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Generalised myasthenia gravis (gMG)
is characterised by impaired synaptic transmission
and damage at the neuromuscular junction (NMJ)1,2
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Acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) proteins are essential to normal signal transduction3,4

Acetylcholine (ACh) binds to AChRs at the NMJ, initiating a cascade that ultimately signals muscle contraction3,4

MuSK contributes to the high-density clustering of AChRs at the NMJ, resulting in increased efficiency of
signal transduction3,4

Most patients with gMG express pathogenic immunoglobulin G (IgG) autoantibodies
that inhibit normal AChR or MuSK function5-7

MG pathophysiology differs depending on which autoantibody is present6,7

AChR antibody positive (Ab+) gMG

IgG1 and IgG3 autoantibodies damage the NMJ through mechanisms such as functional blockade of AChRs (a), cross-linking or
internalisation of AChRs (b) and complement activation (c)3,7,8

Complement component 5 (C5) activation

C5 is a key protein involved in downstream complement activation, leading to the formation of the membrane attack complex
(MAC), which results in NMJ destruction, AChR loss, and subsequent impaired synaptic transmission3,9

MuSK Ab+ gMG

IgG4 autoantibodies cause progressive loss of AChRs at the NMJ and, ultimately, synaptic failure by blocking activation of MuSK (d)
and inhibiting AChR clustering (e), without engaging complement3,6,10

Neonatal Fc receptor (FcRn) recycling

FcRn is part of a natural salvage mechanism that recycles autoantibodies back into circulation, preventing their degradation in the
lysosome. By binding to AChR and MuSK IgG autoantibodies, FcRn allows their pathogenic effects to continue11–13

Ab+, antibody positive; ACh, acetylcholine; AChR, acetylcholine receptor; C5, complement component 5; gMG, generalised myasthenia gravis; FcRn, neonatal Fc receptor; IgG, immunoglobulin G; MAC, membrane attack complex; MG, myasthenia gravis; MuSK, muscle-specific tyrosine kinase; NMJ, neuromuscular junction.

References

1. Cutter G, Xin H, Aban I, et al. Cross-sectional analysis of the Myasthenia Gravis Patient Registry: disability and treatment. Muscle Nerve. 2019;60(6):707–15.
2.Vu T, Harvey B, Suresh N, et al. Eculizumab during pregnancy in a patient with treatment-refractory myasthenia gravis: a case report. Case Rep Neurol. 2021;13(1):65–72.
3.Albazli K, Kaminski HJ, Howard JF Jr. Complement inhibitor therapy for myasthenia gravis. Front Immunol. 2020;11:917.
4.Huang K, Luo YB, Yang H. Autoimmune channelopathies at neuromuscular junction. Front Neurol. 2019;10:516.
5.Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol. 2012;8(5):427–38.
6.Phillips WD, Vincent A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Res. 2016;5:F1000 Faculty Rev-1513.
7.Gilhus NE, Tzartos S, Evoli A, et al. Myasthenia gravis. Nat Rev Dis Primers. 2019;5(1):30.
8.Mantegazza R, Antozzi C. From traditional to targeted immunotherapy in myasthenia gravis: prospects for research. Front Neurol. 2020;11:981.
9.Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33(6):479–92.
10.Borges LS, Richman DP. Muscle-specific kinase myasthenia gravis. Front Immunol. 2020;11:707.
11. Wolfe GI, Ward ES, de Haard H, et al. IgG regulation through FcRn blocking: a novel mechanism for the treatment of myasthenia gravis. J Neurol Sci. 2021;430:118074.
12. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715–25.
13. Gable KL, Guptill JT. Antagonism of the neonatal Fc receptor as an emerging treatment for myasthenia gravis. Front Immunol. 2020;10:3052.