Myasthenia Gravis Related Antibodies

Myasthenia gravis (MG) is a prototypical antibody-mediated autoimmune disease affecting the neuromuscular junction (NMJ). In 2021, the diagnosed prevalence and incidence of MG in the United States were calculated to be 37.0 per 100,000 persons and 3.1 per 100,000 persons, respectively. Patients with MG exhibit a spectrum of weakness, ranging from limited ocular muscle involvement to life-threatening respiratory failure. The disease is characterized by the presence of specific antibodies that target components of the NMJ, primarily the acetylcholine receptor (AChR) and other antigens such as muscle-specific kinase (MuSK) and lipoprotein-related protein 4 (LRP4). Detecting pathogenic antibodies against these synaptic molecules in a patient with the typical clinical features is virtually diagnostic of MG and helps define the disease subtypes.

Fig. 1 Structure of the NMJ.
(Kaminski HJ.; et al. J Clin Invest. 2024)

Autoantibodies in MG

AChR Antibodies

Approximately 85% of MG patients have autoantibodies against AChRs, primarily of the IgG1 and IgG3 subclasses targeting the main immunogenic region (MIR). These antibodies induce pathogenicity through three main mechanisms:

Fig. 3 Mechanisms of AChR autoantibody-mediated pathology.
(Masi G & O'Connor KC. Curr Opin Neurol. 2022)

Activation of the Complement Cascade: Antibodies bind to AChR, activating the classical complement pathway via C1q, leading to (membrane attack complex) MAC formation and postsynaptic membrane lysis, causing severe NMJ damage.

Antibody-Induced Endocytosis of AChRs: Antibodies cross-link AChRs, promoting their internalization and degradation, which reduces AChR density at the NMJ.

Direct Functional Blockade of AChRs: Antibodies directly inhibit AChR function by preventing acetylcholine binding or blocking the ion channel.

MuSK Antibodies

MuSK antibodies in myasthenia gravis (MG) differ fundamentally from acetylcholine receptor (AChR) antibodies. They are predominantly of the IgG4 subclass, which does not activate the classical complement pathway or immune cells due to structural differences in the Fc region. MuSK antibodies primarily bind to the first Ig-like domain of MuSK, particularly around Ile96, disrupting the interaction between MuSK and Lrp4. This blockade reduces MuSK phosphorylation and interrupts the Agrin-Lrp4-MuSK-Dok-7 signaling axis, leading to decreased densities of acetylcholine receptors (AChRs) at the synapse and impaired neuromuscular transmission.

Antibodies to LRP4 & Agrin

LRP4 functions as a critical protein at the NMJ by binding agrin and initiating AChR clustering with the assistance of MuSK. The LRP4 antibodies are primarily IgG1 and IgG2 subtypes and follow similar clinical presentation to a mild form of early-onset MG, inhibit clustering of AChR, and appear not to strongly activate complement. Additionally, Some studies on Agrin autoantibodies suggest they may block Lrp4-Agrin interaction, impairing MuSK activation.

Fig. 4 Structure of Agrin, Lrp4, and MuSK.
(Koneczny I & Herbst R. Cells. 2019)