Abstract Details

Title Molecular and Functional Characterization of Self-Reactive IgA Autoantibodies in Patients with Muscle-specific Tyrosine Kinase Myasthenia Gravis

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S34 - Updates on Myasthenia Gravis (2:12 PM-2:24 PM)

Poster/Presentation
Number 007

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.

Objective

To investigate the presence and functional role of IgA autoantibodies (Abs) in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG).

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.

Authors/Disclosures
Gianvito Masi, MD (Yale University) PRESENTER	Dr. Masi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen.
Kangzhi Chen	Mr. Chen has nothing to disclose.
Minh C. Pham (Yale University)	Mr. Pham has nothing to disclose.
Annabel Wallace	Ms. Wallace has nothing to disclose.
Richard J. Nowak, MD (Yale University School of Medicine)	Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion . Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for argenx. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Nowak has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Immunovant . Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cabaletta Bio . Dr. Nowak has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amgen. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cour Pharma. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janseen . The institution of Dr. Nowak has received research support from UCB. The institution of Dr. Nowak has received research support from Alexion . The institution of Dr. Nowak has received research support from Janseen. The institution of Dr. Nowak has received research support from Immunovant . The institution of Dr. Nowak has received research support from argenx. The institution of Dr. Nowak has received research support from Amgen. Dr. Nowak has a non-compensated relationship as a Member of the Board of Directors with Myasthenia Gravis Foundation of America (MGFA) that is relevant to AAN interests or activities.
Kevin O'Connor (Yale University School of Medicine)	Kevin O'Connor has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Kevin O'Connor has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Kevin O'Connor has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Viela Bio. Kevin O'Connor has stock in Cabaletta.

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