CN112924671A - Biomarker for diagnosing rheumatoid arthritis combined with pulmonary interstitial fibrosis and application thereof - Google Patents
Biomarker for diagnosing rheumatoid arthritis combined with pulmonary interstitial fibrosis and application thereof Download PDFInfo
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- CN112924671A CN112924671A CN202110120979.6A CN202110120979A CN112924671A CN 112924671 A CN112924671 A CN 112924671A CN 202110120979 A CN202110120979 A CN 202110120979A CN 112924671 A CN112924671 A CN 112924671A
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- lectin
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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
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/415—Assays involving biological materials from specific organisms or of a specific nature from plants
- G01N2333/42—Lectins, e.g. concanavalin, phytohaemagglutinin
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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
- G01N2800/102—Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints
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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
- G01N2800/12—Pulmonary diseases
Abstract
The invention discloses application of Con A lectin in preparing a reagent for diagnosing rheumatoid arthritis and pulmonary interstitial fibrosis. The invention detects the glycan profile of the serum IgG molecule of the Rheumatoid Arthritis (RA) patient specifically combined with the agglutinin by adopting the agglutinin microarray, and the result shows that the content of ConA agglutinin combined glycan is increased in the RA patient. Since ConA lectin binds specifically to mannose, this indicates that the expression of mannose levels is elevated in RA patients. Further studies found that ConA lectin-binding glycan levels were expressed higher in RA-associated interstitial lung disease (RA-ILD) patients than in RA non-ILD patients, and ConA lectin-binding glycan levels could be used as a biomarker for RA-ILD disease.
Description
Technical Field
The invention belongs to the field of biological detection, and particularly relates to a biomarker for diagnosing rheumatoid arthritis combined with pulmonary interstitial fibrosis and application thereof.
Background
Rheumatoid Arthritis (RA) is a chronic, highly disabling autoimmune disease, which is frequently repeated and gradually aggravated, and finally results in destruction of joint structure, resulting in disability and loss of labor capacity of patients. In addition to joint manifestations, RA is also involved in multiple organ, multiple system involvement. RA has long been recognized as an "immotile cancer" and, once diagnosed, patients are often suffering from physical and mental suffering. Interstitial Lung Disease (ILD) is a common complication of Rheumatoid Arthritis (RA) with a very poor prognosis accounting for about 7% of rheumatoid arthritis-related deaths. Currently, methods for diagnosing RA-related interstitial lung disease (RA-ILD) are very limited, the diagnosis of RA-related interstitial lung disease (RA-ILD) mainly depends on chest high-resolution CT and lung function examination, lung biopsy has limitation in clinical application due to high invasiveness, and a new biomarker for diagnosing RA-ILD is urgently needed to be found.
Immunoglobulin g (igg) is an important immune effector molecule in serum. IgG molecules can exert different immune effector mechanisms in different diseases through glycosylation modification. For example, IgG molecules with galactose-deficient N-glycans have the effect of promoting the development of inflammation, whereas IgG molecules with sialylated N-glycans have the effect of counteracting inflammation. Therefore, the research of glycosylation becomes a potential tool for deeply understanding the pathogenesis, disease classification, disease evaluation, treatment effect, prognosis judgment and disease outcome of autoimmune diseases.
In view of the important role of glycosylation in the process of disease occurrence and development, the expression of serum IgG glycosylation of RA-ILD patients is screened by a high-flux glycosylation analysis technology, namely a lectin microarray technology, so as to investigate the clinical application value of glycosylation in RA-ILD.
Disclosure of Invention
In order to solve the problems, the invention provides a biomarker for diagnosing rheumatoid arthritis and pulmonary interstitial fibrosis and application thereof.
First, the present invention provides a biomarker for diagnosing rheumatoid arthritis with pulmonary interstitial fibrosis, which is a complex formed by binding of Con a lectin and IgG.
Wherein said IgG comprises mannose.
Secondly, the invention also provides application of the biomarker in preparing a reagent for diagnosing rheumatoid arthritis or rheumatoid arthritis combined with pulmonary interstitial fibrosis.
Specifically, the diagnosis includes: determining the level of complexes formed by the binding of Con a lectin to IgG in a biological sample obtained from a patient presenting rheumatoid arthritis; optionally, the step of (a) is carried out,
comparing the level of the complex formed by the binding of Con A lectin to IgG in the biological sample to control data, wherein a detectably increased level of the complex formed by the binding of Con A lectin to IgG in the sample relative to the control data indicates a likelihood of rheumatoid arthritis.
Further, detectably elevated levels of complexes formed by binding of Con a lectin to IgG, relative to data from rheumatoid arthritis patients without complicated pulmonary interstitial fibrosis, indicates a likelihood of rheumatoid joint complicated pulmonary interstitial fibrosis.
Wherein the biological sample is a serum sample.
Preferably, the level of the complex formed by the binding of Con a lectin to IgG is measured by the steps comprising:
a. contacting a biological sample from a patient with Con a lectin;
b. forming a lectin-glycan complex between IgG and Con a lectin present in the biological sample;
c. washing to remove any unbound IgG;
d. adding a detection antibody that is labeled and reactive with an antibody from the biological sample;
e. washing to remove any unbound labeled detection antibody; and
f. converting the label of the detection antibody to a detectable signal.
Secondly, the invention also provides the application of the Con A agglutinin in preparing a reagent for diagnosing rheumatoid arthritis or rheumatoid arthritis and pulmonary interstitial fibrosis.
Wherein the diagnosing comprises: contacting Con a lectin with a biological sample obtained from a patient presenting rheumatoid arthritis, and determining the level of complexes formed by binding of Con a lectin to IgG; optionally, the step of (a) is carried out,
comparing the level of the complex formed by the binding of Con A lectin to IgG in the biological sample to control data, wherein a detectably increased level of the complex formed by the binding of Con A lectin to IgG in the sample relative to the control data indicates a likelihood of rheumatoid arthritis.
Further, detectably elevated levels of complexes formed by binding of Con a lectin to IgG, relative to data from rheumatoid arthritis patients without complicated pulmonary interstitial fibrosis, indicates a likelihood of rheumatoid joint complicated pulmonary interstitial fibrosis.
Wherein the biological sample is a serum sample.
Wherein the Con A lectin is deposited or immobilized on a solid surface support.
The solid phase surface carrier is preferably in the form of latex beads, porous plates or membrane strips, nano-tubes, flakes with two-dimensional codes and the like.
Wherein the detection antibody is labeled by covalent attachment to an enzyme, a label with a fluorescent compound or metal, or a label with a chemiluminescent compound.
The present study examined the glycan profile of serum IgG molecules of Rheumatoid Arthritis (RA) patients with specific binding to lectins using a lectin microarray, and the results showed that the content of ConA lectin-bound glycans was elevated in RA patients. Since ConA lectin binds specifically to mannose, this indicates that the expression of mannose levels is elevated in RA patients. Further studies found that ConA lectin-binding glycan levels were expressed higher in RA-associated interstitial lung disease (RA-ILD) patients than in RA non-ILD patients, and ConA lectin-binding glycan levels could be used as a biomarker for RA-ILD disease.
Drawings
FIG. 1 shows the layout of a lectin microarray of 56 lectins (three wells) on an array slide.
FIG. 2 shows the ConA lectin signal comparison for the RA-ILD, RA-non ILD, DC and HC groups.
FIG. 3 shows the ConA lectin stamp verification chart of the same lot of the lectin microarray.
FIG. 4 shows the comparison of the ConA lectin blot results of the lectin microarray in the same batch of specimens.
FIG. 5 shows the ConA lectin stamp verification chart of the new batch of specimens.
FIG. 6 comparison of the Con A lectin imprinting results of the samples of the new batch with gray scale values.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Experimental specimen: subjects included in this study were divided into three groups: RA group (35, of which 15 RA-ILDs), disease control group (DC, including 40 other autoimmune diseases, of which 20 systemic lupus erythematosus, 20 idiopathic inflammatory myopathy), healthy control group (HC, including 43 healthy examiners). The subject data are shown in Table 1. Wherein the diagnosis of both the RA group and the DC group meets the diagnosis criteria of the corresponding disease. All the people who entered the group collected fresh blood, and immediately separated serum, and frozen at-80 ℃ for later use.
TABLE 1 lectin microarray assay basic data for 118 subjects
Example 1 lectin microarray analysis of serum IgG glycosylation
A lectin microarray consisting of 56 kinds of lectin microparticles. 56 lectins were fixed in triplicate on a chip, and serum from each patient was diluted 1:200, added to the microarray and incubated overnight at 4 ℃. Then, the anti-IgG-Cy 5 conjugate was hybridized to the microarray chip for 1 hour in a dark environment. The fluorescence intensity of all proteins was analyzed independently. And converts the chip image to a digital format for analysis.
The signal-to-noise ratio (S/N) for each lectin spot was calculated using the signal-to-noise ratio (difference between foreground and background values for the spot) for each lectin spot. To prevent bias of lectin microarrays between arrays, we normalized the S/N data using normalization between arrays. Significant differences in lectin binding were determined by data distribution among groups according to the following rules (1) comparison between groups >1.7 or < 0.588; (2) the test types are compared between groups, if normality is met, T test is selected, otherwise non-parametric test is selected, if P value <0.05 or fisher test P value <0.05 or [ ROC _ AUC > -0.6 and ROC _ P value <0.05) ].
A lectin microarray containing 56 lectins was used to detect the glycosylation state in the experimental samples (FIG. 1). The lectin can be specifically combined with glycan molecules at the tail end of the glycoprotein to form a complex, and the type and content of the glycan on the surface of the target protein can be researched through the specific combination of different lectins and the glycan. Lectin microarrays are now being widely used in glycosylation research due to their high efficiency. After the frozen samples are balanced at room temperature, the samples are added into a lectin microarray to react with the lectin microarray, and then the signal value of each lectin and the specific binding glycan of each lectin can be obtained through the steps of washing, sealing, fluorescent secondary antibody reaction, fluorescence detection and the like, wherein the signal value is related to binding affinity and binding strength.
To ensure that the collected fluorescent signal is derived from a specific binding of IgG, we labeled IgG antibodies with Cy 5. The S/N data for the two lectins satisfying the above two conditions were considered to have significant differences, and 7 lectins were selected in total (Table 2).
Table 2 lectins with significant differences in lectin microarrays
Man: mannose; GlcNAc: n-acetylglucosamine; glc: glucose; GalNAc: n-acetylgalactosamine; gal: galactose; DC: a disease control group; HC: healthy control group. *: p < 0.05; **: p < 0.01.
The affinity signal values for the 7 lectins showed significant differences between the four groups of samples. S/N data show IgG glycosylation changes in the RA-ILD patient group relative to the RA-non ILD, DC and HC groups: (1) increased mannose sugar chains of RA-ILD patients were shown by detecting increased binding to concanavalin A (ConA) (P < 0.05); (2) an increase in N-acetylglucosamine (GlcNAc) in RA-ILD patients was indicated by detecting an increase in binding to Datura agglutinin (DSL) (< 0.05 for all P); (3) an increase in glucose (Glc) in RA-ILD patients was indicated by detecting increased binding to lentil Lectin (LCA) and pea lectin (PSA) (both P < 0.05); (4) an increase in galactose (Gal) in RA-ILD patients (both <0.05) was indicated by detecting increased binding to Moringa oleifera lectin (MNA-M) and peanut lectin (PNA); (5) by detecting a decrease in binding to soybean lectin (SBA), a decrease in N-acetylgalactosamine (GalNAc) in RA-ILD patients was indicated (P both < 0.05). FIG. 2 shows ConA lectin signal comparison for RA-ILD, RA-non ILD, DC and HC groups.
Example 2 serolectin imprinting validation experiment
To further clarify the differential expression glycosylation detected by the lectin microarray, lectin imprinting was performed using 24 specimens (6 RA-ILDs, 6 RA-non ILDs, 6 DCs, 6 HCs) of the same lot and a new 12 specimens (4 RA-ILDs, 3 RA-non ILDs, 3 DCs, 2 HCs, for the basic data shown in table 3) of the same lot of lectin microarray. Serum specimen 1: 100, mixing with a loading buffer solution, boiling for 5 minutes at 100 ℃, performing SDS-PAGE electrophoresis in 10% preformed gel, and electrically transferring proteins in the preformed gel to a PVDF membrane. And (3) sealing the PVDF film which is successfully transferred, hybridizing the PVDF film with Cy 3-labeled lectin, and finally detecting a fluorescence signal by a fluorescence imager. The intensity of the fluorescence signal is proportional to the binding force of the lectin-bound glycoprotein glycosyl groups.
By comparing the results of lectin blotting on a micro-aligned 24-patient batch of lectin samples (fig. 3), the binding strength of serum IgG to ConA lectin was increased in RA-ILD patients compared to RA-non ILD patients, DC and HC (fig. 4). In addition, a comparison of the results of lectin blotting on 12 new batches of patient specimens (fig. 5) revealed that the binding strength of serum IgG to ConA lectin was also significantly increased in RA-ILD patients (P <0.05) compared to RA-non ILD patients, DC and HC (fig. 6).
The above results indicate that ConA lectin-binding glycan-mannose levels are abnormal in the serum of RA-ILD patients, and RA-ILD patients have higher ConA lectin-binding glycan levels than RA-non ILD patients.
Table 3 lectin blot validation of disease data for new batches of patients
The results indicate that ConA lectin-bound glycan levels are elevated in RA patients. Since ConA lectin binds specifically to mannose, this indicates that the expression of mannose levels is elevated in RA patients. Further, Con a lectin-binding glycan levels were expressed higher in RA-ILD patients than in RA-non ILD patients, indicating that Con a lectin-binding glycan levels can serve as a biomarker for RA-ILD.
Claims (10)
1. A biomarker for diagnosing rheumatoid arthritis with pulmonary interstitial fibrosis, which is a complex formed by binding Con A lectin and IgG.
2. Use of the biomarker of claim 1 for the preparation of a reagent for the diagnosis of rheumatoid arthritis or rheumatoid arthritis with pulmonary interstitial fibrosis.
3. The use of claim 2, wherein said diagnosing comprises: determining the level of a complex formed by the binding of Con a lectin to IgG in a biological sample obtained from a patient exhibiting rheumatoid arthritis; optionally, the step of (a) is carried out,
comparing the level of the complex formed by the binding of Con A lectin to IgG in the biological sample to control data, wherein a detectably increased level of the complex formed by the binding of Con A lectin to IgG in the sample relative to the control data indicates a likelihood of rheumatoid joint development.
4. The use of claim 3, wherein a detectably increased level of a complex formed by Con A lectin binding to IgG, relative to data from a patient with rheumatoid arthritis without combined pulmonary interstitial fibrosis, is indicative of a likelihood of rheumatoid joint combined pulmonary interstitial fibrosis.
Use of Con A lectin in the manufacture of a reagent for the diagnosis of rheumatoid arthritis or rheumatoid arthritis with pulmonary interstitial fibrosis.
6. The use of claim 5, wherein said diagnosing comprises: contacting Con a lectin with a biological sample obtained from a patient exhibiting rheumatoid arthritis, and determining the level of complexes formed by binding of Con a lectin to IgG; optionally, the step of (a) is carried out,
comparing the level of the complex formed by the binding of Con A lectin to IgG in the biological sample to control data, wherein a detectably increased level of the complex formed by the binding of Con A lectin to IgG in the sample relative to the control data indicates a likelihood of rheumatoid arthritis.
7. The use of claim 6, wherein a detectably increased level of a complex formed by Con A lectin binding to IgG, relative to data from a rheumatoid arthritis patient without combined pulmonary interstitial fibrosis, is indicative of a likelihood of rheumatoid joint combined pulmonary interstitial fibrosis.
8. The use according to claim 3 or 6, wherein the biological sample is a serum sample.
9. Use according to claim 5 or 6, wherein the level of complexes formed by Con A lectin binding to IgG is measured by the steps comprising:
a. contacting a biological sample from a patient with Con a lectin;
b. forming a lectin-glycan complex between IgG and Con a lectin present in the biological sample;
c. washing to remove any unbound IgG;
d. adding a detection antibody that is labeled and reactive with an antibody from the biological sample;
e. washing to remove any unbound labeled detection antibody; and
f. converting the label of the detection antibody to a detectable signal.
10. Use according to claim 9, wherein the Con a lectin is deposited or immobilized on a solid surface support, preferably in the form of a latex bead, a multi-well plate or membrane strip, a nanotube, a two-dimensional coded sheet or the like, preferably the detection antibody is labeled by covalent attachment to an enzyme, a label with a fluorescent compound or metal, or a label with a chemiluminescent compound.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117426352A (en) * | 2023-12-08 | 2024-01-23 | 中国中医科学院中药研究所 | Construction method and application of interstitial lung disease variable animal model |
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|---|---|---|---|---|
| CN1047392A (en) * | 1989-05-19 | 1990-11-28 | 卫材株式会社 | Diagnostic drug for rheumatoid arthritis |
| CN101074951A (en) * | 2007-06-26 | 2007-11-21 | 大连医科大学 | Immune globulin G-glycosylation inspecting reagent for rheumatic arthritis in early-stage diagnosis and its production |
| WO2016141262A1 (en) * | 2015-03-04 | 2016-09-09 | The Rockefeller University | Anti-inflammatory polypeptides |
| CN108976301A (en) * | 2018-08-09 | 2018-12-11 | 中国人民解放军第二军医大学东方肝胆外科医院 | A kind of preparation method for antibody of the specific glycoprotein of novel serum |
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- 2021-01-28 CN CN202110120979.6A patent/CN112924671A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1047392A (en) * | 1989-05-19 | 1990-11-28 | 卫材株式会社 | Diagnostic drug for rheumatoid arthritis |
| CN101074951A (en) * | 2007-06-26 | 2007-11-21 | 大连医科大学 | Immune globulin G-glycosylation inspecting reagent for rheumatic arthritis in early-stage diagnosis and its production |
| WO2016141262A1 (en) * | 2015-03-04 | 2016-09-09 | The Rockefeller University | Anti-inflammatory polypeptides |
| CN108976301A (en) * | 2018-08-09 | 2018-12-11 | 中国人民解放军第二军医大学东方肝胆外科医院 | A kind of preparation method for antibody of the specific glycoprotein of novel serum |
Non-Patent Citations (3)
| Title |
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| DANICA MISLOVIČOVÁ等: ""Lectinomics I. Relevance of exogenous plant lectins in biomedical diagnostics", 《SECTION CELLULAR AND MOLECULAR BIOLOGY》 * |
| J. STÜMER等: "Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy", 《CLINICAL AND EXPERIMENTAL IMMUNOLOGY》 * |
| 鞠善良: "类风湿关节炎并发间质性肺疾病的临床研究", 《中国优秀博硕士学位论文全文数据库(硕士) 医药卫生科技辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117426352A (en) * | 2023-12-08 | 2024-01-23 | 中国中医科学院中药研究所 | Construction method and application of interstitial lung disease variable animal model |
| CN117426352B (en) * | 2023-12-08 | 2024-03-08 | 中国中医科学院中药研究所 | Construction method and application of interstitial lung disease variable animal model |
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