Cladribine and the Memory B Cell Connection: Rethinking MS Treatment
Multiple sclerosis (MS) is a complex immune-mediated disease where the body’s immune system mistakenly attacks the protective myelin sheath around nerve fibers in the central nervous system. Traditionally, T cells have been considered the main culprits driving this destructive process. However, mounting evidence points to an equally important role for B cells—not just as antibody producers, but as powerful regulators of immune activity.
This is where cladribine, an oral therapy approved for relapsing MS, steps into the spotlight. Although it is given in just two short annual courses, cladribine’s impact on disease activity often lasts well beyond the treatment window. Until recently, the long-term immune mechanisms behind this durability were not fully understood.
A new study by Valerie Teschner and colleagues (2023) provides fresh insights into this mystery. Using cutting-edge single-cell and bulk transcriptomic approaches, the team uncovered that cladribine preferentially and persistently reduces memory B cells, reshaping the immune landscape in ways that may explain its lasting clinical benefits.
What Did the Researchers Do?
The team conducted an open-label, prospective study with 23 patients with relapsing-remitting MS (RRMS). They collected blood samples before treatment and at several time points up to 24 months after cladribine initiation.
To get a comprehensive view of immune changes, they used three complementary techniques:
Flow cytometry to quantify immune cell populations.
Bulk RNA sequencing to profile gene expression in sorted B and T cells.
Single-cell RNA sequencing to capture fine-grained details of immune cell subsets.
They then correlated these immune signatures with clinical outcomes and MRI findings.
Key Findings
1. Memory B Cells Are the Main Target
Cladribine caused a sharp and sustained reduction of memory B cells (CD19+, CD20+, CD27+).
Other B cell types (naïve, transitional, and regulatory B cells) either rebounded or increased, suggesting a selective depletion effect.
T cells were affected too, but the changes were more uniform and less profound.
2. Gene Expression Shifts Toward a Calmer Immune State
At the transcriptomic level, 13.4% of genes in B cells were differentially regulated after treatment, compared to just 1–2% in T cells.
Pro-inflammatory and T cell–activating genes were significantly downregulated.
This shift points toward reduced potential for harmful B–T cell interactions that drive MS pathology.
3. Single-Cell Data Show Subset-Specific Effects
Six distinct B cell clusters were identified, including naïve, transitional, and multiple memory subsets.
The activated memory B cell cluster was strongly reduced at both 12 and 24 months.
Importantly, within each subset, transcriptional profiles stayed stable—indicating that cladribine’s main impact is changing the balance of cell populations, not reprogramming their function.
4. Deeper Reductions Predict Better Outcomes
Patients who remained stable (no relapses, no MRI activity) showed stronger reductions in certain memory B cell subsets compared to patients with ongoing disease activity.
This suggests that the extent of memory B cell depletion could be a biomarker for treatment success.
Why Does This Matter?
The findings highlight a paradigm shift:
Memory B cells, not just T cells, are central drivers of MS.
By selectively targeting memory B cells, cladribine may disrupt the harmful immune dialogue that fuels disease progression.
This selective depletion could also explain why cladribine provides long-term benefits without continuous dosing.
Interestingly, this echoes results from anti-CD20 therapies (like ocrelizumab), which also target B cells but through different mechanisms. Both converge on the idea that controlling memory B cells is key to controlling MS.
Looking Ahead
This study opens new avenues:
Personalized medicine: Measuring changes in memory B cell subsets could help predict which patients will respond best to cladribine.
Mechanistic insights: The link between Epstein–Barr virus (EBV)-infected memory B cells and MS is gaining attention. Cladribine’s selective targeting of this population could be particularly relevant.
Therapy optimization: Understanding the different functional roles of memory B cell clusters might help refine future treatments.
Conclusion
Cladribine doesn’t just suppress the immune system—it fine-tunes it. By preferentially reducing memory B cells, it reshapes the immune environment into a less inflammatory, more balanced state. This may be the secret behind its durable effectiveness in MS.
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:
Teschner, V. E., Fleck, A. K., Walter, C., Schwarze, A. S., Eschborn, M., Wirth, T., ... & Klotz, L. (2023). Single-cell profiling reveals preferential reduction of memory B cell subsets in cladribine patients that correlates with treatment response. Therapeutic Advances in Neurological Disorders, 16, 17562864231211077.
