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Characterising the Molecular Phenotypes of MS: heredity, gene expression modules, dysregulated immune cell subsets and response to therapy

McKay, F., Gatt, P.N., Fewings, N., Schibeci, S.D., Parnell, G., Basuki, M.A.I., Powell, J.E., Goldinger, A., Fabis-Pedrini, M.J., Kermode, A.G., Burke, T., Vucic, S., Stewart, G.J. and Booth, D.R. (2015) Characterising the Molecular Phenotypes of MS: heredity, gene expression modules, dysregulated immune cell subsets and response to therapy. Multiple Sclerosis Journal, 21 (14). NP1-NP32.

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Background: Current MS therapies target the systemic circulation. We previously identified that genes encoding transcription factors were over-represented amongst MS risk factors, and that expression of several of these were altered in MS blood, including EOMES, TBX21 and ZMIZ1. Expression was stable over time, so that it defines a molecular phenotype.

Objectives: Here we tested if this finding could be replicated in independent cohorts, if expression was heritable, longitudinally stable, affected by therapy, and associated with genetic and environmental risk factors. We sought the immune cell subsets expressing these transcription factors, and tested if protein expression was also altered.

Methods: Whole blood mRNA expression was determined in new cohorts of untreated MS (n = 23, Sydney; n = 47, Perth) and healthy controls (n = 23) and protein expression determined by flow cytometry in PBMCs of untreated MS and healthy controls (n = 28, 30 respectively). Effect of major therapies and correlation of gene expression with risk SNP genotypes, and anti-Epstein Barr Virus EBNA-1 titres was assessed, and heritability tested in a large twin cohort.

Results: MS Molecular Phenotypes were replicated in new cohorts. Modules of genes, whose expression correlated with EOMES/TBX21 or ZMIZ1, further defined the phenotypes. CD56+ cells, inflammatory monocytes and plasmacytoid dendritic cells expressed lower levels of Molecular Phenotype transcription factors. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with gene expression, but HLA-DRB1*1501 genotype was. Therapies altered expression levels (e.g. TBX21 returned to control levels on natalizumab) with significant variability between individuals.

Conclusions: EOMES/TBX21 and ZMIZ1 tag molecular phenotypes of MS that are affected by therapy. The phenotypes are due to under-representation and altered state of CD56+ and inflammatory monocytes/pDCs respectively. The dysregulated immune cells are a novel target for therapy and, together with gene expression, represent potential biomarkers of therapeutic response.

Item Type: Journal Article
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
Publisher: SAGE Publications
Copyright: © 2015 SAGE Publications
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