Selective Depletion of Autoreactive Plasma Cells as a Novel Strategy to Treat Acetylcholine Receptor Antibody-Positive Myasthenia Gravis

Authors
Laleh Khodadadi, Deborah Puppe, Dilara S. Cirillo, Carolina Martinez-Cingolani, Jens Klotsche, Andreas Pelz, Siegfried Kohler, Qingyu Cheng, Konstantinos Lazaridis, Michael Fichtner, Jan Pille, Andrey Kruglov, Marina Bondareva, Tobias Alexander, Andreas Radbruch, Andreas Meisel, Falk Hiepe


Lab

Journal
European Journal of Immunology

Abstract
Myasthenia gravis (MG) is a prototypic antibody-mediated autoimmune disease that affects the signal transmission at the neuromuscular junction (NMJ) and is characterized by skeletal muscle fatigability and weakness [1]. In approximately 85% of patients, the main target of autoantibodies is the acetylcholine receptor (AChR). Less common autoantigens include the muscle-specific kinase (MuSK) and the low-density lipoprotein receptor-related protein 4 (LRP4) [2]. The AChR is a pentameric transmembrane protein with a stoichiometry of α2βδε in adults [3]. Binding of antibodies to the extracellular domains leads to steric inhibition of the ligand-binding site between the subunits αε and αδ, antigenic modulation, and complement-dependent degradation of the muscle end-plate [2]. The extracellular domain of the α-subunit (αECD) has a predominant role in MG pathogenesis, as it contains the main immunogenic region (MIR) at the amino acid residues 67–76 [4] and is recognized by two-thirds of the AChR-specific antibodies [5]. Its accessible position toward the synaptic cleft and the occurrence of two MIRs per receptor predispose this subunit for effective antibody binding and subsequent antigenic modulation, explaining the immunogenic potential of the alpha subunit [6]. A recent meta-analysis pointed to a positive correlation between autoantibody levels and disease activity in patients with MG [7]. Nevertheless, it remains controversial whether antibody titres can guide treatment decisions. Anti-MIR antibody titers have been suggested to be a predictor of disease severity [8]. These data suggest a crucial role for AChR αECD-antibodies in MG pathogenesis, making them and the cells secreting them a potential therapeutic target.

Keywords/Topics
autoreactive plasma cells; autoimmunity; myasthenia gravis; selective depletion

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://onlinelibrary.wiley.com/doi/abs/10.1002/eji.70166

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