How Natalizumab Rewires the Immune System in Multiple Sclerosis
Multiple sclerosis (MS) is a complex immune-mediated disease where the body’s immune system mistakenly attacks the central nervous system (CNS). While much of the research historically focused on T cells, it’s now clear that other immune cells—B cells, natural killer (NK) cells, and specialized hybrids—also play pivotal roles.
One of the most effective treatments for relapsing MS, natalizumab, is a monoclonal antibody that blocks the migration of immune cells into the CNS. It works by binding to α4 integrins (specifically VLA-4), which normally act like “molecular grappling hooks” that help immune cells stick to and pass through blood vessel walls into tissues.
A study by Mellergård and colleagues dives deeper than most, examining how natalizumab changes the balance, activation, and functional capacity of many different immune cell types in the blood over the course of one year.
The Study in a Nutshell
Participants: 40 patients with relapsing MS, tracked before starting natalizumab and after one year of monthly infusions.
What they measured:
Absolute numbers and proportions of different lymphocyte populations (T cells, B cells, NK cells, NKT cells).
Markers of activation and co-stimulation (indicators of readiness to respond to threats).
Functional T cell responses to recall antigens (like influenza or tetanus) and mitogens (substances that drive cell division).
Key technology: Advanced flow cytometry and a whole-blood functional assay called FASCIA.
Key Findings
1. More Immune Cells in the Blood – Especially NK and B Cells
Natalizumab dramatically increased the total number of lymphocytes in circulation—almost doubling them on average.
NK cells had the largest jump (+195%), followed by B cells (+105%) and T cells (+73%).
This likely reflects natalizumab’s main mechanism: preventing immune cells from leaving the blood and entering tissues, especially the brain and spinal cord.
2. Shift Toward Cytotoxic Over Regulatory NK Cells
NK cells aren’t all the same. There are regulatory NK cells (CD56^bright) that help control inflammation and cytotoxic NK cells (CD56^dim) that can kill infected or damaged cells.
Cytotoxic NK cells increased, while regulatory NK cells decreased proportionally.
This shift may result from differences in how each subset uses VLA-4 to migrate into tissues.
3. B Cell Subtypes Tilt Toward a Memory Profile
B cells also come in many flavors:
Memory B cells (CD19+CD27+) remember past encounters and mount fast responses, often releasing pro-inflammatory cytokines like TNF.
Regulatory B cells (CD19+CD25+) can suppress overactive immune responses.
Both increased after natalizumab, but memory B cells rose more sharply, which could boost immune readiness but might also carry risks if these cells drive inflammation.
4. Mixed Changes in T Cell Activation Markers
While the overall number of T cells rose, their activation status changed in nuanced ways:
Some markers of activation decreased, suggesting dampened effector T cell activity.
Others, like early activation marker CD69, trended upward.
These shifts hint at a rebalancing of T cell function rather than simple up- or downregulation.
5. Restored T Cell Responsiveness
Before treatment, MS patients showed reduced T cell responses to common recall antigens compared to healthy controls. After a year on natalizumab:
Responses to influenza, PPD (tuberculosis test antigen), and some viruses improved, reaching control levels.
This was due not only to having more T cells in circulation but also to a modest boost in responsiveness on a per-cell basis.
Why This Matters
These results reinforce the idea that natalizumab’s benefits come from more than just keeping immune cells out of the CNS. By altering the balance of cell types and their activation states, natalizumab reshapes the immune system’s readiness.
Potential benefits:
Improved systemic immunity to infections.
Reduced inflammatory infiltration into the CNS.
Potential risks:
Overaccumulation of certain immune cell subsets in the blood might affect infection risk elsewhere, or play a role in complications like PML (a rare but serious brain infection).
Take-Home Message
Natalizumab doesn’t just trap immune cells in the bloodstream—it reshuffles the immune deck, boosting some players and sidelining others. Understanding these shifts can help clinicians fine-tune treatment strategies, weigh risks and benefits, and explore combination therapies that complement natalizumab’s immune choreography.
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:
Mellergård, J., Edström, M., Jenmalm, M. C., Dahle, C., Vrethem, M., & Ernerudh, J. (2013). Increased B cell and cytotoxic NK cell proportions and increased T cell responsiveness in blood of natalizumab-treated multiple sclerosis patients. PLoS One, 8(12), e81685.
