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

Felix Marsh-Wakefield, Thomas Ashhurst, Stephanie Trend, Helen M. McGuire, Pierre Juillard, Anna Zinger, Anderson P. Jones, Allan G. Kermode, Simon Hawke, Georges E. Grau, Prue H. Hart, Scott N. Byrne

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Abstract

Objectives: 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. Methods: 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. Results: Nine distinct CD20+IgDIgG3 + B-cell subsets were identified. Significant changes in the proportion of CD21+CD24+CD27CD38 and CD27+CD38hiCD71hi 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. Conclusion: 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.

Original languageEnglish
Article numbere1133
JournalClinical and Translational Immunology
Volume9
Issue number5
DOIs
Publication statusPublished - 1 May 2020

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    Marsh-Wakefield, F., Ashhurst, T., Trend, S., McGuire, H. M., Juillard, P., Zinger, A., Jones, A. P., Kermode, A. G., Hawke, S., Grau, G. E., Hart, P. H., & Byrne, S. N. (2020). IgG3 + B cells are associated with the development of multiple sclerosis. Clinical and Translational Immunology, 9(5), [e1133]. https://doi.org/10.1002/cti2.1133