Abstract
Objective: To identify by mass cytometry the B cell subsets that are associated with active relapse-remitting multiple sclerosis (MS) disease.
Background: The success of B cell-targeted therapies such as Rituximab and Ocrelizumab suggests that B cells play a prominent role in the pathogenesis of MS. However, not all B cell subsets are pathogenic with some B cells having immune regulatory properties that make them protective from MS disease. Identifying which B cell subsets are associated with active disease will allow for the design of more targeted therapies that inhibit these B cells specifically.
Design/Methods: Mass cytometry combines flow cytometry with mass spectrometry allowing for the simultaneous analysis of over 30 parameters. Peripheral blood mononuclear cells from 7 active (disease activity within 6 months of blood collection, confirmed by MRI) and 8 inactive MS patients were stained with our panel of 35 heavy-metal isotope-conjugated antibodies. Data was analysed using the clustering algorithm FlowSOM.
Results: Mass cytometry allowed us to analyse and phenotype B cell subsets with unparalleled depth, revealing that three major subsets of CD24+ CD38− IgG3+ switched memory B cells were significantly elevated in active MS disease: CD21+ CD27− (p = 0.0228, Kruskal-Wallis test with Dunn’s multiple comparisons test); CD21+ CD27+ (p = 0.0465); and CD21− CD27+ (p = 0078).
Conclusions: IgG3 antibodies are potent activators of the classical complement pathway and may indicate a previously unrecognised role for IgG3+ B cells in MS pathogenesis. If this proves to be the case, then IgG3+ B cells, or their products, may be a biomarker of MS relapse and/or offer a specific target for future disease modifying immunotherapeutic strategies.
Disclosure: Dr. Marsh-Wakefield has nothing to disclose. Dr. Juillard has nothing to disclose. Dr. Ashhurst has nothing to disclose. Dr. McGuire has nothing to disclose. Dr. Hawke has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck, Sanofi Genzyme, and Novartis.Dr. Grau has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck. Dr. Grau has received research support from Merck and Sanofi-Genzyme. Dr. Byrne has nothing to disclose.
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