Neuronal central nervous system syndromes probably mediated by autoantibodies

Abstract

In the last few years, a rapidly growing number of autoantibodies targeting neuronal cell-surface antigens have been identified in patients presenting with neurological symptoms. Targeted antigens include ionotropic receptors such as N-methyl-D-aspartate receptor or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, metabotropic receptors such as mGluR1 and mGluR5, and other synaptic proteins, some of them belonging to the voltage-gated potassium channel complex. Importantly, the cell-surface location of these antigens makes them vulnerable to direct antibody-mediated modulation. Some of these autoantibodies, generally targeting ionotropic channels or their partner proteins, define clinical syndromes resembling models of pharmacological or genetic disruption of the corresponding antigen, suggesting a direct pathogenic role of the associated autoantibodies. Moreover, the associated neurological symptoms are usually immunotherapy-responsive, further arguing for a pathogenic effect of the antibodies. Some studies have shown that some patients’ antibodies may have structural and functional in vitro effects on the targeted antigens. Definite proof of the pathogenicity of these autoantibodies has been obtained for just a few through passive transfer experiments in animal models. In this review we present existing and converging evidence suggesting a pathogenic role of some autoantibodies directed against neuronal cell-surface antigens observed in patients with central nervous system disorders. We describe the main clinical symptoms characterizing the patients and discuss conflicting arguments regarding the pathogenicity of these antibodies.

Associations between HLA and autoimmune neurological diseases with autoantibodies

“…LGI1 is a secreted protein that forms a trans-synaptic complex with ADAM23 (a disintegrin and metalloproteinase 23) and ADAM22, which interact with presynaptic voltage-gated potassium channels (VGKC) and postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), respectively [4,5]. Anti-LGI1 Ab are of IgG4 isotype, and therefore their pathogenic effect is thought to be due to blockage of the interaction between LGI1 and its ligands [4,5].…”

“…Contactin-associated protein-like 2 (CASPR2) plays an important role in the clustering of VGKC at the juxtaparanodes in the peripheral nervous system, but it is also expressed by inhibitory neurons in the central nervous system. Anti-CASPR2 Ab are mainly of IgG4 isotype as is the case with anti-LGI1 Ab [4,5]. They are associated with three major syndromes: LE, neuromyotonia (NMT), and Morvan's syndrome (MoS) [88,89].…”

“…In contrast, the identification of Ab against N-methyl-d-aspartate receptor (anti-NMDAR Ab) and other Ab related to autoimmune encephalitis has led to the description of completely new disorders that have revolutionized neurological practice [3]. Moreover, most of these Ab are thought to be pathogenic [4,5], although the primary trigger of the abnormal immune response is still unknown for the majority of these diseases.…”

Anti-NMAR-Enzephalitis — Mimikry der schizophrenen Erstmanifestation

“…Eine paraneoplastische Genese ist eher nicht die Regel und findet sich bei weit weniger als der Hälfte der Patienten. Wenn Karzinome gefunden werden, so betrifft das mehrheitlich weibliche Patienten (40 %, 12-45 Jahre; dabei Ovarialtumoren: 90 %) und weniger die ohnehin selteneren männlichen Patienten (5 %) [8]. Bezogen auf alle Fälle von Enzephalitis stellt die Anti-NMDAR-Enzephalitis nach der Herpes-Enzephalitis (HSV-1) und der akuten Encephalomyelitis disseminata die dritthäufigste Ursache dar [9].…”

Autoimmune encephalitis in psychiatric institutions: current perspectives

“…Various autoimmune encephalitis have been described, and each of them linked to the presence of specific autoantibodies directed against synaptic and neuronal cell surface antigens. The main targets appear to be N -methyl- d -aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropion acid receptor (AMPAR), leucine-rich glioma inactivated 1 (Lgi1), contactin-associated protein-like 2 (Caspr2), glutamate decarboxylase (GAD) or gamma-aminobutyric acid type B receptor (GABA B R),1,2 but a significant number of autoimmune encephalitis are due to rarer or unidentified targets. Clinical symptoms usually correlate with the associated antibody subtype.…”