New biomarker may help identify MS patients for BTK inhibitors
Balance between 2 molecules seen as inflammation marker
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- A molecule ratio may identify MS patients with brain inflammation.
- This biomarker could help select patients for BTK inhibitor treatment.
- BTK inhibitors reduce inflammation and nerve damage in MS models.
The balance between two immune signaling molecules — CXCL13 and BAFF — may help identify the hard-to-treat inflammation in the brain and spinal cord that’s thought to be a major driver of disability progression in multiple sclerosis (MS), a study found.
The findings may help identify which patients are most likely to benefit from BTK inhibitors — treatments that are believed to target this form of compartmentalized inflammation — and aid in selecting candidates for future clinical trials.
BTK inhibitors have yielded mixed results in clinical trials.
“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 [linked] to MS progression,” Jen Gommerman, co-author of the study and chair of immunology at the University of Toronto, said in a university news story.
The study, “Lymphotoxin-dependent elevated meningeal CXCL13:BAFF ratios drive gray matter injury,” was published in Nature Immunology.
Inflammation drives progressive MS
Unlike the inflammation seen in relapsing forms of MS, where immune cells repeatedly enter the brain and spinal cord to cause damage, progressive forms of the disease are primarily driven by inflammation within the central nervous system.
Immune cells settle in the membranes surrounding the brain and spinal cord, where they form clumps called tertiary lymphoid tissues (TLTs), and continue driving damage in the cortex, the outer layer of the brain, even when peripheral inflammation is well controlled.
TLTs resemble lymph nodes and are composed largely of B-cells, immune cells that produce antibodies and play a prominent role in driving MS. However, exactly how they form and how best to target them has remained unclear.
The researchers conducted a series of experiments in a mouse model of MS-like disease, aiming to uncover the origins of these disease-associated immune structures.
In an initial set of experiments, the researchers treated mice with remibrutinib, one of the BTK inhibitors that’s being investigated as a treatment for MS. BTK is an enzyme involved in the inflammatory activation of B-cells.
The researchers found that treatment led to a reduction in the formation of TLTs in mice and also reduced nerve cell damage in the cortex.
To understand the molecular mechanisms at play, the team examined how treatment affected the levels of various cytokines, signaling molecules that regulate immune cell activity. Results showed that remibrutinib treatment decreased levels of the cytokine CXCL13, while simultaneously increasing levels of the cytokine BAFF.
The balance between these two signaling molecules appeared to govern whether TLTs would form. Specifically, when CXCL13 levels were high and BAFF levels were low, TLTs formed. But when CXCL13 levels were low and BAFF levels were high, the formation of these disease-driving immune complexes was inhibited, and there was less tissue damage.
While their studies mostly focused on mouse models, the scientists also conducted tests on postmortem tissue from MS patients and examined spinal fluid samples from living patients. Consistent with the mouse data, the CXCL13-to-BAFF ratio was significantly higher in people with B-cells in the brain’s membranes or with signs of localized brain inflammation on MRI scans.
“In patients with MS, a high CXCL13:BAFF ratio in the [spinal fluid] was associated with a greater degree of compartmentalized inflammation,” the researchers concluded.
The scientists noted that further work is needed to validate these findings, but expressed hope that this ratio may be used as a biomarker to assess disease progression and guide the development of future MS treatments.
“If we can use the ratio as a proxy to tell which patients should be treated with a drug that targets [this form of] inflammation, that can revolutionize the way we do clinical trials and how we treat patients,” Ramaglia said.
