Breaking the Fortress: How the Immune System and Brain Collide in Multiple Sclerosis
For decades, scientists viewed the brain as a “fortress”—shielded from the chaos of the immune system by the blood-brain barrier (BBB). The central nervous system (CNS), which includes the brain and spinal cord, was thought to be “immunoprivileged,” meaning immune cells rarely entered this sacred space.
But recent discoveries have rewritten this narrative. The brain isn’t isolated—it’s immunofortified, not immunoprivileged. Around the brain lie specialized “moats” such as the meninges and perivascular spaces. These regions host immune sentinels—macrophages, dendritic cells, T cells, and B cells—that quietly monitor for danger. Even more surprisingly, the outermost meningeal layer, the dura mater, contains functional lymphatic vessels that drain immune signals to the cervical lymph nodes. The brain, it turns out, is not cut off from the immune system—it’s constantly communicating with it.
When the Immune System Turns Against Us
Multiple sclerosis (MS) is a striking example of what happens when this delicate dialogue breaks down. MS is a chronic autoimmune disease in which the immune system mistakenly attacks the protective myelin sheath that insulates nerve fibers. The result? Scarring (sclerosis), disrupted electrical signaling, and a gradual loss of motor and cognitive function.
The disease often begins with relapsing-remitting MS (RRMS)—periods of attack and recovery—but can evolve into secondary progressive MS (SPMS), where damage accumulates relentlessly despite the absence of acute relapses.
Much of what we know about MS comes from its animal model, experimental autoimmune encephalomyelitis (EAE). In EAE, mice are immunized with myelin proteins, which primes their immune system to attack the CNS—mimicking human MS.
These studies revealed that T cells, particularly Th1 and Th17 subsets, play central roles in driving disease.
Th1 cells produce interferon-γ (IFN-γ), a cytokine that can both promote and suppress inflammation depending on timing.
Th17 cells secrete interleukin-17 (IL-17), which disrupts the BBB and allows immune cells to flood into the CNS.
However, regulatory T cells (Tregs) and IL-10–producing plasma cells can counteract these inflammatory responses. In MS, these regulatory populations are often defective or reduced.
The B Cell Renaissance
For years, MS research focused almost exclusively on T cells. Then, a surprise: therapies that deplete B cells (like anti-CD20 antibodies) produced dramatic improvements in MS symptoms. Yet these treatments didn’t reduce antibodies in the cerebrospinal fluid (CSF)—suggesting that B cells contribute to MS not only through antibodies but also by producing inflammatory cytokines such as TNF, IL-6, and GM-CSF.
In the healthy brain, B cells help maintain immune balance. In MS, this balance is lost—B cells amplify inflammation and even act as antigen-presenting cells, stimulating autoreactive T cells. This discovery shifted the paradigm, placing B cells alongside T cells as key instigators of neuroinflammation.
Inside the Brain: Glial Cells Join the Battle
Once immune cells infiltrate the CNS, they interact with glial cells—the brain’s resident caretakers.
Microglia, the brain’s macrophages, can become overactivated, releasing toxic molecules and damaging neurons. Yet under the right conditions, they promote repair by clearing myelin debris and secreting growth factors.
Astrocytes, long viewed as mere support cells, are now recognized as powerful regulators of inflammation. They can both protect neurons and, when provoked, turn neurotoxic—producing cytokines and microRNAs that amplify injury.
In progressive MS, inflammation becomes compartmentalized—trapped behind an intact BBB. Clusters of immune cells form tertiary lymphoid tissues (TLTs) within the meninges, particularly the leptomeninges covering the brain’s surface. These immune “fortresses” may continuously release inflammatory molecules into the nearby gray matter, leading to the subpial cortical lesions that underlie cognitive decline and progression.
Why MS Progresses: From Inflammation to Degeneration
Early MS is dominated by waves of immune cell infiltration—an “outside-in” attack. Over time, inflammation becomes locked within the CNS. Microglia remain chronically activated, and astrocytes contribute to a toxic environment. Even without fresh immune assaults, this smoldering inflammation slowly erodes neurons and synapses.
This shift explains why current disease-modifying therapies (DMTs)—which target circulating immune cells—work well for RRMS but fail in SPMS. To halt progression, future therapies must reach the immune “reservoirs” inside the CNS.
Where Do We Go From Here?
The next frontier in MS treatment lies in precision immunology:
Boosting regulatory cells, such as Tregs or IL-10–producing plasma cells, to restore immune tolerance.
Targeting CNS-resident inflammation, perhaps by reprogramming microglia toward neuroprotection.
Employing single-cell and spatial transcriptomics to map immune-glial interactions in human MS tissue.
As Dr. Jennifer Gommerman and colleagues emphasize, understanding MS is about more than treating one disease—it’s about uncovering how the immune system and brain communicate, cooperate, and sometimes, tragically, collide.
Conclusion
Multiple sclerosis offers a powerful window into the immune system’s dialogue with the brain. What was once seen as a passive victim—the CNS—emerges as an active player, constantly engaging with immune cells at its borders. The challenge now is not just to silence inflammation, but to restore harmony between these two vital systems.
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:
Ramaglia, V., Rojas, O., Naouar, I., & Gommerman, J. L. (2021). The ins and outs of central nervous system inflammation—lessons learned from multiple sclerosis. Annual review of immunology, 39(1), 199-226.
