Researchers Identify Potential Cause of Relapses in MS

According to new research published in PNAS, researchers have determined that a molecule that helps blood clot may also play a role in multiple sclerosis (MS) relapses, in addition to discovering a new way of studying the disease in mice that more closely resembles the human form.

MS, which affects about 1 million people globally, damages the brain’s ability to communicate with the rest of the body. Though the damage isn’t permanent at first, many people with MS have relapsing episodes of disability, followed by remissions when their symptoms lessen or disappear. To date, researchers are unsure why these relapses occur.

Researchers have identified CD8+ cells—a part of the immune system that normally kills cells that are cancerous or otherwise infected—as one of the aggressors attacking the brain and the spinal cord of patients with MS. However, in mice models, CD4+ cells are responsible for attacking the brain and spinal cord. Though mice have CD8+ cells, they remain benign in mice with MS. This difference has been a significant hurdle to further research within the space, as new drugs are commonly tested in animal models prior to being studied in human trials.

In this study, researchers identified extracellular vesicles (EVs) as “potent mediators of immunity.” EVs are nano-sized membrane particles that cells release as an intercellular mode of communication. According to the study, there has been a growing interest in EVs due to their emerging roles in disease and potential use as prognostic biomarkers.

Researchers investigated the functional impact of plasma EVs (pEVs) on neuroinflammation and clinical disability in mouse models of central nervous system (CNS) demyelination. This was done by injecting EVs from healthy mice into mice that had MS-like disease. This experiment determined that the mice injected acquired a relapsing-remitting disease and active CD8+, as seen in human patients with MS. Upon examination of the EVs in mice and patients with MS, the researchers found that they each contained fibrinogen, which is a blood clotting factor.

Specifically, the study authors noted that EVs with fibrinogen seemed to activate the CD8+ immune cells, causing relapsing-remitting illness, while mice injected with EVs that did not contain fibrinogen did have their CD8+ cells activated.

“These findings expand our understanding of how fibrinogen contributes to the progression of MS pathology,” Katerina Akassoglou, PhD, senior investigator at Gladstone and a professor of neurology at University of California, San Francisco, said in a statement. "Fibrinogen in exosomes may have far-reaching implications for therapies and as a biomarker for disease progression in MS, and potentially, other neurological diseases."

Overall, the findings highlight the potential of CD8+ T cells in mediating autoimmunity in mice. “With continued study, we consider this pEV-[experimental autoimmune encephalomyelitis] model a means by which to elucidate the etiology of relapse activity in human [relapsing remitting MS],” concluded the authors.

Reference

Willis C, Nicaise A, Menoret A, et al. Extracellular vesicle fibrinogen induces encephalitogenic CD8+ T cells in a mouse model of multiple sclerosis [published online May 8, 2019]. PNAS. doi: org/10.1073/pnas.1816911116.