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.
Competing Interests: The authors declare no conflict of interest.
(© 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)