Ocrelizumab and B Cells: How MS Therapy Reshapes the Immune Landscape

When we think about multiple sclerosis (MS), the image that often comes to mind is one of overactive immune cells attacking the nervous system. For years, the spotlight has been on T cells. But in recent decades, B cells have emerged as key culprits in driving MS inflammation and progression.

One therapy that harnesses this knowledge is ocrelizumab (OCR), a monoclonal antibody that selectively depletes CD20+ B cells. OCR has already proven itself by reducing relapses, slowing progression, and lowering inflammatory activity in MS. But how does it really reshape the different subsets of B cells in the blood? A study presented in Neurology (Hauser et al., 2021) offers some fascinating insights.

Why B Cells Matter in MS
B cells are not just antibody factories. They also act as antigen-presenting cells, secrete inflammatory mediators, and—crucially—persist in the central nervous system (CNS). Memory B cells and plasmablasts in particular have been implicated in chronic inflammation within the CNS. This smoldering immune activity is thought to drive progression in MS, even when overt relapses are absent.

So, targeting B cells makes sense. But not all B cells are equal. Some subsets are more resistant to depletion than others, and understanding these differences may shed light on both treatment responses and the biology of the disease.

The OPERA Trials: A Rich Dataset
The data come from the OPERA I and OPERA II trials (NCT01247324 and NCT01412333), which tested ocrelizumab in relapsing MS. Researchers looked at 1,645 patients, analyzing blood samples at baseline and every six months before each OCR infusion (weeks 24, 48, 72, 96).

Using flow cytometry, they measured:

Total CD19+ B cells
Mature naïve B cells (CD19+/IgD+/CD27−)

Memory B cells (CD19+/CD27+/CD38low)

Double-negative memory B cells (CD19+/IgD−/CD27−)

Plasmablasts/plasma cells (CD19+/CD27++/CD38++)

The big question: Which of these subsets does ocrelizumab deplete, and how strongly?

What They Found
Broad Depletion Across All Subsets
Every B-cell subset measured was significantly depleted with ocrelizumab (p < 0.005). The effect deepened with repeated dosing over time.

Naïve B Cells Drop the Most
Mature naïve B cells were the most sensitive to OCR, showing the strongest depletion across treatment cycles.

Plasmablasts Are the Most Resistant
CD19+/CD27++/CD38++ cells—mostly plasmablasts—showed the least reduction. This makes biological sense: plasmablasts typically lack or express very little CD20, the molecule ocrelizumab targets.

Dose Exposure Matters
Patients in the highest quartile of OCR exposure had greater depletion across all subsets compared to those in the lowest quartile (all p < 0.005).

Why This Matters
Mechanistic clarity: These results reinforce that OCR does not simply “wipe out B cells” but rather reshapes the immune landscape in a nuanced way.

Clinical implications: Since plasmablasts are relatively spared, they may continue to play roles in residual immune activity, especially in the CNS.

Future directions: Understanding which subsets persist may guide next-generation therapies—perhaps targeting plasmablasts or plasma cells more effectively.

Take-Home Message
Ocrelizumab exerts a broad and progressive depletion of circulating B cells, with the sharpest impact on naïve B cells and the weakest on plasmablasts. The degree of depletion tracks with drug exposure, suggesting that both pharmacokinetics and treatment duration shape outcomes.

This study underscores that while OCR is highly effective in MS, the immune story is not as simple as an on/off switch. Instead, it’s a dynamic rebalancing of B-cell subsets—and unraveling that balance could hold the key to understanding long-term treatment effects and disease progression.

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:
Hauser SL, Strauli N, Raievska A, Harp C, Koendgen H, Kletzl H, Bonati U, Jia X, Herman A, Kappos L, Bar-Or A. B-Cell Subset Depletion Following Ocrelizumab Treatment in Patients With Relapsing Multiple Sclerosis. Neurology. 2021;96(15_suppl):4292. doi:10.1212/WNL.96.15_supplement.4292