CN106908600A - One kind is used for detecting system lupus erythematosus（SLE kit) - Google Patents
One kind is used for detecting system lupus erythematosus（SLE kit) Download PDFInfo
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- CN106908600A CN106908600A CN201710167336.0A CN201710167336A CN106908600A CN 106908600 A CN106908600 A CN 106908600A CN 201710167336 A CN201710167336 A CN 201710167336A CN 106908600 A CN106908600 A CN 106908600A
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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
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/10—Musculoskeletal or connective tissue disorders
- G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
- G01N2800/104—Lupus erythematosus [SLE]
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Abstract
It is used for detecting system lupus erythematosus the invention discloses one kind（SLE kit), contains energy specific detection systemic loupus erythematosus（SLE aptamer), the aptamer can specifically bind SERPINA6.Kit of the invention can be used in the expression quantity of quantitative determination SERPINA6 albumen such that it is able to for accurate detection system Erythematosus Disease.
Description
Technical field
The present invention relates to the kit that one kind is used for detecting system lupus erythematosus (SLE).
Background technology
Systemic loupus erythematosus (SLE) is the inflammatory disorderly of the autoimmunity cause of disease (auto immune etiology)
Disorderly, in occurring mainly in young woman.SLE can influence the body organ systems of many, including kidney, skin, joint, nerveous system
System, serous coat, haemocyte and vascular.Although not knowing the specific inducement of SLE, many factors are relevant with advancing of disease, including
Gene, race, hormone and environmental factor.
The presence of polytype antinuclear antibodies is the important serology feature for suffering from SLE, so the quick diagnosis master of SLE at present
If according to autoantibodies inspection, being observed in conjunction with clinical manifestation.Wherein sensitiveness of the antinuclear antibodies (ANA) to SLE
It is 95%, specificity is about 65%, is optimal SLE state of an illness screening index at present, be such as repeatedly negative, then that suffers from SLE can
Energy property is little；Anti-dsDNA antibody (dsDNA) is up to 95% to the specificity of SLE, and sensitiveness is about 70%, to make a definite diagnosis SLE and
Judge that Lupus activity has larger reference value；Anti-Sm antibody is up to 99% to the specificity of SLE, but sensitiveness is only
25%, can be also positive in SLE inertias, therefore many important bases as retrospective diagnosis；In addition anti-ssDNA antibody
(ss-DNA) also can be used as one of SLE diagnosis indexs.To the above four kinds of detection of index in clinic blood examination at present, mainly
Using radioimmunoassay (RIA), although it has preferable sensitivity, specificity and stability, but detection process is more
Loaded down with trivial details, operation inconvenience and can only also analyze a kind of index every time, last it is more long, the amount of diagnostic information that is provided it is limited without
Comprehensively, many deficiencies are that clinical diagnosis and treatment bring inconvenience.
A kind of examination of high mannose type N sugar chain levels in specific detection serum antibody is disclosed in the A of CN 104655852
Agent is being prepared for the application in the diagnosis of systemic loupus erythematosus and/or the diagnostic tool of prognosis evaluation.The serum antibody
Middle high mannose type N sugar chain levels increase closely related with the generation of systemic loupus erythematosus, can be used for systemic red yabbi
The early diagnosis of sore and/or prognosis evaluation, and then for instructing the treatment of systemic loupus erythematosus.But the method is in mouse layer
Whether the experiment carried out on face, can have corresponding identification result to be expected in human body.
The A of CN 105229470 are disclosed for diagnosing, prognosis and method and the examination of systemic lupus erythematosus (SLE)
Agent, it is related to according to red blood cell C4d (EC4d) mark, B cell C4d (BC4d) mark, antinuclear antibodies (ANA).The method
In to relate to numerous marker detection species more, and detection inconvenience.
At present, one of complicated most arduous challenge of autoimmune disease (such as SLE) of clinical treatment is the disease of patient
The accurate and Early Identification of disease.Additionally, do not differentiate send as an envoy to clinician or other people can accurately determine SLE pathology life
The reliability diagnostic flag of reason performance, clinical event, the response to treatment or prognosis.
The content of the invention
A kind of construction method of the stage protein expression difference spectrum model for systemic lupus erythematosus of non-diagnostic purpose, bag
Include following steps:Difference acquisition system patients with SLE group, the PMNC sample of healthy control group；Respectively
Total protein of cell extracting and determination of protein concentration are carried out to each PMNC sample；By the total protein of cell
After through protease digestion, marked with the equivalent dystopy label of relative and absolute quantitation, the equivalent for obtaining relative and absolute quantitation is different
The polypeptide of position label multiple labelling；The polypeptide is separated through strong cation exchange and reversed-phase liquid chromatography, then carries out series connection matter
Spectrum identification and relative quantitative assay, obtain the stage protein expression difference spectrum model for systemic lupus erythematosus, by table
Type identifies that final analysis has obtained the two albumen of SERPINA6 and C4BPA, and it is expressed as biomarker using the albumen
Amount detect and can be used for instructing the early diagnosis in SLE patient.
Invention additionally provides SERPINA6 and C4BPA, the two albumen are used to prepare the mark that SLE patient diagnoses.
In addition, expression of the present invention to SERPINA6 in lupus erythematosus patients blood has carried out quantitative determination.
Still further aspect, the invention provides the aptamer of a species specific identification SERPINA6, its sequence such as SEQ
ID NO：Shown in 1-12.
Still further aspect, the present invention provides a kind of kit, and for specific diagnostic system lupus erythematosus, it is included
Such as SEQ ID NO：Sequence shown in 1-12.
Still further aspect, described aptamer coupling has magnetic bead and selection markers.
Beneficial effect:The present invention is screened by differential protein, test result indicate that SERPINA6 is in systemic loupus erythematosus
There is obvious up-regulated expression, can be used as systemic loupus erythematosus disease clinical diagnosis mark.And the present invention is by specificity
Screening obtain SERPINA6 protein-specifics combination aptamer, can be used in the expression of quantitative determination SERPINA6 albumen
Amount such that it is able to for accurate detection system Erythematosus Disease.
Brief description of the drawings
Fig. 1 is the statistical analysis figure of the concentration of SERPINA6 in blood samples of patients and healthy control group blood.
Fig. 2 is specificity and the sensitivity of ROC curve display protein diagnostic systemic loupus erythematosus.
Specific embodiment
The specific embodiment that the present invention is provided is elaborated below in conjunction with the accompanying drawings.
Embodiment 1
Difference acquisition system patients with SLE 20, the PMNC sample of healthy control group 20；
Total protein of cell extracting and determination of protein concentration are carried out to each PMNC sample respectively；The cell is total
After albumen is through protease digestion, marked with the equivalent dystopy label of relative and absolute quantitation, obtain with respect to and absolute quantitation etc.
Measure the polypeptide of dystopy label multiple labelling；The polypeptide is separated through strong cation exchange and reversed-phase liquid chromatography, then is gone here and there
Connection Mass Spectrometric Identification and relative quantitative assay, obtain the stage protein expression difference spectrum model for systemic lupus erythematosus, lead to
Phenotypic evaluation is crossed, final analysis has obtained the two albumen of SERPINA6 and C4BPA, differential expression significantly, can be as biology
Mark to its expression quantity detect and can be used for instructing the early diagnosis in SLE patient.
In addition measurement patients serum in SERPINA6 concentration apparently higher than control group serum (P ＜ 0.05), referring to Fig. 1.
In addition, setting the cut-off values of SERPINA6 for 100.3ng/ml according to Fig. 2 ROC curves, AUC reaches
0.9801, its Sensitivity and Specificity is all higher than 93%, and positive rate is 95.4%.Statistic analysis result shows, in blood
SERPINA6 concentration is closely related with systemic loupus erythematosus, summary experimental study, it can be deduced that conclusion, SERPINA6 exists
Hypersecretion in Patients with SLE, the particularly preferred mark that can be distinguished as SERPINA6 and normal population
Thing.
The acquisition of the aptamer of embodiment 2
Using SELEX technologies, screening has obtained specifically binding the aptamer of SERPINA6 albumen, the following library of its sequence
For
TACGTAGAATGACTCGTGAG(N)35CAGTACGATGGATGCAGTGA
SER6-1：
TACGTAGAATGACTCGTGAGATAATCACCTTCCCTCACATTACAAATACATTCATCAGTACGATGGATG
CAGTGA
SER6-2：
TACGTAGAATGACTCGTGAGTATTCCAAACAAAAACCTCTCCACATACCTTTTTACAGTACGATGGATG
CAGTGA
SER6-3：
TACGTAGAATGACTCGTGAGCTAAAAAATTTCCTCCCACCCCCAATTCAACTTAACAGTACGATGGATG
CAGTGA
SER6-4：
TACGTAGAATGACTCGTGAGCTTATAAAAATCCAACCCCTACACTACATCACACTCAGTACGATGGATG
CAGTGA
SER6-5：
TACGTAGAATGACTCGTGAGTATATCAAATACCCAACTCCTCCCAATCTACATCCCAGTACGATGGATG
CAGTGA
SER6-6：
TACGTAGAATGACTCGTGAGCATCCCTACTCAATTAATACTAATACCATAATACTCAGTACGATGGATG
CAGTGA
SER6-7：
TACGTAGAATGACTCGTGAGTCCTATATACTACCTCTACAAATTCCACTTCATACCAGTACGATGGATG
CAGTGA
SER6-8：
TACGTAGAATGACTCGTGAGTTCCCATATACATCCCCAACATCTACCTACCCAAACAGTACGATGGATG
CAGTGA
SER6-9：
TACGTAGAATGACTCGTGAGCATACTTCATAATCTTTTCTCCCTCATTTCCATATCAGTACGATGGATG
CAGTGA
SER6-10：
TACGTAGAATGACTCGTGAGAATCTTAAATCCAAAATTACCCCATCTATCCTCCA
CAGTACGATGGATGCAGTGA
SER6-11：
TACGTAGAATGACTCGTGAGCCCTACTTATTCTCATCATCACTCCACCCTACCCTCAGTACGATGGATG
CAGTGA
SER6-12：
TACGTAGAATGACTCGTGAGCACTTACATTACCACAATCTCATTTTATACCATTACAGTACGATGGATG
CAGTGA
The performance measurement of the protein binding aptamer of embodiment 3
There is the characteristic of absorption single stranded DNA based on graphene oxide oxidation, construct oligonucleotide aptamer compatibility and test
Card method.By the SERPINA6 protein targets (1 μ Μ) of fixed concentration respectively with a series of corresponding various concentrations (10,25,
50,75,100,150,200u Μ) candidate oligonucleotide aptamer be incubated, cumulative volume is 300uL, and 37 DEG C of lucifuges are incubated
2h, and target as negative control group is replaced using BB buffer solutions.After hatching combination add optimum amount than GO absorption not with target
The aptamer for combining is marked, lower 520nm transmittings are excited using F-7000 fluorescent spectrophotometer measuring supernatants 490nm after centrifugally operated
Fluorescence intensity, three parallel repetitions of Setup Experiments, experiment is using lucifuge treatment.It is strong with respect to the fluorescence of negative control group with experimental group
Degree, using aptamer concentration as abscissa, nonlinear regression is carried out using the softwares of GraphPad Prism 5.0 as ordinate
The dissociation constant Kd values of the Fitting Calculation aptamer.Result is as follows：
| Title | Dissociation constant Kd (unit nM) |
| SER6-1 | 23.5 |
| SER6-2 | 24.6 |
| SER6-3 | 25.7 |
| SER6-4 | 30.2 |
| SER6-5 | 25.6 |
| SER6-6 | 26.4 |
| SER6-7 | 25.7 |
| SER6-8 | 28.7 |
| SER6-9 | 30.2 |
| SER6-10 | 31.5 |
| SER6-11 | 29.8 |
| SER6-12 | 27.4 |
| BB buffer blanks | Without binding ability |
In addition, being in contact by the albumen with other human bodies in serum, the aptamer that the present invention is provided has preferably knot
Specificity and stability are closed, while also without any hemolytic, with preferable biological characteristics.
The diagnosis of aptamer disease described in embodiment 4
12 aptamers are detected with 10 Patients with SLE patients respectively.
10 blood serum samples and the healthy sample coating of control are added in ELISA Plate hole, and addition passes through biotin labeling
Aptamer 12, add HRP mark streptavidin, 37 DEG C be incubated 1.5 hours；PBS washes three times and adds TMB to be shown afterwards
Color 5 minutes；ELIASA reading after 2M sulfuric acid terminating reactions；Detected, it is as a result shown, compared with healthy volunteer, systematicness
The 0D450 of SERPINA6 albumen significantly raised (p=0.0035) in patients with SLE serum.By standard curve, calculate
Draw, SERPINA6 protein concentrations are all higher than 100.3ng/ml in serum, and the SERPINA6 protein concentrations of normal population are remote
Much smaller than 100ng/ml, as a result prove that 12 aptamers have application prospect in systemic lupus erythematosus diagnosis.
The preferred embodiments of the present invention are these are only, is not intended to limit the invention, for those skilled in the art
For member, all any modification, equivalent substitution and improvements done within the spirit and principles in the present invention etc. should be included in this
Within the protection domain of invention.
Sequence table
The ＞ Shens winters of ＜ 110 are prosperous
The ＞ of ＜ 120 are a kind of to be used for detecting system lupus erythematosus（SLE kit)
〈160〉12
〈210〉1
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-1
TACGTAGAATGACTCGTGAGATAATCACCTTCCCTCACATTACAAATACATTCATCAGTACGATGGATGCAGTGA
〈210〉2
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-2
TACGTAGAATGACTCGTGAGTATTCCAAACAAAAACCTCTCCACATACCTTTTTACAGTACGATGGATGCAGTGA
〈210〉3
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-3
TACGTAGAATGACTCGTGAGCTAAAAAATTTCCTCCCACCCCCAATTCAACTTAACAGTACGATGGATGCAGTGA
〈210〉4
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-4
TACGTAGAATGACTCGTGAGCTTATAAAAATCCAACCCCTACACTACATCACACTCAGTACGATGGATGCAGTGA
〈210〉5
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-5
TACGTAGAATGACTCGTGAGTATATCAAATACCCAACTCCTCCCAATCTACATCCCAGTACGATGGATGCAGTGA
〈210〉6
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-6
TACGTAGAATGACTCGTGAGCATCCCTACTCAATTAATACTAATACCATAATACTCAGTACGATGGATGCAGTGA
〈210〉7
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-7
TACGTAGAATGACTCGTGAGTCCTATATACTACCTCTACAAATTCCACTTCATACCAGTACGATGGATGCAGTGA
〈210〉8
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-8
TACGTAGAATGACTCGTGAGTTCCCATATACATCCCCAACATCTACCTACCCAAACAGTACGATGGATGCAGTGA
〈210〉9
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-9
TACGTAGAATGACTCGTGAGCATACTTCATAATCTTTTCTCCCTCATTTCCATATCAGTACGATGGATGCAGTGA
〈210〉10
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-10
TACGTAGAATGACTCGTGAGAATCTTAAATCCAAAATTACCCCATCTATCCTCCACAGTACGATGGATGCAGTGA
〈210〉11
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-11
TACGTAGAATGACTCGTGAGCCCTACTTATTCTCATCATCACTCCACCCTACCCTCAGTACGATGGATGCAGTGA
〈210〉12
〈211〉75
〈212〉DNA
The ＞ artificial sequences of ＜ 213
〈400〉SER6-12
TACGTAGAATGACTCGTGAGCACTTACATTACCACAATCTCATTTTATACCATTACAGTACGATGGATGCAGTGA
Claims (5)
1. it is a kind of to be used for detecting system lupus erythematosus（SLE kit), it is characterised in that：Contain energy specific detection system
Property lupus erythematosus（SLE aptamer).
2. kit as claimed in claim 1, it is characterised in that：The aptamer can specifically bind SERPINA6.
3. kit as claimed in claim 2, it is characterised in that：The sequence of the aptamer such as SEQ ID NO：1-12 appoints
Shown in one.
4. a kind of aptamer, it is characterised in that：Sequence such as SEQ ID NO：Shown in 1-12 is any.
5. the aptamer described in claim 4 is being prepared for detecting system lupus erythematosus（The application of kit SLE).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710167336.0A CN106908600B (en) | 2017-03-20 | 2017-03-20 | One kind being used for the kit of detection system lupus erythematosus (SLE) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710167336.0A CN106908600B (en) | 2017-03-20 | 2017-03-20 | One kind being used for the kit of detection system lupus erythematosus (SLE) |
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| Publication Number | Publication Date |
|---|---|
| CN106908600A true CN106908600A (en) | 2017-06-30 |
| CN106908600B CN106908600B (en) | 2019-02-15 |
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|---|---|---|---|
| CN201710167336.0A Expired - Fee Related CN106908600B (en) | 2017-03-20 | 2017-03-20 | One kind being used for the kit of detection system lupus erythematosus (SLE) |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105467118A (en) * | 2015-08-30 | 2016-04-06 | 李小彦 | Pancreatic cancer tumor marker and application method thereof |
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2017
- 2017-03-20 CN CN201710167336.0A patent/CN106908600B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105467118A (en) * | 2015-08-30 | 2016-04-06 | 李小彦 | Pancreatic cancer tumor marker and application method thereof |
Non-Patent Citations (2)
| Title |
|---|
| MARIELE GATTO,ET AL.: "Serpins, Immunity and Autoimmunity: Old Molecules,New Functions", 《CLINIC REV ALLERG IMMUNOL》 * |
| QIAN-QIAN SONG,ET AL.: "Genetic variation in the glucocorticoid pathway involved in interindividual differences in the glucocorticoid treatment", 《PHARMACOGENOMICS》 * |
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