Ocrelizumab’s Hidden Effect: How an MS Therapy Rewires B-Cell Communication

Multiple sclerosis (MS) has long been recognized as a disease in which the immune system mistakenly targets the central nervous system (CNS). Over the past two decades, B cells have emerged as crucial players in the disease’s development and progression. This realization led to a therapeutic revolution: drugs that target CD20, a protein found on B cells, have proven remarkably effective in reducing relapses and slowing progression. Among them, ocrelizumab is a frontrunner, approved not only for relapsing-remitting MS (RRMS) but also for primary progressive MS (PPMS).

A study by Ho et al. (2023) explored how ocrelizumab influences not just B cell numbers, but also the broader ecosystem of B-cell regulating factors. Their findings add a fascinating layer to our understanding of why anti-CD20 therapies work so well, and they may even explain some past treatment failures.

The BAFF/APRIL System: A Delicate Balance
To understand this study, we need to introduce the BAFF–APRIL system.

BAFF (B-cell activating factor) and APRIL (A proliferation-inducing ligand) are molecules that promote the survival of B cells and plasma cells.

Their activity is fine-tuned by receptors on B cells: BAFF-R, TACI, and BCMA.

Interestingly, some of these receptors can be shed into circulation as soluble receptors—notably sTACI and sBCMA. In this form, they act as decoys, soaking up BAFF and APRIL before these molecules can signal to cells.

This regulation matters because therapies that tamper with this system can have surprising consequences. For instance, atacicept, a drug designed to mop up BAFF and APRIL by acting like a soluble receptor, actually made MS worse in clinical trials. That paradox hinted at a complex role for these pathways in regulating inflammation.

What Ho et al. Found
The team followed two cohorts of MS patients receiving ocrelizumab, tracking immune cell subsets and BAFF/APRIL system components in both blood and cerebrospinal fluid (CSF) for up to 2.5 years. Here’s what they discovered:

B cells were persistently depleted.

As expected, ocrelizumab efficiently removed circulating CD19+ B cells, along with CD20+ T cells, while leaving overall T cell numbers stable.

BAFF levels rose.

With fewer B cells to “consume” BAFF, levels of this survival factor increased in both blood and CSF.

sTACI levels fell.

This was the standout finding. The soluble decoy receptor sTACI consistently dropped after ocrelizumab therapy. Importantly, this reduction wasn’t mirrored by sBCMA, which remained stable.

New complexes formed.

The researchers developed a specialized ELISA and showed that much of the “missing” sTACI wasn’t gone—it was tied up in sTACI–BAFF complexes. Over time, the proportion of sTACI bound to BAFF rose dramatically, exceeding 80% in some patients.

Implications for APRIL activity.

Because sTACI normally blocks both BAFF and APRIL, a reduction in free sTACI may unleash APRIL signaling. And APRIL, as newer studies suggest, could have protective effects: stimulating astrocytes to produce anti-inflammatory IL-10, and promoting regulatory IgA+ plasma cells that help dampen CNS inflammation.

Why This Matters
These findings offer a potential explanation for a long-standing puzzle in MS treatment:

Why do anti-CD20 therapies succeed where atacicept failed?

Atacicept added more soluble TACI into the system, blocking APRIL and worsening disease. In contrast, ocrelizumab reduces available sTACI, potentially enhancing APRIL’s beneficial effects. This may foster an environment where regulatory plasma cells and IL-10–producing astrocytes keep inflammation in check.

It’s a reminder that the immune system doesn’t operate on a simple “on/off” switch—sometimes blocking one pathway inadvertently silences another that was doing helpful work.

Limitations and Next Steps
Of course, this study has caveats. The researchers could not directly measure BAFF/APRIL activity in MS lesions, only in blood and CSF. And while their data strongly support the idea that reduced sTACI enhances APRIL’s role, the precise downstream effects in patients remain to be fully mapped.

Future directions could include:

Testing whether patients with stronger sTACI reductions respond better clinically.

Exploring animal models with genetically engineered forms of TACI to confirm its role.

Investigating how these dynamics differ between RRMS, SPMS, and PPMS.

Final Thoughts
Ho et al.’s work highlights how ocrelizumab doesn’t just deplete B cells—it reshapes the molecular environment that governs their survival. By tipping the balance of the BAFF–APRIL system, the drug may promote anti-inflammatory pathways that go beyond simple cell depletion. This deeper understanding could pave the way for next-generation therapies that fine-tune B cell regulation more precisely—perhaps even leveraging APRIL’s protective effects rather than suppressing them. 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:
Ho, S., Oswald, E., Wong, H. K., Vural, A., Yilmaz, V., Tüzün, E., ... & Mader, S. (2023). Ocrelizumab treatment modulates B-cell regulating factors in multiple sclerosis. Neurology: Neuroimmunology & Neuroinflammation, 10(2), e200083.