Contributions
Abstract: P429
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Hypothesis: We hypothesized that the different lesion types in the brain of progressive multiple sclerosis (SPMS) patients can be characterized by specific transcriptome signatures. These could unmask complex mechanisms that drive the evolution and fate of lesions, and lead to discovery of biomarkers and potential drug targets that can halt progression.
Methods: With immunohistochemistry, we classified 98 brain areas: NAWM and active lesions representing lesion evolution, and inactive, chronic active and repairing lesions representing the fate of lesions, and also control white matter tissue from 10 MS and 5 non-neurological control brains. We carefully dissected the lesion types out and created the transcriptome profile of each lesion type by next generation RNA sequencing, and normalized the expression against the control tissue. We produced clusters and networks of significant genes using KeyPathwayMiner and TiCoNE. We also extracted key molecules that could influence either the maintenance or halt of active inflammation.
Results: Out of the detected 18000 genes, over 4000 were differentially expressed between MS and controls (FDR< 0.05). Here we found CD26 in NAWM as a potential early marker of lesion evolution. By unsupervised clustering, we observed a gene cluster (n=580) representing the evolution of active lesion from NAWM. The co-enriched network was related to cellular trafficking and immune activation as ICAM, VCAM, HLA-DRs, CD4, CD11c. As for fate of active lesions, we retrieved genes uniquely expressed in each lesion type and mapped them to protein-networks to reveal stage-specific mechanisms. The repair-specific network was related to genes participating in tissue recovery/remodeling and cytotoxic immune response, the inactive-specific network was related to coagulation and homeostatic control, and the chronic active-specific network was related primarily to metabolic changes with ENO1 as a major hub in chronic active subnetworks.
Discussion: Our data support lesion type specific transcriptome signatures. We observed high transcriptional changes across lesion evolution and fate emphasizing the importance to study each lesion type separately not to misinterpret temporal differences. With an unsupervised approach, we created de novo biological pathways containing major hubs and molecules that may control the mechanisms of active lesion evolution, and its fate into inactive, chronic active, or repairing lesion.
Disclosure: ZI 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. RR has served on scientific advisory boards, received research support and speaker honoraria from Novartis, Biogen, MedImmune and Roche.
Abstract: P429
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Hypothesis: We hypothesized that the different lesion types in the brain of progressive multiple sclerosis (SPMS) patients can be characterized by specific transcriptome signatures. These could unmask complex mechanisms that drive the evolution and fate of lesions, and lead to discovery of biomarkers and potential drug targets that can halt progression.
Methods: With immunohistochemistry, we classified 98 brain areas: NAWM and active lesions representing lesion evolution, and inactive, chronic active and repairing lesions representing the fate of lesions, and also control white matter tissue from 10 MS and 5 non-neurological control brains. We carefully dissected the lesion types out and created the transcriptome profile of each lesion type by next generation RNA sequencing, and normalized the expression against the control tissue. We produced clusters and networks of significant genes using KeyPathwayMiner and TiCoNE. We also extracted key molecules that could influence either the maintenance or halt of active inflammation.
Results: Out of the detected 18000 genes, over 4000 were differentially expressed between MS and controls (FDR< 0.05). Here we found CD26 in NAWM as a potential early marker of lesion evolution. By unsupervised clustering, we observed a gene cluster (n=580) representing the evolution of active lesion from NAWM. The co-enriched network was related to cellular trafficking and immune activation as ICAM, VCAM, HLA-DRs, CD4, CD11c. As for fate of active lesions, we retrieved genes uniquely expressed in each lesion type and mapped them to protein-networks to reveal stage-specific mechanisms. The repair-specific network was related to genes participating in tissue recovery/remodeling and cytotoxic immune response, the inactive-specific network was related to coagulation and homeostatic control, and the chronic active-specific network was related primarily to metabolic changes with ENO1 as a major hub in chronic active subnetworks.
Discussion: Our data support lesion type specific transcriptome signatures. We observed high transcriptional changes across lesion evolution and fate emphasizing the importance to study each lesion type separately not to misinterpret temporal differences. With an unsupervised approach, we created de novo biological pathways containing major hubs and molecules that may control the mechanisms of active lesion evolution, and its fate into inactive, chronic active, or repairing lesion.
Disclosure: ZI 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. RR has served on scientific advisory boards, received research support and speaker honoraria from Novartis, Biogen, MedImmune and Roche.