Research News

(Above): Microglial/immune cells (brown) line the edge of a growing brain lesion in MS-affected white matter. The lesion is inside the line.

In a first-of-its-kind analysis, Cleveland Clinic researchers have outlined how immune cells in our brains function differently at the edge of progressive multiple sclerosis (MS) lesions in white matter versus grey matter. 

The Annals of Neurology publication explains that microglia, immune cells that line the edge of demyelinated areas in MS-affected brains (lesions), are pro-inflammatory/destructive in brain white matter, but may be protective in brain grey matter. The findings challenge the dogma that microglia are purely destructive in MS and only serve to fuel inflammation that expands the lesions in affected brains. Microglia may also play a role in slowing down damage, it just depends on where they're located. 

Understanding the different roles these cells play in progressive MS is essential for creating effective therapies that can reach the appropriate types of brain inflammation, says senior author Bruce Trapp, PhD. Current treatments don't directly address compartmentalized inflammation, or localized brain inflammation and damage behind the blood-brain barrier. The field is still learning about what causes this type of inflammation, a hallmark of progressive MS.

"The results indicate a drug that suppresses microglial function is not a one-size-fits-all for progressive MS," says Dr. Trapp, chair of Cleveland Clinic's Department of Neurosciences. "Some microglia may be destructive during MS while others may be protective. Loss of protective function may also play a role in disease progression. Reactivating certain functions of these cells with targeted therapies holds potential for treatment."

A first-of-its-kind analysis 

Progressive MS lesions develop differently depending on location in the brain. Lesions in white matter deeper in the brain are known to slowly expand. Microglia that surround these lesions are thought to play a role in this expansion. The role of microglia in the dynamics of gray matter lesion expansion are understudied because of limitations with imaging and preclinical models.

First author Anthony Chomyk developed a method to isolate microglia lining the lesions from white and gray matter and sequence their RNA to compare what genes were turned "on" or "off" between locations. Which genes are expressed can explain why different cells of the same type behave differently, since all cells in our bodies carry the same DNA. 

For this study, Chomyk analyzed donor brain samples from Cleveland Clinic's Rapid Autopsy Program. Dr. Trapp founded the program in 1994 to advance MS research imaging. It is now one of the largest rapid autopsy programs for MS in the world.

The study also provided insight that will help with detecting both types of lesions. Microglia on the edge of the white matter lesions consume debris from demyelinated nerves, so the cells contain enough iron that it shows up in imaging. 

Chomyk says that the study provides the "bird's eye" view needed for drug development. Investigators could explore the feasibility of targeting microglial function only on the edge of white matter lesions, for example. 

"This study is another step forward in changing our field's perception that all microglia have destructive roles in MS. To change the thought process in any field takes time and additional data that supports this change is needed," Dr. Trapp says. "It's difficult to change accepted perspectives but the lack of effective therapies for progressive MS is telling us that we've missed something."