**3. Conventional etiological mechanisms of neural proteins as antibodies**

The target antigens that play a critical role in neuronal transmission and in plasticity include the N-methyl-D-aspartate (NMDA) receptor, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), the gamma-aminobutyric acid receptor (GABA), the glioma-inactivating leucine-rich protein (LGI1) and the contacting-associated protein 2 (CASPR2), a protein that plays a key role in the normal function of voltage-dependent potassium channels [21].

The structure of NMDA receptors (R-NMDA) are formed by combinations of different subunits: NMDAR1 (NR1), NMDAR2 (NR2), and NMDAR3 (NR3); which form a Ca++ permeable ion channel. A single gene encodes the NR1 subunit; however, transcription can generate at least eight isoforms, whereas for NR2-type subunits there are four different genes encoding NR2A, NR2B, NR2C, and NR2D7 subunits. Functional NMDA receptors are composed of heterotetramers, and formed by two dimers twisted by the subunits NR1-NR2, where in the NR1 subunit it possesses a glycine binding site and each in the NR2 subunit, a glutamate binding site, with two binding sites for glycine (S1) and two for glutamate (S2) in each receptor. The NR1-NR2 dimmer is considered the basic functional structure at each receptor, where different physiological and pharmacological binding sites are found for different ligands [22, 23]. Each ionotropic receptor subunit has similar molecular structure, which is organized into four functional domains, which are: an extracellular domain with the amino (N) terminal (DNT), a ligand binding domain (DBL), a region (M1–M4), where the M2 segment that partially enters the membrane forms the ion channel, and finally, a carboxyl domain (C) in the intracellular region (DCT) (**Figure 1(A)**) [24, 25].

In NMDARAS, IgG antibodies are directed to the N-terminal extracellular domain of the GluN1 subunit of the NMDA receptor (**Figure 1**), specifically an epitope region at GluN1 aa369 [26–28]; the cultures of dissociated rat hippocampal neurons and antibody-containing cerebrospinal fluid (CSF) from patients with NMDARAS have been used to study the molecular mechanism by which IgG antibodies cause hypo function of the NMDAR [29]; antibodies decrease the levels of synaptic NMDA receptor and disrupt NMDA receptor currents in cultured neurons. In addition, antibodies disrupt the interaction between NMDAR and the ephrin B2 receptor (EphB2R), a major stabilizer of NMDARs at postsynaptic sites, facilitating the displacement of NMDARs from the synapse [29]. The antibody does not act as a receptor antagonist, by modulating the physiological receptor binding domain, but causes capping and internalization of the receptor [30]. Antibody-mediated internalization is independent of NMDAR activity and does not occur as a compensatory response to the agonism of the receptor, suggesting that the mechanism of internalization is primarily NMDAR cross-linking by patient antibodies [29].

Besides, anti-AMPA-GluR3B antibodies have been associated with many pathological effects: they activate glutamate, AMPA receptors, and are involved in the processes of "excitotoxicity." The phenomenon is associated with various pathological states of the CNS including: epilepsy, hypoxia/ischemia, and trauma. In animal and *in vitro* models, anti-NMDA-NR1 antibodies may be highly pathogenic, as they may cause a decrease in surface NMDA receptors expressed in hippocampal neurons, and also decrease the density and synaptic localization of receptors NMDA. The expression of these NR1a subunits correlates with the distribution of high-affinity NMDA receptors by agonists. Anti-NMDA-NR1 antibodies induces reduction in expression through cross-linking and internalization of NMDA receptors. Such changes may impair glutamate signaling through NMDA receptors and lead to various abnormal neuronal

Autoimmune Epilepsy: New Development and Future Directions

http://dx.doi.org/10.5772/intechopen.70686

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Nevertheless, anti-AMPA-GluR3B antibodies induce many pathological effects that activate glutamate/AMPA receptors,which are involved in excitotoxic damage, the complement activation is modulated by regulatory proteins in which the activation plays a central role in the pathogenesis of brain damage and induces behavior and motor impairments. It has been observed in animal and *in vitro* models that anti-NMDA-NR1 antibodies can be highly pathogenic, as they may cause a decrease in surface NMDA receptors expressed in hippocampal neurons, and the density and synaptic localization of NMDA, probably by the internalization of receptors, which can impair glutamate signaling through NMDA receptors and lead to various neuronal/behavior/cognitive and psychiatric alterations. Knock-out mice to the GluR2 gene show reduced scanning and motor coordination. In these animals, the AMPA receptor-mediated synaptic transmission is reduced, but the long-term potentiation is better [34]. Knock-out mice to the GluR2 gene also exhibit increased cell death, possibly due to the excitotoxicity related to the greater insertion of the compensating homomeric GluR1 protein

**4. Clinical features of epilepsy-associated autoimmune encephalitis**

appears to represent approximately 40% of all cases [27, 37, 38].

Each of the currently known neuronal cell surface or synaptic autoantibody associates with a specific syndrome or limited set off symptoms (**Table 1**). NMDAR antibody-associated encephalitis is a recently described disorder in which infrequent seizures are associated with the presence of autoantibodies directed against the extracellular domain of the NR1 subunit of the NMDAR. This disorder was first described as a clinical entity in 2005, in one in four young women who developed acute psychiatric symptoms, seizures, memory deficit, in association with the presence of an ovarian teratoma. In a study of 100 patients, it was shown that although the majority are young women (mean age 23 years), the disorder could occur in men and in children. This fact has allowed the number of pediatric cases to grow steadily and

Symptoms of anti-NMDA receptor encephalitis develop and resolve in a multi-stage process; most patients experience a prodromal similar to a viral picture, which is followed by a pattern

/behavioral/cognitive/psychiatric disorders.

in AMPA receptors [35, 36].

**4.1. NMDA receptor**

**Figure 1.** (A) Structure of AMPA receptor subunits. The transmembrane topology is shown, along with the flip/flop alternatively spliced exon, and the two ligand-binding domains (S1 and S2). Glycosylation sites are shown as trees in the N-terminal region; this region is associated with immune response. (B) Flow cytometry demonstrates the presence of T lymphocytes of the CD8+ class with greater activation, as well as B lymphocytes; here it can be known that the immune process has extravasated to the cerebral parenchyma, (C) and (D) the tissue based assay. Mouse brain tissue sections, such as hippocampus are stained with the patient's serum or CSF by indirect immunoperoxidase technique. (C) Shows CSF immunoreaction at the hippocampus level of the cytoplasmic and a neuronal surface in D (anti-human IgG-Px, Abcamab97225). (E) TBA in F, shown a reaction at neuronal surface level that colocalizes with GAD65 / 67 (Alexafluor 546, Invitrogen Molecular probes). (G) Immunoblot, CSF recognizes 100 and 50 Kd proteins(Anti-human IgG-Px, Abcam- ab97225).

Encephalitis associated with antibodies against GABAB1 receptor is generally presented as limbic encephalitis, as well as drug-refractory seizures. In a series of 15 patients, the mean age of presentation was 62 years (range 24–75) and both sexes were similarly affected. About half of the patients had an associated tumor, either a small cell lung carcinoma or a neuroendocrine lung tumor. These patients usually have antibodies to various non-neuronal proteins of uncertain significance, which suggests a susceptibility to autoimmunity [30].

In the knockout mice to the GABAB1 receptor, a variety of neurological and behavioral alterations are found, including spontaneous seizures, increased anxiety, hyperactivity, hyperalgesia and memory impairment, suggesting a dysfunction of the limbic system [31, 32].

In contrast, patients present with limbic encephalitis in conjunction with antibodies to the AMPAR were not present with seizures as frequently: only 3/10 had seizures as presenting feature with one other patient having seizures after a relapse [33].

Besides, anti-AMPA-GluR3B antibodies have been associated with many pathological effects: they activate glutamate, AMPA receptors, and are involved in the processes of "excitotoxicity." The phenomenon is associated with various pathological states of the CNS including: epilepsy, hypoxia/ischemia, and trauma. In animal and *in vitro* models, anti-NMDA-NR1 antibodies may be highly pathogenic, as they may cause a decrease in surface NMDA receptors expressed in hippocampal neurons, and also decrease the density and synaptic localization of receptors NMDA. The expression of these NR1a subunits correlates with the distribution of high-affinity NMDA receptors by agonists. Anti-NMDA-NR1 antibodies induces reduction in expression through cross-linking and internalization of NMDA receptors. Such changes may impair glutamate signaling through NMDA receptors and lead to various abnormal neuronal /behavioral/cognitive/psychiatric disorders.

Nevertheless, anti-AMPA-GluR3B antibodies induce many pathological effects that activate glutamate/AMPA receptors,which are involved in excitotoxic damage, the complement activation is modulated by regulatory proteins in which the activation plays a central role in the pathogenesis of brain damage and induces behavior and motor impairments. It has been observed in animal and *in vitro* models that anti-NMDA-NR1 antibodies can be highly pathogenic, as they may cause a decrease in surface NMDA receptors expressed in hippocampal neurons, and the density and synaptic localization of NMDA, probably by the internalization of receptors, which can impair glutamate signaling through NMDA receptors and lead to various neuronal/behavior/cognitive and psychiatric alterations. Knock-out mice to the GluR2 gene show reduced scanning and motor coordination. In these animals, the AMPA receptor-mediated synaptic transmission is reduced, but the long-term potentiation is better [34]. Knock-out mice to the GluR2 gene also exhibit increased cell death, possibly due to the excitotoxicity related to the greater insertion of the compensating homomeric GluR1 protein in AMPA receptors [35, 36].
