Research Article

Long-term genome-wide blood RNA expression profiles yield novel molecular response candidates for IFN-β-1b treatment in relapsing remitting MS

† Author for correspondence

Department of Neurology, University of Rostock, Gehlsheimer Str. 20, 18047 Rostock, Germany.

Leibniz Institute for Natural Product Research & Infection Biology – Hans Knöll Institute, Jena, Germany

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Email the corresponding author at robert.goertsches@med.uni-rostock.de

Michael Hecker

Leibniz Institute for Natural Product Research & Infection Biology – Hans Knöll Institute, Jena, Germany

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Dirk Koczan

Institute of Immunology, University of Rostock, Schillingallee 70, 18055 Rostock, Germany

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Pablo Serrano-Fernandez

Institute of Immunology, University of Rostock, Schillingallee 70, 18055 Rostock, Germany

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Steffen Moeller

Institute of Immunology, University of Rostock, Schillingallee 70, 18055 Rostock, Germany

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Hans-Juergen Thiesen

Institute of Immunology, University of Rostock, Schillingallee 70, 18055 Rostock, Germany

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Uwe K Zettl

Department of Neurology, University of Rostock, Gehlsheimer Str. 20, 18047 Rostock, Germany.

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Email the corresponding author at robert.goertsches@med.uni-rostock.de

Published Online:5 Feb 2010https://doi.org/10.2217/pgs.09.152

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Abstract

Aims: In multiple sclerosis patients, treatment with recombinant IFN-β (rIFN-β) is partially efficient in reducing clinical exacerbations. However, its molecular mechanism of action is still under scrutiny. Materials & methods: We used DNA microarrays (Affymetrix, CA, USA) and peripheral mononuclear blood cells from 25 relapsing remitting multiple sclerosis patients to analyze the longitudinal transcriptional profile within 2 years of rIFN-β administration. Sets of differentially expressed genes were attained by applying a combination of independent criteria, thereby providing efficient data curation and gene filtering that accounted for technical and biological noise. Gene ontology term-association analysis and scientific literature text mining were used to explore evidence of gene interaction. Results: Post-therapy initiation, we identified 42 (day 2), 175 (month 1), 103 (month 12) and 108 (month 24) differentially expressed genes. Increased expression of established IFN-β marker genes, as well as differential expression of circulating IFN-β-responsive candidate genes, were observed. MS4A1 (CD20), a known target of B-cell depletion therapy, was significantly downregulated after one month. CMPK2, FCER1A, and FFAR2 appeared as hitherto unrecognized multiple sclerosis treatment-related differentially expressed genes that were consistently modulated over time. Overall, 84 interactions between 54 genes were attained, of which two major gene networks were identified at an earlier stage of therapy: the first (n = 15 genes) consisted of mostly known IFN-β-activated genes, whereas the second (n = 12) mainly contained downregulated genes that to date have not been associated with IFN-β effects in multiple sclerosis array research. Conclusion: We achieved both a broadening of the knowledge of IFN-β mechanism-of-action-related constituents and the identification of time-dependent interactions between IFN-β regulated genes.

Keywords:

Papers of special note have been highlighted as: ▪▪ of considerable interest

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Financial & competing interests disclosure

Bayer Health Care and Bayer Vital GmbH (Germany) co-funded this study. The authors are grateful to the individuals who participated in this study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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