CN102707063A - Function of mini-chromosome maintenance complex component in disease diagnosis and prevention of systemic lupus erythematosus - Google Patents
Function of mini-chromosome maintenance complex component in disease diagnosis and prevention of systemic lupus erythematosus Download PDFInfo
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- CN102707063A CN102707063A CN2011100746066A CN201110074606A CN102707063A CN 102707063 A CN102707063 A CN 102707063A CN 2011100746066 A CN2011100746066 A CN 2011100746066A CN 201110074606 A CN201110074606 A CN 201110074606A CN 102707063 A CN102707063 A CN 102707063A
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Abstract
The invention belongs to the field of biotechnology, and discloses a function of a mini-chromosome maintenance complex component which plays an important role in immune dysfunction of systemic lupus erythematosus (SLE). The invention also discloses a method for detecting the level of the mini-chromosome maintenance complex component, and then for the auxiliary diagnosis of the systemic lupus erythematosus. The function of the mini-chromosome maintenance complex component in disease diagnosis and prevention of the systemic lupus erythematosus for the first time demonstrates that the mini-chromosome maintenance complex component family is closely related to the systemic lupus erythematosus, and the regulation and intervention of the mini-chromosome maintain protein level can improve the function of immune cells, and also provides a new drug target for the prevention and treatment of systemic lupus erythematosus.
Description
Technical field:
The invention belongs to biological technical field; Concrete; The present invention discloses minichromosomes and keeps the vital role of albumen in systemic loupus erythematosus; Illustrate minichromosomes and keep the auxiliary detection index that albumen can be used as systemic loupus erythematosus, and reduce minichromosomes and keep the effect of albumen in the systemic loupus erythematosus control.
Background technology:
Systemic loupus erythematosus (SLE) is a kind of autoimmune disease that relates to many systems and internal organs, and it is clinical and immunological phenotype is very complicated various.Systemic loupus erythematosus not only influences humoral immunity, also influences cellular immunity, and complement system also changes, and its influence has almost covered whole immune system.Because the systemic loupus erythematosus cause of disease and pathogenesis are still indeterminate at present, this has brought great difficulty also for the control of systemic loupus erythematosus.
Minute chromosome is kept (mini-chromosome maintenance; Mcm) gene is the oligogene that influences minichromosomes mitosis stability; The minute chromosome of its coding keep albumen (mini-chromosome maintenance complex component, MCM) family be one group with start DIP, duplicate closely-related protein; The overexpression of MCM albumen can be used as the index that detects tumour cell, has important application prospects at aspects such as the diagnosis of the lung cancer and the cancer of the esophagus, prognostic evaluation, clinical treatments.
There is report to show that the MCM gene transcription possibly receive some factors to regulate and in autoimmunity disease, play a role; Yet this area does not also know that minute chromosome keeps the concrete effect of albumen in autoimmune disease, does not more report the relation of itself and systemic loupus erythematosus.
Summary of the invention:
The object of the present invention is to provide minute chromosome to keep the purposes of albumen; Be used for auxiliary detection index as systemic loupus erythematosus; The target spot that perhaps screens as disease therapeuticing medicine; Perhaps keep albumen design EVAC or antibody, directly be used for the control of systemic loupus erythematosus disease to minute chromosome.
First aspect of the present invention, the purposes that provides a kind of minute chromosome to keep albumen is used for the auxiliary detection index as systemic loupus erythematosus; Wherein, described minute chromosome is kept albumen and is had the sequence shown in the SEQ ID:1 (MCM6).
In another embodiment, described minute chromosome is kept albumen and is comprised that also following minute chromosome keeps albumen:
Minute chromosome with nucleotide sequence shown in the SEQ ID:2 is kept albumen;
Minute chromosome with nucleotide sequence shown in the SEQ ID:3 is kept albumen;
Minute chromosome with nucleotide sequence shown in the SEQ ID:4 is kept albumen;
Minute chromosome with nucleotide sequence shown in the SEQ ID:5 is kept albumen;
Minute chromosome with nucleotide sequence shown in the SEQ ID:6 is kept albumen;
Minute chromosome with nucleotide sequence shown in the SEQ ID:7 is kept albumen.
Second aspect of the present invention, the interference fragment that provides a kind of minute chromosome to keep albumen is characterized in that having sequence shown in SEQID:8 and the SEQ ID:10, and wherein said minute chromosome is kept albumen and is had the sequence shown in the SEQ ID:15.This interference fragment can reduce the expression that minute chromosome is kept albumen effectively.
In another embodiment, this interference fragment can reduce the function of BMDC under estrogen and antinuclear antibodies analogies CpG stimulation effectively, keeps the effect of albumen in the systemic loupus erythematosus disease prevention and cure thereby disclosed the reduction minute chromosome.
Description of drawings:
The expression of MCM6 is significantly higher than the normal person among Fig. 1 SLE patient PBMCs;
The expression of MCM6 is significantly higher than the normal person among Fig. 2 SLE patient DCs;
Expression and the estrogen level of MCM6 are proportionate among Fig. 3 SLE patient PBMCs;
Fig. 4 a. is under the stimulation of estrogen and CpG, and the level of MCM family protein all raises;
The b.PCR checking is under the stimulation of estrogen and CpG, and the mRNA level of MCM6 changes;
C.Western Blot checking is under the stimulation of estrogen and CpG, and the protein level of MCM6 changes;
Fig. 5 a. interference fragment can significantly reduce the mRNA expression of MCM6
B. interference fragment can significantly reduce the protein expression level of MCM6
DCs after Fig. 6 a.MCM6 suppresses multiplication capacity under reply estrogen and CpG stimulation does not change;
DCs after b.MCM6 suppresses apoptosis capacity under reply estrogen and CpG stimulation does not change;
DCs after c.MCM6 suppresses phagocytic activity under reply estrogen and CpG stimulation does not change;
The expression of DCs after d.MCM6 suppresses CD86 under reply estrogen and CpG stimulation does not have to change but the expression of CD40 obviously reduces;
DCs after Fig. 7 MCM6 suppresses obviously reduces the stimulation ability of T cell.
Embodiment:
The present invention proved that first minute chromosome is kept protein family and systemic loupus erythematosus (SLE) is closely related, and minute chromosome is kept the auxiliary detection index that albumen can be used as systemic loupus erythematosus through extensive studies.In addition, the present invention has also studied the reduction minute chromosome and has kept the influence of protein expression to immunocyte, thereby for therapy system property lupus erythematosus disease a drug target is provided.The inventor has accomplished the present invention on the basis of the above.
The invention still further relates to the qualitative and said minute chromosome of detection by quantitative and keep the level of albumen; Thereby judge the method for systemic loupus erythematosus; These methods are known in the art, and it includes, but is not limited to: real-time fluorescence quantitative PCR, cluster analysis, western blot etc.Auele Specific Primer or probe that said minute chromosome is kept albumen are also contained in the present invention, and they are used to detect the expression that minute chromosome is kept albumen.
Based on new discovery of the present invention, said minute chromosome is kept albumen has many-sided new purposes.These purposes include, but is not limited to:
1. the kit that is used for preparation system property lupus erythematosus Clinical detection;
2. be used for auxiliary characteristics as the systemic loupus erythematosus Clinical detection;
3. be used to screen the material of preventing and treating systemic loupus erythematosus;
4. be used to carry out the diagnosis and the neurological susceptibility analysis of systemic loupus erythematosus;
5. be used for the ill risk of evaluating system property lupus erythematosus, be convenient to Susceptible population and in time prevent;
6. be used to assess medicine selecting for result of treatment, prognostic analysis and the treatment means of systemic loupus erythematosus;
7. directly systemic loupus erythematosus is treated with its monoclonal antibody.
The invention has the advantages that:
1. prove first that minute chromosome keeps the correlativity of albumen and systemic loupus erythematosus, make its auxiliary characteristics that can become the systemic loupus erythematosus Clinical detection, for the control of this disease provides target spot;
2. analyzed minute chromosome among a large amount of patients SLE and kept the expression of albumen, and contrasted with the normal person, the result accurately and reliably.
Material and method:
1. research object
The present invention collects 36 routine SLE patient's blood samples altogether, is Nanjing drum tower hospital rheumatism immunity section's outpatient service and ward patient, and diagnosis meets the Americanism diseases caused by dampness SLE of association criteria for classification; The male sex's 4 examples wherein; Women's 32 examples, and SLE disease activity property integration (SLEDAI) all is higher than 8 fens, belongs to the active stage patient.Normal control 16 examples are the women, all come from hospital's health check-up normal population.Normal person and patient age do not have significant difference.
2. design of primers
Primer of the present invention is according to the cDNA sequence that Genebank provides, utilize the Lasergene software design following primer:
MCM6 RT-PCR primer:
Positive-sense strand 5 ' AAG TAT TCC CCG GAG TTT AGA GG 3 ' SEQ ID 11
Antisense strand 5 ' GAC ACC GCG TTT TAC TTC ATC ATT 3 ' SEQ ID 12
MCM6 real-time fluorescence quantitative PCR primer:
Positive-sense strand 5 ' GAA CGG GAT CAA TGG CTA CAA TG 3 ' SEQ ID 13
Antisense strand 5 ' GCT CGC TCC TCT TTA ATG CTG ACT 3 ' SEQ ID 14
Primer is synthetic by Invitrogen company.
3.PBMCs and the separation and purification of DCs
The present invention adopts asepsis to extract the anticoagulation 50ml of Freshman peripheral blood anticoagulant heparin (20U/ml); Use the PBS that contains 2% hyclone pH 7.2 by 1: 1 (V/V) dilution proportion fresh anticoagulation; Dilution back blood slowly is added on the lymphocyte separation medium along the centrifuge tube tube wall, and centrifugal (1800r/min 30min) gets middle white cloud and mist confluent monolayer cells; With phosphate buffer (PBS) washing 2 times, for use.
After PBMCs is ready to, utilize the separation magnetic bead of mDCs, operation steps to specifications, purifying mDCs detects its purity with flow cytometer behind the purifying, and its purity can reach more than 98%.The counting back is for use.
4. BMDC separates and cultivates
The present invention under germ-free condition, get 4 age in week the C57BL/6 mouse femur and shin bone, collect bone marrow cell suspension, add 1640 complete culture solutions (containing 10ng/mlmGM-CFS, 1ng/ml mIL-4 and 10%FBS) after the splitting erythrocyte and cultivate 48h at the CO2 incubator; Suspension cell is removed in piping and druming gently; Only keep attached cell, add fresh above-mentioned complete medium, carry out once half amount every three days and change liquid; Continue to be cultured to the 6th day; Collect the immature dendritic cell that all half attached cells are the mouse bone marrow cells source, obtain DCs also with CD11c streaming antibody labeling, flow cytometer detects cell purity.
5.RNA extraction and reverse transcription
The every hole of six orifice plates or add 1ml Trizol with the cell of homalographic is transferred to liquid in the centrifuge tube of 1.5ml after the piping and druming repeatedly; Sample solution was left standstill in 15～30 ℃ 5 minutes; The back concuss of the chloroform (Chloroform) of adding 0.2ml is 15 seconds in every pipe sample; Sample left standstill 3 minutes in 15～30 ℃ after, centrifugal 15 minutes at 4 ℃ with the speed of 12000g; Get the colourless water in upper strata, add isopyknic isopropyl alcohol (Isopropanol) precipitated rna, put upside down mixing gently 10 times, left standstill 15 minutes at 15～30 ℃; Speed with 12000g is centrifugal 15 minutes at 4 ℃; Remove supernatant, with the washing with alcohol RNA deposition of 1ml 75%, with the speed of 7500g 4 ℃ centrifugal 5 minutes, except that drying behind the supernatant 15 minutes; With the water-soluble RNA of separating that does not contain RNA enzyme (RNasefree), short molten after 10 minutes, in 55 to 60 ℃ with spectrophotometer measurement concentration and purity.
6. the extraction of total protein
Cell is removed supernatant of culture medium; And wash twice with the PBS of precooling, add contain the cell pyrolysis liquid of protease inhibitors after, scrape cell harvesting in the EP pipe of 1.5ml with cell; 4 ℃ were rocked cracking 20 minutes; 12000g is centrifugal 15 minutes then, and getting supernatant is that protein lysate is frozen, subsequent use in-70 ℃.Before protein lysate uses, survey protein concentration with the BCA method earlier, read the OD562 value, calculate protein concentration according to typical curve, it is 100 μ g that the adjusting protein concentration makes the upward appearance total protein concentration of each sample.
7. real-time fluorescence quantitative PCR
The application of sample system is: SYBR Green Master Mix 10 μ l, primer (positive-sense strand 0.25 μ l, antisense strand 0.25 μ l), dilution template cDNA 1 μ l, ddH well
2O 8.5 μ l.Each appearance is established 3 to 4 multiple holes and is set confidential reference items as contrast, different being controlled within 0.5 of CT value difference between multiple hole.Reaction finishes the back and calculates 2 according to the confidential reference items value
-Δ Δ CT, and do normalization and handle.
8. Western blotting
After sample adds 100 ℃ of albumen sample-loading buffers and boils 5～10min, the polyacrylamide gel electrophoresis with 10%, after electrophoresis finished, 80min was to the pvdf membrane of 0.45 μ m for the transfer printing of 80V constant voltage.After transfer printing finishes, seal the pvdf membrane that contains sample 2 hours with 5% skimmed milk power room temperature of TBS preparation.The by specification use amount adds 1: the 1000 anti-mouse X-press of dilution rabbit monoclonal antibody then, hatches anti-spending the night for 4 ℃; TBS washes 3 times, each 10 minutes; The HRP-goat-anti rabbit two that adds dilution in 1: 1000 is anti-, and 37 ℃ were reacted 2 hours.TBS washes 3 times, each 10 minutes.Develop with the chemiluminescence imager at last and the preservation image.
9. the design of interference fragment and disturb step
The interference fragment that the present invention adopts utilizes the online design software design of the Dharmacon home page of company, and the interference fragment sequence that obtains is following:
siMCM6-0015’GGG?UAG?UGA?UGG?AGAAAU?U?3’SEQ?ID?8；
siMCM6-0025’GGAAAU?CGAAUC?AGA?GAU?A?3’SEQ?ID?9；
siMCM6-0035’GGG?AAAAGG?UGU?UUG?AAA?U?3’SEQ?ID?10；
Wherein siMCM6-002 can cause Apoptosis, need not so give up.
Interference fragment is synthetic by Invitrogen company.
10. apoptosis detection method (Annexin V&PI two dye methods)
With the PBS washed cell twice of precooling, the centrifugal then supernatant of abandoning combines the liquid re-suspended cell with ready 1 * Annexin, and ratio is per 1 * 10
6Individual cell combines liquid with 1 * Annexin of 1ml; The PI working fluid that then in the resuspended liquid of per 100 μ l Annexin, adds the 100 μ g/ml of 10 μ l Annexin V dye liquors and 2 μ l; After the incubated at room 15 minutes, combine the liquid washing once, use the flow cytometer check and analysis then with 1 * Annexin.
11. phagocytic activity detection method
After in cell, adding 0.2mg/ml FITC-dextran (sigma), in incubator, cultivate 30-45min for 37 ℃, let it engulf.Other establish add FITC-dextran in 4 ℃ of cultured cells as contrast.After cultivate finishing, each appearance with the outer fluorescence of blue (1.2mg/ml) deactivation born of the same parents of 300 μ l platform phenol after with fluorescence intensity in the streaming detection cell, 37 ℃ are directly proportional with the phagocytic activity of cell with the difference of 4 ℃ fluorescence intensity.
12. mix the lymph reaction
Taking-up mouse lymph knot grinds the back with lymph node and crosses the screen cloth collecting cell, uses immunomagnetic beads method (Miltenyi Biotec) sorting CD4 positive T cell then.DC cell and the T cell that sorts out were cultivated three days by different proportion altogether.In last 12 hours that cultivate, add tritium-labeled thymine, cultivate and finish the T cell quantity that insert with its tritium of instrument detecting the back, its quantity is directly proportional with its competence for added value.
Embodiment 1: the expression that (PBMCs) middle minute chromosome is kept albumen 6 in the Patients with SLE PMBC is significantly higher than the normal person;
The present invention has got 22 routine SLE patients and 10 routine normal persons' blood sample; Isolate PBMCs with lymphocyte separation medium; Utilize Trizol to extract total RNA then, become cDNA, utilize real-time quantitative PCR to detect the level of the mRNA of MCM6 then with the reverse transcriptase reverse transcription.The result finds that the mRNA level of the MCM6 among the SLE patient PBMCs will be significantly higher than normal person (Fig. 1).
Embodiment 2: the expression that (DCs) middle minute chromosome is kept albumen 6 in the Patients with SLE BMDC is significantly higher than the normal person;
The present invention has got 5 routine patients and 4 routine normal persons' blood sample; Isolate PBMCs with lymphocyte separation medium; Utilize magnetic bead to isolate BMDC again; And then utilize Trizol to extract total RNA, and become cDNA with the reverse transcriptase reverse transcription, utilize real-time quantitative PCR to detect the mRNA level of MCM6.The result shows that the expression of the MCM6 in the SLE patient BMDC also is significantly higher than normal person (Fig. 2).
Embodiment 3: (PBMCs) middle minute chromosome is kept albumen 6 in the Patients with SLE PMBC expression and estrogen level are proportionate;
The present invention has got 11 routine SLE patients' blood sample, isolates PBMCs with lymphocyte separation medium, utilizes Trizol to extract total RNA then, becomes cDNA with the reverse transcriptase reverse transcription, utilizes real-time quantitative PCR to detect the level of the mRNA of MCM6 then.Simultaneously, utilize the Architect i2000SR system of Abbott company to detect estrogenic level among the patients serum.The result shows, expression and the estrogen level that minute chromosome is kept albumen 6 in (PBMCs) in the Patients with SLE PMBC be proportionate (Fig. 3).
Embodiment 4: under the stimulation of estrogen and CpG, the level that minute chromosome is kept protein family albumen all raises;
The present invention has carried out the detection of full genome chip to the dendron shape of in vitro culture, and through result's analysis is found, the mRNA that minichromosomes is kept protein family albumen is expressed under E2, CpG, E2 and the CpG synergy all obviously rise, and (Fig. 4 a).In addition, the present invention also uses the method for RT-PCR (Fig. 4 b) and western blot (Fig. 4 c) further to verify this phenomenon.
Embodiment 5: interference fragment can significantly suppress the expression that minute chromosome is kept albumen 6;
The present invention is directed to minute chromosome keep albumen 6 the cDNA sequences Design interference fragment, it is characterized in that having SEQID8 and the described sequence of SEQ ID9.In dendritic cells in vitro, the result shows with this fragment transfection, and interference fragment can significantly suppress minute chromosome in the BMDC to be kept the mRNA of albumen 6 (Fig. 5 a) and protein expression level (Fig. 5 b).
Embodiment 6: BMDC reply estrogen and replying of CpG that minute chromosome is kept after albumen 6 inhibition have been played inhibiting effect;
The present invention has verified that interference fragment suppresses the function that minute chromosome is kept albumen 6 back BMDCs; Find that minute chromosome keeps the expression of albumen 6 and reduce propagation, apoptosis, the phagocytic function that does not influence BMDC (Fig. 6 a); Do not influence the expression of its CD86 molecule, but the expression of CD40 but obviously is inhibited (Fig. 6 b) yet.
Embodiment 7: the BMDC that minute chromosome is kept after albumen 6 suppresses obviously weakens the stimulation ability of T cell.
The present invention has verified that minute chromosome keeps BMDC after albumen 6 suppresses to the effect of other immunocytes, find that minute chromosome is kept albumen 6 and suppressed after, BMDC obviously weakens (Fig. 7) to the activation capacity of T cell.
According to these embodiment; The present invention has proved that minute chromosome keeps the substantial connection of albumen and systemic loupus erythematosus; In the PBMCs and DCs of Patients with SLE; Can both detect high-caliber minute chromosome and keep the expression of albumen, this has disclosed it and can be used as an auxiliary detection index of systemic loupus erythematosus.Systemic loupus erythematosus is accompanied by immune disorder, especially the overactivity of immunocyte.The present invention is through experiment in vitro, proved artificially having reduced after minute chromosome keeps the expression of albumen 6, can obviously reduce the activation levels of immunocyte and the interaction between them.This also makes minute chromosome keep the target spot that albumen becomes systemic loupus erythematosus prevention and treatment, and also possibly directly use the treatment that its antibody carries out systemic loupus erythematosus.
After having read above-mentioned teachings of the present invention, those skilled in the art can do various changes to the present invention, and these equivalent form of values fall within the application's appending claims institute restricted portion equally.
Claims (7)
1. a minichromosomes is kept the purposes of albumen, it is characterized in that, as the clinical auxiliary detection index of systemic loupus erythematosus; Wherein, described minichromosomes is kept albumen and is had the sequence shown in the SEQ ID:1.
2. purposes as claimed in claim 1 is characterized in that, described minichromosomes is kept albumen and comprised that also being selected from down the minichromosomes of organizing keeps albumen:
Minute chromosome with nucleotide sequence shown in the SEQ ID:2 is kept albumen;
Minute chromosome with nucleotide sequence shown in the SEQ ID:3 is kept albumen;
Minute chromosome with nucleotide sequence shown in the SEQ ID:4 is kept albumen;
Minute chromosome with nucleotide sequence shown in the SEQ ID:5 is kept albumen;
Minute chromosome with nucleotide sequence shown in the SEQ ID:6 is kept albumen;
Minute chromosome with nucleotide sequence shown in the SEQ ID:7 is kept albumen.
3. a minichromosomes is kept the interference fragment of albumen, it is characterized in that, can reduce the expression that minichromosomes is kept albumen, has sequence shown in SEQ ID:8 and the SEQ ID:10; Wherein said minichromosomes is kept albumen and is had the sequence shown in the SEQ ID:15.
4. like the said purposes of claim 3, it is characterized in that chaff interference can also be the interference fragment that is building up in the carrier.
5. like claim 3 and the described EVAC of claim 4, it is characterized in that, can also keep the EVAC of albumen design to having claim 1 and the said sequence minichromosomes of claim 2.
6. a minichromosomes is kept the purposes of albumen, it is characterized in that, is used to prepare its polyclonal antibody; Or be used to prepare its monoclonal antibody;
Wherein, minichromosomes is kept albumen and is had claim 1 and the described sequence of claim 2.
7. like claim 5 and the said purposes of claim 6, it is characterized in that said material also can be used for the control of systemic loupus erythematosus.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114073770A (en) * | 2020-08-21 | 2022-02-22 | 广州市妇女儿童医疗中心 | Application of MCM8-cGAS-STING-I type interferon signal channel as disease target |
| US11391744B2 (en) | 2015-06-08 | 2022-07-19 | Arquer Diagnostic Limited | Methods and kits |
| US11519916B2 (en) | 2015-06-08 | 2022-12-06 | Arquer Diagnostics Limited | Methods for analysing a urine sample |
-
2011
- 2011-03-28 CN CN2011100746066A patent/CN102707063A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11391744B2 (en) | 2015-06-08 | 2022-07-19 | Arquer Diagnostic Limited | Methods and kits |
| US11519916B2 (en) | 2015-06-08 | 2022-12-06 | Arquer Diagnostics Limited | Methods for analysing a urine sample |
| CN114073770A (en) * | 2020-08-21 | 2022-02-22 | 广州市妇女儿童医疗中心 | Application of MCM8-cGAS-STING-I type interferon signal channel as disease target |
| WO2022037679A1 (en) * | 2020-08-21 | 2022-02-24 | 广州市妇女儿童医疗中心 | Use of mcm8-cgas-sting-i-type interferon signal pathway as disease target |
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Application publication date: 20121003 |