The neonatal Fc Receptor (FcRn) in generalized myasthenia gravis (gMG)

Figure 1: Pathogenic IgG autoantibodies attack AChR, MuSK, and LRP4 at the NMJ.

Generalized myasthenia gravis (gMG) is a chronic, incapacitating, immunoglobulin G (IgG)-mediated autoimmune disease that causes intense muscle weakness and extreme fatigue.^1-4 It is driven by pathogenic IgG autoantibodies against key components of the neuromuscular junction (NMJ), including acetylcholine receptors (AChR), muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) (Fig. 1). When directed against AChR, IgG autoantibodies can often lead to the failure of neuromuscular transmission and skeletal muscle weakness through 3 distinct pathogenic actions: functional blockade of AChR, internalization and degradation of AChR, and activation of the complement system.^3-5

Figure 2: IgG binds to FcRn, avoiding lysosomal degradation and returning to circulation.

The pathogenic activity of IgG autoantibodies is perpetuated by neonatal Fc receptor (FcRn)-mediated recycling. Present in several cell types, including vascular endothelial cells, FcRn specifically binds to all IgG antibodies and rescues them from lysosomal degradation (Fig. 2). This extends their half-life to approximately 4 times that of other antibodies not recycled by FcRn, such as IgA and IgM. In prolonging their half-life, FcRn has been shown to help maintain the high concentrations of IgG antibodies, including pathogenic antibodies observed in gMG.^6-8

FcRn-mediated IgG recycling is being explored in gMG.^9,10

Watch the video to learn more about FcRn-mediated IgG recycling in gMG.