Summary: A long-term study has identified a potential biomarker that could help detect which patients are progressing to more severe forms of multiple sclerosis. The researchers found that a high CXCL13 to BAFF ratio indicates compartmentalized inflammation in the leptomeninges, a hallmark of progressive MS.
This ratio was elevated in a newly developed mouse model that precisely mimics gray matter damage, and 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 mixed results in trials, in part because participants were not screened for this pattern of inflammation.
Key facts
Biomarker Discovery: High CXCL13 to BAFF Ratio Marks Leptomeningeal Inflammation Associated with Progressive MS. Treatment relevance: BTK inhibitors normalize this ratio in mouse models, suggesting a specific therapeutic window. Precision medicine potential: Measuring this ratio can identify which patients will respond to medications targeting progressive MS.
Source: University of Toronto
A new study led by the University of Toronto has discovered a potential biomarker linked to multiple sclerosis (MS) disease progression that could help identify patients most likely to benefit from new medications.
The findings were published today in Nature Immunology and were validated in both mouse and human models.
“We believe we have discovered a potential biomarker that indicates that a patient is experiencing so-called ‘compartmentalized inflammation’ in the central nervous system, a phenomenon closely related to the progression of MS,” says Jen Gommerman, professor and chair of immunology at U of T’s Temerty School of Medicine. “It’s been very difficult to know who is progressing and who is not.”
Canada has one of the highest rates of MS in the world, with more than 4,300 Canadians diagnosed with the condition each year, according to MS Canada.
About 10 percent 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 most common form of the condition, may also develop progressive MS.
“We have immunomodulatory drugs that can modulate the relapsing-remitting phase of the disease,” says Valeria Ramaglia, a scientist at the Krembil Brain Institute of the University Health Network and assistant professor of immunology at Temerty Medicine.
“But for progressive MS, the picture is completely different. We don’t have 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 replicated the pathology of progressive MS.
To understand the mechanisms that drive progressive MS, researchers developed a new mouse model that mimics the damage to the brain’s gray matter seen in people with progressive MS. A hallmark feature of this so-called gray matter injury is compartmentalized inflammation in the leptomeninges, a thin sheath-like plastic membrane that covers the brain and spinal cord.
Using their mouse model, they also observed an approximately 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-inhibiting drugs, which are currently being tested in clinical trials to combat progressive MS, the researchers mapped a circuit in the brain that led to gray 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 of leptomeningeal inflammation.
To test the validity of their findings in humans, the researchers measured the CXCL13-BAFF ratio in postmortem brain tissues from people with 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.
So far, BTK inhibitors have had mixed results in clinical trials with people with MS. Ramaglia says that without an easy way to detect leptomeningeal inflammation, the trials likely included participants who did not have this feature and were unlikely to benefit from the drug. Any positive results from people with compartmentalized inflammation would be diluted.
“If we can use the ratio as an indicator to know which patients should be treated with a drug targeting leptomeningeal inflammation, that can revolutionize the way we conduct clinical trials and how we treat patients,” Ramaglia says.
While building his own research program at the Krembil Brain Institute, Ramaglia continues to collaborate with Gommerman to explore how the CXCL13-BAFF relationship can be used to advance precision medicine for people with MS. They are working with the pharmaceutical companies behind the BTK inhibitor trials to see if the participants who responded most to the drugs also had high ratios of CXCL13 to BAFF.
Ramaglia also plans 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 researcher.
“Jen’s lab was a great springboard for me. She gave me the space and independence to develop 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 ratio of CXCL13 to BAFF, indicating compartmentalized inflammation related to MS progression.
A: It can identify which patients will benefit from BTK inhibitor drugs that are currently showing mixed results in trials.
A: Through a new mouse model with gray matter injury and human postmortem tissue and cerebrospinal fluid samples.
Editorial notes:
This article was edited by a Neuroscience News editor. Magazine article reviewed in its entirety. 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: Image is credited to Neuroscience News.
Original research: Open access.
“Elevated lymphotoxin-dependent meningeal 1 CXCL13:BAFF ratios cause gray matter injury” by Jennifer Gommerman et al. nature immunology
Abstract
Elevated lymphotoxin-dependent meningeal 1 CXCL13:BAFF ratios cause gray matter lesions
In multiple sclerosis (MS), B cell-rich tertiary lymphoid tissues (TLTs) in the cerebral leptomeninges are associated with cortical gray matter injury.
Using a Th17 cell-driven experimental autoimmune encephalomyelitis model in mice, we found that Bruton’s tyrosine kinase inhibitors (BTKi) prevented TLT formation and cortical pathology in a B-cell-activating factor (BAFF)-dependent manner.
BTKi reduced the 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.
Furthermore, we observed high ratios of CXCL13:BAFF in the postmortem cerebrospinal fluid of patients with MS and pathologically confirmed leptomeningeal inflammation, as well as in living patients with MS and radiologically confirmed paramagnetic edge lesions.
In summary, using experimental autoimmune encephalomyelitis, we reveal a molecular circuit leading to TLT formation and cortical injury with translational relevance for the detection of this pathology in MS patients.
