Commentary
Article
Evolving Clinical Insights Into Neuroimmune Mechanisms and Multiple Sclerosis Progression
Jack P. Antel, MD, professor of neurology and neurosurgery at McGill University, reflected on key advances in neuroimmune research and their implications for understanding and treating MS.
Jack P. Antel, MD
(Credit: ACTRIMS)
Recent advancements in understanding neuroimmune interactions have possibly influenced how clinicians help patients manage their multiple sclerosis (MS) significantly. Prior research has highlighted the pivotal roles of peripheral immune cells in initiating central nervous system (CNS) inflammation. Notably, B cells have been identified as key players not only through antibody production but also via antigen presentation and cytokine secretion.1 Furthermore, studies have revealed that CNS-resident cells were not merely passive bystanders but actively participate in disease progression through complex signaling pathways. Thus, these insights potentially paved the way for novel therapeutic strategies aimed at modulating both peripheral and central immune responses in MS.
At the recently concluded 2025 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, held February 27 to March 1, in West Palm Beach, Florida, former ACTRIMS president Jack P. Antel, MD, professor of neurology and neurosurgery at McGill University, presented the Kenneth P. Johnson Memorial Lecture. The annual lecture, named in honor of the late Kenneth P. Johnson, MD, provides an opportunity for attendees to hear from an expert selected for their knowledge, accomplishments, and contributions related to MS. In Antel’s lecture, he reviewed the evolution of neuroimmune research, highlighting how foundational studies have influenced both current insights and the ongoing development of MS therapies.2
Following the presentation of his lecture, Antel sat down with NeurologyLive® to further talk about how historical and recent research into neuroimmune interactions has shaped our understanding of MS. He explained the origins of autoimmune models, contrasting them with the chronic and relapsing nature of MS, and emphasized the importance of early immune-targeting interventions. Antel highlighted the limitations of systemic immune suppression in halting disease progression and underscored the need to better understand compartmentalized CNS pathology. He also outlined unanswered questions in the field, including disease triggers, and potential shared mechanisms across neurological diseases.
NeurologyLive: What key lessons from past research on neuroimmune interactions have the most impact on shaping our understanding of MS?
Jack P. Antel, MD: When I was asked for the ACTRIMS presentation—and it was a pleasure to give the Kenneth Johnson Lecture, and as I mentioned to the audience, Ken was my attending neurologist when I started my training. When one looks back on neuroimmune interactions, the classic way the field started goes back about 130 years to Pasteur, where the injection of material outside of the brain, which was neural tissue containing material—as it happened, it had inactivated rabies virus—resulted in inflammation and some demyelination in the CNS. That led to an animal model called experimental encephalomyelitis, or autoimmune encephalomyelitis (EAE), and that set the precedent that a disease activated outside the brain could induce inflammation inside the brain and was this the same as MS?
I think what we have learned along the way is that the course of MS has been rather different. In that initial model, and even in the humans who were immunized back in the day with neural tissue, most of the events were a one-time, uniphasic inflammatory disease, rather than what MS has shown—if untreated, it will go on to be a relapsing disease, often with a progressive component. Patients, after a relapse, actually have some degree of recovery. I think what we've learned—or have to learn—is that something else is contributing to driving the course of the disease.
In addition, we've learned that if you wipe out the systemic immune system in patients with established MS—and it's already ongoing—you will not arrest the disease, and you can still get progression. I think what we've been learning is what occurs when the immune system from outside the brain gets into the brain or the CNS. What is that interaction? What's driving the process? We're trying to learn about immune-brain interactions, if you will.
It's bidirectional: the immune system acts on the brain; brain cells can talk to the immune system. Many of the brain cells—the glial cells—can themselves interact with the targets of MS, which are the myelinating cells and the axons. I think the other issue that has come up from the study of neuroimmune interactions is that most of us have always thought in terms of injury and disease—why do we get this animal disease, EAE, why do we get MS? The other side is whether the immune system and the components of the brain can contribute to injury and repair. So neuroimmune interactions are 2-faced: one is the injury side that we can learn about, the other is can we harness it or modulate it to be protective or contribute to repair?
How has our growing knowledge of neuroimmune mechanisms influenced the development of MS therapies over time?
Again, if we look back and in the MS field, we've been very fortunate in the last generation. If we compare ourselves to the generation before us. They didn't have the tools that we have particularly the imaging tools like MRI, which allowed us to see the disease, and also the technology for making therapy, especially recombinant molecules.
If we look back 2 generations ago, the idea in MS was you knew that some people would have a rather benign course, so why don’t you wait to see what happens? And only if they're in trouble would you start introducing the therapies. Now, I think what we've clearly learned is that the systemic immune system coming to the brain is initiating the relapses that cause much of the disability, and that early initiation of therapy is a key aspect of what we have to do.
Then I think we've also realized that at some point, systemic therapy is not sufficient. Whether we're going to have to direct therapies to whatever these mechanisms are in the brain, we are going to have to target those activities if we're going to shut down the ongoing disease that we currently call secondary progressive or progressive forms of MS.
What are some of the biggest unanswered questions or debates in the field of neuroimmunology that could impact the future of MS care going forward?
One of the biggest issues is—we've been talking about how events outside the brain, the immune system outside the brain, are getting into the brain and contributing to events occurring within the brain compartment. I think one of the major issues is, are they linked? Is the whole disease triggered by the initial events outside the CNS? If we could know what those triggers are—and there's a lot of interest now, for example, in EB virus changing the immune system—then are we going to, if we shut down or change the events outside the brain early enough, shut down the entire spectrum?
The other question is, is there something about the brain that is personalized? In other words, is the genetic makeup of your brain cells such—or has the environment you’ve been exposed to changed the properties of the CNS environment—that in some patients, an initial inflammation occurs as a one-time event and shuts down, and in others, it sets off this cascade? I think the challenge, the main issue, is the linkage—what has changed in the CNS environment?
Another important issue is, in addition to the major destructive component of disease, the more subtle—or almost sublethal—events. Why do people with MS, even if they're walking around, not feel perfectly well? Or why do they complain that they may have brain fog, if you will? What are the subtle changes in the nervous system?
And the final component I would say is some of these principles of inflammation-related changes in the brain in MS, are they shared with other diseases? We should look across diseases. Are there shared principles that we could apply, both for protection and repair?
Transcript edited for clarity.Click here for coverage of 2025 ACTRIMS Forum.
