Abstract
Background and Objectives To assess the molecular landscape of B-cell subpopulations across different compartments in patients with neuromyelitis optica spectrum disorder (NMOSD).
Methods We performed B-cell transcriptomic profiles via single-cell RNA sequencing across CSF, blood, and bone marrow in patients with NMOSD.
Results Across the tissue types tested, 4 major subpopulations of B cells with distinct signatures were identified: naive B cells, memory B cells, age-associated B cells, and antibody-secreting cells (ASCs). NMOSD B cells show proinflammatory activity and increased expression of chemokine receptor genes (CXCR3 and CXCR4). Circulating B cells display an increase of antigen presentation markers (CD40 and CD83), as well as activation signatures (FOS, CD69, and JUN). In contrast, the bone marrow B-cell population contains a large ASC fraction with increased oxidative and metabolic activity reflected by COX genes and ATP synthase genes. Typically, NMOSD B cells become hyperresponsive to type I interferon, which facilitates B-cell maturation and anti–aquaporin-4 autoantibody production. The pool of ASCs in blood and CSF were significantly elevated in NMOSD. Both CD19− and CD19+ ASCs could be ablated by tocilizumab, but not rituximab treatment in NMOSD.
Discussion B cells are compartmentally fine tuned toward autoreactivity in NMOSD and become hyperreactive to type I interferon. Inhibition of type I interferon pathway may provide a new therapeutic avenue for NMOSD.
Glossary
- AQP4=
- aquaporin-4;
- ASC=
- antibody-secreting cell;
- BCR=
- B-cell receptor;
- FACS=
- fluorescence activated cell sorting;
- GO=
- Gene Ontology;
- GSVA=
- Gene Set Variation Analysis;
- IFN=
- interferon;
- IFNAR-IN=
- interferon-α/β receptor-inhibitor;
- mAb=
- monoclonal antibody;
- MS=
- multiple sclerosis;
- NMOSD=
- neuromyelitis optica spectrum disorder;
- scRNA-seq=
- single-cell RNA sequencing;
- UMAP=
- uniform manifold approximation and projection for dimension reduction;
- UMI=
- unique molecular identifier
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
↵* These authors contributed equally to this work.
The Article Processing Charge was funded by the authors.
- Received March 23, 2021.
- Accepted in final form July 21, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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