IgG₃ ⁺ B cells are associated with the development of multiple sclerosis

Disease-modifying therapies (DMTs) targeting B cells are amongst the most effective for preventing multiple sclerosis (MS) progression. IgG₃ antibodies and their uncharacterised B-cell clones are predicted to play a pathogenic role in MS. Identifying subsets of IgG₃ ⁺ B cells involved in MS progression could improve diagnosis, could inform timely disease intervention and may lead to new DMTs that target B cells more specifically.

We designed a 31-parameter B-cell-focused mass cytometry panel to interrogate the role of peripheral blood IgG₃ ⁺ B cells in MS progression of two different patient cohorts: one to investigate the B-cell subsets involved in conversion from clinically isolated syndrome (CIS) to MS; and another to compare MS patients with inactive or active stages of disease. Each independent cohort included a group of non-MS controls.

Nine distinct CD20⁺IgD^-IgG₃ ⁺ B-cell subsets were identified. Significant changes in the proportion of CD21⁺CD24⁺CD27^-CD38^- and CD27⁺CD38^hiCD71^hi memory B-cell subsets correlated with changes in serum IgG₃ levels and time to conversion from CIS to MS. The same CD38^- double-negative B-cell subset was significantly elevated in MS patients with active forms of the disease. A third CD21⁺CD24⁺CD27⁺CD38^- subset was elevated in patients with active MS, whilst narrowband UVB significantly reduced the proportion of this switched-memory B-cell subset.

We have identified previously uncharacterised subsets of IgG₃ ⁺ B cells and shown them to correlate with autoimmune attacks on the central nervous system (CNS). These results highlight the potential for therapies that specifically target IgG₃ ⁺ B cells to impact MS progression.