Specific Induction of Double Negative B Cells During Protective and Pathogenic Immune Responses.

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

doi:10.3389/fimmu.2020.606338

Abstract

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.

Highlights

Circulating B cell subsets are grossly classified as naïve, memory B cells and antibody secreting B cells that are generated following established maturation pathways [1]
We recently showed that CD27-IgD-CD20low double negative (DN) B cells are elevated in the peripheral blood (PB) of patients with active neuromyelitis optica spectrum disorder (NMOSD) and are closely related to disease relevant aquaporin-4 specific CSF B cell clones [6]
Little is known about the origin and function of DN B cells and the involvement in other inflammatory neurological diseases, including infectious disease and autoimmune diseases of the peripheral or central nervous system

Summary

Introduction

Circulating B cell subsets are grossly classified as naïve, memory B cells and antibody secreting B cells (plasmablasts and plasma cells) that are generated following established maturation pathways [1]. Novel B cells subsets including activated naive B cells [2] and double negative (DN) B cells [3] have gathered attention due to their expansion and activation in autoimmune disorders such as systemic lupus erythematosus. We recently showed that CD27-IgD-CD20low double negative (DN) B cells are elevated in the peripheral blood (PB) of patients with active neuromyelitis optica spectrum disorder (NMOSD) and are closely related to disease relevant aquaporin-4 specific CSF B cell clones [6]. Besides systemic lupus erythematosus (SLE) [2, 10,11,12], peripheral blood DN B cells have been shown to be elevated in rheumatoid arthritis (RA) [13, 14], Hashimoto’s thyreoiditis [15], and inflammatory bowel disease [16]. DN B cells are expanded following viral infection [17,18,19], bacterial sepsis [20], active malaria [21, 22], and immunogenic tumors such as non-small cell lung cancer [23]

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