**Autoimmune Epilepsy: New Development and Future Directions Directions**

**Autoimmune Epilepsy: New Development and Future** 

DOI: 10.5772/intechopen.70686

Sandra Orozco-Suarez, Angélica Vega-Garcia, Iris Feria-Romero, Lourdes Arriaga-Pizano, Emmanuel Rodriguez-Chavez and Israel Grijalva Iris Feria-Romero, Lourdes Arriaga-Pizano, Emmanuel Rodriguez-Chavez and Israel Grijalva

Sandra Orozco-Suarez, Angélica Vega-Garcia,

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

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

#### **Abstract**

[33] Merrit HH, Putnam TJ. Sodium diphenyl hydantoinate in the treatment of convulsive disorders. Journal of the American Medical Association. 1938;**111**(12):1068-1073. ISSN

[34] Merrit HH, Putnam TJ. Sodium diphenyl hydantoinate in the treatment of convulsive seizures. Toxic symptoms and their prevention. Archives of Neurology and Psychiatry.

[35] Merrit HH, Putnam TJ. Further experiences with the use of sodium diphenyl hydantoinate in the treatment of convulsive disorders. The American Journal of Psychiatry.

[36] Richards RK, Everett GM. Tridione: A new anticonvulsant drug. The Journal of Laboratory and Clinical Medicine. 1946;**31**(12):1330-1336. View at Google Scholar. View

[37] Schindler W, Blattner H. Über derivative des iminodibenzyls Iminostilben-Derivative.

[38] Vossen R. Uber die antikonvulsive Wirking von Succinimiden. Deutsche Medizinische

[39] Meunier H, Carraz G, Meunier Y, et al. Propriétés pharmacodynamiques de l'acide

[40] Buchtal F, Svensmark O. Aspects of the pharmacology of phenytoin (dilantin) and phenobarbital relevant to their dosage in the treatment of epilepsy. Epilepsia. 1960;**1**:373-

[41] Loiseau PJ. Clinical experience with new antiepileptic drugs: antiepileptic drugs in Europe. Epilepsia. 1999;**40**(6):S3-S8. View at Google Scholar. View at Scopus

[42] Magiorkinis E, Diamantis A, Sidiropoulou K,Panteliadis C. Highlights in the history of epilepsy: The last 200 years. Epilepsy Research and Treatment. 2014;**2014**. Article ID

[43] Gibbs FA, Gibbs E. Atlas of Electroencephalography. Oxford, UK: Boston City Hospital;

Helvetica Chimica Acta. 1961;**44**(3):562-753. View at Google Scholar

n-dipropylacetique. Therapie. 1963;**18**:435-438. View at Google Scholar

Wochenschrift. 1958;**83**:1227-1230. View at Google Scholar

582039. 13 pages. http://dx.doi.org/10.1155/2014/582039

384. View at Google Scholar. View at Scopus

0098-7484

12 Seizures

at Scopus

1941

1939;**42**(6):1053-1058. ISSN 0096-688

1940;**96**(5):1023-1027. ISSN 0002-953X

In recent years, there has been accumulating evidence to support an autoimmune etiology for some patients with drug-resistant seizures, typically in the context of an antibody-mediated encephalopathy; any seizure disorder that may be caused by pathogenic autoantibodies, are an example of autoimmune epilepsy. Autoimmunity is characterized by loss of immune tolerance that causes the destruction of cells and tissues. The largest complex histocompatibility system has had a strong association with autoimmune disease, although certain genes encoding cytokines and co-stimulatory molecules increase genetic susceptibility. In spite of having scientific advances in this research area, the conditions underlying mechanisms are unknown. **Goal**: this chapter aims to present in synthesized form, the genetic, immunological, and environmental factors role in the autoimmunity to epilepsy, as well as the therapeutic approach that has been used to control seizures, mainly where there is a suspected anti-neuronal-antibodies circulation. **Methods**: a review of the work achieved during the last years in patients with this condition provides information and experience in the diagnosis and treatment of this epilepsy type. For this, a systematic search of PUBMED is conducted using the search terms "autoimmune and epilepsy, auto antibodies and epilepsy, NMDA and epilepsy, AMPA and epilepsy, and GAD and epilepsy." The list of identified articles was complemented by additional searches for relevant articles in the reference section of the publications captured by the initial search.

**Keywords:** epilepsy, autoimmune encephalitis, NMDAr, immunotherapy

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

## **1. Introduction**

Epilepsy is considered, as one disease with the highest prevalence of 1% population suffering from it. This pathology is defined as a cerebral disorder that is characterized by the predisposition to generate epileptic seizures, as well as the neurobiological, cognitive, psychological and social factors associated with this condition [1]. There is evidence that specific neuronal auto antibodies with pathogenic potential may be present in a subset of patients with epilepsy. Importantly, it has recently been shown that some patients with these serum auto antibodies and mainly in CSF are often refractory to treatment with standard antiepileptic drugs (AEDs) and, on the other hand, may respond well to immunomodulatory therapies. In this way, it has been possible to make a therapeutic approach. The autoimmune basis led to the introduction of immunotherapy (IT) in some drug-resistant syndromes [2], prompted by an intensive search for self-antibodies (Abs) in epilepsy. The findings of limbic encephalitis associated with self-Abs against neuronal plasma membrane (receptors, ion channels) and intracellular proteins have further fueled this search. As seizures are key to the infestation manifest, this disorder serves as a model for understanding epilepsy-immune system interaction [3], evoking the possibility that said antibodies could cause patients with epilepsy alone, and leading to the search for self-Acs in patients with pharmacoresistant epilepsy (PE). Recent prospective study found neuronal auto-Acs in about 10% of pediatric patients with seizures, a rate twice as high as in controls with other systemic diseases; this creates a quandary for clinicians as to when treatment should be chosen in pharmaco-resistant epilepsy patients [4].

repertoire. Peripheral tolerance mechanisms include clonal anergy (absence of co-stimulatory molecules), unawareness and suppression by the activation of CD4 + CD25 + FOXP3 + regulatory T cells. In the antigen recognition, the segments α1 and β1 of the HLA molecules (both polymorphic), the processed peptide and the TCR are involved [7]. In fact, some processed peptides are only exposed in certain HLA molecules. So the molecules of the HLA itself also determine which peptide can be recognized by the mature T lymphocytes TCR. The HLA molecules of an individual, determine their immune response at two levels: during negative selection in the thymus and in the selection of peptides at the periphery [7, 8]. By the other way, the new lines of AEs research focused on the genes coding for molecules involved in the central tolerance and peripheral induction. These genes found on any chromosome encode for proteins involved in the lymphocytes and molecules selection, acting as death receptors or co-stimulatory molecules. Most AEs caused the difficulty in knowing the triggering agents. The AEs caused by a mutation in a single gene (monogenic), which are small, provide clinical and experimental evidence of the contribution of different control mechanisms of self-

Autoimmune Epilepsy: New Development and Future Directions

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

15

In epilepsy, there are no studies associating autoimmunity with genetic factors; however, studies have focused on other autoimmune diseases and focuses are mainly associated with major histocompatibility system. Several alleles of classical human leukocyte antigen (HLA) genes in the MHC locus have been linked to autoimmune diseases. The genes coding for HLA molecules are located on the short arm of chromosome 6 in the region of the major histocompatibility complex (MHC). The HLA-I genes encoded by the HLAA, B, C, E, F, and G genes are expressed in all the genes encoding the class I, II, and III molecules. The nucleated cells and the platelets and HLA-II molecules are products of the HLA-DP, DQ, DR, DM, DO genes and are constitutively expressed in B lymphocytes, monocytes, macrophages, dendritic cells, endothelial cells, intestinal epithelial cells, cells early hematopoietic and activated T lymphocytes. The class III region called HLA non-classical contains a collection of approximately 20 genes. This region includes those encoding complement proteins, components involved in the intracellular processing of peptides (TAP1, TAP2) and epithelial cell surface molecules (MICA-MICB) [10, 11]. The fundamental function of molecules HLA-I and HLA-II is to bind their own and foreign peptides in order to transport them to the cell membrane. Once exposed, they are recognized by the TCR, so they have a central role in the execution of the immune response. HLA-I molecules primarily present cytosolic (such as a viral or tumor) peptides to CD8+ cytotoxic T cells, whereas HLA class II molecules generally have extracellular peptides (such as bacterial) to CD4+ helper T lymphocytes. This functional division of peptide presentation ensures the activation of T cells (CD8+ and CD4+) and therefore the appropriate immune response for each type of antigen [10]. The HLA system has two fundamental properties that make it difficult to understand, the genes involved in the predisposition to AEs: polymorphism and linkage disequilibrium (LD) [12]. I-II molecules are the most polymorphic of the whole genome. This property determines that for each loci, there are multiple alleles whose DNA sequences only differ by a few nucleotides. These local mutations are known as single nucleotide polymorphism (NSP). Genes located in the MHC region have a

reactivity [9].

**2.1. Genetic diagnostics of epilepsies**

## **2. Genetic and clinical heterogeneity of epilepsy**

Autoimmune conditions are the result of multifactorial processes involving dysregulation of both the innate and adaptive immune system, and the possession of predisposing gene alleles, which ultimately at a certain moment in time "trigger" a sustained loss of self-tolerance resulting in an immune-mediated damage of autologous tissues [5]. The innate immune response is the host's first line of defense against invading microorganisms, while the adaptive immune responds to the infection in a time-delayed but antigen-specific manner. Adaptive immune responses are driven by specific components of bacteria or antigen, require several days to develop, and exhibit immunological memory for a lifetime, such that a second exposure to the same antigen results in an accelerated and specific response. Cell populations of the innate immune system, such as dendritic cells (DCs), which are antigen-presenting cells, promote primary T cells and B cell responses and therefore relate innate and adaptive immunity [6]. T cells that are reactive to self- antigens are largely deleted in the thymus in an active process termed thymic or central tolerance induction. Central tolerance induction occurs in both the immature thymus T cells and bone marrow for B cells. During the ontogeny of lymphocytes, T lymphocytes receptors (TCRs) that recognize high affinity, self-peptides exposed in The HLA molecules are deleted by clonal deletion, in order to avoid self-reactive clones. Only the clones whose TCRs recognize their own peptides with medium affinity, mature in secondary lymphoid organs. This shows that the HLA molecules themselves determine the TCR repertoire. Peripheral tolerance mechanisms include clonal anergy (absence of co-stimulatory molecules), unawareness and suppression by the activation of CD4 + CD25 + FOXP3 + regulatory T cells. In the antigen recognition, the segments α1 and β1 of the HLA molecules (both polymorphic), the processed peptide and the TCR are involved [7]. In fact, some processed peptides are only exposed in certain HLA molecules. So the molecules of the HLA itself also determine which peptide can be recognized by the mature T lymphocytes TCR. The HLA molecules of an individual, determine their immune response at two levels: during negative selection in the thymus and in the selection of peptides at the periphery [7, 8]. By the other way, the new lines of AEs research focused on the genes coding for molecules involved in the central tolerance and peripheral induction. These genes found on any chromosome encode for proteins involved in the lymphocytes and molecules selection, acting as death receptors or co-stimulatory molecules. Most AEs caused the difficulty in knowing the triggering agents. The AEs caused by a mutation in a single gene (monogenic), which are small, provide clinical and experimental evidence of the contribution of different control mechanisms of selfreactivity [9].

#### **2.1. Genetic diagnostics of epilepsies**

**1. Introduction**

14 Seizures

Epilepsy is considered, as one disease with the highest prevalence of 1% population suffering from it. This pathology is defined as a cerebral disorder that is characterized by the predisposition to generate epileptic seizures, as well as the neurobiological, cognitive, psychological and social factors associated with this condition [1]. There is evidence that specific neuronal auto antibodies with pathogenic potential may be present in a subset of patients with epilepsy. Importantly, it has recently been shown that some patients with these serum auto antibodies and mainly in CSF are often refractory to treatment with standard antiepileptic drugs (AEDs) and, on the other hand, may respond well to immunomodulatory therapies. In this way, it has been possible to make a therapeutic approach. The autoimmune basis led to the introduction of immunotherapy (IT) in some drug-resistant syndromes [2], prompted by an intensive search for self-antibodies (Abs) in epilepsy. The findings of limbic encephalitis associated with self-Abs against neuronal plasma membrane (receptors, ion channels) and intracellular proteins have further fueled this search. As seizures are key to the infestation manifest, this disorder serves as a model for understanding epilepsy-immune system interaction [3], evoking the possibility that said antibodies could cause patients with epilepsy alone, and leading to the search for self-Acs in patients with pharmacoresistant epilepsy (PE). Recent prospective study found neuronal auto-Acs in about 10% of pediatric patients with seizures, a rate twice as high as in controls with other systemic diseases; this creates a quandary for clinicians as to when treatment should be chosen in pharmaco-resistant epilepsy patients [4].

Autoimmune conditions are the result of multifactorial processes involving dysregulation of both the innate and adaptive immune system, and the possession of predisposing gene alleles, which ultimately at a certain moment in time "trigger" a sustained loss of self-tolerance resulting in an immune-mediated damage of autologous tissues [5]. The innate immune response is the host's first line of defense against invading microorganisms, while the adaptive immune responds to the infection in a time-delayed but antigen-specific manner. Adaptive immune responses are driven by specific components of bacteria or antigen, require several days to develop, and exhibit immunological memory for a lifetime, such that a second exposure to the same antigen results in an accelerated and specific response. Cell populations of the innate immune system, such as dendritic cells (DCs), which are antigen-presenting cells, promote primary T cells and B cell responses and therefore relate innate and adaptive immunity [6]. T cells that are reactive to self- antigens are largely deleted in the thymus in an active process termed thymic or central tolerance induction. Central tolerance induction occurs in both the immature thymus T cells and bone marrow for B cells. During the ontogeny of lymphocytes, T lymphocytes receptors (TCRs) that recognize high affinity, self-peptides exposed in The HLA molecules are deleted by clonal deletion, in order to avoid self-reactive clones. Only the clones whose TCRs recognize their own peptides with medium affinity, mature in secondary lymphoid organs. This shows that the HLA molecules themselves determine the TCR

**2. Genetic and clinical heterogeneity of epilepsy**

In epilepsy, there are no studies associating autoimmunity with genetic factors; however, studies have focused on other autoimmune diseases and focuses are mainly associated with major histocompatibility system. Several alleles of classical human leukocyte antigen (HLA) genes in the MHC locus have been linked to autoimmune diseases. The genes coding for HLA molecules are located on the short arm of chromosome 6 in the region of the major histocompatibility complex (MHC). The HLA-I genes encoded by the HLAA, B, C, E, F, and G genes are expressed in all the genes encoding the class I, II, and III molecules. The nucleated cells and the platelets and HLA-II molecules are products of the HLA-DP, DQ, DR, DM, DO genes and are constitutively expressed in B lymphocytes, monocytes, macrophages, dendritic cells, endothelial cells, intestinal epithelial cells, cells early hematopoietic and activated T lymphocytes. The class III region called HLA non-classical contains a collection of approximately 20 genes. This region includes those encoding complement proteins, components involved in the intracellular processing of peptides (TAP1, TAP2) and epithelial cell surface molecules (MICA-MICB) [10, 11]. The fundamental function of molecules HLA-I and HLA-II is to bind their own and foreign peptides in order to transport them to the cell membrane. Once exposed, they are recognized by the TCR, so they have a central role in the execution of the immune response. HLA-I molecules primarily present cytosolic (such as a viral or tumor) peptides to CD8+ cytotoxic T cells, whereas HLA class II molecules generally have extracellular peptides (such as bacterial) to CD4+ helper T lymphocytes. This functional division of peptide presentation ensures the activation of T cells (CD8+ and CD4+) and therefore the appropriate immune response for each type of antigen [10]. The HLA system has two fundamental properties that make it difficult to understand, the genes involved in the predisposition to AEs: polymorphism and linkage disequilibrium (LD) [12]. I-II molecules are the most polymorphic of the whole genome. This property determines that for each loci, there are multiple alleles whose DNA sequences only differ by a few nucleotides. These local mutations are known as single nucleotide polymorphism (NSP). Genes located in the MHC region have a high genetic association. This property is known as linkage disequilibrium (LD) and describes the tendency of certain genes to inherit together given their closeness. The above determines that the frequency of these genes (in a single haplotype) in the population is greater than their individual inheritance [13, 14]. Inside the AEs gene, the greatest association is with the molecules of the HLA. The siblings concordance with identical HLA is 15% compared to 1% for siblings with a non-identical HLA. This figure is indicative of the strong association between HLA molecules and a risk to develop an autoimmune disease. In some diseases, this association is stronger as in ankylosing spondylitis (AS), while in others, it is weaker than in the myasthenia gravis (MG) [15].

Nevertheless, infections can also modify the clinical manifestations associated with autoimmune epilepsy (AE) in such a way that infections are involved in the induction and protection of AEs in genetically predisposed individuals. This dual role underlying mechanism com-

Autoimmune Epilepsy: New Development and Future Directions

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

17

**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

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

pression offers new ways of controlling and treating these diseases [20].

region (DCT) (**Figure 1(A)**) [24, 25].

patient antibodies [29].

Genetic study with a cohort of 24 cases of Rasmussen (RE) autoimmune encephalitis, the human leukocyte antigen (HLA) class I and class II genes were sequenced; they got the association of three C\*07 alleles: 02:01:01, DQA1\*04:01:01, and DQB1\*04:02:01, that increased the relative risk of RE. It has been shown that HLA-B\*07:02 is a risk factor for Graves' disease. In addition, 33% of patients in that study had HLA-A\*03:01:01:01, which is considered a risk factor to multiple sclerosis. 17% of patients had a combination of three HLA class II alleles that were associated with type 1 diabetes; DQA1\*, 05\*01:01:01, DQB1\*02:01:01 and 20% patients showed a combination of HLA alleles (DQA1\*01:02:01:01, DQB1\*06:02:01, DRB1\*15:01:01:01), that have been linked to the risk of developing multiple sclerosis [15].

The same way, anti-leucine-rich glioma-inactivated (LGI1) encephalitis was associated [16] with the DRB1\*07:01-DQB1\*02:02 haplotype (10 patients, 91%) in HLA class II genes, as well as with B\*44:03 (8 patients, 73%) and C\*07:06 (7 patients, 64%) in the HLA class I region. The prevalence of these alleles in anti-LGI1 encephalitis was significantly higher than that in the epilepsy controls or healthy controls. By contrast, anti-NMDAR encephalitis was not associated with HLA genotypes. Additional analysis using HLA-peptide binding prediction algorithms and computational docking underpinned the close relationship; this finding suggests that most anti-LGI1 encephalitis develop in a population with specific HLA subtypes [17].

#### **2.2. Influence of environmental factors**

The concordance values between monozygotic twins are indicative of the role of environmental factors in the development of autoimmunity. Within this group are infections (viruses, parasites, bacteria, and fungi), hormones and immune system regulation loss. The action mechanism proposed for these factors is based on the release of pro-inflammatory substances inducing the danger signals expression and the consequent activation of auto-reactive T lymphocyte clones.

T cell TCRs recognize different peptides in the groove of the HLA molecule as long as they maintain the same charge distribution and spatial orientation. Hence, own and foreign molecules that have this similarity are recognized by lymphocytes and produce an immune response [18]. The creation of an inflammatory microenvironment increases the presence of antigens due to tissue damage and the expression of co-stimulatory molecules. In this medium, the anergized T lymphocytes may activate and stimulate the immune response against antigens themselves [19].

Nevertheless, infections can also modify the clinical manifestations associated with autoimmune epilepsy (AE) in such a way that infections are involved in the induction and protection of AEs in genetically predisposed individuals. This dual role underlying mechanism compression offers new ways of controlling and treating these diseases [20].

high genetic association. This property is known as linkage disequilibrium (LD) and describes the tendency of certain genes to inherit together given their closeness. The above determines that the frequency of these genes (in a single haplotype) in the population is greater than their individual inheritance [13, 14]. Inside the AEs gene, the greatest association is with the molecules of the HLA. The siblings concordance with identical HLA is 15% compared to 1% for siblings with a non-identical HLA. This figure is indicative of the strong association between HLA molecules and a risk to develop an autoimmune disease. In some diseases, this association is stronger as in ankylosing spondylitis (AS), while in others, it is weaker than in

Genetic study with a cohort of 24 cases of Rasmussen (RE) autoimmune encephalitis, the human leukocyte antigen (HLA) class I and class II genes were sequenced; they got the association of three C\*07 alleles: 02:01:01, DQA1\*04:01:01, and DQB1\*04:02:01, that increased the relative risk of RE. It has been shown that HLA-B\*07:02 is a risk factor for Graves' disease. In addition, 33% of patients in that study had HLA-A\*03:01:01:01, which is considered a risk factor to multiple sclerosis. 17% of patients had a combination of three HLA class II alleles that were associated with type 1 diabetes; DQA1\*, 05\*01:01:01, DQB1\*02:01:01 and 20% patients showed a combination of HLA alleles (DQA1\*01:02:01:01, DQB1\*06:02:01, DRB1\*15:01:01:01),

The same way, anti-leucine-rich glioma-inactivated (LGI1) encephalitis was associated [16] with the DRB1\*07:01-DQB1\*02:02 haplotype (10 patients, 91%) in HLA class II genes, as well as with B\*44:03 (8 patients, 73%) and C\*07:06 (7 patients, 64%) in the HLA class I region. The prevalence of these alleles in anti-LGI1 encephalitis was significantly higher than that in the epilepsy controls or healthy controls. By contrast, anti-NMDAR encephalitis was not associated with HLA genotypes. Additional analysis using HLA-peptide binding prediction algorithms and computational docking underpinned the close relationship; this finding suggests that most anti-LGI1 encephalitis develop in a population with specific HLA subtypes [17].

The concordance values between monozygotic twins are indicative of the role of environmental factors in the development of autoimmunity. Within this group are infections (viruses, parasites, bacteria, and fungi), hormones and immune system regulation loss. The action mechanism proposed for these factors is based on the release of pro-inflammatory substances inducing the danger signals expression and the consequent activation of auto-reactive T lym-

T cell TCRs recognize different peptides in the groove of the HLA molecule as long as they maintain the same charge distribution and spatial orientation. Hence, own and foreign molecules that have this similarity are recognized by lymphocytes and produce an immune response [18]. The creation of an inflammatory microenvironment increases the presence of antigens due to tissue damage and the expression of co-stimulatory molecules. In this medium, the anergized T lymphocytes may activate and stimulate the immune response

that have been linked to the risk of developing multiple sclerosis [15].

the myasthenia gravis (MG) [15].

16 Seizures

**2.2. Influence of environmental factors**

against antigens themselves [19].

phocyte clones.
