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

doi:10.1002/cti2.1133

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

Clin Transl Immunology. 2020 Apr 29;9(5):e01133. doi: 10.1002/cti2.1133. eCollection 2020 May.

Authors

Felix Marsh-Wakefield^{1

2

3}, Thomas Ashhurst^{1

3

4

5

6}, Stephanie Trend^{7

8}, Helen M McGuire^{1

3

5

9}, Pierre Juillard^{1

2}, Anna Zinger², Anderson P Jones⁷, Allan G Kermode^{8

10}, Simon Hawke^{2

11}, Georges E Grau^{1

2}, Prue H Hart⁷, Scott N Byrne^{1

3

12}

Affiliations

¹ School of Medical Sciences Faculty of Medicine and Health The University of Sydney Sydney NSW Australia.
² Vascular Immunology Unit Department of Pathology The University of Sydney Sydney NSW Australia.
³ Charles Perkins Centre The University of Sydney Sydney NSW Australia.
⁴ Viral Immunopathology Laboratory Department of Pathology The University of Sydney Sydney NSW Australia.
⁵ Ramaciotti Facility for Human Systems Biology The University of Sydney Sydney NSW Australia.
⁶ Sydney Cytometry Facility Charles Perkins Centre The University of Sydney and Centenary Institute Sydney NSW Australia.
⁷ Telethon Kids Institute University of Western Australia Perth WA Australia.
⁸ Centre for Neuromuscular and Neurological Disorders Perron Institute for Neurological and Translational Science University of Western Australia Perth WA Australia.
⁹ Translational Immunology Laboratory Department of Pathology The University of Sydney Sydney NSW Australia.
¹⁰ Institute for Immunology and Infectious Disease Murdoch University Perth WA Australia.
¹¹ Central West Neurology and Neurosurgery Orange NSW Australia.
¹² Centre for Immunology and Allergy Research Westmead Institute for Medical Research Westmead NSW Australia.

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⁺IgD^-IgG₃ ⁺ B-cell subsets were identified. Significant changes in the proportion of CD21⁺CD24⁺CD27^-CD38^- and CD27⁺CD38^hiCD71^hi 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.

Keywords: B cells; clinically isolated syndrome; mass cytometry; multiple sclerosis; phototherapy.