How Natalizumab Fuels Risk in MS Through Rogue Th17 Cells

Natalizumab (NAT) has long been hailed as one of the most powerful tools in the fight against relapsing-remitting multiple sclerosis (RRMS). By blocking immune cells from entering the brain, it dramatically reduces disease activity. But for some patients, stopping the treatment leads to something far worse than before — a sudden and severe disease rebound. A new study by Janoschka et al., published in PNAS, digs deep into the biology behind this phenomenon and uncovers a critical clue: a stealthy buildup of highly aggressive immune cells known as Th17 cells.

Background: The Mystery of MS Rebound
Multiple sclerosis is an autoimmune disease in which the immune system attacks the brain and spinal cord. Natalizumab works by blocking VLA-4, a molecule that helps immune cells cross into the brain. But when NAT treatment is stopped — often due to risks like progressive multifocal leukoencephalopathy (PML) — the disease can return with a vengeance. What causes this rebound? Scientists have long suspected a type of immune cell called Th17 might be involved, but the details remained murky.

The Discovery: Th17 Cells Become More Aggressive Over Time
This new study followed MS patients who had been on NAT either short-term ( < 6 months) or long-term (>12 months). Researchers focused on a specific subset of Th17 cells marked by two surface proteins: MCAM and CCR6. Here’s what they found: During long-term NAT treatment, these MCAM++Th17 cells increased in number.

These cells began producing more pro-inflammatory cytokines — the molecular weapons of immune attack.

They showed signs of higher metabolic activity, especially glycolysis, a hallmark of “pathogenic” Th17 cells that can cause tissue damage in the brain.

Pathogenic by Design: A Signature of Danger
The team conducted RNA sequencing to look at gene activity in these Th17 cells. The results were striking:

Over 40 known “pathogenicity genes” were significantly upregulated.

Key genes included transcription factors like RORA, RUNX3, and STAT3, all known to promote autoimmune behavior.

At the same time, genes responsible for restraining inflammation (e.g., IL10RA, IL4R) were dialed down.

In other words, long-term NAT use doesn't just hold immune cells at bay — it seems to transform some of them into ticking time bombs.

What These Cells Do: Damage Brain Cells and Breach the Barrier
The researchers went further: they tested these Th17 cells in lab settings.

Brain endothelial cells, which form the protective blood-brain barrier (BBB), were disrupted when exposed to Th17 cells from long-term NAT patients.

Oligodendrocytes, the cells that make myelin (the insulation around nerves), were more likely to die when exposed to these cells — suggesting direct damage by Th17 cells.

The culprit? A pro-apoptotic pathway involving FAS-FASL signaling that triggers cell death — and could be blocked with inhibitors in the lab.

And Then It Gets Personal: Why Some Patients Rebound
In a final set of experiments, the team looked at patients who actually experienced disease rebound after stopping NAT. Their Th17 cells were even more ominous:

Unique pathogenic genes were turned on, including IFNG, CCL20, and GPR65, all linked to aggressive inflammation.

These cells were better at crossing into the brain, as seen in humanized mouse models.

Brain biopsies from a rebound patient revealed a high number of MCAM+ cells infiltrating the brain tissue — a signature absent in regular MS lesions.

Clinical Implication: A Blood Test for Risk?
This study points to a powerful possibility: monitoring MCAM+CCR6+Th17 cells in a patient’s blood could help predict whether they’re at risk for rebound if NAT treatment is stopped. That opens the door to more personalized care — potentially choosing a safer exit strategy or additional therapy for high-risk patients.

Takeaway
Natalizumab is a game-changer for MS — but it comes with hidden risks. This study reveals that long-term use may silently foster highly aggressive Th17 cells, setting the stage for a rebound when treatment stops. Monitoring these cells could help doctors anticipate — and maybe prevent — the storm before it hits.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Janoschka et al. Enhanced pathogenicity of Th17 cells due to natalizumab treatment: Implications for MS disease rebound. PNAS, 2023.