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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.

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Biomedical Research Institute, Hasselt University and School of Life Sciences, Transnational University Limburg, 3500 Hasselt, Belgium.
Department of Pathology, Yale School of Medicine, New Haven, CT 06520.
Department of Neurology, Yale School of Medicine, New Haven, CT 06519.
Rehabilitation and MS-Center, 3900 Pelt, Belgium.
Departamento de Inmunologia, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.
Department of Neurology, Yale School of Medicine, New Haven, CT 06519;
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520; and.
Department of Pathology, Yale School of Medicine, New Haven, CT 06520;
Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511.


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.


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