Myasthenia Gravis: Pathogenic Effects of Autoantibodies on Neuromuscular Architecture

Abstract

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and therefore a severe fatigable skeletal muscle weakness. In this review, we give an overview of the history and clinical aspects of MG, with a focus on the structure and function of myasthenic autoantigens at the NMJ and how they are affected by the autoantibodies' pathogenic mechanisms. Furthermore, we give a short overview of the cells that are implicated in the production of the autoantibodies and briefly discuss diagnostic challenges and treatment strategies.

Keywords: AChR; Agrin; Lrp4; MuSK; autoantibodies; autoimmunity; history; immunopathogenesis; myasthenia gravis; neuromuscular junction.

Figure 1

Schematic presentation of the AChR and its cross-linking via the MIR. (A) Ribbon diagram of a single AChR α subunit viewed in an orientation such that the central axis of the pentamer is to the side (right). The membrane is indicated as a grey rectangle. α-helices M1–M4 are membrane-spanning and form the ion-permeable gate of the AChR. The MIR (shown in red) is located between β2- and β3-strands. (B) Ribbon diagram of the whole receptor viewed from the synaptic cleft. AChR α in blue with the MIR in red, AChR β in magenta, AChR δ in cyan, and AChR γ in grey. The MIR is shown in red. (C) Schematic presentation of autoantibody-induced inter-molecular cross-linking via the MIR. The molecular models were drawn using the molecular coordinates from the density maps deposited in the Protein Data Bank (PDB file accession number 3BG9 [112]) and the Web-based 3D Structure Viewer iCn3D.

Figure 2

Structure of Agrin, Lrp4, and MuSK. (A) Neuronal Agrin is anchored in the basal lamina via its laminin-binding NtA-domain. The third LG domain contains the B/Z splice insert (in red), which forms a loop critical for Lrp4 binding. (B) Lrp4 is comprised of a large extracellular domain, one transmembrane domain and a short cytoplasmic tail. The BP domains 1–3 and LDLa repeats 4–8 are sufficient for binding to MuSK. The first BP domain is critical for Agrin binding with supporting function of LDLa repeats 6–8 (dotted line). (C) MuSK interacts with Lrp4 via the Ig1 domain. Ig1 is also important for homodimerization. The kinase domain is phosphorylated and activated upon Agrin-induced binding of Lrp4. MuSK autoantibodies are predominantly directed against the Ig1 domain, less against the Ig2 domain (shown as red arrowhead), and occasionally against the CRD (dotted line). BP, β-propeller; CRD, cysteine-rich domain; LDLa, low-density lipoprotein receptor domain class A; KD, kinase domain; Lam EGF-like, laminin EGF-like; LG, laminin globular-like; NtA, N-terminal Agrin.

Figure 3

Pathogenic mechanisms of MG autoantibodies at the NMJ. (A) At the healthy NMJ, neural Agrin stimulation induces interaction between Lrp4 and MuSK, leading to MuSK autophosphorylation and activation and the phosphorylation and clustering of AChRs. A retrograde signal for presynaptic development is sent via Lrp4. (B) MG antibodies of IgG1 and IgG3 subclass against AChR have three pathogenic mechanisms: (1) Cross-linking and increased turnover of AChR lead to reduced AChR levels at the NMJ, (2) activation of the classical complement cascade, formation of the membrane attack complex (MAC) and complement-mediated damage of the postsynaptic membrane, and (3) direct block of function by preventing the binding of acetylcholine. (C) Bispecific IgG4 antibodies of IgG4 subclass against MuSK bind monovalently to MuSK and block Lrp4-MuSK interaction, thus interrupting the agrin-Lrp4-MuSK-Dok7 signaling axis and causing reduced densities of AChR at the synapse. A further effect is the disruption of a retrograde signal from Lrp4 to the motor neuron. Divalent binding of MuSK IgG leads to dimerization, autophosphorylation, and activation of MuSK independent of Agrin stimulation and causes the formation of ectopic AChR clusters. Created with BioRender.