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Oligodendrocytes and Their Precursors May Play a More Complex Role in Multiple Sclerosis Progression, Suggesting a Potential Therapeutic Target

Article In Brief

Figure

Oligodendrocyte precursor cells clear myelin debris and interact with immune cells in the context of myelin damage (as in multiple sclerosis).

A subset of oligodendrocytes and their progenitor cells may have more in common with immune cells, suggests a study in a mouse model of multiple sclerosis. The oligodendrocytes may be important targets for modulation of autoimmunity and have a higher impact on the disease than previously thought, the study authors suggest.

Oligodendrocytes make myelin, and myelin is the target of immune attack in multiple sclerosis (MS). But a new study suggests that oligodendrocytes and oligodendrocyte precursor cells (OPCs) may play a far more complex role in MS patho-genesis.

In a mouse model of the disease, some of these cells appear to take on the role of antigen-presenting cells, expressing characteristic antigen-presenting genes and activating T cells, meaning they are likely to be contributing directly to the neuroinflammatory process.

“This changes our conception of what these cells can do, and what their roles are in the brain,” said Steven A. Goldman, MD, PhD, professor of neurology and co-director of the Center for Translational Neuromedicine of the University of Rochester Medical Center, who was not involved in the research. “It also presents us with a potential new therapeutic target for interrupting the autoimmune response.”

The discovery of an antigen-presenting phenotype in oligodendrocytes and OPCs came as a surprise to the study's principal investigator, Gonçalo Castelo-Branco, PhD, associate professor and principal investigator at the Karolinska Institute in Stockholm. In previous work his group had shown that oligodendrocytes were a heterogeneous group of cells, divisible into multiple subclasses based on their patterns of gene expression. The main aim of the current study, published in the December 2018 issue of Nature Medicine, was to begin to understand the transcriptional states of OPCs in the experimental autoimmune encephalitis (EAE) mouse model of MS, using single-cell RNA sequencing, which provides a highly detailed snapshot of gene activity within a single cell.

Experimental Methods, Findings

To do so, Dr. Castelo-Branco and first authors Ana Mendanha Falcão, PhD, and David van Bruggen, MSc, isolated single cells from the spinal cord of EAE mice at the peak of disease activity. They separated oligodendrocytes and OPCs from other cell types using standard cell markers and performed RNA sequencing. As in their previous work, they found that cells of the oligodendrocyte lineage were classifiable into several subpopulations.

The investigators identified a subset of OPCs and oligodendrocytes that expressed all the key genes involved in major histocompatibility class II (MHC-II) antigen presentation, including H2-A and H2-B, the mouse equivalents of the class II human leukocyte antigen (HLA) genes. In both the mouse and humans, expression of these genes has been taken as the hallmark of the so-called “professional” antigen-presenting cells, namely B cells, dendritic cells, and macrophages, which display antigens to T cells and thus stimulate them.

“We were surprised to see this,” Dr. Castelo-Branco said, “since it implies that these cells have the capacity to communicate with T cells and activate them.”

When they co-cultured OPCs from control mice with activated T cells from EAE mice, they observed that about 4 percent of the OPCs began to express MHC-II genes within 72 hours, “indicating that EAE-specific immune cells are inducing MHC-II expression in the OPCs,” they concluded. They also observed the OPCs engaging in phagocytosis, another behavior related to immune activation.

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“This study shows that oligodendrocyte lineage cells have the potential to be active participants in the central nervous system [CNS] immune response in MS patients. These cells have largely been considered incidental targets of CNS inflammation, but this work, along with other studies, suggest that immune cell–oligodendrocyte interactions likely influence the MS disease course.”—DR. BRIAN POPKO

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“Our study indicates that oligodendrocytes and OPCs might be a target for therapy, aimed to modulate their activation of T cells.”—DR. GONÇALO CASTELO-BRANCO

The team then used immunohistochemistry on oligodendrocytes and OPCs from post- mortem brain tissue from two people with MS and found that a small proportion of the oligodendrocyte lineage cells expressed MHC-II genes, just as in the mice, suggesting that oligodendrocytes and OPCs perform the same role in human MS as it does in EAE.

The prevailing view of MS pathogenesis is the “outside-in” hypothesis, Dr. Castelo-Branco said, in which the inciting event occurs in the periphery, followed by infiltration of autoreactive T cells into the central nervous system.

The alternative, “inside-out” view, posits that the inciting event occurs in the brain. “Our data suggest that the OPCs might be contributing to the initial step,” supporting the inside-out model. Alternatively, said Dr. Castelo-Branco, there could be a combination of peripheral and central events, with OPCs playing an accelerator role by contributing to an autoimmune cascade begun elsewhere. Further work will be needed to place this new activity of oligodendrocyte lineage cells within current models, or to build a new model to accommodate these findings.

More studies will be needed to confirm that the activation seen in vitro also occurs in vivo, Dr. Castelo-Branco noted. Assuming it does, he said, “our study indicates that oligodendrocytes and OPCs might be a target for therapy, aimed to modulate their activation of T cells.”

Expert Commentary

Commenting on the study, Brian Popko, PhD, professor of neurological disorders at the University of Chicago, said: “This study shows that oligodendrocyte lineage cells have the potential to be active participants in the central nervous system [CNS] immune response in MS patients. These cells have largely been considered incidental targets of CNS inflammation, but this work, along with other studies, suggest that immune cell–oligodendrocyte interactions likely influence the MS disease course,” and thus may be important targets for modulation of autoimmunity. Dr. Popko's own work has shown that oligodendrocytes participate in neuroimmune network signaling during the development of EAE.

“This study expands the scope of the known cell biology of the oligodendrocyte progenitor cell,” said Dr. Goldman of the University of Rochester Medical Center. “The OPC has been mysterious,” he added, given that the brain seems to contain far more of them than should be needed merely to replace oligodendrocytes. “So what are these cells doing?” The robust expression of MHC-II genes in response to systemic immune activation strongly suggests that OPCs “are driving and continuing the autoimmune reaction,” he said.

What isn't yet clear is what the normal function of antigen presentation by OPCs might be, Dr. Goldman said, “but it's a good bet that the expression of MHC-II genes by OPCs is part of a normal mechanism, contributing to immune surveillance for pathogens,” and that any contribution to neuroinflammation is a consequence of that role.

The involvement of oligodendrocyte lineage cells in autoimmunity “presents a potential therapeutic target,” said Dr. Goldman, either through preventing expression of the MHC-II genes or interfering with their ability to present antigens to T cells. “While most current therapeutic strategies for MS suppress peripheral T cells, or infiltration of T cells into the brain, this opens up the possibility of targeting cells within the brain to minimize their presentation of antigens to T cells. That is a new avenue for treatment, and it has potentially important therapeutic implications.”

Disclosures

Dr. Castelo-Branco disclosed that his research group has received research funding from F. Hoffmann– La Roche, Ltd. for other research projects in this area.

Link Up for More Information

• Falcão AM, van Bruggen D, Marques S, et al. Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis https://www.nature.com/articles/s41591-018-0236-y. Nat Med 2018;24(12):1837–1844.