Genomic effects of interferon-beta in multiple sclerosis patients
Santos, Roseane Maia
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Multiple sclerosis (MS) is demyelinating, autoimmune disease of the central nervous system and the most common cause of acquired neurological dysfunction during young adulthood. The cause of MS is unknown but it is widely accepted that MS is a complex polygenic disease involving the interplay of multiple genes, gene-gene interactions and post-transcriptional regulatory mechanisms. Interferon-beta (IFNβ) is an approved immunomodulatory agent that slows the progression of disability in MS patients and is indicated for the treatment of the relapsing-remitting form of the disease. The unpredictable course of MS after diagnosis is an important motivation for identifying biomarkers for monitoring the response to therapy because no single marker has been shown to be a useful metric. Our hypothesis was that gene expression patterns would provide a biological tool to predict differences between MS patients in response to IFNβ therapy. The specific aims were: (1) Identify patterns of gene expression in lymphocytes of MS patients during and after exacerbation phase; (2) Develop and validate a real-time quantitative polymerase chain reaction (real-time QPCR) methodology to quantify IFNβ-modulated genes; (3) Validate previous results obtained in our laboratory from DNA arrays using the real-time QPCR; (4) Identify panels of genes uniquely expressed in the peripheral blood mononuclear cells of MS patients during administration of IFNβ-1a; (5) Assess the dynamics of gene expression of INFβ-modulated genes to elucidate relevant aspects of the MS disease. A significant number of genes were identified from DNA arrays: during exacerbation and recovery the biological processes involved were protein catabolism, T-cell proliferation and cell cycle regulation, all of them mostly localized within the nucleus and the comparison between exacerbation and remission showed localization preferably in the cytoplasm. The real-time QPCR assays developed in our study identified at least 4 IFNβ-modulated genes (Mx1, Mx2, STAT1 and TRAIL) that can be used as markers for IFNβ response. The pharmacodynamic measurements of mRNAs of IFNβ-modulated genes related to the mechanisms of neuroprotection and bone metabolism, brought new insights to better understand IFNβ effects, providing new tools for monitoring the therapy that could be used in the near future to individualize dosing regimens.