New Study Suggests Oligodendrocytes Contribute to the Origin and Progression of Multiple Sclerosis

Summary: Single-cell analysis of oligodendrocyte lineage cells in a mouse model of multiple sclerosis reveals immune-like properties and disease-specific roles that could open new therapeutic avenues beyond immune suppression.

Source: Karolinska Institute

Researchers at Karolinska Institutet have mapped oligodendrocyte lineage cells in the central nervous system of a mouse model of multiple sclerosis (MS) and found that these cells may play an important and previously underappreciated role in disease onset and progression. The study, published in Nature Medicine, highlights how myelin-producing cells and their precursors acquire immune-related features during disease and suggests new targets for treatments that extend beyond the immune system alone.

Multiple sclerosis affects roughly 2.5 million people worldwide. In MS, the immune system attacks myelin, the fatty insulating layer that coats nerve fibers in the brain and spinal cord, disrupting electrical signal transmission and producing the neurological symptoms associated with the disease. While immune dysfunction has long been the focus of MS research and therapy, this new work points to intrinsic changes in oligodendrocytes and oligodendrocyte precursor cells (OPCs) that may actively shape disease progression.

“This study provides a fresh perspective on how multiple sclerosis might begin and evolve,” says Gonçalo Castelo-Branco, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. “Most current therapies aim to suppress immune activity. Our data show that the cells targeted by the immune system in the brain and spinal cord — oligodendrocytes and their progenitors — change their properties during disease and could influence MS more directly than previously recognized.”

Immune-like features in myelin-producing cells

Using single-cell RNA sequencing, the team profiled the gene expression of individual oligodendrocyte lineage cells from the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE), a widely used model that recapitulates several aspects of MS. This high-resolution approach allowed the researchers to distinguish distinct subpopulations of oligodendrocytes and OPCs and to identify disease-specific transcriptional programs.

Surprisingly, some oligodendrocyte lineage cells in the EAE model expressed genes associated with antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and MHC-II), pathways typically associated with immune cells. These cells also expressed genes related to phagocytosis and immunomodulation, indicating that they can participate in clearing damaged myelin and interact functionally with immune cells.

OPCs were shown to communicate with immune cells and influence their behavior. In functional assays, OPCs demonstrated the ability to phagocytose myelin debris, and subsets of MHC-II–expressing OPCs could activate memory and effector CD4-positive T cells. These results imply that oligodendroglia are not merely passive victims in MS but can act as active immunomodulators within the central nervous system.

Genetic links and relevance to human disease

Beyond mouse models, the researchers detected similar disease-specific oligodendrocyte populations in human MS brain samples. They also found that a number of genes previously identified as MS susceptibility loci—genes often attributed to immune cell function—are expressed in oligodendrocytes and OPCs. This overlap suggests that genetic risk for MS may in part be mediated through cell-intrinsic changes in the oligodendrocyte lineage.

“Taken together, our results indicate that oligodendrocytes and their progenitors could play a significant role either in triggering MS or in shaping its course,” says Ana Mendanha Falcão, joint first author of the study with David van Bruggen. “Understanding these disease-specific cell states may point to new therapeutic strategies that target the central nervous system directly, rather than focusing solely on peripheral immune suppression.”

Methods and next steps

The key method in this study was single-cell transcriptomics, which measures the gene expression profiles of individual cells. This technique allowed the team to resolve molecular differences among closely related cell types and to identify biomarkers for disease-specific oligodendrocyte populations. While the majority of experiments were performed in mice, several observations were validated in human tissue, strengthening the clinical relevance of the findings.

Future work will aim to define precisely how these oligodendrocyte lineage cells influence immune responses and neurological damage in MS, and whether targeting their disease-specific states can slow or prevent progression. The authors emphasize that expanding our focus beyond immune suppression could yield complementary therapeutic approaches aimed directly at the central nervous system.

Funding: The research received support from multiple organizations, including the European Research Council, Marie Skłodowska‑Curie Actions, the European Committee for Treatment and Research of Multiple Sclerosis (ECTRIMS), the Swedish Research Council, the Swedish Brain Foundation, the Ming Wai Lau Centre for Reparative Medicine, the Petrus and Augusta Hedlund Foundation, and Karolinska Institutet.

Source: Karolinska Institute
Publisher: NeuroscienceNews.com
Original research: “Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis” by Ana Mendanha Falcão, David van Bruggen, Sueli Marques, Mandy Meijer, Sarah Jäkel, Eneritz Agirre, Samudyata, Elisa M. Floriddia, Darya P. Vanichkina, Charles ffrench-Constant, Anna Williams, André Ortlieb Guerreiro-Cacais & Gonçalo Castelo-Branco. Published in Nature Medicine, November 12, 2018. doi: 10.1038/s41591-018-0236-y

Abstract

Multiple sclerosis is hallmarked by immune-mediated damage to myelin, the insulating material produced by oligodendrocytes. Single-cell transcriptomic analysis of oligodendrocyte lineage cells from the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE) revealed unique oligodendrocytes and OPCs that appear only in disease. These disease-specific populations exhibit alternative splicing events and express genes linked to antigen processing and presentation (MHC-I and MHC-II) as well as immunoprotective pathways. OPCs demonstrated phagocytic capacity and MHC-II–expressing OPCs were capable of activating CD4-positive T cells. Comparable cell populations were observed in human MS tissue, and many genes associated with MS susceptibility are active in the oligodendrocyte lineage. These findings suggest that oligodendrocytes and their progenitors are active participants in MS pathology and may represent novel targets for CNS-directed immunomodulatory therapies.