When Genes and Immunity Collide: Why Some African Ancestry MS Patients Rebound Faster After Anti-CD20 Therapy

Multiple sclerosis (MS) is an autoimmune disease in which the body’s immune system mistakenly attacks the central nervous system (CNS), damaging the protective myelin sheath around nerve fibers. For decades, MS was considered mainly a T-cell–driven disease, but research has since revealed that B cells—a class of immune cells responsible for antibody production—also play a central role.

Anti-CD20 therapies, such as ocrelizumab (Ocrevus) and rituximab (Rituxan), have revolutionized MS treatment by targeting and depleting B cells, effectively suppressing disease activity. However, patients vary in how quickly their B cells return—or “replete”—after treatment. Notably, clinicians have observed that patients of African ancestry sometimes experience faster B cell repletion, potentially influencing treatment efficacy and relapse risk.

A study led by Dr. Gregg Silverman and colleagues at NYU Grossman School of Medicine, published in Frontiers in Immunology (June 2025), dives deep into the genetic and immunologic factors behind this phenomenon.

The Study: Investigating Why Some Patients’ B Cells Bounce Back Faster
The research team enrolled 43 patients of African ancestry with multiple sclerosis (and a few with neuromyelitis optica). All were receiving anti-CD20 therapy. Among them:

20 were “early repleters” (ER): their B cells returned to detectable levels within six months after infusion.

23 were “normal repleters” (NR): their B cells remained depleted for the expected duration.

The study examined both extrinsic factors (like anti-drug antibodies that might neutralize treatment) and intrinsic factors (genetic variations that influence immune cell behavior).

Key Findings
1. Anti-Drug Antibodies Can Weaken Therapy
Two early repleters developed anti-ocrelizumab antibodies, neutralizing the drug and leading to a complete loss of detectable ocrelizumab in the blood. These patients’ B cells rebounded much earlier than expected.

This suggests that some patients’ immune systems may “fight back” against the therapeutic antibody, reducing its effectiveness.

2. Genetics Matter—A Lot
Even in patients without anti-drug antibodies, early B cell recovery was linked to distinct genetic signatures.

The researchers analyzed over 240,000 immune-related single nucleotide polymorphisms (SNPs) and found thousands of variants more common among early repleters. These genetic differences were enriched in pathways related to:

B cell survival and differentiation

Inflammatory signaling

Cytokine production

Leukocyte activation

Key genes included BAFF (TNFSF13B), STAT3, IL2RA, BACH2, and FCGR2A—all known to regulate immune responses or influence MS risk.

One particularly interesting variant in BAFF, a cytokine critical for B cell survival, could alter how long BAFF mRNA lasts in cells, possibly enhancing B cell recovery after depletion.

3. Distinct Patterns of Immune Reconstitution
Early repleters had lower levels of serum BAFF, consistent with rapid consumption as B cells repopulated. Yet, their overall immune cell balance—such as T cell populations—remained similar to normal repleters, indicating that the phenomenon was specific to B cells.

4. MS Risk Genes May Overlap with Early Repletion Genes
Several genetic variants previously associated with MS susceptibility in African ancestry populations—including WWOX, CLEC16A, STAT3, and IL2RA—were also enriched among early repleters.

This overlap hints that the same genes that increase disease risk might also affect treatment response. Why This Matters
This study sheds light on an important pharmacogenetic difference that could influence how well anti-CD20 therapies work in certain populations.

For patients of African ancestry:

Faster B cell repletion may mean shorter duration of immune suppression, potentially reducing treatment effectiveness over time.

Anti-drug antibodies may render therapies less potent, leading to breakthrough disease activity.

Genetic screening could, in the future, help identify patients who might need more frequent infusions or alternative therapeutic strategies.

As the authors note, this is a pilot study with a small sample size—but it highlights a clear need for larger, multi-center studies exploring how genetics and ancestry shape MS treatment outcomes.

Implications for Precision Medicine
The findings point toward a future where MS treatment is personalized not just to disease subtype, but also to genetic background and immune reconstitution profiles.

Monitoring B cell counts and testing for anti-drug antibodies could help neurologists optimize treatment intervals and avoid under-treatment.

For researchers, the study provides a roadmap for integrating genomic data with immunophenotyping to understand therapy resistance in autoimmune diseases.

Conclusion
The NYU team’s work emphasizes that one-size-fits-all therapy may not be enough in MS care. By identifying both B cell–extrinsic (anti-drug antibodies) and intrinsic (genetic polymorphisms) factors influencing immune repletion, they’ve taken a key step toward personalized immunotherapy—especially for underrepresented populations in MS research.

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:
Silverman GJ, Amarnani AN, Arbini AA, Kim A, Kopinsky H, Fenyo D, Kister I. (2025). B cell-extrinsic and intrinsic factors linked to early immune repletion after anti-CD20 therapy in patients with multiple sclerosis of African ancestry. Frontiers in Immunology, 16:1590165. DOI: 10.3389/fimmu.2025.1590165