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J Immunol. 2019 Aug 7. pii: ji1801236. doi: 10.4049/jimmunol.1801236. [Epub ahead of print]

Phenotypic and Ig Repertoire Analyses Indicate a Common Origin of IgD-CD27- Double Negative B Cells in Healthy Individuals and Multiple Sclerosis Patients.

Author information

1
Biomedical Research Institute, Hasselt University and School of Life Sciences, Transnational University Limburg, 3500 Hasselt, Belgium.
2
Department of Pathology, Yale School of Medicine, New Haven, CT 06520.
3
Department of Neurology, Yale School of Medicine, New Haven, CT 06519.
4
Rehabilitation and MS-Center, 3900 Pelt, Belgium.
5
Departamento de Inmunologia, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.
6
Department of Neurology, Yale School of Medicine, New Haven, CT 06519; kevin.oconnor@yale.edu steven.kleinstein@yale.edu veerle.somers@uhasselt.be.
7
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520; and.
8
Department of Pathology, Yale School of Medicine, New Haven, CT 06520; kevin.oconnor@yale.edu steven.kleinstein@yale.edu veerle.somers@uhasselt.be.
9
Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511.

Abstract

IgD-CD27- double negative (DN) B cells with proinflammatory characteristics are abnormally elevated in a proportion of multiple sclerosis (MS) patients. In this study, the origin and selection characteristics of DN B cells were studied in MS patients and healthy controls (HC). Expression of developmental markers on peripheral blood DN, IgD-CD27+ class-switched memory (CSM) and IgD+CD27- naive B cells of HC (n = 48) and MS patients (n = 96) was determined by flow cytometry. High-throughput adaptive immune receptor repertoire sequencing was performed on peripheral blood DN and CSM B cells of HC and MS patients (n = 3 each). DN B cells from HC and MS patients showed similar phenotypic and Ig repertoire characteristics. Phenotypic analysis indicated a mature state of DN B cells by low CD5, CD10, and CD38 expression. However, the frequency of CD95+ and IgA+ cells was lower in DN versus CSM B cells. DN B cells are Ag experienced, as shown by somatic hypermutation of their Ig genes in adaptive immune receptor repertoire sequencing, although they showed a lower mutation load than CSM B cells. Shared clones were found between DN and CSM B cells, although >95% of the clones were unique to each population, and differences in V(D)J usage and CDR3 physicochemical properties were found. Thus, DN B cells arise in HC and MS patients via a common developmental pathway that is probably linked to immune aging. However, DN and CSM B cells develop through unique differentiation pathways, with most DN B cells representing an earlier maturation state.

PMID:
31391234
DOI:
10.4049/jimmunol.1801236

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