Peripheral B-cell dysregulation is associated with relapse after long-term quiescence in patients with multiple sclerosis

Felix Marsh-Wakefield; Pierre Juillard; Thomas M Ashhurst; Annette Juillard; Diana Shinko; Givanna H Putri; Mark N Read; Helen M McGuire; Scott N Byrne; Simon Hawke; Georges E Grau

doi:10.1111/imcb.12552

Peripheral B-cell dysregulation is associated with relapse after long-term quiescence in patients with multiple sclerosis

Immunol Cell Biol. 2022 Jul;100(6):453-467. doi: 10.1111/imcb.12552. Epub 2022 May 12.

Authors

Felix Marsh-Wakefield^{1

2

3}, Pierre Juillard¹, Thomas M Ashhurst^{4

5}, Annette Juillard¹, Diana Shinko^{4

6}, Givanna H Putri⁷, Mark N Read⁷, Helen M McGuire^{6

8}, Scott N Byrne^{5

9}, Simon Hawke^{1

10}, Georges E Grau¹

Affiliations

¹ Vascular Immunology Unit, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
² Liver Injury and Cancer Program, Centenary Institute, Sydney, NSW, Australia.
³ Human Cancer and Viral Immunology Laboratory, The University of Sydney, Sydney, NSW, Australia.
⁴ Sydney Cytometry Core Research Facility, The University of Sydney, Sydney, NSW, Australia.
⁵ School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁶ Ramaciotti Facility for Human Systems Biology, The University of Sydney, Sydney, NSW, Australia.
⁷ School of Computer Science, The University of Sydney, Sydney, NSW, Australia.
⁸ Translational Immunology Group, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁹ Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia.
¹⁰ Central West Neurology and Neurosurgery, Orange, NSW, Australia.

Abstract

B cells play a major role in multiple sclerosis (MS), with many successful therapeutics capable of removing them from circulation. One such therapy, alemtuzumab, is thought to reset the immune system without the need for ongoing therapy in a proportion of patients. The exact cells contributing to disease pathogenesis and quiescence remain to be identified. We utilized mass cytometry to analyze B cells from the blood of patients with relapse-remitting MS (RRMS) before and after alemtuzumab treatment, and during relapse. A complementary RRMS cohort was analyzed by single-cell RNA sequencing. The R package "Spectre" was used to analyze these data, incorporating FlowSOM clustering, sparse partial least squares-discriminant analysis and permutational multivariate analysis of variance. Immunoglobulin (Ig)A⁺ and IgG₁ ⁺ B-cell numbers were altered, including higher IgG₁ ⁺ B cells during relapse. B-cell linker protein (BLNK), CD40 and CD210 expression by B cells was lower in patients with RRMS compared with non-MS controls, with similar results at the transcriptomic level. Finally, alemtuzumab restored BLNK, CD40 and CD210 expression by IgA⁺ and IgG₁ ⁺ B cells, which was altered again during relapse. These data suggest that impairment of IgA⁺ and IgG₁ ⁺ B cells may contribute to MS pathogenesis, which can be restored by alemtuzumab.

Keywords: Alemtuzumab; B cells; mass cytometry; multiple sclerosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alemtuzumab / therapeutic use
Chronic Disease
Humans
Immunoglobulin A
Immunoglobulin G
Multiple Sclerosis* / drug therapy
Multiple Sclerosis, Relapsing-Remitting* / drug therapy
Recurrence

Substances

Immunoglobulin A
Immunoglobulin G
Alemtuzumab