WO2018088803A1

WO2018088803A1 - Autoimmune encephalitis type determination method using hla genotype testing

Info

Publication number: WO2018088803A1
Application number: PCT/KR2017/012614
Authority: WO
Inventors: 주건; 이상건; 정근화; 이순태; 김만호; 김태준
Original assignee: (주) 어드밴스드 엔티; (주)에이엔티랩스
Priority date: 2016-11-08
Filing date: 2017-11-08
Publication date: 2018-05-17
Also published as: KR102064895B1; KR20190057145A

Abstract

The present invention relates to a method for providing autoimmune encephalitis disease-related information, comprising the steps of: obtaining a biological sample isolated from a subject; identifying an HLA genotype from the biological sample; and providing autoimmune encephalitis-related information according to the HLA genotype.

Description

Autoimmune Encephalitis Type Discrimination Using HLA Genotyping

The present invention relates to a method of determining the type of autoimmune encephalitis using HLA genotyping.

Encephalitis is a neurological disorder that leaves serious aftereffect disorders if the correct diagnosis and proper treatment are not made promptly. Encephalitis can be roughly divided into infectious encephalitis and autoimmune encephalitis.

Autoimmune encephalitis is a newly discovered disease in recent decades. About 20-30% of all encephalitis patients are autoimmune encephalitis. In the case of autoimmune encephalitis, diagnosis is usually made through autoantibody detection, but a variety of causative antibodies and new antibodies continue to be discovered, which makes it difficult to accurately diagnose existing antibody test kits alone.

As such, existing diagnostic methods have difficulty in discriminating and accurately detecting infectious encephalitis and autoimmune encephalitis, and thus require a faster and more accurate method for providing information related to encephalitis disease and a device for providing information.

An object of the present invention is to provide a method for determining the detailed type of autoimmune encephalitis through HLA genotyping.

Method for providing information about autoimmune encephalitis disease according to the present invention comprises the steps of obtaining a biological sample isolated from the sample, identifying the HLA genotype from the biological sample and provides information related to the autoimmune encephalitis disease according to the HLA genotype It includes a step.

The providing of the information according to the present invention may include providing information related to autoimmune encephalitis disease according to a comparison between the identified HLA genotype and the genotype of the reference allele.

In addition, the reference allele according to the present invention is the HLA-DRB1 * 07: 01 allele, the HLA-DQB1 * 02: 02 allele, the HLA-B * 44: 03 allele and the HLA-C * 07: 06 allele It is characterized by any one of.

In addition, the information related to the autoimmune encephalitis disease according to the present invention is characterized by including the possibility of the occurrence of autoimmune encephalitis disease.

In addition, the possibility of occurrence of the autoimmune encephalitis disease according to the present invention is the HLA-DRB1 * 07: 01 allele, HLA-DQB1 * 02: 02 allele, HLA-B * 44: 03 allele and HLA-C * If at least one allele of the 07:06 allele is present in the biological sample, the likelihood of developing an autoimmune encephalitis disease is higher.

In addition, the autoimmune encephalitis diseases according to the present invention include anti-LGI1 encephalitis diseases and anti-NMDAR encephalitis diseases.

In addition, the biological sample according to the invention is characterized in that any one selected from synovial fluid, blood, lymph, urine, tear fluid, saliva or feces.

In addition, the presence of the biological sample according to the present invention is characterized by any one method selected from HLA-genotyping, serotyping assay or HLA microcytotoxicity assay.

In addition, the kit for predicting autoimmune encephalitis disease according to an embodiment of the present invention is HLA-DRB1 * 07: 01 allele, HLA-DQB1 * 02: 02 allele, HLA-B * 44: 03 allele and HLA-C * 07: 06 Includes means for detecting any of the alleles.

The method for providing information on autoimmune encephalitis disease according to the present invention provides an information on autoimmune encephalitis disease using HLA genotyping, thereby providing a more accurate and rapid treatment of autoimmune encephalitis disease.

FIG. 1 shows HLA-DRB1 * 07: 01-DQB1 * 02: 02, HLA-DRB1 * 07 in an experimental group of autoimmune encephalitis patients including anti-LGI1 encephalitis and anti-NMDAR encephalitis and a control group including epilepsy patients and the general population. : 01 allele, HLA-DQB1 * 02: 02 allele, HLA-B * 44: 03 allele, HLA-C * 07: 06 allele and HLA-C * 07: 06-B * 44: 03-DRB1 The carrier frequency of * 07: 01-DQB1 * 02: 02 is shown in a bar graph.

2 shows the HLA alleles found in patients with anti-LGI1 encephalitis.

Figure 3 shows that a portion of the LGI1 fragment and the HLA-DRB1 * 07: 01-DRA1 * 01: 01 heterodimer is bound.

EMBODIMENT OF THE INVENTION Hereinafter, preferable implementation of this invention is demonstrated in detail below. It should be understood, however, that the present invention may be embodied in many different forms and should not be limited to the described embodiments. It should be noted that the embodiments of the present invention described below are intended to sufficiently convey the spirit of the present invention to those skilled in the art.

"Human leukocyte antigen (HLA)" refers to human leukocyte antigen. HLA is located on chromosome 6p21.31 and comprises a region of about 3.6 Mbp depending on haplotype. HLA molecules are encoded by three gene groups, HLA class I, HLA class II and HLA class III genes. HLA class I proteins are encoded by the genes HLA-A, HLA-B, and HLA-C. HLA allele naming is done according to the 2010 WHO Naming Committee for Factors in the HLA System. Several digits are used to identify the HLA allele. Certain HLA loci (HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, and HLA-DP) are separated by the symbol * from the two digits assigning serological equivalents of the antigen.

In one example, HLA-A * 2402 represents a group of alleles from the HLA-A locus. "Two digit" resolution refers to a group of alleles composed of various alleles that encode similar antigens or share high sequence homology. This is followed by a colon and / or a two or three digit number, which identifies a particular coding protein (this level describes a "subtype" or "allele subtype"). In one example, HLA-A * 2402 is a specific allele within a group of alleles encoding HLA-A having a specific amino acid sequence. This “four digit” resolution represents a particular genomic sequence variation in the allele family that results in a difference in amino acid sequence of the encoded polypeptide product. Alleles can be further defined using additional colons and numbers that indicate synonymous DNA substitutions within the coding region of the allele or indicate DNA differences within the non-coding regions (9 digit level).

In one example, the “HLA-A * 2402 allele group” is an allele group (or type) from the HLA-A locus that consists of various alleles that encode HLA-A24 serological antigens or share high sequence homology. Refers to.

"Product of HLA-DRB1 * 07: 01, HLA-DQB1 * 02: 02, HLA-B * 44: 03 or HLA-C * 07: 06 allele" means HLA-DRB1 * 07: 01, HLA-DQB1 * Nucleic acid products of 02:02, HLA-B * 44: 03 or HLA-C * 07: 06 alleles and HLA-DRB1 * 07: 01, HLA-DQB1 * 02: 02, HLA-B * 44: 03 or HLA -Polypeptide product of the C * 07: 06 allele.

"Polypeptide products of HLA-DRB1 * 07: 01, HLA-DQB1 * 02: 02, HLA-B * 44: 03 or HLA-C * 07: 06 alleles" means HLA-DRB1 * 07: 01, HLA-DQB1 * 02: 02, polypeptide encoded by HLA-B * 44: 03 or HLA-C * 07: 06 allele, HLA-DRB1 * 07: 01, HLA-DQB1 * 02: 02, HLA-B * 44: 03 or a fragment of the polypeptide encoded by the HLA-C * 07: 06 allele and each serological antigen. "Nucleic acid product of HLA-DRB1 * 07: 01, HLA-DQB1 * 02: 02, HLA-B * 44: 03 or HLA-C * 07: 06 allele" means HLA-DRB1 * 07: 01, HLA-DQB1 * 02: 02, any DNA (genome, cDNA, etc.) or RNA product (e.g., pre-mRNA, mRNA, microRNA, etc.) of the HLA-B * 44: 03 or HLA-C * 07: 06 allele And fragments thereof.

Specimens according to the invention include mammals, preferably humans. More preferably, genetic variation and frequency of the drug response between races and ethnicities may be considered, and thus the specimen may be Korean.

The biological sample is not limited thereto, but is preferably selected from synovial fluid, blood, lymph, urine, tear fluid, saliva, oral mucosal cells or feces.

The experimental steps used for the examples of the present invention can be described as follows.

1. Target Selection

From June 2015 to December 2015, experiments were performed in patients with anti-LGI1 or anti-NMDAR encephalitis who visited or enrolled in a neurology department at a particular hospital. Clinically suspected, encephalitis patients were diagnosed based on the antibody diagnostics described below. First, patients with autoimmune encephalitis were defined as patients with acute appearance of typical symptoms including memory impairment, consciousness impairment and abnormal behavior. Selective causes of subacute encephalitis, such as infection, were excluded.

Next, the serum and cerebrospinal fluid of the patients were screened for the presence of brain activating autoantibodies using immunostaining with the brain of rats. Thereafter, cell-based synaptic-autoantibodies comprising anti-NMDAR, LGI1, CASPR2 (Contactin-associated protein-like 2), AMPA1, AMPA2, and GABAB-R (γ-aminobutyric-acid type B receptors) Test with immunocytochemistry kit (Euroimmun AG, Lubeck, Germany). Typical paraneoplastic autoantibodies, including anti-Hu, Yo, Ri, Ma2, CV2 / CRMP5 and Amphiphysin, were tested using an immunoblotting kit (Euroimmun). Demographic, clinical and diagnostic results of enrolled patients were analyzed.

2. HLA Genotyping

Genomic DNA was extracted from the peripheral blood of anti-LGI1 encephalitis patients or anti-NMDAR encephalitis patients and analyzed for HLA genotype by the method described above. The genotypes of the HLA-A, -B, -C, -DRB1, and -DQB1 genes of each subject were determined by direct DNA sequencing according to proven protocols (Biowitthus, Seoul, Korea). ) Was determined. In addition, HLA-C * 07: 01 and HLA-C * 07: 06 were identified by sequencing exon 5 and exon 6. HLA-A, -B and -C belong to HLA class I and HLA-DRB1 and -DQB1 belong to HLA class II. For the experiment, two controls were set up and the HLA genotyping data of epilepsy patients who visited the hospital due to the side effects of anti-epilemic drugs were compared with the epilepsy patient controls. In addition, the frequency of the previously reported HLA allele in the Korean population was used as the value of the normal control group.

3. Statistical Analysis

Fisher's exact assay was used to compare the frequency of HLA alleles or haplotypes between autoimmune encephalitis patients and normal controls. The association between HLA data and autoimmune encephalitis was expressed in odds ratio and 95% confidence intervals. For the comparison of HLA alleles and haplotypes, the Bonferroni method using multiple comparisons was used. The p-value determined by Fisher's exact assay is corrected by multiplying the total number of alleles detected at each locus, with 24 HLA-A, 44 B, 22 C, and 33 DRB1, DQB1 has 15 alleles. Only two-tailed corrections below 0.05 were considered statistically significant. Haplotypes were measured using Arlequin software version 3.5.2.2. The linkage disequilibrium value (LD) of the two-locus haplotype is the difference between the frequency of the measured haplotype and the product of the two alleles. The relative linkage disequilibrium value (RLD) is defined as the ratio of the absolute value of the maximum possible value (LD≥0) or the minimum possible value (LD <0) among the values that the LD may have. Statistical analysis was performed using SPSS software version 21.0 (SPSS, Chicago, IL, USA).

4. Prediction of HLA Peptide Binding

NetMHC 4.0 was used to predict HLA class I peptide binding, and ProPred and NetMHCII 2.2 were used to predict HLA class II peptide binding. NetMHC 4.0, ProPred and NetMHCII 2.2 are known to be the most accurate methods for predicting binding of Major histocompatibility complex (MHC) class I and II peptides. ProPred and the two NetMHC servers each use different algorithms called quantitative matrices and artificial neural networks. The LGI1 protein sequence obtained from UniProt accession number O95970 was submitted to each server. 14 HLA-A alleles, 18 HLA-B alleles, and 10 HLA-C alleles were collected from the overlap between alleles detected in the experiment and alleles provided by the NetMHC server, and HLA class I It was used in the analysis to predict the binding of. Fourteen HLA-DR alleles from the ProPred server and eleven HLA-DR alleles and six HLA-DQ alleles from the NetMHCII server were used for the comparison to predict binding of HLA class II.

5.in silico Docking

Computerized docking was performed to confirm the expected binding of the HLA-DRB1 * 07: 01 allele with the LGI1 fragment. Since the crystallographic structure of HLA-DRB1 * 07: 01 is not determined experimentally, homology models created using Swiss-Model and UCSF Chimera from the template structure of HLA-DRB1 * 01: 01 (Protein Data Bank code 3PDO) A heterodimer structure containing HLA-DRB1 * 07: 01 was used. The tertiary structure of the LGI1 fragment could be predicted from the PEPstrMOD server. Hydrogen was added using AutuDock Tools 1.5.6rc3, Gasteiger charge was assigned, and rotatable bonds were assigned to proteins. Using the AutoDock Vina software, the gap and twist number of the total peptide bonds were set to zero, followed by docking LGI1 fragments into the HLA-DRB1 * 07: 01 allele.

1. HLA genotyping in patients with autoimmune encephalitis

HLA genotyping was performed in 11 anti-LGI1 encephalitis patients and 17 anti-NMDAR encephalitis patients. The clinical characteristics of the patients and the distribution of HLA alleles are shown in Tables 1, 2 and 3 below.

Table 1 shows the clinical characteristics such as age, symptoms, cerebrospinal fluid (CSF, cerebrospinal fluid), and brain MRI in the anti-LGI1 encephalitis patients and anti-NMDAR encephalitis patients participated in the experiment in terms of the number and percentage of patients. will be. At this time, Pleocytosis in CSF * was defined as the leukocytes 5 / μl, CSF protein increase was defined as 45 mg / ㎗.

Table 2 above shows the clinical symptoms of 11 anti-LGI encephalitis patients and the clinical symptoms of 17 anti-NMDAR encephalitis patients. At this time, the * in Table 2 means the previous rib fracture, ** means to be hospitalized from the beginning of the onset.

Table 3 shows the HLA genotyping results of 11 anti-LGI1 encephalitis patients and 17 anti-NMDAR encephalitis patients. At this time, the P value of the underlined allele indicates that it is less than 0.05.

2. Subtypes of Unique HLA Alleles in Patients with Anti-LGI1 Encephalitis

From Tables 4 and 5 below it can be seen that anti-LGI1 encephalitis is associated with a unique HLA allele subtype.

Table 4 shows the frequency distribution of selected alleles or carrier frequency of selected haplotypes in the epilepsy patient control group, the normal control group and the autoimmune encephalitis patient group. In this case, Haplotype # 1 * means HLA-DRB1 * 07: 01-DQB1 * 02: 02, Haplotype # 2 * means HLA-C * 07: 06-B * 44: 03, and Haplotype # 3 * Means HLA-C * 07: 06-B * 44: 03 * DRB1 * 07: 01-DQB1 * 02: 02.

Table 5 shows a statistical analysis of alleles or haplotypes selected from the epilepsy patient control group and the normal control group compared to the autoimmune encephalitis patients experimental group. In this case, Haplotype # 1 * means HLA-DRB1 * 07: 01-DQB1 * 02: 02, Haplotype # 2 * means HLA-C * 07: 06-B * 44: 03, and Haplotype # 3 * Means HLA-C * 07: 06-B * 44: 03 * DRB1 * 07: 01-DQB1 * 02: 02.

The frequency of the HLA alleles obtained from Tables 4 and 5 is shown as a bar graph in FIG. 1.

FIG. 1A shows a bar graph of the frequency of HLA-DRB1 * 07: 01-DQB1 * 02: 02 haplotypes. The horizontal axis of the bar graph shows the LGI1 patient experimental group, the epilepsy patient experimental group, the normal control group, and the NMDAR patient experimental group, and the vertical axis of the bar graph represents the carrier frequency.

Referring to FIG. 1A, 10 anti-LGI1 patients (91% of 11 anti-LGI1 encephalitis patients) had both HLA-DRB1 * 07: 01 allele and HLA-DQB1 * 02: 02 allele . However, the frequency of HLA-DRB1 * 07: 01-DQB1 * 02: 02 haplotype was 9% in the epilepsy group and 12% in the healthy control group. . This confirms that the frequency of the HLA-DRB1 * 07: 01 allele and HLA-DQB1 * 02: 02 allele is important in the association between haplotype and anti-LGI1 encephalitis (** p <0.001, OR = 106.7). vs epilepsy patients, ** p <0.001, OR = 73.6 vs normal controls).

1B shows the frequency of the HLA-DRB1 * 07: 01 allele in a bar graph. The horizontal axis of the bar graph represents the LGI1 patient experimental group, the epilepsy patient experimental group, the normal control group and the NMDAR patient experimental group, and the vertical axis of the bar graph represents the carrier frequency (** p <0.001).

1C shows the frequency of the HLA-DQB1 * 02: 02 allele in a bar graph. The horizontal axis of the bar graph represents the LGI1 patient experimental group, the epilepsy patient experimental group, the normal control group and the NMDAR patient experimental group, and the vertical axis of the bar graph represents the carrier frequency (** p <0.001).

Referring to B and C of FIG. 1, when each allele is analyzed separately, both the HLA-DRB1 * 07: 01 allele and the HLA-DQB1 * 02: 02 allele are independently associated with anti-LGI1 encephalitis You can see this.

1D shows a bar graph of the frequency of the HLA-B * 44: 03 allele. The horizontal axis of the bar graph represents the LGI1 patient experimental group, the epilepsy patient experimental group, the normal control group and the NMDAR patient experimental group, and the vertical axis of the bar graph represents the carrier frequency (** p <0.001).

Figure 1 E shows the frequency of the HLA-C * 07: 06 allele in a bar graph. The horizontal axis of the bar graph represents the LGI1 patient experimental group, the epilepsy patient experimental group, the normal control group and the NMDAR patient experimental group, and the vertical axis of the bar graph represents the carrier frequency (** p <0.001).

Referring to D and E of FIG. 1, the frequency of the HLA-B * 44: 03 and HLA-C * 07: 06 alleles among the subtypes of HLA class I were all high in the experimental group of patients with anti-LGI1 encephalitis. And it was confirmed that the frequency higher than that in the normal control group (both p <0.001). The HLA-B * 44: 03 allele was found in 8 anti-LGI1 encephalitis patients, 73% of 11 anti-LGI1 encephalitis patients, and the HLA-C * 07: 06 allele was found in 11 anti-LGI1 encephalitis patients Seven of these patients were found in anti-encephalitis patients.

FIG. 1F shows a bar graph of the frequency of HLA-C * 07: 06-B * 44: 03-DRB1 * 07: 01-DQB1 * 02: 02 haplotype. The horizontal axis of the bar graph represents the LGI1 patient experimental group, the epilepsy patient experimental group, the normal control group and the NMDAR patient experimental group, and the vertical axis of the bar graph represents the carrier frequency (** p <0.001).

In addition, the relationship between the specific HLA type and anti-LGI1 encephalitis can be confirmed through FIG.

2 is a visualization of HLA alleles in a specific experimental group of patients with anti-LGI1 encephalitis. The solid line in bold between the HLA-DQB1 allele and the HLA-DRB1 allele indicates an absolute linkage disequilibrium (relative relative disequilibrium factor = 1) and is defined between the HLA-B allele and the HLA-C allele. The dashed line represents moderate linkage disequilibrium (relative linkage disequilibrium coefficient = 0.75).

From these results, the HLA-DRB1 * 07: 01-DQB1 * 02: 02 haplotype of HLA class II shows the strongest susceptibility to anti-LGI1 encephalitis, the HLA-B * 44: 03 allele and HLA of HLA class I -C * 07: 06 allele also showed significant association with anti-LGI1 encephalitis.

3. Lack of HLA Susceptibility Locus for Anti-NMDAR Encephalitis

The anti-NMDAR encephalitis experimental group showed no special association with any HLA allele. It can be seen from Table 4 and Table 5 that the HLA-A * 02: 06 and HLA-B * 40: 06 alleles show a high frequency in patients with anti-NMDAR encephalitis, but the difference is not statistically significant. Can be.

In addition, the HLA-DRB1 * 07: 01-DQB1 * 02: 02 haplotype, which was frequently seen in patients with anti-LGI1 encephalitis, was observed only in one of 17 anti-NMDAR encephalitis patients. The HLA-B * 44: 03 allele was observed in two anti-NMDAR encephalitis patients, and the HLA-C * 07: 06 allele was observed in one anti-NMDAR encephalitis patient.

4. HLA-DRB1 * 07: 01 Predicting Binding of Allele and LGI1 and Using Computerized Docking

The HLA peptide binding prediction algorithm established the association between HLA allele subtypes and anti-LGI1 encephalitis. Using algorithms using quantitative matrices and artificial neural networks, it was expected that of all available HLA class II alleles, the HLA-DRB1 * 07: 01 allele had the highest affinity for the LGI1 sequence. Predicted by an algorithm using quantitative matrix (ProPred), the HLA-DRB1 * 07: 01 allele predicted the highest score of 9.4, out of 14 HLA-DR alleles, and the target sequence was 'FLFTPSLQL' and LGI1. The 87th amino acid position from the N-terminus of the protein. Predicted by an algorithm using an artificial neural network (NetMHCII), among the available HLA-DR alleles and HLA-DQ alleles, the HLA-DRB1 * 07: 01 allele is the highest with the same key sequences 'FLFTPSLQL' and 3.7 nM It was predictable to have affinity.

Therefore, it can be seen that the 'FLFTPSLQL' sequence, which is part of the Leucine-rich repeat domain of the LGI1 protein, is likely to be a ligand of the HLA-DRB1 * 07: 01 allele. In predicting HLA class I peptide binding, the HLA-A * 31: 01 allele was predicted to have the highest affinity of 2.4 nM. In this case, the lower the affinity in binding prediction, the higher the affinity. Although it is not logical to directly compare the binding affinity between HLA class I and II alleles, there are 13 HLA-A alleles, 18 HLA-B alleles and 10 except for the HLA-A * 31: 01 allele. None of the HLA-C alleles predicted to have higher affinity than the HLA-DRB1 * 07: 01 allele. The affinity between the HLA-B * 44: 03 allele and the LGI1 protein was predicted to be 145.32 nM, but the HLA-C * 07: 06 allele was unpredictable.

Through this, docking using a ligand and a computer of the HLA-DRB1 * 07: 01 allele was performed. A computer-aided docking program combines a heterodimer consisting of the 'FLFTPSLQL' sequence, the HLA-DRB1 * 07: 01 allele and the HLA-DRA1 * 01: 01 allele with a -12.9 kcal / mol docking score (ΔG). Predicted to be.

Figure 3 shows that the HLA-DRB1 * 07: 01 allele, the heterodimer of the HLA-DRA1 * 01: 01 allele and the 'FLFTPSLQL' sequence of the LGI1 fragment are bound.

HLA-DRB1 * 07: 01-DQB1 * 02: 02 haplotype found in 10 of 11 patients and HLA-C * 07: 06-B * 44: 03-DRB1 found in 7 patients * 07: 01-DQB1 * 02: 02 The distribution of HLA alleles in anti-LGI1 encephalitis characterized by haplotype can be found to be generally uniform.

As such, the technical configuration of the present invention described above can be understood by those skilled in the art that the present invention can be implemented in other specific forms without changing the technical spirit or essential features of the present invention.

Therefore, the exemplary embodiments described above are to be understood as illustrative and not restrictive in all aspects, and the scope of the present invention is indicated by the following claims rather than the foregoing detailed description, and the meaning and scope of the claims and their All changes or modifications derived from equivalent concepts should be construed as being included in the scope of the present invention.

Claims

Obtaining a biological sample isolated from the sample;

Identifying HLA genotypes from the biological sample; And

Providing autoimmune encephalitis disease information according to the HLA genotype;

How to provide information about autoimmune encephalitis disease.
The method of claim 1,

Providing the information,

Providing information on the likelihood of occurrence of a specific autoimmune encephalitis disease in accordance with the comparison of the identified HLA genotype with the genotype of the reference allele.

How to provide information about autoimmune encephalitis disease.
The method of claim 2,

The reference allele is any one of the HLA-DRB1 * 07: 01 allele, the HLA-DQB1 * 02: 02 allele, the HLA-B * 44: 03 allele and the HLA-C * 07: 06 allele Characterized

How to provide information about autoimmune encephalitis disease.
The method of claim 3,

The specific autoimmune encephalitis disease comprises at least one of an anti-LGI1 encephalitis disease or an anti-NMDAR encephalitis disease

How to provide information about autoimmune encephalitis disease.
The method of claim 4, wherein

The possibility of developing the autoimmune encephalitis disease

At least one allele of the HLA-DRB1 * 07: 01 allele, the HLA-DQB1 * 02: 02 allele, the HLA-B * 44: 03 allele and the HLA-C * 07: 06 allele may be used in the biological sample. If present in

Characterized by a higher probability of developing autoimmune encephalitis disease than normal

How to provide information about autoimmune encephalitis disease.
The method of claim 1,

The biological sample is derived from synovial fluid, blood, lymph, urine, tear fluid, saliva, or feces.

Whichever one is chosen,

How to provide information about autoimmune encephalitis disease.
The method of claim 1,

The presence of the biological sample is by any one method selected from HLA-genotyping, serotyping assay, or HLA microcytotoxicity assay,

How to provide information about autoimmune encephalitis disease.
Means for detecting alleles of any of the HLA-DRB1 * 07: 01 alleles, the HLA-DQB1 * 02: 02 alleles, the HLA-B * 44: 03 alleles and the HLA-C * 07: 06 alleles Containing

Predictive kit for autoimmune encephalitis disease.
The method of claim 8,

The autoimmune encephalitis disease comprises at least one of an anti-LGI1 encephalitis disease and an anti-NMDAR encephalitis disease

Predictive kit for autoimmune encephalitis disease.