Multiple sclerosis (MS) is a disability of long-term inflammatory illness in which your own immune cells mistakenly cause damage to myelin, the insulating sheath on nerves in your brain and spine. Treatments that temporarily deplete a type of B cell in the body’s immune system have also proven effective in reducing flare-ups and halting the progress of MS.
According to new Neuroscience News, based on the work of Professor Anne-Katrin Prbstel et al., this has generated an open question: “Why do these B-cell depletion therapies work so well and not only target bad cells but also even activate the helpful ones?” The key problem under investigation here is an unravelled gut-brain immune circuit: “How treatment targeted at depletion of B cells stimulates a naturally occurring gut immune B cell subset to home in the blood and CNS to suppress MS.”
Contribution of B cells in immune function
The basic principle underlying this research was that B cells are not all “bad” in MS; some play a role in driving the disease, and others support the immune system to turn off autoimmunity or have immune modulatory roles. Others keep immunity in check, acting as a “brake”; others stimulate myelin-damaging inflammation on myelin, and others have the opposite effect! Myelin targets immune B cells, and in MS, autoimmune reactions targeting myelin drive pathology and, in other contexts, can maintain an anti-inflammatory setting, keeping autoimmunity in check.
B cell depletion therapy, in particular treatment with an anti-CD20 monoclonal antibody, has historically been considered primarily a method of depleting damaging immune cells to decrease inflammation. This study introduces an additional dimension, the finding that depletion therapy appears to rebalance the body’s immune regulators and recruit regulatory B cells from the gut to the brain and spinal cord. In plain language, an agent that blocks an inflammatory immune attack also recruits a natural “peacekeeper” from the intestinal system into the brain system.
Read More: Study Reveals Potential Link Between Multiple Sclerosis and Reduced Alzheimer’s Risk
Control group & experimental group design
The cross-tissue human study analyses immune cells from the blood, cerebrospinal fluid (CSF), and intestinal mucosal tissue of MS patients treated with B-cell depleting therapies and control individuals and integrates deep single-cell transcriptomic and proteomic profiling with flow cytometry and immune receptor repertoire analysis to map the changes in individual B-cell subsets.
The researchers examined MS patients treated with anti-CD20 B-cell depletion therapy and compared them to control patients and to a preclinical autoimmune encephalomyelitis (EAE) model, the latter to offer a complementary analysis of possible mechanistic aspects. Among the partner centres was the University Hospital Bonn (UKB), with cooperation from the universities of Basel, Bonn, Toronto, Yale, and the Université de Lausanne as well as UMC Amsterdam. The principal investigator was Prof. Anne-Katrin Prbstel. The first authors were Dr Tradite Neziraj and Dr Elisabeth Pssnecker, with the publication in “Science Translational Medicine”: “Anti-CD20 B cell depletion is associated with elevated mucosal-originating circulating regulatory IgA B cells in multiple sclerosis.”
Correlation between B cell regulatory factors and disease control
The main point to take away is the observation of a higher frequency of regulatory, mucosal-derived IgA-expressing B cells in the circulation and CSF of the MS patients who received treatment with anti-CD20. Furthermore, the study highlights increased clonal overlap between the gut mucosal B cells and B cells found in the peripheral tissues (e.g., circulating and in the brain), which suggests these are B cells that are emigrating from the intestines.
The new finding highlights the following: B-cell-depleting therapies alter levels of B-cell-regulating molecules, such as BAFF (B-cell-activating factor) and APRIL (APRIL is for a proliferation-inducing ligand), and patients with higher levels of these molecules performed better overall with anti-CD20 treatment, he said. This meant that higher levels of B-cell-regulating factors coupled with the rise in protective gut-derived B cells correlated with better disease outcomes with both the suppression of neuroinflammation and the prevention of its worsening, and this suggests a difference in the presence of recruiting these protective regulatory cells as opposed to a general immune suppression.
Results from the author’s lens
The scientists conclude that the anti-CD20 B cell depletion drugs use the body’s normal protective strategies of mucosal immune regulation along with killing autoimmune B cells. B cells are not just eradicated; instead, their elimination changes the circumstances of the body such that these good B cells of the intestine can come out of their reservoir and help decrease inflammation in the central nervous system.
However, even from their point of view, this novel intestinal gut-brain-immune circuit provides interesting possibilities as a treatment target in the future; MS therapy can also focus on stimulating and drawing to the intestine particular intestinal regulatory B cells, which will make them more active and attract new cells there, thus making it a much more specific treatment that does not endanger general immunosuppression. Beyond MS, this manipulation could perhaps in the future lead to approaches for other autoimmune diseases and inflammatory disorders in which an impairment of the intestine, the associated microorganism, and the mucosal-related lymphocyte compartment contribute to their pathology.
Conclusion
In conclusion, our data suggest that anti-CD20 B-cell depletion in Multiple Sclerosis treatment induces higher levels of mucosa-derived, systemically circulating IgA⁺ regulatory B-cells and a greater overlap between gut and systemically circulated B-cell receptor repertoires, suggesting increased traffic of the protective regulatory cells from the gut to the CNS. This increase in the B-cell modifying factors is associated with increased favourable outcomes, suggesting a role for the gut-derived regulatory immune cells in mediating the benefits of B-cell depletion.
And the lesson for MS immunotherapy is not just to damp down the problematic immune system activity but also to harness and build up the body’s inherent regulators, particularly in the gut mucosa. Thinking of the gut as a source of the ‘good’ protective immune cells offers potential for more targeted, possibly gentler approaches to this and other neuroinflammatory disorders.
References +
- Neuroscience News. (2026d, July 22). B-cell depletion recruits protective gut cells in MS. Neuroscience News. https://neurosciencenews.com/b
- Greenfield, A. L., & Hauser, S. L. (2018). B‐cell therapy for multiple sclerosis: Entering an era. Annals of Neurology, 83(1), 13–26. https://doi.org/10.1002/ana.25119
