2. Antibodies

Antibodies associated with LE are thought to be of peripheral origin that penetrates a leaky blood–brain barrier (BBB) or to be synthesized intrathecally. Most AE has higher serum than CSF antibody levels, implicating that antibodies are likely to be initiated by a peripheral immune response [12]. The autoantibodies are predominantly of IgG1 subclass. However, LGI1 and CASPR2 antibodies are mainly IgG4 subclass [13,14]. IgG4 antibody is hetero-bispecific (continuously undergoing half antibody exchange), hence less effective than IgG1 in crosslinking and internalizing the target antigen and does not fix complement [15]. In general, IgG1-associated AE (e.g., N-methyl-D-asparate receptor [NMDAR], γ-aminobutyric acid-B receptor [GABA-BR], and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor [AMPAR]) have more inflammatory signs than IgG4-associated AE (e.g., LGI1 and CASPR2) [16]. Nevertheless, complement-mediated neuronal loss was still observed in LGI1 and CASPR2-associated neurologic syndromes [17,18]. These patients had higher complement-fixing IgG1 subclass with more prolonged clinical course, more severe cognitive impairment, and frequent hippocampal atrophy in advanced stages of the disease [13,19].

Antibodies associated with LE target: (1) cell-surface receptors (GABA, AMPA, and glycine receptors); (2) ion channels (voltage-gated potassium channels [VGKC]); (3) neighboring proteins that stabilize channel complex into the membrane (LGI1 and CASPR2); (4) enzymes that catalyze the formation of neurotransmitters glutamic acid decarboxylase (GAD); and (5) intracellular proteins (Hu, Ma2, collapsin response-mediator protein-5 [CRMP5], and amphiphysin) [20]. These antibodies are classified as neuronal cell surface, synaptic vesicle, and intracellular antibodies according to the location of their targeting antigens. Antibodies against intracellular antigens are also known as onconeural antibodies because of their large association with tumors, and cause paraneoplastic syndromes (PNS) [21]. Pathologic effects include direct blockage of receptors and ion channels, indirect disruption with neighboring molecules interaction, and crosslinking and internalization of receptors to deplete them from the cell surface (Figure 1).

Figure 1. Antibodies and their pathogenic effects in limbic encephalitis. The pathologic effects of antibodies include blocking of receptors or ion channels, disruption of interaction with neighboring molecules, and crosslinking and internalization of receptors from cell surface. (1) CASPR2 and contactin2 antibodies inhibit the interaction between these proteins and reduce the clustering and surface expression of VGKC; (2) LGI1 antibody disrupts interaction between protein components such as LGI1 to ADAM22/23, downregulates VGKC and reduces AMPAR clustering and synaptic transmission; (3) AMPAR antibody causes cross-linking and receptor internalization; (4) NMDAR* antibody causes cross-linking and receptor internalization; (5) mGluR5 antibody causes decreased synaptic mGluR5 cluster density; (6) GAD antibodies target mostly the GAD65 subunits but also the GAD67 subunits, disrupting GABAergic signaling; (7) GABA-BR antibody prevents ligand binding to the receptor and alters receptor function; (8) GlyR antibody probably acts as antagonist to disrupt receptor function. Ab: antibody; ADAM: a disintegrin and metalloproteinase; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor; CASPR2: contactin associated protein-like 2; GABA-AR: γ-aminobutyric acid-A receptor; GABA-BR: γ-aminobutyric acid-B receptor, GAD: glutamic acid decarboxylase; GlyR: glycine receptor; LGI1: leucine-rich, glioma inactivated 1; mGluR5: metabotropic glutamate receptor 5; NMDAR: N-methyl-D-asparate receptor; PSD-95: postsynaptic density protein 95; VGKC: voltage-gated potassium channels.