PMID- 37564637 OWN - NLM STAT- MEDLINE DCOM- 20230816 LR - 20230816 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease. PG - 1212757 LID - 10.3389/fimmu.2023.1212757 [doi] LID - 1212757 AB - Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity via interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies. CI - Copyright (c) 2023 Vakrakou, Karachaliou, Chroni, Zouvelou, Tzanetakos, Salakou, Papadopoulou, Tzartos, Voumvourakis, Kilidireas, Giannopoulos, Tsivgoulis and Tzartos. FAU - Vakrakou, Aigli G AU - Vakrakou AG AD - First Department of Neurology, Medical School, National and Kapodistrian University of Athens, Athens, Greece. FAU - Karachaliou, Eleni AU - Karachaliou E AD - Second Department of Neurology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece. FAU - Chroni, Elisabeth AU - Chroni E AD - Department of Neurology, School of Medicine, University of Patras, Patras, Greece. FAU - Zouvelou, Vasiliki AU - Zouvelou V AD - First Department of Neurology, Medical School, National and Kapodistrian University of Athens, Athens, Greece. FAU - Tzanetakos, Dimitrios AU - Tzanetakos D AD - Second Department of Neurology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece. FAU - Salakou, Stavroula AU - Salakou S AD - Second Department of Neurology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece. FAU - Papadopoulou, Marianna AU - Papadopoulou M AD - Second Department of Neurology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece. AD - Department of Physiotherapy, University of West Attica, Athens, Greece. FAU - Tzartos, Socrates AU - Tzartos S AD - Tzartos NeuroDiagnostics, Athens, Greece. AD - Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece. AD - Department of Pharmacy, University of Patras, Patras, Greece. FAU - Voumvourakis, Konstantinos AU - Voumvourakis K AD - Second Department of Neurology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece. FAU - Kilidireas, Constantinos AU - Kilidireas C AD - First Department of Neurology, Medical School, National and Kapodistrian University of Athens, Athens, Greece. AD - Department of Neurology, Henry Dunant Hospital Center, Athens, Greece. FAU - Giannopoulos, Sotirios AU - Giannopoulos S AD - Second Department of Neurology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece. FAU - Tsivgoulis, Georgios AU - Tsivgoulis G AD - Second Department of Neurology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece. AD - Department of Neurology, The University of Tennessee Health Science Center, Memphis, TN, United States. FAU - Tzartos, John AU - Tzartos J AD - Second Department of Neurology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece. LA - eng PT - Journal Article PT - Review DEP - 20230726 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Autoantibodies) RN - 0 (Immunoglobulin G) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - 0 (Receptors, Cholinergic) SB - IM MH - Humans MH - Autoantibodies MH - *Immunoglobulin G MH - Immunotherapy MH - *Myasthenia Gravis MH - Receptor Protein-Tyrosine Kinases MH - Receptors, Cholinergic PMC - PMC10410455 OTO - NOTNLM OT - CAAR-T cells OT - FcRn OT - IgG4 OT - MuSK OT - Myasthenia Gravis OT - anti-CD20 COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/08/11 06:43 MHDA- 2023/08/14 06:42 PMCR- 2023/01/01 CRDT- 2023/08/11 04:03 PHST- 2023/04/26 00:00 [received] PHST- 2023/07/05 00:00 [accepted] PHST- 2023/08/14 06:42 [medline] PHST- 2023/08/11 06:43 [pubmed] PHST- 2023/08/11 04:03 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1212757 [doi] PST - epublish SO - Front Immunol. 2023 Jul 26;14:1212757. doi: 10.3389/fimmu.2023.1212757. eCollection 2023.