Making breakthroughs in multiple sclerosis research

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease in which the immune system attacks the myelin that surrounds our nerves. The resulting myelin damage means electrical impulses can’t be normally conducted to and from the brain, resulting in symptoms that vary widely but can include muscle weakness, vision changes and memory and speech issues. It’s estimated that 2.8 million people are living with MS globally, and that number has climbed 500,000 since 2013. This means that about 1 in 3,000 people in the world currently live with MS.

MS is unpredictable and incurable, and many questions about the disease’s origins, progress and diagnosis remain unanswered. Understanding the cause of MS poses a key challenge for researchers and requires examining the complex processes that cause neuronal tissue deterioration. Uncovering the molecular mechanisms that drive neurodegeneration could lead to the identification of new targets for quicker diagnosis and more effective therapies to slow progression.

The neurological landscape is an intricate environment. The number of neurons (about 100 billion) and synaptic connections (over 100 trillion!) present in the human brain is staggering – and scientists still don’t know how many different kinds of neurons the human brain has, although they believe that they’re the most diverse kinds of cells in the body. Although new technologies, such as CRISPR, gene editing and advancements in microscopy, have allowed researchers to better understand the molecular mechanisms in the brain and the central nervous system (CNS), these tools have also presented their own challenges, such as limited efficiency and precision and difficulties in preparing samples.

There are also specific challenges that arise when dealing with neurological samples. Brain and neural tissue are autofluorescent, meaning they have a high level of the natural fluorescence that occurs in biological structures. Autofluorescence can affect assay sensitivity by leading to poor-quality images that make it hard to detect stains targeting specific cells. Neural tissue is also highly heterogeneous – made up of diverse cell types and structures. Because of this, conventional imaging techniques, such as MRI, CT and PET scans, can’t decipher different cell types and nuanced spatial relationships in the study of neurodegenerative disease or neuro-oncology.

How spatial biology can help glean better insights into the brain

Gaining insight into the detail and specificity of the inner workings of the brain and CNS can help researchers understand the pathology of neurodegenerative and autoimmune diseases like MS. Using spatial biology tools to study biological systems at the cellular level enables deep characterization of the diversity of neural tissues. Imaging Mass Cytometry™ (IMC™) platforms simultaneously uncover the spatial distribution of 40-plus distinct molecular markers, allowing researchers to explore the complexity and heterogeneity that affect disease progression and immune response. IMC technology also uses metal-labeled antibodies, which eliminates autofluorescence interference and avoids emission overlap issues associated with fluorescence-based readouts.

Because IMC produces clear, easy-to-interpret signals from neural tissue, it has been used to make important breakthroughs in MS research. One hallmark study by Park at al. was the first to reveal the cellular spatial organization in MS lesions. The team used IMC technology to examine the myeloid and astrocyte landscape in early and late acute MS brain lesions. They discovered that phenotypic clustering based on differential expression of 13 glial activation markers produced multiple myeloid cell and astrocyte phenotypes that occupied specific lesion zones. IMC provided “a wealth of data on cellular spatial organization that is not accessible with standard histology.”

In research by Ramaglia et al., IMC technology was used to enable the simultaneous imaging of 15-plus proteins within staged MS lesions to discover the phenotype and location of multiple immune cell subsets. The team found that IMC reproduced immunohistochemistry- and immunofluorescence (IF)-equivalent staining patterns with no apparent changes in specificity compared with standard IF and that the IMC approach provided better confidence in cell identity. The study found that microglial cells lost their homeostatic phenotype and acquired an activated state. It also identified an abundance of CD4+CD38+HLA+ “chronically activated” T cells found in pre-active lesion sites, suggesting their involvement in early stages of lesion formation. “The IMC approach in combination with parallel high throughput techniques has the potential to profoundly impact our knowledge of the nature of the inflammatory response and tissue injury in the MS brain.”

Generate actionable insights with single-cell proteomics

Single-cell analysis using blood samples can also help shed light on the MS landscape. CyTOF™ technology, a cytometric technique that measures metal-conjugated antibodies bound to cell antigens, overcomes many challenges experienced with fluorescence approaches and enables the simultaneous assessment of a much higher number of parameters. CyTOF systems allow for a large amount of data to be analyzed and turned into action in a quick and efficient way, making the technology key to successful drug development. In a study by Mathias et al., the team used a 38-parameter CyTOF panel to analyze B, T, and innate immune cell markers and CNS migratory markers in their effort to characterize the dynamics of peripheral immune cells on ocrelizumab (OCRE) in people with MS. Their data suggests that OCRE acts on CD8+ T cells by depleting the memory compartment. These changes in CD8+ T cells may enhance the action of OCRE on an MS course but may also contribute to an increased occurrence of infections in these patients.