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.
Highlights
Acquired myasthenia gravis (MG) is an autoimmune disorder caused by pathogenic autoantibodies that bind to membrane proteins at the neuromuscular junction, leading to muscle weakness [1]
We first tested whether B cell clones persisted across pre- and post-RTX repertoires by sequencing the B cell receptor (BCR) repertoire of unselected PBMCs at high depth using a bulk approach to capture a large number of sequences for identifying persistent clones
Recent studies have demonstrated the remarkable benefits of RTX-mediated B cell depletion therapy (BCDT) in muscle-specific kinase (MuSK) MG; relapses have been observed in some patients and are associated with the presence of circulating plasmablasts that express MuSK-specific autoantibodies [9, 10, 15, 16, 35, 36]
Summary
Acquired myasthenia gravis (MG) is an autoimmune disorder caused by pathogenic autoantibodies that bind to membrane proteins at the neuromuscular junction, leading to muscle weakness [1]. Through binding MuSK, serum-derived autoantibodies impair clustering of AChRs, and neuromuscular transmission, thereby causing disease [5]. A fraction of patients treated with the anti-CD20 BCDT agent rituximab (RTX) experienced postrituximab (post-RTX) relapses despite initial symptomatic responses and a fall in MuSK autoantibody titer [9, 12,13,14]. Post-RTX relapse in MuSK MG is associated with the presence of circulating plasmablast expansions, which include those that secrete MuSK-specific autoantibodies [15, 16]. Previous studies have shown that antigen-experienced plasma cells or plasmablasts are resistant to BCDT owing to their low CD20 expression [17,18,19,20]. The characteristics of antigen-experienced B cells that resist depletion remain unclear
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