A University of Toronto (U of T) based research team, co-led by Dr. Jennifer Gommerman from U of T's Temerty Faculty of Medicine and Dr. Valeria Ramaglia from U of T and UHN’s Krembil Brain Institute, has discovered how progressive multiple sclerosis (MS) develops. Their findings also point to a promising biomarker—a measurable biological sign of disease—that could help clinicians better identify, and eventually treat, individuals living with this debilitating form of the disease.
Progressive MS is notoriously difficult to diagnose and treat because its underlying inflammation occurs deep within the brain and is challenging to measure in living patients. The findings of this study offer a way to better understand this hidden process and determine which patients are most likely to benefit from current or emerging therapies.
Inflammation and Immune Activity in MS
MS is a degenerative autoimmune disease. An autoimmune disease occurs when the immune system attacks healthy cells or tissues. In the case of MS, it attacks myelin—the protective insulation surrounding nerve fibres in the grey matter of the central nervous system (CNS), including the brain and spinal cord. This damage disrupts neuron-to-neuron communication and leads to symptoms such as muscle weakness, vision problems, pain, and changes in mood or behaviour. In progressive MS, these symptoms worsen over time, leading to increasing disability.
MS is characterized by “compartmentalized” inflammation, which occurs when the immune response that causes inflammation moves from the surrounding tissues to specific compartments of the CNS. In progressive MS, inflammation has been observed in the meninges—the thin, protective layers that surround the CNS. This inflammation can lead to the formation of small lymph node-like structures made of clusters of immune cells, including B cells, in the meninges.
Although previous studies have linked meningeal lymph node-like structures to grey matter injury in progressive MS, the mechanism connecting them remained unclear.
A New Model to Explore Disease Mechanisms
“To close this knowledge gap, we recognized we needed to innovate,” says Dr. Ramaglia. “Utilizing a novel lab model that accurately reproduced the grey matter injury seen in progressive MS was an essential first step."
Using their new model, developed at U of T, the team examined how immune proteins behave during grey matter injury. The results revealed striking changes in two immune proteins: CXCL13 and BAFF, proteins that help control immune cells. At the onset of injury, CXCL13 increased by 800-fold, while BAFF levels decreased significantly.
When the team introduced a Bruton’s tyrosine kinase inhibitor (BTKi)—a drug that blocks the BTK protein, which mediates immune cell activity—the effects of brain injury were reversed: CXCL13 decreased and BAFF increased, restoring a ratio of CXCL13:BAFF comparable to that seen in uninjured models. BTKi treatment also reduced both the number and size of lymph node-like structures in the meninges. Together, these results revealed that meningeal inflammation and grey matter injury are driven by a balance of CXCL13 and BAFF and depend on BTK signalling.
Identifying a Potential Biomarker
These discoveries led the researchers to propose that the CXCL13:BAFF ratio could serve as a biomarker for meningeal inflammation and possibly compartmentalized inflammation deeper in the brain. To test their hypothesis, the Gommerman-Ramaglia team examined brain tissue samples from individuals with MS. They found that patients with a greater number of immune cells in the brain’s protective layers—indicating more severe inflammation—also had elevated CXCL13:BAFF ratios.
A separate analysis of MRI data from another patient group further supported this finding. Individuals with parametric rim lesions (PRLs), brain lesions that are another marker of progressive MS, also showed higher CXCL13:BAFF ratios compared to individuals without these lesions.
Although further studies are necessary, if validated, this ratio may give clinicians a practical tool to identify patients experiencing the type of inflammation associated with progressive MS.
Looking Ahead: Potential Impact and What’s Next
By unravelling the circuitry that contributes to progressive MS, this research offers insights that could help shape future treatment strategies. It identifies possible new avenues for therapeutic development, as well as sheds light on factors that may explain why existing treatments have been less effective in progressive disease. The team also believes it could support recruitment for ongoing clinical trials of BTK inhibitors and help improve how patients who are most likely to respond to a treatment are identified.
“With Canada having one of the highest rates of MS worldwide, it seems fitting that this advancement in our understanding is homegrown”, notes Dr. Gommerman.
As she builds her own research program at Krembil Brain Institute, Dr. Ramaglia continues to collaborate with Dr. Gommerman to explore how the ratio could advance precision medicine in MS. Building on this study, Dr. Ramaglia plans to focus next on investigating whether the CXCL13:BAFF ratio can be used to help predict which individuals with early MS may go on to develop the progressive form of the disease. This could mean earlier diagnosis and better treatment options for people living with progressive MS.
Dr. Ramaglia credits Dr. Gommerman’s mentorship as instrumental to her growth as an independent scientist and helping to set her up for success as she transitioned to her new role as an independent Principal Investigator at Krembil Brain Institute.
*Check out the University of Toronto Temerty Faculty of Medicine’s feature on this work here.
---
The first author of this study is Dr. Ikbel Naouar, a Senior Research Associate at the University of Toronto.
Drs. Valeria Ramaglia and Jennifer Gommerman are co-senior authors of this study. Dr. Ramaglia is a Scientist at UHN’s Krembil Brain Institute and an Assistant Professor of Immunology at the University of Toronto. Dr. Gommerman is a Professor of Immunology at the University of Toronto, and a Tier 1 Canada Research Chair in Tissue-Specific Immunity.
This work was supported by the National Multiple Sclerosis Society, MS Canada, the Canadian Institutes of Health Research, the United States Department of Defense, and UHN Foundation. Support from the National Multiple Sclerosis Society and the United States Department of Defense was given to Drs. Gommerman and Dr. Ramaglia. Support from MS Canada and the Canadian Institutes of Health Research was given to Dr. Gommerman.
Dr. Gommerman shares a patent for the treatment of autoimmune disease, such as multiple sclerosis, or inflammation, which includes at least the administration of B-cell activating factor (BAFF). Drs. Cenni and Nuesslein-Hildesheim are employees of Novartis. For a complete list of competing interests, see the publication.
Naouar I, Pangan A, Zuo M, Raza SA, Champagne-Jorgensen K, Patel J, Wang A, Pu A, Ward L, Ahn JSY, Sayeed FN, Zhu J, Pössnecker E, Cenni B, Nuesslein-Hildesheim B, Browning JL, Probste A-K, Reich DS, Gommerman JL*, Ramaglia V*. Lymphotoxin-dependent elevated meningeal 1 CXCL13:BAFF ratios drive grey matter injury. Nat Immunol.