Autoantibodies in neuromuscular disorders: a review of their utility in clinical practice

Abstract

A great proportion of neuromuscular diseases are immune-mediated, included myasthenia gravis, Lambert-Eaton myasthenic syndrome, acute- and chronic-onset autoimmune neuropathies (anti-MAG neuropathy, multifocal motor neuropathy, Guillain-Barré syndromes, chronic inflammatory demyelinating polyradiculoneuropathy, CANDA and autoimmune nodopathies), autoimmune neuronopathies, peripheral nerve hyperexcitability syndromes and idiopathic inflammatory myopathies. The detection of autoantibodies against neuromuscular structures has many diagnostic and therapeutic implications and, over time, allowed a better understanding of the physiopathology of those disorders. In this paper, we will review the main autoantibodies described in neuromuscular diseases and focus on their use in clinical practice.

Keywords: autoantibodies; clinical practice; detection method; neuromuscular diseases; review.

Figure 1

Main antibodies in neuromuscular disorders. (A) Neuromuscular junction. P/Q type anti-VGCC antibodies are directed against the voltage-gated calcium channel (VGCC or Cav2.1) in the axonal terminal, thus blocking calcium influx, acetylcholine vesicle fusion, and neuromuscular transmission. Anti-AChR antibodies target the nicotinic acetylcholine muscle receptor, preventing muscular membrane depolarization and generation of muscle action potential. Anti-LRP4 and anti-MuSK antibodies target the LRP4/MuSK complex, implicated in formation and maintenance of the neuromuscular junction and in acetylcholine receptor clustering. (B) Autonomic ganglia. Anti-ganglionic-α3-AChR antibodies are directed against the ganglionic acetylcholine receptor, preventing post-synaptic depolarization, blocking autonomic neurotransmission. P/Q type anti-VGCC antibodies also blocks the Cav2.1 present in presynaptic axonal terminal. (C) Dorsal root ganglia and dorsal horn. Leucin-rich glioma inactivated 1 (LGI1) was shown to be expressed in dorsal root ganglia and spinal cord dorsal horn, and is the target of anti-LGI1 antibodies. In central nervous system synapses, LGI1 binds to ADAM22/23 at the presynaptic side and modulate Kv1.1 (or voltage gated potassium channel; VGKC) channel; at the post-synaptic side, LGI1 binds to ADAM22 and modulate AMPA receptor. LGI1 therefore modulates central nervous system synaptic transmission. Anti-FGFR3 antibodies are directed against fibroblast growth factor receptor 3, which was shown to be expressed in small and large sensory neurons of the dorsal root ganglia in adult rats. Pathogenicity of anti-FGFR3 antibodies is currently unknown. (D) Peripheral nerve. Anti-gangliosides antibodies target gangliosides, glycoproteins that are expressed on neuronal membranes, Schwann cells and myelin. Anti-MAG antibodies recognizes myelin associated glycoprotein, a glycoprotein localized in periaxonal Schwann cells, which has function in glia-axon interaction. At the nodal and paranodal region, contactin 1, contactin-associated protein 1, neurofascin 155 and neurofascin 186, have different function such as axon-myelin and axon-Schwann cell binding and sodium channel clustering. Antibodies against paranodal/nodal proteins are responsible for auto-immune nodopathies. Contactin-associated protein 2 is expressed in the juxtaparanodal region (and also in dorsal root ganglia), connects to contactin 2 and organizes Kv1.1 (VGKC). Antibodies directed against Caspr2 cause peripheral nerve hyperexcitability. Collapsin response mediator protein-5 has been shown to be expressed in unmyelinated Schwann cells, and is involved in axon-Schwann cell interactions. Antibodies against CRMP5 are probably nonpathogenic, and a marker of paraneoplastic neurological syndrome. ACh, acetylcholine; AChR, Acetylcholine receptor; Cav2.1, voltage-dependent calcium channel 2.1; Caspr1, contactin-associated protein 1; Caspr2, contactin-associated protein 2; CNTN1, contactin 1; CNTN2, contactin 2; CRMP5, Collapsin response mediator protein-5; FGFR3, fibroblast growth factor 3; Kv1.1, voltage-gated potassium channel; LRP4, lipoprotein-related protein 4; MAG, myelin associated glycoprotein; MuSK, muscle kinase; NF155, neurofascin-155; NF186, neurofascin-186; VGCC, voltage gated calcium channel; VGKC, voltage-gated potassium channel.