Immune cell, fat metabolism changes may help explain MS progression

More activity among certain immune cells, as well as differences in immune signaling molecules, iron regulation, and fat metabolism, may explain why multiple sclerosis (MS) progresses more over time in some people than in others, researchers report.

These findings may help to better understand the molecular mechanisms leading to disease progression, and to identify new targets that prevent such progression from happening.

The study, “Dysregulation of humoral immunity, iron homeostasis, and lipid metabolism is associated with multiple sclerosis progression,” was published in Multiple Sclerosis and Related Disorders.

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Study into gene expression patterns and MS progression

Most people with MS initially are diagnosed with relapsing-remitting disease (RRMS), which is marked by disease relapses, where symptoms suddenly worsen, followed by periods of remission where symptoms ease or disappear entirely.

Over time, RRMS patients can progress to secondary progressive MS (SPMS), where symptoms gradually worsen independent of relapse activity. Progressive types of MS, like SPMS, are much harder to treat than RRMS.

Previous studies have shown that there are notable changes in gene expression patterns (that is, which genes are turned on or turned off) in immune cells of people with RRMS. These changes help to drive the inflammatory attack on the brain and spinal cord that causes MS, and understanding these changes has helped in facilitating the development of RRMS treatments.

Gene expression patterns in SPMS are less well characterized. Some studies have compared the expression profiles in people with SPMS against those with RRMS, but such comparisons are inherently unbalanced. People with RRMS, by definition, generally are younger and have a shorter disease duration.

Researchers at the University of Michigan Medical School set out to compare the gene expression profiles in SPMS against profiles seen in people with benign MS — a term broadly used to refer to MS that’s not very active.

For this study, the researchers specifically defined people with benign MS as those with minimal to no disability at least 15 years after being diagnosed with MS, despite not receiving any MS treatments.

“BMS [benign MS] is distinct from SPMS in that it lacks disease progression. Since patients with BMS have a similar disease duration to SPMS and differ primarily in the rate of progression, they serve as an ideal comparator to identify mechanisms underlying MS progression,” the researchers wrote.

A better understanding of the mechanisms that drive progression, the scientists added, “may provide better drug targets for preventing or slowing disease progression in SPMS.”

The study included analyses of gene activity from 38 people with SPMS and 13 individuals with benign MS. Data covering 24 people with RRMS and 15 people without MS also were included for comparisons.

Activity of 200 genes seen to differ between people with SPMS, benign MS

Comparisons between SPMS and benign MS found more than 200 individual genes expressed at significantly altered levels between the two MS types. Scientists then looked at what’s known about the function of these genes, aiming to identify broader biological pathways that are altered.

Results indicated that people with SPMS had notably more activity among genes involved in the activation of B-cells, a type of immune cell known to play a central role in driving MS.

“We identified a group of B cell-associated genes … which represented one of the most highly disparate categories between BMS and SPMS participants,” the researchers wrote.

SPMS patients also had more expression of genes related to the activation of another type of MS-driving immune cell, called natural killer or NK cells. These findings “support the importance of NK cells in contributing to the MS disease course,” the researchers said.

There also were notable differences in the activity of genes related to cytokines, which are signaling molecules that coordinate the activity of immune cells, and antigen presentation, the molecular process by which immune cells recognize threats.

Differences also seen in genes regulating metals, lipid metabolism

Other noted differences included genes related to the metabolism of lipids (fat molecules) and the regulation of metals like iron in the body. “It is not surprising that lipids are implicated in the progression of MS,” the researchers noted, “as lipids are one of the main components of the myelin sheath,” the fatty covering around nerve fibers that is damaged in MS.

Changes in iron regulation may contribute to oxidative stress, a type of cell damage thought to contribute to nerve cell degeneration in MS and other neurological disorders, they added.

“Our study demonstrates that the peripheral immunological profile in SPMS shows characteristics consistent with other neurodegenerative diseases, which include the interrelated features of increased proinflammatory cytokines, metal ion [dysregulation], altered lipid metabolism and processing, and elevated oxidative stress,” the researchers wrote.

“We also provide further evidence that B cells play a prominent role in the pathophysiology of MS,” they concluded.

This study is limited by its small size, the researchers noted. They also highlighted that it’s impossible to say with certainty which changes in gene expression might be directly involved in driving MS, and which might be caused as a consequence of MS-related damage.

Further studies will be needed to validate the results and address these remaining questions, the team said.