How Brain Cells Drive the Silent Progression of Multiple Sclerosis
For decades, multiple sclerosis (MS) has been viewed primarily as an inflammatory disease — one in which the immune system attacks the brain and spinal cord, leading to relapses and the formation of new lesions. However, as neurologists and researchers have long observed, disability in MS often continues to worsen even when relapses stop and no new inflammatory lesions appear. What causes this steady decline has remained one of the biggest mysteries in MS research.
A review by Leila Husseini, Anastasia Geladaris, and Martin Weber, published in Trends in Neurosciences (2024), provides a much-needed conceptual update on what drives progression in MS — and how we might eventually stop it.
From “Relapsing” to “Progressive”: Rethinking MS Pathogenesis
Traditionally, MS was divided into relapsing-remitting and progressive forms. Relapses were seen as bursts of inflammation, while progression was viewed as a later, separate degenerative phase. But this dichotomy is fading.
The new understanding is that inflammation and neurodegeneration coexist from the very beginning of the disease. What changes over time is where and how they act.
In early stages, inflammation in the white matter leads to visible lesions and relapses. Later, inflammation becomes “smoldering” — trapped within the brain and spinal cord — driving slow but relentless tissue damage and neurodegeneration even in the absence of new lesions. This process is called Progression Independent of Relapse Activity (PIRA).
A “Generalized CNS Disease”
Pathological studies have revealed that MS is not just about lesions — it’s a widespread disease of the entire central nervous system. Damage extends into areas that appear “normal” on MRI, known as normal-appearing white matter (NAWM) and normal-appearing gray matter (NAGM). These regions show subtle but important changes: axonal injury, microglial activation, and biochemical alterations in myelin and lipids.
This diffuse injury helps explain why patients can continue to worsen even when new lesions stop forming. The brain is no longer functioning in its normal state; instead, it’s caught in a cycle of chronic, self-perpetuating inflammation and neurodegeneration.
The Central Role of Glial Cells: Microglia and Astrocytes
The stars of this new story are microglia and astrocytes, the brain’s resident immune and support cells. Once considered mere bystanders, they are now recognized as key drivers of progression.
Microglia: From Protectors to Perpetrators
Microglia act as the brain’s immune sentinels. In MS, they become chronically activated — producing inflammatory molecules like TNF-α and IL-1β, as well as reactive oxygen and nitrogen species that damage neurons and myelin.
At the same time, transcriptomic studies reveal that these microglia differ depending on their location: some focus on lipid metabolism in white matter, others on iron and glycolysis in gray matter, suggesting regional specialization of injury.
Astrocytes: The Double-Edged Sword
Astrocytes, which normally maintain the blood–brain barrier and support neurons, also become reactive. Some adopt neuroprotective roles, but others contribute to disease by secreting inflammatory cytokines (IL-6, CCL2) and growth factors that sustain local inflammation and damage the brain’s repair capacity.
Reactive astrocytes even remodel the extracellular matrix, forming a scar-like environment that blocks remyelination.
Together, microglia and astrocytes form a self-reinforcing loop of inflammation and degeneration — a hallmark of progressive MS.
How Neurons Lose the Battle
As inflammation simmers within the CNS, neurons face multiple assaults:
Oxidative stress damages mitochondria, starving neurons of energy.
Glutamate excitotoxicity overstimulates neurons and oligodendrocytes, leading to cell death.
Loss of “don’t-eat-me” signals (like CD200 and CD47) removes inhibitory checks on microglial aggression.
Myelin loss deprives axons of metabolic support, forcing them to expend more energy to conduct signals.
Inflammatory cytokines heighten neuronal sensitivity to toxic insults.
The result is a brain in metabolic crisis — a system consuming more energy than it can produce.
The Challenge of Therapy: Reaching Beyond Inflammation
While current disease-modifying therapies effectively suppress new relapses and lesions, they do little to halt progression. The review highlights several reasons:
Most drugs target the peripheral immune system, while progressive MS involves inflammation behind the blood–brain barrier.
The pathological culprits — microglia and astrocytes — are inside the CNS, protected from many circulating drugs.
To treat progression, therapies must cross the blood–brain barrier and reprogram glial cells from destructive to supportive states.
Promising approaches include:
Bruton’s tyrosine kinase (BTK) inhibitors, which can dampen microglial activation.
S1P receptor modulators, which influence astrocyte signaling (though their clinical benefit for progression remains modest).
Deep B-cell depletion within the CNS, aimed at breaking the cycle of glial–B-cell crosstalk that sustains inflammation.
A Future of Combined Strategies
The authors emphasize that progression is not a separate disease, but an evolution of the same process under different conditions. Therefore, future therapies must address both inflammation and neurodegeneration — not sequentially, but simultaneously.
This means combining anti-inflammatory, neuroprotective, and remyelination-promoting approaches tailored to the stage of the disease.
Key Takeaways
Progression in MS begins early and reflects chronic CNS-intrinsic inflammation.
PIRA (progression independent of relapse activity) is now a central concept in understanding MS.
Microglia and astrocytes are at the heart of neurodegeneration — both as drivers and as potential therapeutic targets.
New therapies must reach behind the blood–brain barrier to modulate glial function and promote repair.
Future research will depend on unraveling how these processes interact and how they can be safely modified.
Final Thoughts
As Husseini and colleagues conclude, progressive MS is not merely a failure of repair or a byproduct of aging. It is a biologically active process, fueled by persistent glial dysfunction and self-sustaining inflammation. Understanding and targeting these cellular mechanisms offers the best hope yet for halting progression — and for giving people with MS not just more years, but better ones.
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:
Husseini, L., Geladaris, A., & Weber, M. S. (2024). Toward identifying key mechanisms of progression in multiple sclerosis. Trends in Neurosciences, 47(1), 58-70.
