Reemergence of pathogenic, autoantibody-producing B cell clones in myasthenia gravis following B cell depletion therapy

Abstract-Text (inkl. Referenzen)

Introduction: Myasthenia gravis (MG) is a prototypical autoantibody-mediated autoimmune disorder. In a small subset of patients, muscle-specific tyrosine kinase (MuSK) autoantibodies are present. MuSK MG patients respond well to CD20-mediated B cell depletion therapy (BCDT). However, relapse often occurs.

Methods: We developed a fluorescently labeled antigen to enrich for MuSK-specific B cells, which was validated with a novel Nalm6 cell line expressing a human MuSK-specific B cell receptor. B cells (≈ 2.6 million) from nine unique MuSK MG patients were screened for MuSK specificity. Human recombinant MuSK monoclonal antibodies (mAbs) were generated, characterized and the presence of persistent clonal relatives was investigated through B cell receptor repertoire tracing.

Results: We successfully isolated two MuSK-specific B cells from two of these patients. Both mAbs were strong MuSK binders and showed pathogenic capacity when tested in an AChR clustering assay. Clonal variants were detected at multiple timepoints spanning more than five years and reemerged after BCDT-mediated remission, predating disease relapse by several months.

Summary: These findings demonstrate that a reservoir of rare pathogenic MuSK autoantibody-expressing B cell clones survive BCDT and reemerge into circulation prior to manifestation of clinical relapse. Overall, this study provides both a mechanistic understanding of MuSK MG relapse and a valuable candidate biomarker for relapse prediction.