IgG(3) (+) B cells are associated with the development of multiple sclerosis

OBJECTIVES: Disease‐modifying therapies (DMTs) targeting B cells are amongst the most effective for preventing multiple sclerosis (MS) progression. IgG(3) antibodies and their uncharacterised B‐cell clones are predicted to play a pathogenic role in MS. Identifying subsets of IgG(3) (+) 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. METHODS: We designed a 31‐parameter B‐cell‐focused mass cytometry panel to interrogate the role of peripheral blood IgG(3) (+) 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. RESULTS: Nine distinct CD20(+)IgD(−)IgG(3) (+) B‐cell subsets were identified. Significant changes in the proportion of CD21(+)CD24(+)CD27(−)CD38(−) and CD27(+)CD38(hi)CD71(hi) memory B‐cell subsets correlated with changes in serum IgG(3) 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. CONCLUSION: We have identified previously uncharacterised subsets of IgG(3) (+) 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 IgG(3) (+) B cells to impact MS progression.