabis-Pedrini; Allan G Kermode; Therese Burke; Steve Vucic; Graeme J Stewart; David R Booth

doi:10.1016/j.clim.2015.12.015

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

Clin Immunol. 2016 Feb:163:96-107. doi: 10.1016/j.clim.2015.12.015. Epub 2016 Jan 4.

Authors

Affiliations

¹ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales 2145, Australia. Electronic address: fiona.mckay@sydney.edu.au.
² Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales 2145, Australia. Electronic address: prudence.gatt@sydney.edu.au.
³ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales 2145, Australia. Electronic address: nicole.fewings@sydney.edu.au.
⁴ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales 2145, Australia. Electronic address: grant.parnell@sydney.edu.au.
⁵ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales 2145, Australia. Electronic address: Stephen.schibeci@sydney.edu.au.
⁶ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales 2145, Australia. Electronic address: monicabasuki@gmail.com.
⁷ Institute for Molecular Bioscience, University of Queensland, Saint Lucia, Brisbane, 4072, Australia. Electronic address: joseph.powell@uq.edu.au.
⁸ University of Queensland Diamantina Institute, Translational Research Institute and The Queensland Brain Institute, University of Queensland, Australia. Electronic address: a.goldinger@uq.edu.au.
⁹ Western Australian Neuroscience Research Institute, University of Western Australia, Nedlands, Western Australia 6009, Australia. Electronic address: marzena.pedrini@wanri.uwa.edu.au.
¹⁰ Western Australian Neuroscience Research Institute, University of Western Australia, Nedlands, Western Australia 6009, Australia; Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia 6150, Australia. Electronic address: kermode@me.com.
¹¹ Western Clinical School, University of Sydney, Westmead Hospital, Sydney, New South Wales 2145, Australia. Electronic address: therese.burke@sydney.edu.au.
¹² Western Clinical School, University of Sydney, Westmead Hospital, Sydney, New South Wales 2145, Australia. Electronic address: s.vucic@neura.edu.au.
¹³ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales 2145, Australia. Electronic address: graeme.stewart@sydney.edu.au.
¹⁴ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales 2145, Australia. Electronic address: david.booth@sydney.edu.au.

PMID: 26762769
DOI: 10.1016/j.clim.2015.12.015

Abstract

Multiple Sclerosis (MS) is an autoimmune disease treated by therapies targeting peripheral blood cells. We previously identified that expression of two MS-risk genes, the transcription factors EOMES and TBX21 (ET), was low in blood from MS and stable over time. Here we replicated the low ET expression in a new MS cohort (p<0.0007 for EOMES, p<0.028 for TBX21) and demonstrate longitudinal stability (p<10(-4)) and high heritability (h(2)=0.48 for EOMES) for this molecular phenotype. Genes whose expression correlated with ET, especially those controlling cell migration, further defined the phenotype. CD56+ cells and other subsets expressed lower levels of Eomes or T-bet protein and/or were under-represented in MS. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with ET expression, but HLA-DRB1*1501 genotype was. ET expression was normalised to healthy control levels with natalizumab, and was highly variable for glatiramer acetate, fingolimod, interferon-beta, dimethyl fumarate.

Keywords: Biomarker; EOMES; Gene expression; MS risk gene; Multiple sclerosis; Natalizumab; TBX21.

Publication types

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

MeSH terms

Adult
Aged
CD56 Antigen
Case-Control Studies
Cell Movement
Dimethyl Fumarate / therapeutic use
Epstein-Barr Virus Nuclear Antigens / blood
Female
Fingolimod Hydrochloride / therapeutic use
Gene Expression Regulation
Genetic Predisposition to Disease
Glatiramer Acetate / therapeutic use
HLA-DRB1 Chains / genetics
Humans
Immunologic Factors / therapeutic use
Immunosuppressive Agents / therapeutic use
Interferon-beta / therapeutic use
Longitudinal Studies
Male
Middle Aged
Multiple Sclerosis / drug therapy
Multiple Sclerosis / genetics*
Natalizumab / therapeutic use
Polymorphism, Single Nucleotide
T-Box Domain Proteins / genetics*
Young Adult

Substances

CD56 Antigen
EOMES protein, human
Epstein-Barr Virus Nuclear Antigens
HLA-DRB1 Chains
HLA-DRB1*15:01 antigen
Immunologic Factors
Immunosuppressive Agents
NCAM1 protein, human
Natalizumab
T-Box Domain Proteins
T-box transcription factor TBX21
Glatiramer Acetate
Interferon-beta
Dimethyl Fumarate
Fingolimod Hydrochloride
EBV-encoded nuclear antigen 1