Fibrinogen-containing Vesicles in Blood May Play Key Role in MS Relapses, Mouse Study Suggests

Vesicles in the blood that contain a protein called fibrinogen important for blood clotting were found to be “sufficient and required” for the occurrence of spontaneous disease relapses in mouse models of multiple sclerosis (MS), a study reports.

In mice, these vesicles were associated with immune cell infiltration, inflammation, and loss of myelin in the central nervous system. The vesicles were also detected in the bloodstream of MS patients.

According to the researchers, this may help them understand why some patients go through recurrent disease flares (relapses) between periods where symptoms lessen (remission), as well as to help find early biomarkers for the disease.

The study, Extracellular vesicle fibrinogen induces encephalitogenic CD8+ T cells in a mouse model of multiple sclerosis,” was published in the journal PNAS.

For reasons that remain unclear, in MS patients, some cells of the immune system turn against neurons and other cells of the central nervous system (CNS) — the brain and spinal cord — progressively destroying the insulating layer around nerve fibers, called myelin.

A particular kind of immune cells, known as CD8+ T-cells — a part of the immune system that normally eliminates cells infected by viruses, certain bacteria, or cancer cells — seem to be a major culprit in this harmful autoimmune response.

Although the self-attacking immune response is not exactly the same in mouse models of MS, new research by investigators from UConn Health, the University of Illinois at Chicago (UIC), and the Gladstone Institutes found a trigger that activates CD8+ T-cells and drives disease flares in these mice. And the mechanism they uncovered may well be very close to what happens in humans with relapsing-remitting MS (RRMS).

The team was interested in studying extracellular vesicles, or EVs, which are small “blobs” secreted by cells, often containing proteins and genetic information, which work as carriers conveying messages between cells. EVs have been grabbing increasing attention from scientists due to their role as mediators of cell communication, implicated in inflammation and disease.

To test the role of blood EVs in MS, the researchers injected EVs from normal, healthy mice into mice with an experimental MS-like disease, an MS mouse model called experimental autoimmune encephalomyelitis, or EAE. This induced spontaneous relapsing-remitting disease-like manifestations in the mice, associated with the activation of CD8+ T-cells, similar to the human disease.

Researchers found that EVs triggered the accumulation of active CD8+ T-cells and neuroinflammation associated with demyelination of the CNS.

A more detailed analysis revealed that the content of EVs from the blood of mice matched patients with RRMS, with both containing fibrinogen, a protein important for blood clotting and wound healing.

A reverse experiment supported the role of fibrinogen in triggering CD8+ T-cell-mediated relapses, showing that an injection of EVs that did not contain fibrinogen could not cause the relapsing-remitting illness in the mouse model of MS.

These data suggest that fibrinogen in plasma EVs contributes to the “perpetuation of neuroinflammation and relapses,” the researchers wrote.

“These findings expand our understanding of how fibrinogen contributes to the progression of MS pathology,” Katerina Akassoglou, PhD, senior investigator at Gladstone, professor of neurology at UC San Francisco, and one of the study authors, said in a UConn press release written by Kim Krieger.

Akassoglou, who has pioneered studies in the role of blood-clotting factors like fibrinogen in MS, added that “fibrinogen in exosomes may have far-reaching implications for therapies and as a biomarker for disease progression in MS and potentially, other neurological diseases.”

Understanding the causes of relapses “is a key step on the path to a cure for MS,” said study co-author Ernesto Bongarzone, PhD, a neuroscientist and professor at UIC. “The results of this study and the identification of fibrinogen as a key molecule contributing to relapses are exciting steps forward.”

The research also identified a robust mouse model of relapsing-remitting disease driven by CD8+ T-cells, which better mimics human disease.

“There’s all these clinically important questions we can now ask,” said Stephen Crocker, PhD, a UConn neuroscientist who directed the study.

They now plan to further study this model to gain more insights on MS remission and relapses, and the involvement of EVs.