title: The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies.
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.
authors.affiliation: 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.
authors.forename: Fiona C
authors.initials: FC
authors.lastname: McKay
authors.affiliation: 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.
authors.forename: Prudence N
authors.initials: PN
authors.lastname: Gatt
authors.affiliation: 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.
authors.forename: Nicole
authors.initials: N
authors.lastname: Fewings
authors.affiliation: 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.
authors.forename: Grant P
authors.initials: GP
authors.lastname: Parnell
authors.affiliation: 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.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schibeci
authors.affiliation: 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.
authors.forename: Monica A I
authors.initials: MA
authors.lastname: Basuki
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Saint Lucia, Brisbane, 4072, Australia. Electronic address: joseph.powell@uq.edu.au.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Powell
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute and The Queensland Brain Institute, University of Queensland, Australia. Electronic address: a.goldinger@uq.edu.au.
authors.forename: Anita
authors.initials: A
authors.lastname: Goldinger
authors.affiliation: Western Australian Neuroscience Research Institute, University of Western Australia, Nedlands, Western Australia 6009, Australia. Electronic address: marzena.pedrini@wanri.uwa.edu.au.
authors.forename: Marzena J
authors.initials: MJ
authors.lastname: Fabis-Pedrini
authors.affiliation: 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.
authors.forename: Allan G
authors.initials: AG
authors.lastname: Kermode
authors.affiliation: Western Clinical School, University of Sydney, Westmead Hospital, Sydney, New South Wales 2145, Australia. Electronic address: therese.burke@sydney.edu.au.
authors.forename: Therese
authors.initials: T
authors.lastname: Burke
authors.affiliation: Western Clinical School, University of Sydney, Westmead Hospital, Sydney, New South Wales 2145, Australia. Electronic address: s.vucic@neura.edu.au.
authors.forename: Steve
authors.initials: S
authors.lastname: Vucic
authors.affiliation: 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.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Stewart
authors.affiliation: 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.
authors.forename: David R
authors.initials: DR
authors.lastname: Booth
mesh_terms: D000328:Adult; D000368:Aged; D019002:CD56 Antigen; D016022:Case-Control Studies; D002465:Cell Movement; D000069462:Dimethyl Fumarate / Q000627:therapeutic use; D019309:Epstein-Barr Virus Nuclear Antigens / Q000097:blood; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D000068717:Glatiramer Acetate / Q000627:therapeutic use; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016899:Interferon-beta / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics*; D000069442:Natalizumab / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D020825:T-Box Domain Proteins / Q000235:genetics*; D055815:Young Adult; D000098815:T-bet Transcription Factor
chemical_list: D019002:CD56 Antigen; C491199:EOMES protein, human; D019309:Epstein-Barr Virus Nuclear Antigens; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; C522918:NCAM1 protein, human; D000069442:Natalizumab; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D000068717:Glatiramer Acetate; D016899:Interferon-beta; D000069462:Dimethyl Fumarate; D000068876:Fingolimod Hydrochloride; C417029:EBV-encoded nuclear antigen 1
keywords: Biomarker; EOMES; Gene expression; MS risk gene; Multiple sclerosis; Natalizumab; TBX21