Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis

• Published in: Nature medicine Vol. 24; no. 12; pp. 1837 - 1844
• Main Authors: Falcão, Ana Mendanha, van Bruggen, David, Marques, Sueli, Meijer, Mandy, Jäkel, Sarah, Agirre, Eneritz, Samudyata, Floriddia, Elisa M, Vanichkina, Darya P, Ffrench-Constant, Charles, Williams, Anna, Guerreiro-Cacais, André Ortlieb, Castelo-Branco, Gonçalo
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.12.2018
• Subjects: Alternative splicing; Alternative Splicing - genetics; Animals; Antigen presentation; Antigen Presentation - genetics; Antigen processing; Autoimmune diseases; Biomarkers; CD4 antigen; Cell Lineage - genetics; Effector cells; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - physiopathology; Experimental allergic encephalomyelitis; Gene Expression Regulation - genetics; Genes; Glial stem cells; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class II - genetics; Humans; Immune System; Immunological memory; Immunomodulation; Immunomodulators; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Memory cells; Mice; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - physiopathology; Myelin; Myelin Sheath - genetics; Oligodendrocyte Precursor Cells - metabolism; Oligodendrocyte Precursor Cells - pathology; Oligodendrocytes; Oligodendroglia - metabolism; Single-Cell Analysis; Spinal cord; Transcriptome - genetics
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-018-0236-y

Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.