Figure 2.

Autoimmune diseases of peripheral nerve and neuromuscular junction: (A) Peripheral nerve: Guillain Barre syndrome and its variants have been linked to autoantibodies to gangliosides (glycosphingolipids) which are abundant in peripheral nerves. Autoantibodies cause segmental demyelination and disruption of Na channel clustering. GM1 and GalNAc-GD1a ganglioside are most abundant in axolemma of motor nerves and nodes of Ranvier and are associated with motor phenotypes. GQ1b is enriched in oculomotor cranial nerves and is linked with Miller Fisher syndrome. Multifocal motor neuropathy (MMN) is linked to anti-GM1 ganglioside antibodies. MGUS neuropathy is linked to autoantibodies to myelin associated glycoprotein (MAG). Chronic inflammatory demyelinating polyneuropathy (CIDP) is linked to autoantibodies (in <10% patients) to the nodal and paranodal adhesion proteins neurofascin 186 and 155 (NF186, NF155); contactin 1 (CNTN1); contactin associated protein (CASPR1 and 2) which disrupt axon-Schwann cell contacts. Adhesion molecules are attached to the cytoskeleton by proteins such as Ankyrin/Spectrin. (B) Neuromuscular junction: Myasthenia gravis caused by autoantibodies to the (i) post synaptic Acetylcholine receptor (AChR); IgG1 and IgG3 autoantibodies activate the complement cascade leading to structural damage to postsynaptic membrane and loss of AChR. (ii) Muscle skeletal receptor tyrosine protein kinase (MUSK). MUSK autoantibodies (Fab- arm exchanged monovalent IgG4) block agrin (released from motor nerve terminals) induced MUSK—LRP4 (low density lipoprotein receptor related protein 4) interaction, and disrupt clustering of AChR. Dok7, Downstream of tyrosine kinase 7: cytoplasmic protein that activates MUSK in concert with agrin and LRP4. Lambert-Eaton myasthenic syndrome is caused by autoantibodies to presynaptic P/Q type voltage gated calcium channels (VGCC) disrupting Ca²⁺ influx; Ca²⁺ is essential for release of ACh from presynaptic vesicles. Antigenic targets of autoantibodies are shown in red text in all figures. Autoantibodies associated with inflammatory myopathies are shown in Table 3.