Shining a spotlight on multiple sclerosis with single cell technologies
- 2.8 million people live with MS worldwide
- 200 people are diagnosed every week
- Zero cures are known
These are the sobering statistics about multiple sclerosis (MS), a demyelinating autoimmune disorder that causes “lesions” in subcortical white matter. People with MS may experience pain, numbness, tingling, fatigue, blindness, paralysis, and/or mood and memory changes, either concurrently or at different times as the disease progresses. This complexity also extends to the cellular level: while microglia, astrocytes, lymphocytes, and other immune cells are all implicated in MS, attempts to investigate their exact contributions have faced a “black box” due to the heterogeneity of the brain and immune systems.
Two of the speakers from our upcoming MS Spotlight Webinar Series, however, recently published papers underscoring how they are surmounting these challenges to shed light on the causes of, and prospective therapeutics for, this debilitating disease.
Illuminating an axis of illness
Not all lesions in MS are created equal: some disappear on their own after weeks to months, while others remain chronically active and accelerate clinical decline. A new study identified the specific glia associated with inflammation in these active lesions using the Chromium Single Cell 3’ platform to perform single nuclei RNA-seq and examine transcriptional profiles from the core, edge, and periplaque of active lesions, as well as in healthy white matter (1).
They identified two cell populations that were present exclusively at the active edge of lesions and termed these microglia inflamed in MS (MIMS) and astrocytes inflamed in MS (AIMS). Specific to the active edge was an upregulation of the complement factor C1q, which was expressed primarily by MIMS.
After discovering patients carrying clinically relevant numbers of active lesions were significantly more likely to have more complement-associated risk variants, the researchers tested the role of C1q in a mouse model of MS (experimental autoimmune encephalomyelitis, EAE). EAE mice with C1q ablated specifically in microglia showed lower reactive gliosis and decreased expression of a disease-associated microglial marker, suggesting C1q as a critical mediator. This was supported in a separate experiment, where administering a C1q-blocking antibody reduced both detectable C1q levels and the number of activated microglia.
Shedding light on mechanisms of an mRNA vaccine for EAE
Potential therapies for MS require a careful balancing act of inhibiting self-reactive T cells without causing increased inflammation or impeding systemic immunity. Researchers recently took a slightly different approach to achieving this goal by developing an mRNA vaccine coding for a self-antigen to help promote antigenic tolerance in EAE mice (2).
Unmodified mRNA has been observed to induce inflammation, so researchers created mRNAs encoding an epitope of myelin oligodendrocytic glycoprotein using a modified noninflammatory mRNA. This mRNA induced the expansion of autoimmune-suppressive T cells with a low inflammatory cytokine response and no detectable impairment of normal immune responses.
Importantly, this mRNA strongly suppressed clinical signs of EAE in mice. Treated mice showed heavily reduced infiltrating T cells in the brain and spinal cord, along with no signs of demyelination in the spinal cord. These findings were accompanied by a lack of increased autoantibody responses (a major concern given antigen tolerization can exacerbate existing autoimmune responses).
Using the Chromium 3’ Single Cell platform, they then characterized the cellular architecture of EAE mice treated with this mRNA compared to control mice and mice given an irrelevant noninflammatory RNA. While eight antigen-specific T-cell clusters were found in all conditions, vaccine treatment greatly increased the prevalence of effector T regulatory cells compared to other conditions. Markers of effector T regulatory cells and their suppressive functions were greatly enriched in vaccine-treated mice versus controls and mice treated with irrelevant RNA, demonstrating a remodeling of T-cell architecture consistent with the observed reduction in EAE clinical signs.
Lighting the road ahead
Sitting at the nexus of the two most heterogeneous systems in our body, it is little wonder that the underpinning biology of MS is so complex. The multitude of cell types and subtypes involved in MS, each with its own context-dependent function, demonstrates the need for approaches that can resolve an ever-changing cellular landscape—and researchers like these are using new tools to make the difficult road ahead a little brighter. These studies shone a spotlight on how single cell sequencing technologies can help unmask the complex biology of MS, but there’s more to explore.
Join us for our MS Spotlight Webinar Series to watch these authors go deeper into their findings and see how other researchers are reimagining the way they study MS with single cell and spatial tools. Register now.
- M Absinta et al. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature 597: 709–714 (2021). doi: 10.1038/s41586-021-03892-7
- C Krienke et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science 371: 145–153 (2021). doi: 10.1126/science.aay3638