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Specific induction of double negative B cells during protective and pathogenic immune responses

By Christoph Ruschil, Gisela Gabernet, Gildas Lepennetier, Simon Heumos, Miriam Kaminski, Zsuzsanna Hrasko, Martin Irmler, Johannes Beckers, Ulf Ziemann, Sven Nahnsen, Greg P. Owens, Jeffrey L. Bennett, Bernhard Hemmer, Markus C. Kowarik

Posted 11 Sep 2020
bioRxiv DOI: 10.1101/2020.09.08.285148

Double negative (DN) (CD19+CD20lowCD27−IgD−) B cells are expanded in patients with autoimmune and infectious diseases; however their role in the humoral immune response remains unclear. Using systematic flow cytometric analyses of peripheral blood B cell subsets, we observed an inflated DN B cell population in patients with variety of active inflammatory conditions: myasthenia gravis, Guillain-Barré syndrome, neuromyelitis optica spectrum disorder, meningitis/encephalitis, and rheumatic disorders. Furthermore, we were able to induce DN B cells in healthy subjects following vaccination against influenza and tick borne encephalitis virus. Transcriptome analysis revealed a gene expression profile in DN B cells that clustered with naïve B cells, memory B cells, and plasmablasts. Immunoglobulin VH transcriptome sequencing and analysis of recombinant antibodies revealed clonal expansion of DN B cells, that were targeted against the vaccine antigen. Our study suggests that DN B cells are expanded in multiple inflammatory neurologic diseases and represent an inducible B cell population that responds to antigenic stimulation, possibly through an extra-follicular maturation pathway. ### Competing Interest Statement C. Ruschil: reports no disclosures. G. Gabernet: reports no disclosures. G. Lepennetier: reports no disclosures. S. Heumos: reports no disclosures. M. Kaminski: reports no disclosures. Z. Hrasko reports no disclosures. M. Irmler: reports no disclosures. J. Beckers: reports no disclosures. U. Ziemann: has received grants from European Research Council (ERC), German Research Foundation (DFG), German Federal Ministry of Education and Research (BMBF), Bristol Myers Squibb, Janssen Pharmaceutica NV, Servier, Biogen Idec GmbH, and personal fees from Bayer Vital GmbH, Pfizer GmbH, CorTec GmbH, all not related to this work S. Nahnsen: reports no disclosures. G. P. Owens: reports no disclosures. J. L. Bennett: serves as a consultant for Clene Nanomedicine, Viela Bio, Chugai Pharmaceutical, EMD Serono, Equillium, Alexion, Roche, Genentech, and Novartis; and receives research support from Mallinckrodt. B. Hemmer: has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare and TG therapeutics; he or his institution have received speaker honoraria from Desitin; holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. M. C. Kowarik: receives financial support from Merck, Sanofi-Genzyme, Novartis, Biogen, Celgene and Roche, all not related to this study.

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