Contributions
Abstract: EP1601
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 25 Biomarkers
Biomarkers may predict the natural disease course in relapsing-remitting MS (RRMS), identify patients with need of early aggressive treatment, and may help in determining transition from RRMS to progressive disease early.
Here we used a translational multi-omics approach to identify potential biomarkers in the cerebrospinal fluid (CSF) of patients with RRMS, and secondary/primary progressive MS (SPMS/PPMS).
Demyelination was induced in mice by cuprizone (CPZ) administration for 4 weeks, while acute and full remyelination was induced by suspending CPZ for 2 and 14 days. The 4x44K Agilent Whole Mouse Genome Microarray detected 1239 differentially expressed genes in the de- and remyelinated corpus callosum. Comparison of these genes to the transcriptome of MS lesions identified 91 overlapping homologous genes and 7 susceptibility genes. By liquid chromatography mass spectrometry (LC-MS/MS), we detected 19 proteins of these 98 genes in pooled CSF of PPMS, RRMS and SPMS, respectively. We selected additional 32 out of the 98 genes based on biological function, and designed 132 peptides representing these 51 homologous proteins. In 97 individual CSF samples of 30 PPMS, 27 SPMS and 41 RRMS, we measured the levels of the 132 peptides by targeted proteomics, i.e. parallel reaction monitoring (PRM). Four proteins were differentially regulated among MS subgroups: tyrosine protein kinase receptor UFO (UFO-Axl), TIMP-1, apolipoprotein C-II (APOC2), and beta-2-microglobulin (B2M). Their genes were up-regulated during acute remyelination in the mouse brain. Immunohistochemistry indicated TIMP1 expression by oligodendrocyte precursor cells, while UFO-Axl and APOC2 by macrophages/microglia within demyelinating lesions. By using MesoScale, we correlated the concentration of 36 inflammatory molecules, neurofilament light chain (NF-L) and the 4 peptides in the CSF of 17 RRMS patients. The level of UFO-Axl and TIMP-1 negatively correlated with the concentration of IL-6; UFO-Axl also negatively correlated with concentration of MCP-1. B2M negatively correlated with the concentration of TARC. In contrast, APOC2 showed positive correlation with the concentration of IL-16, IL-2 and eotaxin-3.
This proof of concept study suggests that pathology-based translational multi-omics may identify potential biomarkers in MS.
Supported: Lundbeckfonden R118-A11472, OTKA-NN109841, OTKA-K77892, Region of Southern Denmark 14/24200, Jascha Fonden 5589, Direktør Ejnar Jonasson kaldet Johnsen og hustrus mindelegat 5609, Odense University Hospital (OUH) A474, Fonden for Lægevidenskabensfremme 13-267.
Disclosure:
Zsolt Illes has served on scientific advisory boards, served as a consultant, received support for congress participation, received speaker honoraria, and received research support from Biogen, Merck-Serono, Sanofi-Genzyme, Lundbeck, and Novartis.
Finn Sellebjerg has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, EMD Serono, Genzyme, Lundbeck, Merck, Novartis and Teva.
Abstract: EP1601
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 25 Biomarkers
Biomarkers may predict the natural disease course in relapsing-remitting MS (RRMS), identify patients with need of early aggressive treatment, and may help in determining transition from RRMS to progressive disease early.
Here we used a translational multi-omics approach to identify potential biomarkers in the cerebrospinal fluid (CSF) of patients with RRMS, and secondary/primary progressive MS (SPMS/PPMS).
Demyelination was induced in mice by cuprizone (CPZ) administration for 4 weeks, while acute and full remyelination was induced by suspending CPZ for 2 and 14 days. The 4x44K Agilent Whole Mouse Genome Microarray detected 1239 differentially expressed genes in the de- and remyelinated corpus callosum. Comparison of these genes to the transcriptome of MS lesions identified 91 overlapping homologous genes and 7 susceptibility genes. By liquid chromatography mass spectrometry (LC-MS/MS), we detected 19 proteins of these 98 genes in pooled CSF of PPMS, RRMS and SPMS, respectively. We selected additional 32 out of the 98 genes based on biological function, and designed 132 peptides representing these 51 homologous proteins. In 97 individual CSF samples of 30 PPMS, 27 SPMS and 41 RRMS, we measured the levels of the 132 peptides by targeted proteomics, i.e. parallel reaction monitoring (PRM). Four proteins were differentially regulated among MS subgroups: tyrosine protein kinase receptor UFO (UFO-Axl), TIMP-1, apolipoprotein C-II (APOC2), and beta-2-microglobulin (B2M). Their genes were up-regulated during acute remyelination in the mouse brain. Immunohistochemistry indicated TIMP1 expression by oligodendrocyte precursor cells, while UFO-Axl and APOC2 by macrophages/microglia within demyelinating lesions. By using MesoScale, we correlated the concentration of 36 inflammatory molecules, neurofilament light chain (NF-L) and the 4 peptides in the CSF of 17 RRMS patients. The level of UFO-Axl and TIMP-1 negatively correlated with the concentration of IL-6; UFO-Axl also negatively correlated with concentration of MCP-1. B2M negatively correlated with the concentration of TARC. In contrast, APOC2 showed positive correlation with the concentration of IL-16, IL-2 and eotaxin-3.
This proof of concept study suggests that pathology-based translational multi-omics may identify potential biomarkers in MS.
Supported: Lundbeckfonden R118-A11472, OTKA-NN109841, OTKA-K77892, Region of Southern Denmark 14/24200, Jascha Fonden 5589, Direktør Ejnar Jonasson kaldet Johnsen og hustrus mindelegat 5609, Odense University Hospital (OUH) A474, Fonden for Lægevidenskabensfremme 13-267.
Disclosure:
Zsolt Illes has served on scientific advisory boards, served as a consultant, received support for congress participation, received speaker honoraria, and received research support from Biogen, Merck-Serono, Sanofi-Genzyme, Lundbeck, and Novartis.
Finn Sellebjerg has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, EMD Serono, Genzyme, Lundbeck, Merck, Novartis and Teva.