CN1163755C - Diagnosis of demylelinating or spongiform disease - Google Patents
Diagnosis of demylelinating or spongiform disease Download PDFInfo
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- CN1163755C CN1163755C CNB998136948A CN99813694A CN1163755C CN 1163755 C CN1163755 C CN 1163755C CN B998136948 A CNB998136948 A CN B998136948A CN 99813694 A CN99813694 A CN 99813694A CN 1163755 C CN1163755 C CN 1163755C
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- 102000006386 Myelin Proteins Human genes 0.000 claims abstract description 19
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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
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
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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
- G01N33/6854—Immunoglobulins
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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
- G01N2800/28—Neurological disorders
- G01N2800/2814—Dementia; Cognitive disorders
- G01N2800/2828—Prion diseases
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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
- G01N2800/28—Neurological disorders
- G01N2800/285—Demyelinating diseases; Multipel sclerosis
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Abstract
A method for diagnosing spongiform disease or demyelinating disease in vertebrates, including BSE, MS and CJD, which comprises assaying a biological sample for antibodies which bind to myelin and/or myelin neurofilaments or to one or more antigenic (immunogenic) parts thereof.
Description
Technical field
The present invention relates to the diagnosis of animal and human's demyelinating disease and spongiform encephalopathy, relate in particular to the diagnosis of people BSE and similar or relevant disease.
Background technology
In the International Application No. WO 98/13694A of our co-applications pending trial, we disclose a kind of new mammal spongiform encephalopathy and the diagnostic test of other demyelinate illness.Be disclosed in our above-mentioned experiment in first to file based on a kind of generation model that is applicable to the pathological condition of the various ways that in people and other animals, occurs.For the spongy disease of ox, it is a kind of to the replacement based on the present theory that forms prion that this model provides.Briefly, this new model according to this model, after mammal contacts some bacterium with simulation myelin peptide sequence, can produce a kind of active immunity reaction based on the molecular simulation phenomenon.In relating to the bacterium that produces the active immunity reaction, the most important thing is the acinetobacter calcoaceticus kind, especially acinetobacter calcoaceticus.Developed this para-infectious possibility of early treatment based on this diagnostic test of this new model, for example, prevented further automatically-immune attack animal self myelin by using a kind of suitable microbiotic.
Our application WO98/13694A discloses the mammiferous spongiform encephalopathy of a kind of detection and other demyelinating disease, BSE (BSE) particularly, the method of multiple sclerosis (MS) and Creutzfeldt-Jakob disease (CJD), it comprises the acinetobacter kind that contains peptide sequence ISRFAWGEV that exists in the detection mammal, for example antibody of acinetobacter calcoaceticus.As described in this application formerly, the similar peptide sequence in this peptide sequence simulation mammal myelin and induce antibody with the myelinic cross reaction of mammal.This application formerly discloses the diagnostic kit that detects above-mentioned disease by described method.
In our 99/47932 kind of International Application No. WO, we have proved conclusively acinetobacter calcoaceticus IgA antibody horizontal rising in the patients serum who suffers from multiple sclerosis (MS) and Creutzfeldt-Jakob disease (CJD).
We be that we have described further experiment in the patented claim of GB 9825948.4 at the first to file application number, this experiment conclusive evidence exists anti-ox myelin and the neurofilament antibody of anti-ox in dying from the cow's serum of BSE.These antibody belong to the IgA type.In the patients serum who suffers from MS and CJD, also obtain analog result.These results have confirmed the validity of above-mentioned model, and can draw such conclusion, and promptly we have found to comprise that vertebrate the people is for example taken place in the domestic animal in the cattle breeding field with other or the universal model of the origin of contingent similar disease.Our nearest result of study also provides early stage confirmation these diseases, especially the further experiment basis of the initial BSE of ox.These further experiments can be to based on detecting at the acinetobacter calcoaceticus kind, and for example the experiment of the IgA antibody of acinetobacter calcoaceticus substituting or replenishing.
Summary of the invention
Therefore the present invention comprises diagnosis spongy disease of vertebrate or demyelinating disease, the method that comprises BSE, MS and CJD, it comprises the antibody in the analysis of biological samples, especially IgA antibody, this antibodies myelin and/or neurofilament or its antigen (immunogene) part comprise peptide components described below.
The present invention preferably includes dissecting needle to vertebrate for example ox or people's myeloidin and/or neurofilament antibody.Yet, can select to use from other species, through estimating those myelins and the neurofilament that has enough homologys with the ox of binding antibody or human myelin and neurofilament.
In implementing this method, positive findings represent antibody horizontal on the antibody horizontal of control sample at least about two standard deviations.
The present invention also comprises a kind of diagnostic kit that detects spongy disease of vertebrate or demyelinating disease, comprises for example testing antigen, myelin or neurofilament or its antigen (immunogene) part.
Experiment antigen that uses in the describing method of front and diagnostic kit can be myelin or neurofilament peptide components, for example has one of following sequence of serial ID Nos 1-8, promptly, 1.NEALEK the above-mentioned sequence of 2.LKKVHEE 3.EALEKQL 4.ELEDKQN5.EALEKQL 6.KKVHEE 7.EIRDLR 8.EQEIRDLR extracts from protein information resource (Protein Information Resource) database, discharging number is 44.
In diagnostic kit of the present invention, antigen (c) has sequence ISRFAWGEV.
Since IgA antibody in immune response than high specific, can draw such conclusion, promptly the acinetobacter calcoaceticus infection mechanism is through the body mucosal route, original position is enteron aisle or nasal cavity.Possible nasal cavity is an infection site, causes owing to suck the dust that carries acinetobacter calcoaceticus that is formed by dry sewage or animal wastes.This mechanism prompting is necessary to improve the sanitary condition in the cattle breeding work.
Description of drawings
Show result among attached Fig. 1 and 2 for BSE.
Show result in the accompanying drawing 3 for MS and CJD.
Accompanying drawing 4 has shown contrast (CVL) (CVL=center ridge Vertebrate laboratory (the Central Veterinary Laboratory of this experiment with healthy " biosome " contrast or trouble other diseases, UK obtains suffering from the animal blood serum of other diseases from there) result after relatively.
Embodiment
Embodiment
Experiment
Describe in the application of our the co-applications pending trial that the analysis of above-mentioned biosome is mentioned in front, so its content is by with reference to inserting this paper.The following description of carrying out as experiment antigen with myelin protein or neurofilament of similar analysis program.In accompanying drawing 1-4, A＜30M=age, A＞30M=age was greater than 30 months less than 30 months, the AS=ankylosing spondylitis, C=contrast, RA=rheumatoid arthritis, CVA=cerebrovas-cularaccident, ENC=viral encephalitis and MAN INDEX=myelin acinetobacter calcoaceticus neurofilament index.
The ELISA experiment
(1) draws 200ul antigen suspending liquid A or B, place the flat hard polystyrene droplet plate in 96 holes under 4 ℃, to spend the night.(antigen A is the ox myelin, from Sigma Chemical Company, and Fancy Road, Poole, Dorset, BH12 4XA, UK, concentration is 5ug/ml, antigen B is the ox neurofilament, equally from Sigma, concentration is 5ug/ml).
(2) then with phosphate buffered saline (PBS) (PBS) flushing that contains 0.1% (v/v) Tween 20 3 times.
(3) in each hole, add the confining liquid (0.2%w/v ovalbumin, 0.1%v/v Tween) of 300ul in PBS, then 37 ℃ of insulations 1 hour.
(4) use PBS.Tween 20 washing plates three times then.
(5) get 200ul blood serum sample (experiment or contrast) with PBS with 1/200 dilution proportion.Add Tween, then 37 ℃ of insulations 2 hours.
(6) use PBS.Tween 20 washing plates three times then.
(7) get 200ul in conjunction with rabbit anti--peroxidase of Niu IgA (alpha chain) with PBS with 1/4000 dilution proportion.
(8) use PBS.Tween 20 washing plates three times then.
(9) (2, the citrate/phosphate buffer that contains the 0.98mM hydrogen peroxide (pH 4.1) of 2 '-azine two (3-benzyl ethyl-thiazoline-6-sulfonic acid) at room temperature kept 20 minutes every hole adding 200ul 0.5mg/ml, formed the color of colorimetric analysis.
(10) use 100ul 2mg/ml sodium fluoride stopped reaction then, measure optical density at wavelength 630nm place with trace-ELISA plate reader.
(11) all are analyzed all and carry out under the situation of numbering, so that the source of the clear serum of studying of experimenter (experiment or contrast).
(12) all experiments are carried out twice.
The peptide that above-mentioned experimental arrangement can be chosen myelin or neurofilament or be derived from them carries out with the same manner.
This analysis is that diagnosis is suffered from the ox of BSE and suffered from the people's of MS and CJD new method, has wherein described the experiment that can measure the antibody of anti-two kinds of brain antigens in ox or the human serum.Any positive reaction of readings signify that exceeds 2 standard deviations than normal healthy controls.And experiment is for two kinds of antigens: (A) the ox myelin protein and (B) the ox neurofilament will all be positive (high 2 standard deviations).
This is describe to measure the BSE infected cattle and suffer among MS and the CJD patient, the automatic antibody of anti-brain antigen analysis first.
Result for BSE shows in attached Fig. 1 and 2.
Result for MS and CJD shows in accompanying drawing 3.
The experiment of in our above-mentioned international application, describing can with experimental group of the present invention altogether.This combination experiment is specially adapted to detect the application of BSE.This combination experiment also can be called as " MAN experiment ", and it is based on the mensuration respectively of the specific antibodies of the automatic antibody of anti-ox myelin (white matter of brain) and anti-ox neurofilament (ectocinerea) and anti-metatrophic bacteria acinetobacter calcoaceticus.
The antibody of anti-ox myelin and neurofilament automatic antibody of ox and anti-acinetobacter calcoaceticus is measured at each animal used as test according to the method for former description.According to following algorithm, obtain the MAN index then by taking advantage of optical density :=
The automatic antibody of the automatic antibody x of myelin IgA acinetobacter calcoaceticus antibody x neurofilament,
It is the product of M * A * N.
Accompanying drawing 4 has shown contrast (CVL) (CVL=center ridge Vertebrate laboratory (the Central Veterinary Laboratory of this experiment with healthy " biosome " contrast or trouble other diseases, UK obtains suffering from the animal blood serum of other diseases from there) result after relatively.
The MAN experiment is at the contrast calibration of " biosome " land for growing field crops, and described contrast is the land for growing field crops animal that only is made of green grass and hay from feed.The MAN experiment is a kind of empirical experiment, if only test healthy ox, obtains low-down MAN exponential quantity.
When experiment is suspected when the cow's serum of BSE is arranged, when the MAN index than high 3 standard deviation intervals of control value, regard as positive reaction.
Claims (33)
1. an antibody test vertebrate spongiform disease or the demyelinating disease by existing in the analysis vertebrate comprises BSE, and the diagnostic kit of MS and CJD comprises following as experiment antigen:
(a) myelin or its one or more antigen part; With
(b) neurofilament or its one or more antigen part; With
(c) antibody for acinetobacter has specific antigen, described acinetobacter calcoaceticus
Belong to and contain the vertebrate myelinic peptide sequence of simulation.
2. according to the diagnostic kit of claim 1, wherein this acinetobacter contains sequence ISRFAWGEV.
3. according to the diagnostic kit of claim 1 or 2, acinetobacter wherein is an acinetobacter calcoaceticus.
4. according to the diagnostic kit of claim 1 or 2, wherein antigen (c) is complete acinetobacter bacterium.
5. according to the diagnostic kit of claim 3, wherein antigen (c) is complete acinetobacter bacterium.
6. according to the diagnostic kit of claim 1 or 2, wherein antigen (c) is the peptide with the vertebrate myelinic sequence of simulation.
7. according to the diagnostic kit of claim 3, wherein antigen (c) is the peptide with the vertebrate myelinic sequence of simulation.
8. according to the diagnostic kit of claim 6, wherein antigen (c) has sequence ISRFAWGEV.
9. according to the diagnostic kit of claim 7, wherein antigen (c) has sequence ISRFAWGEV.
10. according to the diagnostic kit of claim 1 or 2, the experiment antigen that wherein is used to detect neurofilament antibody is to have the NEALEK of being selected from, LKKVHEE, EALEKQL, ELEDKQN, KKVHEE, the peptide of the sequence of EIRDLR or EQEIRDLR.
11. according to the diagnostic kit of claim 3, the experiment antigen that wherein is used to detect neurofilament antibody is to have the NEALEK of being selected from, LKKVHEE, EALEKQL, ELEDKQN, KKVHEE, the peptide of the sequence of EIRDLR or EQEIRDLR.
12. according to the diagnostic kit of claim 4, the experiment antigen that wherein is used to detect neurofilament antibody is to have the NEALEK of being selected from, LKKVHEE, EALEKQL, ELEDKQN, KKVHEE, the peptide of the sequence of EIRDLR or EQEIRDLR.
13. according to the diagnostic kit of claim 5, the experiment antigen that wherein is used to detect neurofilament antibody is to have the NEALEK of being selected from, LKKVHEE, EALEKQL, ELEDKQN, KKVHEE, the peptide of the sequence of EIRDLR or EQEIRDLR.
14. according to the diagnostic kit of claim 6, the experiment antigen that wherein is used to detect neurofilament antibody is to have the NEALEK of being selected from, LKKVHEE, EALEKQL, ELEDKQN, KKVHEE, the peptide of the sequence of EIRDLR or EQEIRDLR.
15. according to the diagnostic kit of claim 7, the experiment antigen that wherein is used to detect neurofilament antibody is to have the NEALEK of being selected from, LKKVHEE, EALEKQL, ELEDKQN, KKVHEE, the peptide of the sequence of EIRDLR or EQEIRDLR.
16. according to the diagnostic kit of claim 8, the experiment antigen that wherein is used to detect neurofilament antibody is to have the NEALEK of being selected from, LKKVHEE, EALEKQL, ELEDKQN, KKVHEE, the peptide of the sequence of EIRDLR or EQEIRDLR.
17. according to the diagnostic kit of claim 9, the experiment antigen that wherein is used to detect neurofilament antibody is to have the NEALEK of being selected from, LKKVHEE, EALEKQL, ELEDKQN, KKVHEE, the peptide of the sequence of EIRDLR or EQEIRDLR.
18., be used for the IgA detection of antibodies according to the diagnostic kit of claim 1 or 2.
19., be used for the IgA detection of antibodies according to the diagnostic kit of claim 3.
20., be used for the IgA detection of antibodies according to the diagnostic kit of claim 4.
21., be used for the IgA detection of antibodies according to the diagnostic kit of claim 5.
22., be used for the IgA detection of antibodies according to the diagnostic kit of claim 6.
23., be used for the IgA detection of antibodies according to the diagnostic kit of claim 7.
24., be used for the IgA detection of antibodies according to the diagnostic kit of claim 8.
25., be used for the IgA detection of antibodies according to the diagnostic kit of claim 9.
26., be used for the IgA detection of antibodies according to the diagnostic kit of claim 10.
27., be used for the IgA detection of antibodies according to the diagnostic kit of claim 11.
28., be used for the IgA detection of antibodies according to the diagnostic kit of claim 12.
29., be used for the IgA detection of antibodies according to the diagnostic kit of claim 13.
30., be used for the IgA detection of antibodies according to the diagnostic kit of claim 14.
31., be used for the IgA detection of antibodies according to the diagnostic kit of claim 15.
32., be used for the IgA detection of antibodies according to the diagnostic kit of claim 16.
33., be used for the IgA detection of antibodies according to the diagnostic kit of claim 17.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9825948.4A GB9825948D0 (en) | 1998-11-26 | 1998-11-26 | Diagnosis of spongiform disease |
| GB9825948.4 | 1998-11-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1338053A CN1338053A (en) | 2002-02-27 |
| CN1163755C true CN1163755C (en) | 2004-08-25 |
Family
ID=10843113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998136948A Expired - Fee Related CN1163755C (en) | 1998-11-26 | 1999-11-25 | Diagnosis of demylelinating or spongiform disease |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1133696A1 (en) |
| JP (1) | JP2002530679A (en) |
| CN (1) | CN1163755C (en) |
| AU (1) | AU764960B2 (en) |
| BR (1) | BR9915695A (en) |
| CA (1) | CA2350658A1 (en) |
| GB (1) | GB9825948D0 (en) |
| MX (1) | MXPA01005158A (en) |
| NZ (1) | NZ512335A (en) |
| WO (1) | WO2000031545A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100947577B1 (en) | 2000-06-26 | 2010-03-15 | 엔씨 메디컬 리서치 가부시키가이샤 | Cell fraction containing cells capable of differentiating into nervous system cells |
| DE10112097A1 (en) * | 2001-03-12 | 2002-10-02 | Ingrid Menzel | Methods for determining the pathogenesis and / or for diagnosing 'transmissible spongiform encephalopathies |
| AU2002339114A1 (en) * | 2001-11-09 | 2003-05-19 | King's College London | Diagnosis demyelinating or spongiform disease |
| CA2532130C (en) * | 2003-09-20 | 2016-07-19 | Electrophoretics Limited | Diagnostic method for brain damage-related disorders |
| CN107362357B (en) | 2013-02-06 | 2021-04-27 | Nc医学研究公司 | Cell therapy for the treatment of neurodegeneration |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9620195D0 (en) * | 1996-09-27 | 1996-11-13 | King S College London | Diagnosis and prevention of spongiform diseases |
| GB9805913D0 (en) * | 1998-03-19 | 1998-05-13 | Kings College University Of Lo | Diagnosis of ms |
-
1998
- 1998-11-26 GB GBGB9825948.4A patent/GB9825948D0/en not_active Ceased
-
1999
- 1999-11-25 JP JP2000584308A patent/JP2002530679A/en active Pending
- 1999-11-25 NZ NZ512335A patent/NZ512335A/en unknown
- 1999-11-25 EP EP99956219A patent/EP1133696A1/en not_active Withdrawn
- 1999-11-25 CA CA002350658A patent/CA2350658A1/en not_active Abandoned
- 1999-11-25 MX MXPA01005158A patent/MXPA01005158A/en unknown
- 1999-11-25 BR BR9915695-4A patent/BR9915695A/en not_active IP Right Cessation
- 1999-11-25 AU AU12862/00A patent/AU764960B2/en not_active Ceased
- 1999-11-25 WO PCT/GB1999/003936 patent/WO2000031545A1/en not_active Application Discontinuation
- 1999-11-25 CN CNB998136948A patent/CN1163755C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002530679A (en) | 2002-09-17 |
| NZ512335A (en) | 2003-10-31 |
| WO2000031545A1 (en) | 2000-06-02 |
| GB9825948D0 (en) | 1999-01-20 |
| CA2350658A1 (en) | 2000-06-02 |
| CN1338053A (en) | 2002-02-27 |
| AU764960B2 (en) | 2003-09-04 |
| EP1133696A1 (en) | 2001-09-19 |
| BR9915695A (en) | 2001-08-14 |
| AU1286200A (en) | 2000-06-13 |
| MXPA01005158A (en) | 2002-06-04 |
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