How a Single DNA Letter Might Predict Brain Inflammation in MS Patients on Natalizumab
Multiple Sclerosis (MS) is a complex immune-mediated disease that attacks the central nervous system. It's influenced by many factors, from immune system dynamics to genetic makeup. One of the front-line treatments for MS—natalizumab—works by blocking immune cells (particularly lymphocytes) from entering the brain and spinal cord. But even with this powerful therapy, not all patients respond equally.
A new study led by Dr. Melissa Chu and her team at the Royal Melbourne Hospital has uncovered a compelling clue as to why: a single-letter change (SNP) in a gene called MERTK may make some patients more prone to brain inflammation, even while on natalizumab.
MERTK and HLA-DRB1*1501: Two Immune Regulators Under the Microscope
The researchers focused on two key players:
MERTK (Mer Tyrosine Kinase): A gene involved in calming down the immune response, especially in monocytes and macrophages (types of white blood cells).
HLA-DRB1*1501: A well-known MS risk gene involved in T cell immune responses.
Interestingly, MERTK helps regulate immune cell behavior, acting like a "peacekeeper" by promoting anti-inflammatory effects. A known variant in this gene—rs7422195—comes in two forms: G (the common version) and A (the minor variant). Prior studies suggested that this variation influences how much MERTK is made in certain immune cells.
The big question: Does this genetic variation affect disease activity in people with MS, even when they’re receiving strong immune-suppressing drugs like natalizumab?
The Study Design: Zooming In on the Genetics of MS Patients on Natalizumab
Between 2020 and 2022, the team recruited 100 people with relapsing-remitting MS from a single clinic in Melbourne. All participants were being treated with natalizumab and were genotyped to determine their MERTK and HLA status.
Participants underwent:
Blood testing for MERTK and HLA-DRB1*1501 genotyping
MRI brain scans to assess radiological disease activity
Review of clinical records for MS relapses
The researchers tracked two main outcomes:
Clinical relapses (physical symptoms)
Radiological activity (new or enlarging lesions on MRI scans)
Key Findings: One Genetic Variant, Big Impact on Brain Inflammation
Main Discovery:
People carrying at least one copy of the A variant of the MERTK SNP (GA or AA genotypes) had a dramatically increased risk (18.7x) of developing new or enlarging brain lesions on MRI, compared to those with the GG genotype—even though they were on natalizumab.
But What About Symptoms?
Surprisingly, this higher lesion burden didn't translate into more clinical relapses. This disconnect between MRI and clinical symptoms is not unusual in MS and highlights how inflammation can simmer below the surface.
What About HLA-DRB1*1501?
Despite its well-established role as an MS risk gene, HLA-DRB1*1501 didn’t significantly influence disease activity in this study, either alone or in combination with the MERTK SNP.
What Does This Mean? Interpreting the Genetic Signal
This finding challenges some assumptions.
In earlier studies, GG genotype was thought to reduce MERTK expression, potentially leading to more inflammation. But in this study, patients with the GA/AA genotypes—expected to express more MERTK—had more brain lesions.
Why might this happen?
One theory is that the GG genotype may trigger a compensatory increase in MERTK expression in people with MS, acting as a built-in protective response.
Another possibility: GA/AA genotypes might disrupt the balance of immune regulation, particularly in innate immune cells like monocytes, which can still access the brain even during natalizumab therapy.
Why This Matters for MS Patients and Doctors
Personalized medicine: Genetic profiling may one day help doctors predict how a patient will respond to MS therapies like natalizumab.
Better biomarkers: Understanding how SNPs like MERTK rs7422195 influence disease could help tailor imaging and treatment plans.
Expanding treatment insights: This study shines light on the role of non-lymphocyte immune activity, which has been less studied but may still drive disease even when lymphocytes are blocked.
Limitations to Keep in Mind
The study was retrospective and conducted at a single center, which may limit generalizability.
The sample size (100 patients), while reasonable, may not capture all genetic subtleties.
Larger, multi-center studies will be needed to validate these findings and explore how they translate into clinical outcomes over longer periods.
Looking Ahead: A New Layer in MS Genetics and Treatment
This research adds a fascinating piece to the MS puzzle. While natalizumab remains one of the most effective drugs for controlling MS, individual genetic differences can still influence how well it works—particularly when it comes to unseen inflammation in the brain.
If confirmed by future studies, MERTK rs7422195 could become a useful biomarker for identifying patients who might need closer monitoring—even when their symptoms are under control.
And more broadly, it’s a reminder that the immune system is a nuanced, multi-layered network—and targeting one part doesn’t always mean the rest will stay quiet.
Final Thoughts
The intersection of genetics and immune therapy is opening new frontiers in MS care. By unpacking how a single nucleotide can shape immune behavior, Dr. Chu and her team have nudged us a step closer to truly personalized MS treatment.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Chu, M. M., Li, V., Kalincik, T., Lui, E., Seet, M. R., Jackson, S., & Kilpatrick, T. (2025). A single nucleotide polymorphism in the MerTK gene is associated with increased radiological disease activity in patients with Multiple Sclerosis on natalizumab therapy. Multiple Sclerosis and Related Disorders, 106635.
