CN113917155B - Biomarkers for diagnosis of neuromyelitis optica lineage diseases and uses thereof - Google Patents

Biomarkers for diagnosis of neuromyelitis optica lineage diseases and uses thereof Download PDF

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CN113917155B
CN113917155B CN202111134919.6A CN202111134919A CN113917155B CN 113917155 B CN113917155 B CN 113917155B CN 202111134919 A CN202111134919 A CN 202111134919A CN 113917155 B CN113917155 B CN 113917155B
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CN113917155A (en
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李芮冰
王成彬
王进洋
王佳楠
谢伟
刘佳玉
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First Medical Center of PLA General Hospital
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to a biomarker for diagnosing diseases of the neuromyelitis optica lineage and application thereof, wherein the biomarker comprises a combination of GFAP protein, nfL protein and UCHL1 protein; the application provided by the invention comprises the following steps: the use of an agent for detecting a biomarker in a sample for the preparation of a diagnostic product for neuromyelitis spectrum diseases, and a diagnostic product for neuromyelitis spectrum diseases. The biomarker can be used for early diagnosis, disease development and prognosis monitoring of neuromyelitis optica diseases, has the advantages of high sensitivity and high specificity, and has important scientific research and clinical application values.

Description

Biomarkers for diagnosis of neuromyelitis optica lineage diseases and uses thereof
Technical Field
The invention relates to the technical field of disease diagnosis, in particular to a biomarker for diagnosing neuromyelitis optica spectrum diseases and application thereof.
Background
The neuromyelitis optica spectrum disease (Neuromyelitis optica spectrum disorder, NMOSD) is a central nervous system inflammatory demyelinating disease characterized by severe recurrence and frequent exacerbations, primarily involving the optic nerve and spinal cord.
Multiple sclerosis (multiple sclerosis, MS) is an autoimmune disease characterized by inflammatory demyelinating lesions of the central nervous system, which has been recognized as two different phenotypes of the same disease by NMOSD and MS for a long time, and has not been broken until the discovery of Aquaporin 4 antibodies (aqp 4-IgG) and anti-myelin glial glycoprotein antibodies (Myelin oligodendrocyte glycoprotein antibody, MOG-IgG). Myelin oligodendrocyte glycoprotein antibody-related disease (MOG-IgGassociated disease, MOGAD) is now considered a unique disease type, not as a subtype of NMOSD, due to differences in clinical and immunological mechanisms.
The pathological mechanism of AQP4-IgG+NMOSD is mainly expressed as follows: AQP4-IgG breaks the blood brain barrier and attacks aquaporins on astrocyte foot processes, causing a strong inflammatory response, resulting in oligodendrocyte and nerve damage, and significant myelin sheath, etc.
In carrying out the invention, the inventors have found that there are at least the following problems in the prior art: although international diagnostic standards for NMOSD have been established, there is still a difficulty in achieving early diagnosis of NMOSD due to similar clinical symptoms and imaging performance, and the unknown or total negative antibodies in some patients. Compared with the prior lumbar puncture and imaging examination, the blood examination is more noninvasive and convenient, is more beneficial to the periodic review and diagnosis of patients, and although the prior study shows that various proteins and enzymes are increased to different degrees when the nervous system diseases occur, the blood biomarker is not applicable to clinic at present.
Based on the above problems, there is an urgent need for a set of biomarkers and diagnostic products made therefrom for early diagnosis, disease progression and prognosis monitoring of neuromyelitis optica diseases, without the need for extraction of cerebrospinal fluid for detection of AQP4-IgG or for imaging examinations.
Disclosure of Invention
The invention discloses a biomarker for diagnosing neuromyelitis optica spectrum diseases and application thereof, and aims to solve the technical problems in the prior art.
To achieve the above object, the first aspect of the present invention provides a biomarker for diagnosis of neuromyelitis optica lineage diseases, the biomarker comprising a combination of GFAP protein, nfL protein and UCHL1 protein.
As a preferable technical scheme, the amino acid sequence of the GFAP protein is shown as SEQ ID NO. 1, SEQ ID NO. 2 or SEQ ID NO. 3, the amino acid sequence of the NfL protein is shown as SEQ ID NO. 4, and the amino acid sequence of the UCHL1 protein is shown as SEQ ID NO. 5.
As a preferred technical scheme, the GFAP protein, nfL protein and UCHL1 protein are derived from peripheral blood samples, serum samples or plasma samples.
In a second aspect, the invention provides the use of a reagent for detecting a biomarker according to the first aspect of the invention, as described above, in a sample in the manufacture of a diagnostic product for neuromyelitis optica disease.
As a preferred embodiment, the reagent comprises a reagent for detecting the expression level of the biomarker in a sample by a protein immunoassay technique and a mass spectrometry technique.
As a preferred embodiment, the agent comprises an agent that specifically binds to the biomarker.
As a preferred embodiment, the reagent comprises an anti-GFAP protein antibody, an anti-NfL protein antibody and an anti-UCHL 1 protein antibody.
Preferably, the sample is selected from serum samples.
In a third aspect the invention provides a diagnostic product for neuromyelitis optica spectrum disease comprising reagents for detecting a biomarker according to the first aspect of the invention; the diagnostic product comprises a kit.
Further, the kit also comprises a quality control product, a fluorescent marker, magnetic beads, and an avidin-coupled enzyme and a substrate.
The technical scheme adopted by the invention has the following beneficial effects:
(1) The biomarker composition consisting of the GFAP protein, the NfL protein and the UCHL1 protein is used for early diagnosis, disease development and prognosis monitoring of the neuromyelitis spectrum diseases, has the advantages of high sensitivity and high specificity, and has important scientific research and clinical application values.
(2) The biomarkers provided by the invention can be made into diagnostic products, such as kits and the like, for diagnosing NMOSD, so as to predict the risk of a subject to suffer from NMOSD, or to monitor the recurrence of NMOSD of a patient or subject.
(3) The biomarker provided by the invention can be used for performing early diagnosis on AQP4-IgG+NMOSD without extracting cerebrospinal fluid to detect AQP4-IgG or performing imaging examination, so that the pain of a patient is small, the detection can be performed by a protein immunoassay technology, and the detection efficiency is high; meanwhile, the integration of data information and clinical information obtained through a histology technology is helpful for better understanding the pathological process of the AQP4-IgG+NMOSD and searching for a new intervention target of the AQP4-IgG+NMOSD, so that the clinical management of an AQP4-IgG+NMOSD patient is improved.
(4) The biomarker composition provided by the invention can be used for anchoring and diagnosing neuromyelitis pedigree diseases by using only three proteins, and has the advantages of small quantity, stronger pertinence and more efficient detection.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for the description of the embodiments are briefly described below to form a part of the present invention, and the exemplary embodiments of the present invention and the description thereof illustrate the present invention and do not constitute undue limitations of the present invention. In the drawings:
FIG. 1 shows the variation in the amounts of sGFAP, sNfL, and sUCHL1 in four groups of samples (29 AQP4-IgG+NMOSD patients, 13 MOGAD patients, 20 MS patients, and 9 healthy normal individuals) in example 3 of the present invention;
FIG. 2 shows the difference in levels of sGFAP, sNfL, and sUCHL1 in the convalescence and remission of the four specimens of example 3 of the present invention;
FIG. 3 shows the results of ROC curve analysis of predictive diagnosis of NMOSD patients in combination with sGFAP, sNfL and sUCHL1 in example 3 of the present invention;
FIG. 4 shows the diagnostic potential analysis of sGFAP, sNfL and sUCHL1 for early diagnosis of disease in example 3 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below with reference to specific embodiments of the present invention and corresponding drawings. In the description of the present invention, it should be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Before describing the examples, it is necessary to provide some remark descriptions: the adoption of reagents of different factories and different batches can cause the difference of experimental results, and belongs to the normal phenomenon. In the small-scale experiment, in order to ensure the repeatability between parallel experiments, the reagents are suggested to be prepared, fully mixed and split-packed, so as to ensure the uniformity of the reagents for each experiment.
Noun interpretation referred to in the following examples:
the value of about Index (Youden Index), also called the correct diagnostic Index, ranges from (0-1), with a value closer to 1 representing better diagnostic accuracy, the diagnostic criteria being defined in this application at the maximum of the correct diagnostic Index.
Subject performance characteristics (receiver operating characteristic, ROC) reflect a balance between sensitivity and specificity, with area under the ROC curve being an important test accuracy indicator, the larger the area under the ROC curve, the greater the diagnostic value of the test.
Sensitivity (true positive rate): the greater the sensitivity, the better the sensitivity, and the ideal sensitivity is 100%.
Specificity (true negative rate): the greater the specificity, the better the ideal specificity is 100%.
Recurrence period: the disease condition is relieved for at least 1 month, and new symptoms or aggravated original symptoms appear after the disease condition is relieved.
Remission period: symptoms were relieved for at least one month and the condition was stable (only for regular maintenance treatment admission).
GFAP: colloid fiber acid protein; sfgfap: serum glial fibrillary acidic protein; wherein GFAP is mainly distributed in astrocytes of the central nervous system, and participates in the constitution of cytoskeleton and maintains its tensile strength.
NfL: a neurofilament light chain; sNfL: serum neuregulin light chain; nfL is the skeleton protein of axons.
UCHL1: ubiquitin carboxy terminal hydrolase L1; sUCHL1: serum ubiquitin carboxy terminal hydrolase L1; UCHL1 is highly expressed in the blood brain barrier.
sYau: serum Tau protein; tau protein is the highest content microtubule-associated protein.
NMOSD diagnostic criteria:
1. AQP4-igg+nmosd diagnostic criteria:
1) At least 1 core clinical profile; 2) Detecting the positive of the AQP4-IgG by a reliable method; 3) Other diagnostics are excluded.
2. NMOSD diagnostic criteria for AQP4-IgG negative or unknown AQP4-IgG status:
in 1 or more clinical episodes, at least 2 core clinical symptoms and all of the following conditions are met: 1) At least 1 clinical feature is ON, acute LET or bulbar end syndrome; 2) Spatially diverse (2 or more distinct clinical core features; 3) MRI additional conditions are satisfied.
3. Core clinical symptoms:
a. optic Neuritis (ON); b. acute myelitis; c. finally, the regional syndrome has no episodic hiccup, nausea and vomiting which can be explained by other reasons; d. other brainstem syndromes; e. symptomatic narcolepsy, inter-brain syndrome, brain MRI with inter-brain lesions characteristic of NMOSD; f. brain syndromes are accompanied by brain lesions characteristic of NMOSD.
4. NMOSD MRI additional conditions in AQP4-IgG negative or unknown state:
a. acute ON: brain MRI has one of the following manifestations: 1) Brain MRI is normal or has only nonspecific white matter lesions; 2) An optic nerve length T2 signal or T1 enhancement signal >1/2 optic nerve length, or a lesion afflicts an optic cross;
b. acute myelitis: a long spinal cord lesion >3 consecutive pyramidal segments, or a patient with a history of myelitis has corresponding spinal cord atrophy >3 consecutive pyramidal segments;
c. and finally syndrome: posterior/posterior bulbar lesions;
d. acute brainstem syndrome: periventricular canal lesions.
Example 1
In this example, a biomarker for diagnosis of neuromyelitis optica lineage disease is provided, which is a combination of GFAP protein, nfL protein and UCHL1 protein; wherein the amino acid sequence of the GFAP protein is shown as SEQ ID NO. 1, SEQ ID NO. 2 or SEQ ID NO. 3, the amino acid sequence of the NfL protein is shown as SEQ ID NO. 4, and the amino acid sequence of the UCHL1 protein is shown as SEQ ID NO. 5.
Preferably, the three proteins contained in the above biomarker may be derived from a peripheral blood sample, a serum sample, a plasma sample, a urine sample, a saliva sample, or a tissue sample; in a more preferred embodiment, the above biomarkers are derived from serum, i.e. the biomarkers comprise a sffap protein, a sNfL protein and a sghl 1 protein.
Example 2
The embodiment provides a kit for diagnosing neuromyelitis optica pedigree diseases, which comprises detection reagents, standard substances and quality control substances. Wherein the detection reagent selects a reagent that is capable of specifically binding to biomarker 1 in example 1 and that can detect the level of biomarker expression in the sample by a protein immunoassay technique; the test sample is a serum sample.
Preferably, the detection reagent is selected to be detectable by ELISA or Simoa, and in a more preferred embodiment, is selected to be detectable by Simoa. Because the content of the biomarker in serum is lower, the sensitivity of Simoa (Single-molecular Array) is improved by more than 1000 times compared with ELISA, and independent identification and calculation of Single-molecule signals can be realized, particularly, the Simoa can detect ultra-low abundance nerve factors such as NfL, tau, pTau, A beta 40, abeta 42 and the like in serum/plasma, so that the Simoa is more preferable.
Further, the detection reagent contains anti-sGFAP protein antibodies, anti-sNfL protein antibodies and anti-sUCHL 1 protein antibodies, and is used for capturing and specifically binding with the biomarker.
Example 3
In this example, the serum of both disease group and healthy control group was derived from whole blood, and was stored at-80℃until use, and was taken out for analysis.
1. Experimental materials:
there were 71 samples, 9 healthy control samples from healthy adult human subjects (Heather control, HCs), 29 samples for the neuromyelitis optica (AQP 4-igg+nmosd) spectrum disease positive for aquaporin antibodies, 13 samples for MOGAD and 20 samples for MS from serum samples from clinically confirmed patients. Of these, 29 AQP4-IgG+NMOSD specimens, 13 MOGAD specimens and 20 MS specimens were provided by the first medical center of the general Hospital of the people's liberation army of China.
2. Sample preparation:
1) Centrifuging the sample at 10,000g for 5min to remove impurities;
2) 71 serum samples were tested at 4-fold dilution.
3. Standard preparation:
diluted standards A-H provided from the kit were added to 96-well plates.
4. Quality control preparation
And adding the quality Control products Control 1 and Control 2 provided by the kit into a 96-well plate.
4. Loading reagent
1) A reagent support for loading magnetic beads, detectors, SBG and biotin-labeled detection reagents to a Sioma HD-X Analyzer (Quantix) platform;
2) Loading RGP into the test tube holder;
3) Creating a 96-well plate layout on a computer;
4) A 96-well plate was loaded onto the reagent support.
5. Full-automatic detection
1) Transferring the sample to a Simoa Disc, and dropping the magnetic beads into a small hole on the optical Disc;
2) Oil seal for sealing signal in micropore
3) Taking a picture through a digital imaging system;
4) The concentration of the analyte is analyzed by an image analysis system.
The level changes of the biomarkers (sGFAP protein, sNfL protein and sUCHL1 protein) in each serum sample (HCs 9, AQP4-IgG+NMOSD29, MOGAD13 and MS 20) were obtained using the above detection system, and the results are shown in Table 1. Referring to FIG. 1, 29 cases of AQP4-IgG+NMOSD patients had a median sGFAP of 155.11pg/mL, a median sNfL of 10.71pg/mL, and a median sUCHL1 of 14.34pg/mL; the average level of sGFAP was changed to 131.88pg/mL, the average level of sNfL was changed to 8.24pg/mL, and the median level of sUCHL1 was changed to 6.48pg/mL in 13 MOGAD patients; the median level of sGFAP was varied to 136.00pg/mL, the median level of sNfL was varied to 17.36pg/mL, and the median level of sUCHL1 was varied to 8.51pg/mL in 20 MS patients; the median level of sGFAP for 9 HCs was 61.89pg/mL, the median level of sNfL was 5.28pg/mL, and the median level of sUCHL1 was 4.90pg/mL.
Referring to fig. 1 and table 1, the values of sffap and sffl were significantly higher for all disease groups than for healthy groups, and all p <0.05, but only the level of sghl 1 differentiated AQP4-igg+nmosd (14.34 pg/mL) from MOGAD, MS and HC groups (6.48 pg/mL, 8.51pg/mL, 4.90pg/mL; all p < 0.05), respectively; further, the concentrations of sGFAP [155.11 (90.35, 366.64) pg/mL ] and sUCHL1[14.34 (8.93,18.80) pg/mL ] were generally increased in AQP4-IgG+NMOSD patients compared to the other three groups.
Table 1 level changes in sGFAP, sNfL and sUCHL1 between different groups of sample serum
AQP4-igg+nmosd = aquaporin 4 positive neuromyelitis optica spectrum disease; MOGAD = myelin oligodendrocyte glycoprotein antibody-related disease; ms=multiple sclerosis; HCs = healthy control. The differences between groups were checked using non-parameters (two-tailed MannWhitney U test), and the values are shown as median and quartile ranges (IQR). The AQP4-igg+nmosd group compared to HC group: a.p <0.05, b.p <0.001, c.p <0.0001. Compared to the MOGAD group: d.p <0.05, e.p <0.01. Compared to MS group: f.p <0.05. Double tail P <0.05 was considered to have significant differences.
Further, the level differences of the biomarkers in the relapse and remission phases of AQP4-igg+nmosd patients, MOGAD patients and MS patients were examined using the above-described detection system, and the results are shown in table 2. Referring to FIG. 2, 29 cases of AQP4-IgG+NMOSD patients had a median level change of 233.29 in sGFAP during relapse c pg/mL, median change in remission of 82.53 f The median level change of sNfL in the recurrence phase in pg/mL was 18.35 c pg/mL, median level change in remission of 6.30 e The median level change of sUCHL1 in the recurrence period of pg/mL is 16.76 c pg/mL, median level change in remission of 8.33 e pg/mL; the median level change in sGFAP during relapse period was 144.27 in 13 MOGAD patients c,g pg/mL, median change in remission of 59.28pg/mL, median change in sNfL in relapse of 10.46 b,g pg/mL, median level change in remission period of 5.01pg/mL, median level change in recurrence period of sUCHL1 of 6.48 e pg/mL, median level change in remission is 11.16pg/mL; the median level change of sGFAP in relapse period of 20 MS patients was 136.72 c,d pg/mL, median change in remission of 134.50pg/mL, median change in sNfL in relapse of 21.29 b pg/mL, median level change in remission period of 4.75pg/mL, median level change in recurrence period of sUCHL1 of 9.00 a,e pg/mL, median level change in remission was 8.01pg/mL.
Further, the grouping is performed according to the stage of each group of patients. The levels of sffap, sNfL and sghl 1 were significantly elevated in relapsing patients compared to AQP4-igg+nmosd remitting patients (all p < 0.001). In the MOGAD group, the recurrent stage had levels of sffap and sNfL alone higher than remission [144.27 (124.71, 201.12) vs.59.28 (41.83, 76.72) pg/mL;10.46 (7.71, 16.62) vs.5.01 (4.10,5.89) pg/mL; all p <0.05]. However, in the MS group, the level of sNfL recurrence was only higher than in the remission stage [21.29 (12.27,36.17) vs.4.75 (4.21,7.90) pg/mL, p=0.017 ].
Further, referring to fig. 2 and table 2, ms patients had higher sfl levels than all NMOSD subgroups at relapse, and had sffap levels only higher than the remission NMOSD subgroups at remission. This difference indicates that NMOSD remission sfkap levels drop more than MS remission. The levels of sffap and sNfL were significantly elevated for each disease group relapse phase cohort compared to HC groups (p < 0.01), whereas only the level of sUCHL1 was able to distinguish AQP4-igg+nmosd patients from other groups of patients at relapse (MOGAD: p=0.004; MS: p=0.007).
Table 2, differences in levels of sGFAP, sNfL and sUCHL1 in the recurrent and remission phases of each group of diseases
The differences between groups were examined using non-parameters (two-tailed MannWhitney U test), and the values were shown as median and a quartile range (IQR) of 25-75%. Compared to HC group: a.p <0.05, b.p <0.001, c.p <0.0001. Compared with the AQP4-IgG+NMOSD recurrence group: d.p <0.05, e.p <0.01, f.p <0.001. Compared to the relief queue for MOGAD: g.p <0.05. Compared to MS mitigation queues: h.p <0.05. Double tail P <0.05 was considered to have significant differences.
Further, the present invention found that most AQP4-igg+nmosd patients were delayed for approximately 2 months (25% of the delay time) from onset of symptoms to definitive diagnosis. Therefore, to evaluate sGFAP, sNfL, sUCHL 1's potential for early diagnosis of AQP4-IgG+NMOSD, 2 months or less was selected as the site for early diagnosis, and AQP4-IgG+NMOSD patients were divided into two groups of NMOSD2 months or less and NMOSD > 2 months. The results show that both sGFAP and sUCHL1 are able to perform differential diagnosis (P < 0.05) early in AQP4-IgG+NMOSD patients, as shown in FIG. 4.
The data were analyzed and collated using SPSS 25.0,GraphPad Prism 8,Medcalc 19.0 according to the data summarized in tables 1 and 2 and are presented by figures 1-4. The distribution of the data was analyzed using the Shapiro-Wilk test. The data of the invention are non-normally distributed, so the data are represented by median and quartile spacing; the predictive diagnostic value of the biomarkers for AQP4-igg+nmosd was analyzed using ROC curves according to the maximum approximate log index. Adopting single-factor and multi-factor linear regression to analyze the relationship between sGFAP, sNfL and sUCHL1 and clinical factors; a two-tailed P value <0.05 is considered statistically significant. As can be seen from fig. 3, the AUCs of sGFAP, sNfL, sUCHL1 are 0.651,0.554 and 0.731, respectively. The AUC of the AQP4-IgG+NMOSD diagnosis in combination with sGFAP, sNfL, sUCHL1 was 0.771 (sensitivity 58.62% and specificity 90.24%).
According to analysis, sGFAP, sNfL, sUCHL1 in the embodiment of the invention can early differential diagnosis of AQP4-IgG+NMOSD and monitor disease activity; and the combination sGFAP, sNfL, sUCHL can improve the diagnosis efficiency of NMOSD.
The invention has the beneficial effects that:
(1) The biomarker composition consisting of the GFAP protein, the NfL protein and the UCHL1 protein is used for early diagnosis, disease development and prognosis monitoring of the neuromyelitis spectrum diseases, has the advantages of high sensitivity and high specificity, and has important scientific research and clinical application values.
(2) The biomarkers provided by the invention can be made into diagnostic products, such as kits and the like, for diagnosing NMOSD, so as to predict the risk of a subject to suffer from NMOSD, or to monitor the recurrence of NMOSD of a patient or subject.
(3) The biomarker provided by the invention can be used for performing early diagnosis on AQP4-IgG+NMOSD without extracting cerebrospinal fluid to detect AQP4-IgG or performing imaging examination, so that the pain of a patient is small, the detection can be performed by a protein immunoassay technology, and the detection efficiency is high; meanwhile, the integration of data information and clinical information obtained through a histology technology is helpful for better understanding the pathological process of the AQP4-IgG+NMOSD and searching for a new intervention target of the AQP4-IgG+NMOSD, so that the clinical management of an AQP4-IgG+NMOSD patient is improved.
(4) The biomarker composition provided by the invention can be used for anchoring and diagnosing neuromyelitis pedigree diseases by using only three proteins, and has the advantages of small quantity, stronger pertinence and more efficient detection.
The embodiments of the present invention have been described above with reference to the accompanying drawings, but the present invention is not limited to the above-described embodiments, which are merely illustrative and not restrictive, and many forms may be made by those having ordinary skill in the art without departing from the spirit of the present invention and the scope of the claims, which are to be protected by the present invention.
SEQUENCE LISTING
<110> Wang Jinyang, li Ruibing
<120> biomarkers for diagnosis of neuromyelitis optica lineage diseases and uses thereof
<130> 2021.9.14
<160> 5
<170> PatentIn version 3.5
<210> 1
<211> 432
<212> PRT
<213> Homo sapiens
<400> 1
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405 410 415
Asp Gly Glu Val Ile Lys Glu Ser Lys Gln Glu His Lys Asp Val Met
420 425 430
<210> 2
<211> 431
<212> PRT
<213> Homo sapiens
<400> 2
Met Glu Arg Arg Arg Ile Thr Ser Ala Ala Arg Arg Ser Tyr Val Ser
1 5 10 15
Ser Gly Glu Met Met Val Gly Gly Leu Ala Pro Gly Arg Arg Leu Gly
20 25 30
Pro Gly Thr Arg Leu Ser Leu Ala Arg Met Pro Pro Pro Leu Pro Thr
35 40 45
Arg Val Asp Phe Ser Leu Ala Gly Ala Leu Asn Ala Gly Phe Lys Glu
50 55 60
Thr Arg Ala Ser Glu Arg Ala Glu Met Met Glu Leu Asn Asp Arg Phe
65 70 75 80
Ala Ser Tyr Ile Glu Lys Val Arg Phe Leu Glu Gln Gln Asn Lys Ala
85 90 95
Leu Ala Ala Glu Leu Asn Gln Leu Arg Ala Lys Glu Pro Thr Lys Leu
100 105 110
Ala Asp Val Tyr Gln Ala Glu Leu Arg Glu Leu Arg Leu Arg Leu Asp
115 120 125
Gln Leu Thr Ala Asn Ser Ala Arg Leu Glu Val Glu Arg Asp Asn Leu
130 135 140
Ala Gln Asp Leu Ala Thr Val Arg Gln Lys Leu Gln Asp Glu Thr Asn
145 150 155 160
Leu Arg Leu Glu Ala Glu Asn Asn Leu Ala Ala Tyr Arg Gln Glu Ala
165 170 175
Asp Glu Ala Thr Leu Ala Arg Leu Asp Leu Glu Arg Lys Ile Glu Ser
180 185 190
Leu Glu Glu Glu Ile Arg Phe Leu Arg Lys Ile His Glu Glu Glu Val
195 200 205
Arg Glu Leu Gln Glu Gln Leu Ala Arg Gln Gln Val His Val Glu Leu
210 215 220
Asp Val Ala Lys Pro Asp Leu Thr Ala Ala Leu Lys Glu Ile Arg Thr
225 230 235 240
Gln Tyr Glu Ala Met Ala Ser Ser Asn Met His Glu Ala Glu Glu Trp
245 250 255
Tyr Arg Ser Lys Phe Ala Asp Leu Thr Asp Ala Ala Ala Arg Asn Ala
260 265 270
Glu Leu Leu Arg Gln Ala Lys His Glu Ala Asn Asp Tyr Arg Arg Gln
275 280 285
Leu Gln Ser Leu Thr Cys Asp Leu Glu Ser Leu Arg Gly Thr Asn Glu
290 295 300
Ser Leu Glu Arg Gln Met Arg Glu Gln Glu Glu Arg His Val Arg Glu
305 310 315 320
Ala Ala Ser Tyr Gln Glu Ala Leu Ala Arg Leu Glu Glu Glu Gly Gln
325 330 335
Ser Leu Lys Asp Glu Met Ala Arg His Leu Gln Glu Tyr Gln Asp Leu
340 345 350
Leu Asn Val Lys Leu Ala Leu Asp Ile Glu Ile Ala Thr Tyr Arg Lys
355 360 365
Leu Leu Glu Gly Glu Glu Asn Arg Ile Thr Ile Pro Val Gln Thr Phe
370 375 380
Ser Asn Leu Gln Ile Arg Gly Gly Lys Ser Thr Lys Asp Gly Glu Asn
385 390 395 400
His Lys Val Thr Arg Tyr Leu Lys Ser Leu Thr Ile Arg Val Ile Pro
405 410 415
Ile Gln Ala His Gln Ile Val Asn Gly Thr Pro Pro Ala Arg Gly
420 425 430
<210> 3
<211> 438
<212> PRT
<213> Homo sapiens
<400> 3
Met Glu Arg Arg Arg Ile Thr Ser Ala Ala Arg Arg Ser Tyr Val Ser
1 5 10 15
Ser Gly Glu Met Met Val Gly Gly Leu Ala Pro Gly Arg Arg Leu Gly
20 25 30
Pro Gly Thr Arg Leu Ser Leu Ala Arg Met Pro Pro Pro Leu Pro Thr
35 40 45
Arg Val Asp Phe Ser Leu Ala Gly Ala Leu Asn Ala Gly Phe Lys Glu
50 55 60
Thr Arg Ala Ser Glu Arg Ala Glu Met Met Glu Leu Asn Asp Arg Phe
65 70 75 80
Ala Ser Tyr Ile Glu Lys Val Arg Phe Leu Glu Gln Gln Asn Lys Ala
85 90 95
Leu Ala Ala Glu Leu Asn Gln Leu Arg Ala Lys Glu Pro Thr Lys Leu
100 105 110
Ala Asp Val Tyr Gln Ala Glu Leu Arg Glu Leu Arg Leu Arg Leu Asp
115 120 125
Gln Leu Thr Ala Asn Ser Ala Arg Leu Glu Val Glu Arg Asp Asn Leu
130 135 140
Ala Gln Asp Leu Ala Thr Val Arg Gln Lys Leu Gln Asp Glu Thr Asn
145 150 155 160
Leu Arg Leu Glu Ala Glu Asn Asn Leu Ala Ala Tyr Arg Gln Glu Ala
165 170 175
Asp Glu Ala Thr Leu Ala Arg Leu Asp Leu Glu Arg Lys Ile Glu Ser
180 185 190
Leu Glu Glu Glu Ile Arg Phe Leu Arg Lys Ile His Glu Glu Glu Val
195 200 205
Arg Glu Leu Gln Glu Gln Leu Ala Arg Gln Gln Val His Val Glu Leu
210 215 220
Asp Val Ala Lys Pro Asp Leu Thr Ala Ala Leu Lys Glu Ile Arg Thr
225 230 235 240
Gln Tyr Glu Ala Met Ala Ser Ser Asn Met His Glu Ala Glu Glu Trp
245 250 255
Tyr Arg Ser Lys Phe Ala Asp Leu Thr Asp Ala Ala Ala Arg Asn Ala
260 265 270
Glu Leu Leu Arg Gln Ala Lys His Glu Ala Asn Asp Tyr Arg Arg Gln
275 280 285
Leu Gln Ser Leu Thr Cys Asp Leu Glu Ser Leu Arg Gly Thr Asn Glu
290 295 300
Ser Leu Glu Arg Gln Met Arg Glu Gln Glu Glu Arg His Val Arg Glu
305 310 315 320
Ala Ala Ser Tyr Gln Glu Ala Leu Ala Arg Leu Glu Glu Glu Gly Gln
325 330 335
Ser Leu Lys Asp Glu Met Ala Arg His Leu Gln Glu Tyr Gln Asp Leu
340 345 350
Leu Asn Val Lys Leu Ala Leu Asp Ile Glu Ile Ala Thr Tyr Arg Lys
355 360 365
Leu Leu Glu Gly Glu Glu Asn Arg Ile Thr Ile Pro Val Gln Thr Phe
370 375 380
Ser Asn Leu Gln Ile Arg Gly Gln Tyr Ser Arg Ala Ser Trp Glu Gly
385 390 395 400
His Trp Ser Pro Ala Pro Ser Ser Arg Ala Cys Arg Leu Leu Gln Thr
405 410 415
Gly Thr Glu Asp Gln Gly Lys Gly Ile Gln Leu Ser Leu Gly Ala Phe
420 425 430
Val Thr Leu Gln Arg Ser
435
<210> 4
<211> 543
<212> PRT
<213> Homo sapiens
<400> 4
Met Ser Ser Phe Ser Tyr Glu Pro Tyr Tyr Ser Thr Ser Tyr Lys Arg
1 5 10 15
Arg Tyr Val Glu Thr Pro Arg Val His Ile Ser Ser Val Arg Ser Gly
20 25 30
Tyr Ser Thr Ala Arg Ser Ala Tyr Ser Ser Tyr Ser Ala Pro Val Ser
35 40 45
Ser Ser Leu Ser Val Arg Arg Ser Tyr Ser Ser Ser Ser Gly Ser Leu
50 55 60
Met Pro Ser Leu Glu Asn Leu Asp Leu Ser Gln Val Ala Ala Ile Ser
65 70 75 80
Asn Asp Leu Lys Ser Ile Arg Thr Gln Glu Lys Ala Gln Leu Gln Asp
85 90 95
Leu Asn Asp Arg Phe Ala Ser Phe Ile Glu Arg Val His Glu Leu Glu
100 105 110
Gln Gln Asn Lys Val Leu Glu Ala Glu Leu Leu Val Leu Arg Gln Lys
115 120 125
His Ser Glu Pro Ser Arg Phe Arg Ala Leu Tyr Glu Gln Glu Ile Arg
130 135 140
Asp Leu Arg Leu Ala Ala Glu Asp Ala Thr Asn Glu Lys Gln Ala Leu
145 150 155 160
Gln Gly Glu Arg Glu Gly Leu Glu Glu Thr Leu Arg Asn Leu Gln Ala
165 170 175
Arg Tyr Glu Glu Glu Val Leu Ser Arg Glu Asp Ala Glu Gly Arg Leu
180 185 190
Met Glu Ala Arg Lys Gly Ala Asp Glu Ala Ala Leu Ala Arg Ala Glu
195 200 205
Leu Glu Lys Arg Ile Asp Ser Leu Met Asp Glu Ile Ser Phe Leu Lys
210 215 220
Lys Val His Glu Glu Glu Ile Ala Glu Leu Gln Ala Gln Ile Gln Tyr
225 230 235 240
Ala Gln Ile Ser Val Glu Met Asp Val Thr Lys Pro Asp Leu Ser Ala
245 250 255
Ala Leu Lys Asp Ile Arg Ala Gln Tyr Glu Lys Leu Ala Ala Lys Asn
260 265 270
Met Gln Asn Ala Glu Glu Trp Phe Lys Ser Arg Phe Thr Val Leu Thr
275 280 285
Glu Ser Ala Ala Lys Asn Thr Asp Ala Val Arg Ala Ala Lys Asp Glu
290 295 300
Val Ser Glu Ser Arg Arg Leu Leu Lys Ala Lys Thr Leu Glu Ile Glu
305 310 315 320
Ala Cys Arg Gly Met Asn Glu Ala Leu Glu Lys Gln Leu Gln Glu Leu
325 330 335
Glu Asp Lys Gln Asn Ala Asp Ile Ser Ala Met Gln Asp Thr Ile Asn
340 345 350
Lys Leu Glu Asn Glu Leu Arg Thr Thr Lys Ser Glu Met Ala Arg Tyr
355 360 365
Leu Lys Glu Tyr Gln Asp Leu Leu Asn Val Lys Met Ala Leu Asp Ile
370 375 380
Glu Ile Ala Ala Tyr Arg Lys Leu Leu Glu Gly Glu Glu Thr Arg Leu
385 390 395 400
Ser Phe Thr Ser Val Gly Ser Ile Thr Ser Gly Tyr Ser Gln Ser Ser
405 410 415
Gln Val Phe Gly Arg Ser Ala Tyr Gly Gly Leu Gln Thr Ser Ser Tyr
420 425 430
Leu Met Ser Thr Arg Ser Phe Pro Ser Tyr Tyr Thr Ser His Val Gln
435 440 445
Glu Glu Gln Ile Glu Val Glu Glu Thr Ile Glu Ala Ala Lys Ala Glu
450 455 460
Glu Ala Lys Asp Glu Pro Pro Ser Glu Gly Glu Ala Glu Glu Glu Glu
465 470 475 480
Lys Asp Lys Glu Glu Ala Glu Glu Glu Glu Ala Ala Glu Glu Glu Glu
485 490 495
Ala Ala Lys Glu Glu Ser Glu Glu Ala Lys Glu Glu Glu Glu Gly Gly
500 505 510
Glu Gly Glu Glu Gly Glu Glu Thr Lys Glu Ala Glu Glu Glu Glu Lys
515 520 525
Lys Val Glu Gly Ala Gly Glu Glu Gln Ala Ala Lys Lys Lys Asp
530 535 540
<210> 5
<211> 223
<212> PRT
<213> Homo sapiens
<400> 5
Met Gln Leu Lys Pro Met Glu Ile Asn Pro Glu Met Leu Asn Lys Val
1 5 10 15
Leu Ser Arg Leu Gly Val Ala Gly Gln Trp Arg Phe Val Asp Val Leu
20 25 30
Gly Leu Glu Glu Glu Ser Leu Gly Ser Val Pro Ala Pro Ala Cys Ala
35 40 45
Leu Leu Leu Leu Phe Pro Leu Thr Ala Gln His Glu Asn Phe Arg Lys
50 55 60
Lys Gln Ile Glu Glu Leu Lys Gly Gln Glu Val Ser Pro Lys Val Tyr
65 70 75 80
Phe Met Lys Gln Thr Ile Gly Asn Ser Cys Gly Thr Ile Gly Leu Ile
85 90 95
His Ala Val Ala Asn Asn Gln Asp Lys Leu Gly Phe Glu Asp Gly Ser
100 105 110
Val Leu Lys Gln Phe Leu Ser Glu Thr Glu Lys Met Ser Pro Glu Asp
115 120 125
Arg Ala Lys Cys Phe Glu Lys Asn Glu Ala Ile Gln Ala Ala His Asp
130 135 140
Ala Val Ala Gln Glu Gly Gln Cys Arg Val Asp Asp Lys Val Asn Phe
145 150 155 160
His Phe Ile Leu Phe Asn Asn Val Asp Gly His Leu Tyr Glu Leu Asp
165 170 175
Gly Arg Met Pro Phe Pro Val Asn His Gly Ala Ser Ser Glu Asp Thr
180 185 190
Leu Leu Lys Asp Ala Ala Lys Val Cys Arg Glu Phe Thr Glu Arg Glu
195 200 205
Gln Gly Glu Val Arg Phe Ser Ala Val Ala Leu Cys Lys Ala Ala
210 215 220

Claims (5)

1. Use of a reagent for detecting a biomarker in a sample in the preparation of a diagnostic product for a aquaporin 4 antibody-positive neuromyelitis optica (neuromyelitis optica) spectrum disease, wherein the biomarker consists of a GFAP protein, a NfL protein and a UCHL1 protein, the amino acid sequence of the GFAP protein is shown as seq id No. 1, seq id No. 2 or seq id No. 3, the amino acid sequence of the NfL protein is shown as seq id No. 4, and the amino acid sequence of the UCHL1 protein is shown as seq id No. 5; the diagnostic product enables early diagnosis and prognostic monitoring of patients with aquaporin 4antibody positive neuromyelitis optica lineage disease, the early diagnosis being a diagnosis of patients with aquaporin 4antibody positive neuromyelitis optica lineage disease within two months from onset of symptoms, the biomarker being up-regulated in the early diagnosis stage and the recurrent stage, the biomarker being down-expressed in the remission stage.
2. The use of claim 1, wherein the reagent comprises a reagent for detecting the expression level of the biomarker in a sample by a protein immunoassay technique and a mass spectrometry technique.
3. The use of claim 2, wherein the agent comprises an agent that specifically binds to the biomarker.
4. The use according to claim 3, wherein the agent comprises an anti-GFAP protein antibody, an anti-NfL protein antibody and an anti-UCHL 1 protein antibody.
5. The use according to claim 1, wherein the sample is selected from serum samples.
CN202111134919.6A 2021-09-27 2021-09-27 Biomarkers for diagnosis of neuromyelitis optica lineage diseases and uses thereof Active CN113917155B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106461645A (en) * 2014-04-07 2017-02-22 铁马诊断公司 Traumatic brain injury and neurodegenerative biomarkers, methods, and systems
CN111521812A (en) * 2019-12-25 2020-08-11 广州瑞博奥生物科技有限公司 Neuromyelitis optica pedigree disease biomarker group and application thereof, protein chip and kit

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106461645A (en) * 2014-04-07 2017-02-22 铁马诊断公司 Traumatic brain injury and neurodegenerative biomarkers, methods, and systems
CN111521812A (en) * 2019-12-25 2020-08-11 广州瑞博奥生物科技有限公司 Neuromyelitis optica pedigree disease biomarker group and application thereof, protein chip and kit

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Neurofilament Light,GFAP, Tau, and UCHL1: Do We Need a Correction Factor in Evaluating Blood Levels? (4912);Enrique Alvarez等;《Neurology》;第94卷;第1-7页 *
Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD;Mitsuru Watanabe等;《Neurology》;第93卷;第1-14页 *
Serum Neurofilament Light Chain Levels (sNfL) Correlate Best with Attack-related Disability in Neuromyelitis Optica (4105);O. Atkas等;《Neurology》;第94卷;第1-7页 *

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