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Single-cell repertoire tracing identifies rituximab-resistant B cells during myasthenia gravis relapses
Ruoyi Jiang, … , Steven H. Kleinstein, Kevin C. O’Connor
Ruoyi Jiang, … , Steven H. Kleinstein, Kevin C. O’Connor
Published June 23, 2020
Citation Information: JCI Insight. 2020;5(14):e136471. https://doi.org/10.1172/jci.insight.136471.
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Research Article Immunology

Single-cell repertoire tracing identifies rituximab-resistant B cells during myasthenia gravis relapses

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Abstract

Rituximab, a B cell–depleting therapy, is indicated for treating a growing number of autoantibody-mediated autoimmune disorders. However, relapses can occur after treatment, and autoantibody-producing B cell subsets may be found during relapses. It is not understood whether these autoantibody-producing B cell subsets emerge from the failed depletion of preexisting B cells or are generated de novo. To further define the mechanisms that cause postrituximab relapse, we studied patients with autoantibody-mediated muscle-specific kinase (MuSK) myasthenia gravis (MG) who relapsed after treatment. We carried out single-cell transcriptional and B cell receptor profiling on longitudinal B cell samples. We identified clones present before therapy that persisted during relapse. Persistent B cell clones included both antibody-secreting cells and memory B cells characterized by gene expression signatures associated with B cell survival. A subset of persistent antibody-secreting cells and memory B cells were specific for the MuSK autoantigen. These results demonstrate that rituximab is not fully effective at eliminating autoantibody-producing B cells and provide a mechanistic understanding of postrituximab relapse in MuSK MG.

Authors

Ruoyi Jiang, Miriam L. Fichtner, Kenneth B. Hoehn, Minh C. Pham, Panos Stathopoulos, Richard J. Nowak, Steven H. Kleinstein, Kevin C. O’Connor

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Figure 3

Example lineage tree of a disease-relevant B cell clone spanning both the pre- and post-RTX repertoire.

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Example lineage tree of a disease-relevant B cell clone spanning both th...
Sequences isolated from plasmablasts using single-cell PCR (scPCR) sequencing-based approaches and tested as monoclonal antibodies are denoted as “Plasmablast scPCR” (black dots); 3 of these bind MuSK and are denoted as “MuSK binding” (black arrowheads). Lineage tree topology and branch lengths were estimated using maximum parsimony, with edge lengths representing the expected number of nucleotide substitutions per site (see scale) as estimated using dnapars v3.967 (89). Tips are colored by antibody isotype, and each internal branch is colored by whether its descendant node was determined to have occurred in the pre- or post-RTX repertoire using a constrained maximum parsimony algorithm (see Methods).

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