Molecular and Functional Characterization of Self-Reactive IgA Autoantibodies in Patients with Muscle-specific Tyrosine Kinase Myasthenia Gravis
Gianvito Masi1, Kangzhi Chen1, Minh Pham1, Annabel Wallace1, Richard Nowak1, Kevin O'Connor1
1Yale University
Objective:
To investigate the presence and functional role of IgA autoantibodies (Abs) in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG).
Background:
In MuSK MG, pathogenic IgG autoantibodies — mostly IgG4 — disrupt a key signaling cascade at the neuromuscular junction, leading to the dispersal of acetylcholine receptor (AChR) clusters and muscle weakness. Anti-CD20 B-cell depletion is clinically effective and results in a dramatic reduction of MuSK-specific IgG titers. Whether immunoglobulins of other isotypes contribute to the autoimmune response against MuSK remains undetermined, but compelling evidence from other autoimmune conditions suggests that IgA, an antibody isotype mainly found at mucosal sites, can exhibit self-reactivity and may be involved in disease pathogenesis.
Design/Methods:
Longitudinally collected sera from a MuSK MG cohort were screened for MuSK-specific IgA using an optimized, live cell-based assay. An established B-cell culturing strategy was employed to isolate MuSK-specific IgA B cells and generate patient-derived recombinant monoclonal Abs (mAbs). An in vitro disease model with pathogenic MuSK-specific fabs emulating IgG4 functional monovalency was leveraged to assess the functional effect of IgA mAbs on AChR clustering.
Results:
MuSK-specific IgA Abs were detected in 3 out of 26 (11.5%) MuSK MG patients and coexisted with MuSK IgG. Notably, in a patient with longitudinal samples spanning over 11 years of disease activity, we tracked a prolonged MuSK-specific IgA response that resisted multiple anti-CD20 therapeutic cycles. IgA1 mAbs from the three patients bound to different MuSK domains, competed with IgG4 mAbs for MuSK recognition, and antagonized IgG4-mediated pathogenic effects in vitro.
Conclusions:
MuSK-specific IgA Abs were found in a subset of patients with MuSK MG and antagonized the pathogenic effects of MuSK IgG4 in vitro. The detection of MuSK-specific IgA B cells may signal a previously unappreciated role of mucosal immunity in MuSK MG and other IgG4-mediated diseases, thus representing a worthy focus for future research.
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