Summary: A long-term study has identified a promising biomarker that could indicate which patients are moving toward more severe, progressive forms of multiple sclerosis (MS). Researchers found that an elevated CXCL13-to-BAFF ratio corresponds with compartmentalized inflammation in the leptomeninges — a characteristic feature of progressive MS.
This elevated ratio appeared in a newly developed mouse model that recreates grey-matter damage seen in progressive MS and was also observed in human brain tissue and cerebrospinal fluid. The marker could help clinicians and researchers identify patients most likely to respond to BTK inhibitors, a class of drugs with mixed results in trials that may be explained by enrolling participants without this inflammation pattern.
Key Facts
- Biomarker Discovery: A high CXCL13-to-BAFF ratio identifies leptomeningeal inflammation associated with progressive MS.
- Treatment Relevance: In experimental models, BTK inhibitors restore CXCL13 and BAFF toward normal levels, suggesting a potential targeted treatment window.
- Precision Medicine Potential: Measuring this ratio could select patients likely to benefit from therapies aimed at the leptomeningeal inflammatory process.
Source: University of Toronto
A team led by researchers at the University of Toronto has uncovered a candidate biomarker linked to MS disease progression that may improve how patients are selected for new therapies.
The results appear in Nature Immunology and were validated in both a mouse model and samples from people with MS.
“We believe we have identified a biomarker that signals compartmentalized inflammation in the central nervous system — a process strongly associated with MS progression,” says Jen Gommerman, professor and chair of immunology at the University of Toronto’s Temerty Faculty of Medicine. “Until now, distinguishing who is progressing has been very challenging.”
Canada has one of the highest MS incidence rates globally, with thousands of new diagnoses each year. About 10 percent of people with MS are diagnosed with progressive disease at onset, and many with the more common relapsing-remitting form later develop progressive features characterized by gradual disability accumulation.
“We have effective immunomodulatory drugs for the relapsing phase, but options for progressive MS remain limited,” explains Valeria Ramaglia, a scientist at the Krembil Brain Institute and assistant professor of immunology at Temerty Medicine. “Progressive MS requires different strategies.”
To study mechanisms behind progressive MS, the team created a mouse model that reproduces grey-matter injury and the leptomeningeal inflammation seen in people with progressive disease. The leptomeninges are a thin membrane that surrounds the brain and spinal cord and, when inflamed, can host B cell–rich tertiary lymphoid tissues linked to nearby cortical damage.
In this model the researchers detected a dramatic increase in CXCL13 — an immune chemokine — alongside markedly reduced levels of BAFF, a protein that supports B cell survival. The result was an approximately 800-fold rise in CXCL13 relative to BAFF in affected leptomeninges.
Treating these mice with Bruton’s tyrosine kinase (BTK) inhibitors, which are under investigation for progressive MS, prevented formation of tertiary lymphoid tissues and reduced cortical pathology. BTK inhibitor treatment also normalized CXCL13 and BAFF toward levels seen in healthy controls, supporting the idea that the CXCL13-to-BAFF ratio reflects the underlying inflammatory circuit.
To translate these findings to humans, the group measured the CXCL13-to-BAFF ratio in postmortem brain tissue from individuals with MS and in cerebrospinal fluid from living patients. In both settings, a high ratio correlated with evidence of compartmentalized leptomeningeal inflammation and with radiological markers associated with progressive disease.
BTK inhibitors have produced mixed outcomes in clinical trials. The researchers suggest this may be because trials enrolled participants without leptomeningeal inflammation, diluting benefits concentrated in the subgroup that actually has that pathology. Using the CXCL13-to-BAFF ratio as a selection biomarker could therefore refine trials and clinical use so that treatments are targeted to patients most likely to benefit.
“If the ratio can reliably indicate who has leptomeningeal inflammation, it could transform clinical trial design and clinical practice,” Ramaglia says. She and Gommerman are collaborating with trial sponsors to assess whether trial responders had higher CXCL13-to-BAFF ratios at baseline.
Ramaglia also plans to study whether CXCL13 and BAFF levels measured early in disease predict later progression, which would further support using this biomarker for prognosis and early intervention.
Ramaglia credits her time as a research associate in Gommerman’s lab for helping launch her independent research program. “Jen’s mentorship gave me the freedom to develop my own projects,” she says.
Funding: This work was supported by the Canadian Institutes of Health Research, MS Canada, the National Multiple Sclerosis Society and the U.S. Department of Defense.
Key Questions Answered:
A: A high CXCL13-to-BAFF ratio that signals compartmentalized leptomeningeal inflammation linked to MS progression.
A: It may identify patients most likely to benefit from BTK inhibitors, improving patient selection for trials and targeted therapy.
A: Validation came from a new grey-matter injury mouse model and from human postmortem tissue and cerebrospinal fluid samples that showed the same pattern.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by 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 CXCL13:BAFF ratios drive grey matter injury” by Jennifer Gommerman et al., Nature Immunology.
Abstract
Lymphotoxin-dependent elevated meningeal CXCL13:BAFF ratios drive grey matter injury
In multiple sclerosis, B cell–rich tertiary lymphoid tissues in the leptomeninges are associated with cortical grey matter injury. Using a Th17-driven experimental autoimmune encephalomyelitis model in mice, the study found that Bruton’s tyrosine kinase inhibitors prevented tertiary lymphoid tissue formation and cortical pathology in a BAFF-dependent manner. BTK inhibition reduced lymphotoxin ligand expression, and adding a lymphotoxin-β receptor agonist reversed the protective effects. Tertiary lymphoid tissue presence and cortical damage correlated with a high CXCL13-to-BAFF ratio in the leptomeninges, which BTK inhibition lowered. High CXCL13-to-BAFF ratios were also observed in postmortem cerebrospinal fluid from patients with confirmed leptomeningeal inflammation and in living patients with radiological evidence of progressive lesions. These results outline a molecular circuit linking leptomeningeal inflammation to cortical injury and offer translational markers for detecting this pathology in people with MS.