Extinguishing Fires in the Brains of MS Patients

A closer look at the brains of patients with aggressive, debilitating forms of multiple sclerosis (MS) reveals some striking features. Among them, the presence of “smoldering” inflammatory hotspots. After intense scrutiny, neuroscientists have finally nailed down the cells that drive these regions of heightened inflammation, findings that lay the groundwork for next-generation therapies to treat progressive MS.

Previously, neural immune cells called microglia were thought to be responsible for initiating and expanding these neural lesions. Microglia are dispersed throughout the brain and spinal cord are among the core protectors of the central nervous system, removing damaged cells and resisting infections. However, in MS patients, microglia go into overdrive, churning out a cocktail of inflammatory factors that devastate surrounding neural tissues. However, the other cells that may be contributing to this uncontrolled inflammation have remained elusive.

Fortunately, single-cell RNA sequencing technology is helping to shed light on these long-standing mysteries, empowering scientists with the ability to collect data on gene activity signatures within individual cells. Researchers at the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) leveraged this platform to analyze a panel of post-mortem brain tissues from MS patients and healthy controls.

In their work, detailed in the high-impact journal Nature, the researchers describe the genetic profiling of a total of over 66,000 brain cells. The data collected was consolidated as the first cellular blueprint of MS chronic lesions, which included valuable data on both gene expression on an individual cell level and how these cells interact with each other.

Fascinatingly, the team’s analysis revealed that microglia only made up around a quarter of the immune cells present in MS brain lesions—a diverse ecosystem of immune cells including astrocytes and lymphocytes operated in unison to contribute to the elevated inflammation.

“Our dataset is very rich. The beauty of having such a detailed map is that now we have a better understanding of the entire network of cells involved in smoldering inflammation,” said Martina Absinta, one of the researchers involved in the study.

The investigation also revealed a clear connection between a complement protein called complement component 1q (C1q) and rampant neuroinflammation in the brains of MS patients. Experimental mouse models lacking the C1q gene displayed much less tissue inflammation than their wild-type counterparts. Together, the authors believe that their discoveries finally open up exciting new possibilities in MS drug development, which up to now have offered no clinical solutions for neither directly targeting active brain lesions nor curing the disease altogether.