Summary: A long-term study has identified a potential biomarker that could help detect which patients are progressing toward more severe forms of multiple sclerosis. Researchers discovered that a high ratio of CXCL13 to BAFF indicates compartmentalized inflammation in the leptomeninges, a hallmark of progressive MS.
This ratio was elevated in a newly developed mouse model that accurately mimics grey-matter damage, and it also appeared in human brain tissues and cerebrospinal fluid. The biomarker may help determine which patients are most likely to benefit from BTK inhibitors, which have shown uneven results in trials partly because participants were not screened for this inflammation pattern.
Key Facts
- Biomarker Discovery: A high CXCL13-to-BAFF ratio marks leptomeningeal inflammation associated with progressive MS.
- Treatment Relevance: BTK inhibitors normalize this ratio in mouse models, suggesting a targeted therapeutic window.
- Precision Medicine Potential: Measuring this ratio may identify which patients will respond to drugs aimed at progressive MS.
Source: University of Toronto
A new University of Toronto-led study has discovered a possible biomarker linked to multiple sclerosis (MS) disease progression that could help identify patients most likely to benefit from new drugs.
The findings were published today in Nature Immunology and validated in both mouse models and humans.
“We think we have uncovered a potential biomarker that signals a patient is experiencing so-called ‘compartmentalized inflammation’ in the central nervous system, a phenomenon which is strongly liked to MS progression,” says Jen Gommerman, a professor and chair of immunology at U of T’s Temerty Faculty of Medicine. “It’s been really hard to know who is progressing and who isn’t.”
Canada has one of the highest rates of MS in the world with over 4,300 Canadians diagnosed with the condition each year, according to MS Canada.
Roughly 10 per cent of people with MS are initially diagnosed with progressive MS, which leads to a gradual worsening of symptoms and increasing disability over time. Patients initially diagnosed with relapsing-remitting MS, the more common form of the condition, can also go on to develop progressive MS.
“We have immunomodulatory drugs that can modulate the relapsing and remitting phase of the disease,” says Valeria Ramaglia, a scientist at the University Health Network’s Krembil Brain Institute and an assistant professor of immunology at Temerty Medicine.
“But for progressive MS, the landscape is completely different. We have no effective therapies.”
Ramaglia, who co-led the study with Gommerman, notes that until their study, the research field did not have a good model that replicates the pathology of progressive MS.
To understand the mechanisms driving progressive MS, the researchers developed a new mouse model that mimics the damage in the brain’s grey matter seen in people with progressive MS. A hallmark of this so-called grey matter injury is compartmentalized inflammation in the leptomeninges, a thin plastic wrap-like membrane that encases the brain and spinal cord.
Using their mouse model, they also observed a roughly 800-fold increase in an immune signal called CXCL13 and significantly lower levels of another immune protein called BAFF.
By treating these mice with BTK inhibitor drugs — which are currently being tested in clinical trials to target progressive MS — the researchers mapped out a circuit in the brain that led to grey matter injury and inflammation. They also found that BTK inhibitors restored CXCL13 and BAFF levels to those seen in healthy mice.
These results led the researchers to hypothesize that the ratio of CXCL13 to BAFF could be a surrogate marker for leptomeningeal inflammation.
To test the validity of their findings in humans, the researchers measured the CXCL13-to-BAFF ratio in postmortem brain tissues from people who had MS and in the cerebrospinal fluid of a living cohort of people with MS. In both cases, a high CXCL13-to-BAFF ratio was associated with greater compartmentalized inflammation in the brain.
Thus far, BTK inhibitors have seen mixed results in clinical trials with people with MS. Ramaglia says that without an easy way to detect leptomeningeal inflammation, the trials likely enrolled participants who did not have this feature and were unlikely to benefit from the drug. Any positive results from people with compartmentalized inflammation would then be diluted.
“If we can use the ratio as a proxy to tell which patients should be treated with a drug that targets leptomeningeal inflammation, that can revolutionize the way we do clinical trials and how we treat patients,” says Ramaglia.
As she builds her own research program at the Krembil Brain Institute, Ramaglia is continuing to collaborate with Gommerman to explore how the CXCL13-to-BAFF ratio can be used to advance precision medicine for people with MS. They are working with the pharmaceutical companies behind the BTK inhibitor trials to look at whether the participants who responded the most to the drugs also had high ratios of CXCL13 to BAFF.
Ramaglia is also planning to look at CXCL13 and BAFF levels in people with early MS to see if it can predict who is likely to develop progressive MS later.
She credits her time as a research associate in Gommerman’s lab as playing a key role in helping her become an independent investigator.
“Jen’s lab was a huge stepping stone for me. She gave me the space and independence to build my own research.”
Funding: This research was supported by the Canadian Institutes of Health Research, MS Canada, the National Multiple Sclerosis Society and the United States Department of Defense.
Key Questions Answered:
A: A high CXCL13-to-BAFF ratio, which signals compartmentalized inflammation linked to MS progression.
A: It may identify which patients will benefit from BTK inhibitor drugs currently showing mixed results in trials.
A: Through a new grey-matter–injury mouse model and human postmortem tissue and cerebrospinal fluid samples.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this multiple sclerosis research news
Author: Betty Zou
Source: University of Toronto
Contact: Betty Zou – University of Toronto
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Lymphotoxin-dependent elevated meningeal 1 CXCL13:BAFF ratios drive grey matter injury” by Jennifer Gommerman et al. Nature Immunology
Abstract
Lymphotoxin-dependent elevated meningeal 1 CXCL13:BAFF ratios drive grey matter injury
In multiple sclerosis (MS), B cell-rich tertiary lymphoid tissues (TLTs) in the brain leptomeninges associate with cortical gray matter injury.
Using a model of Th17 cell-driven experimental autoimmune encephalomyelitis in mice, we found that inhibitors of Bruton’s tyrosine kinase (BTKi) prevented TLT formation and cortical pathology in a B cell activating factor (BAFF)-dependent manner.
BTKi reduced expression of lymphotoxin ligands, and cotreatment with a lymphotoxin-β receptor agonist abrogated the benefits of BTKi. TLT and cortical pathology tracked with a high CXCL13:BAFF ratio in the leptomeninges, which was reduced by BTKi.
Moreover, we observed high CXCL13:BAFF ratios in post mortem cerebral spinal fluid from patients with MS and pathologically confirmed leptomeningeal inflammation, as well as in living patients with MS and radiologically confirmed paramagnetic rim lesions.
In summary, using experimental autoimmune encephalomyelitis, we revealed a molecular circuit that leads to TLT formation and cortical injury with translational relevance for detection of this pathology in patients with MS.
