Autoimmune Disorders of the Nervous System: Pathophysiology, Clinical Features, and Therapy

Abstract

Remarkable discoveries over the last two decades have elucidated the autoimmune basis of several, previously poorly understood, neurological disorders. Autoimmune disorders of the nervous system may affect any part of the nervous system, including the brain and spinal cord (central nervous system, CNS) and also the peripheral nerves, neuromuscular junction and skeletal muscle (peripheral nervous system, PNS). This comprehensive overview of this rapidly evolving field presents the factors which may trigger breakdown of self-tolerance and development of autoimmune disease in some individuals. Then the pathophysiological basis and clinical features of autoimmune diseases of the nervous system are outlined, with an emphasis on the features which are important to recognize for accurate clinical diagnosis. Finally the latest therapies for autoimmune CNS and PNS disorders and their mechanisms of action and the most promising research avenues for targeted immunotherapy are discussed.

Keywords: autoimmunity; clinical; nervous system; pathophysiology; therapy.

Figure 1

Autoimmmune diseases of the CNS: (A) Excitatory synapses: NMDAR encephalitis is caused by anti–NMDA receptor (NMDAR) antibodies binding and cross-linking GluN1 subunits, disrupting interaction of NMDAR with ephrin type B receptor 2 (EPHB2) causing internalization of NMDAR and impaired glutamergic transmission. LGI1 encephalitis is caused by auto-antibodies to leucine rich glioma inactivated protein 1 (LGI1), a neuronal glycoprotein secreted into the synapse. LGI1 interacts with presynaptic disintegrin and metalloproteinase domain-containing protein 2 (ADAM23) and postsynaptic ADAM22, modulates AMPA receptor trafficking and presynaptic Kv1, voltage gated potassium channel function. PSD95, post-synaptic density protein 95. Other receptors targeted: AMPAR; mGluR1/5. Inhibitory synapses: Autoantibodies to GABA type A receptor (GABA_AR) on inhibitory synapses may lead to encephalitis with intractable seizures. Autoantibodies to the glycine receptor (GlyR) cause painful spasms; progressive encephalitis with rigidity and myoclonus (PERM). Stiff person syndrome can also be caused by auto-antibodies to amphiphysin, a presynaptic protein expressed in all synapses, important in clathrin mediated endocytosis leading to a decreased number of presynaptic vesicles filled with neurotransmitter available for exocytosis. Higher tonic activity may make inhibitory synapses (release of GABA and glycine) especially vulnerable. GABARAP, GABA associated receptor protein. GAD, decarboxylates glutamate to GABA (not shown). (B) Neuromyelitis optica (NMO) is caused by auto-antibodies to Aquaporin 4 (AQP4) water channel expressed widely in the body including on astrocytic foot processes abutting capillary endothelial cells and ependymal cells. Predominant pathology is in spinal cord, optic nerve and brain peri-ependymal regions.

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.