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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 4

Persistent B cell clones are disproportionately represented by the ASC phenotype.

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Persistent B cell clones are disproportionately represented by the ASC p...
(A) Unbiased clustering of single-cell transcriptomes from all study subjects is visualized by t-distributed stochastic neighbor embedding (t-SNE) and colored based on B cell subset assignment. (B) V(D)J sequences associated with persistent B cell clones are visualized over the t-SNE plot labeled in A. B cells are colored black or red if the heavy chain V(D)J sequence paired with the cell is part of a persistent B cell clone. B cells are colored red if the heavy chain V(D)J sequence paired with the cell has the same V(D)J sequence as one present in a pre-RTX bulk repertoire and black if the clonal relative differs by 1 or more SHM. (C) The relative fractions of persistent compared with nonpersistent B cells for the memory B cell cluster compared with ASC cluster. A 1-tailed t test was used to assess the significance of the null hypothesis that ASCs would not be enriched compared with memory B cells. Horizontal bars show the average frequency of a given B cell subset across patients. Frequencies belonging to the same patient are paired with a gray line. Data for the same n = 3 patients are shown for all panels. Violin plots are used in place of error bars to show the full range of values. Statistical differences are shown only when significant (***P < 0.001; **P < 0.01; *P < 0.05).

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