Helper T-cells Drive Transition from RRMS to SPMS, Study Suggests

A group of helper T-cell (Th cells), a type of immune cell, could be responsible for the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS), with important implications for diagnosing and treating SPMS, a new study found.

The study, “Involvement of cytotoxic Eomes-expressing CD4+ T cells in secondary progressive multiple sclerosis,” was published in the journal PNAS by a team of researchers from the National Center of Neurology and Psychiatry in Tokyo.

SPMS is established as a stage of multiple sclerosis that follows RRMS, but the mechanisms driving the transition are not well understood, and progression is difficult to predict.

Recently, however, scientists linked the transition to processes mediated by immune-regulating T-cells.

“Understanding the role of T-cells in SPMS development could lead to the identification of key cellular and molecular components that may serve as potential therapeutic targets or useful biomarkers,” the researchers wrote.

In a previous study in mice, this team identified a subset of Th cells (also called CD4+ T-cells) that was crucial for chronic inflammation of the central nervous system. That particular subset of Th cells expressed the transcription factor Eomes (Eomes+ Th cells). Transcription factors are proteins that bind to DNA to regulate the process by which information in a gene is ultimately converted into a protein.

Now, the team investigated whether Eomes+ Th cells also play a role in human disease.

Their study included 39 people with RRMS, 25 with primary progressive multiple sclerosis (PPMS), 66 patients with SPMS, and 42 healthy individuals.

First, the researchers looked at Eomes+ Th cells in peripheral blood samples. They found the proportion of Eomes+ Th cells among the CD4+ T-cell population to be higher in SPMS patients, compared with healthy individuals or those with RRMS and PPMS. An increase in Eomes+ Th cells was seen in more than half of the SPMS group, but only in a few patients with RRMS, one PPMS patient, and one healthy individual.

“These results indicate a significant link of Eomes+ Th cells with SPMS,” the researchers wrote.

Next, the team applied a mathematical model that divided SPMS patients into two groups according to their proportion of Eomes+ Th cells: high or low. A high proportion of Eomes+ Th cells was found to be linked to disability progression in these people.

By looking at the medical records of patients six to 12 months after Eomes+ Th cells levels were determined, the researchers saw that more than 81% of those in the high group had progressive disease versus 22% in the low group.

Progressive disease in SPMS patients with a high proportion of Eomes+ Th cells could be predicted with an accuracy of over 80%, suggesting Eomes might be used as a biomarker to identify people with SPMS at risk of worsening disease, they wrote.

The Eomes+ Th cells make a protein called granzyme B that is primed to destroy other cells. The proportion of Eomes+ Th cells expressing granzyme B was higher in SPMS patients than in healthy individuals or people with RRMS.

Furthermore, through an autopsy study of people with SPMS, the researchers found that brain tissues were infiltrated with Eomes+ Th cells expressing granzyme B, suggesting it might be involved in disease development.

Overall, these findings “indicate that granzyme B-expressing Eomes+ T helper cells are involved in the pathogenesis [development] of SPMS,” the researchers concluded. “We speculate that the measurement of Eomes+ Th cells, or related biomarkers, will not only provide basic information for the pathogenesis of SPMS but could also provide targets for future clinical studies and clinical trials for the development of new drugs.”

However, “future studies should be carried out to confirm the relevance of our findings,” they added.