CN113985035A - Application of chemokine CCL28 as marker in preparation of Sjogren syndrome diagnostic reagent - Google Patents
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Abstract
The invention provides an application of a chemokine CCL28 as a marker in preparation of a Sjogren syndrome diagnostic reagent. The detection sample of the diagnostic reagent is serum. The reagent is used for judging whether a subject has Sjogren syndrome or not and judging the damage degree of salivary glands of the Sjogren syndrome by monitoring the concentration of CCL28 in serum of the subject. When the concentration of CCL28 in the serum of the subject is lower than 900-990pg/ml, judging that the subject has Sjogren syndrome. The diagnostic reagent of the invention has simple and convenient operation, reliability and high sensitivity and specificity, and can be used for clinical diagnosis and disease condition evaluation.
Description
Technical Field
The invention relates to the technical field of medical biological detection, in particular to application of a chemotactic factor CCL28 as a marker in preparation of a Sjogren syndrome diagnostic reagent.
Background
Sjogren's Syndrome (SS) is a chronic inflammatory autoimmune disease that affects primarily the exocrine glands, also known as autoimmune exocrine gland epithelioitis or autoimmune exocrine disease. Clinically, there are symptoms of multiple system damage caused by the involvement of other exocrine glands and other organs except glands, besides dry mouth and eyes due to the impaired function of salivary glands and lacrimal glands. There are several autoantibodies and hyperimmune globulinemia in the serum. The disease is divided into primary and secondary types.
The primary sicca syndrome belongs to global diseases, and the prevalence rate of the primary sicca syndrome in the population of China is 0.3% -0.7%, and the prevalence rate of the primary sicca syndrome in the population of the elderly is 3% -4%. The female is common in this disease, and the ratio of male to female is 1: 9 to 20. The onset age is usually 40 to 50 years old. Also found in children.
Primary sicca syndrome (pSS) is a common systemic autoimmune disease, although the disease is usually characterized by eye dryness and mouth dryness caused by exocrine gland injury, if diagnosis and treatment are not timely, systemic injuries including kidney, lung, nervous system, blood system and the like can be caused, the life quality of a patient is seriously affected, and even death is caused. At present, effective laboratory indexes are lacked in diagnosis and disease judgment of pSS, and although serum SSA antibodies have auxiliary diagnostic value on pSS, the sensitivity is only about 67 percent, and the specificity is worse. The diagnosis of pSS is based primarily on an integrated system combining pathology, serum SSA antibodies, tears and salivary secretion, which is very complex, resulting in a large number of misdiagnoses and missed diagnoses. At present, the disease condition judgment of pSS is mainly based on pSS activity integral ESSDAI recommended by European rheumatism alliance, the integral system is very complex and comprises 12 indexes, wherein pathological examination is invasive examination, is difficult to perform in clinical practical work and is easy to cause iatrogenic damage to patients. However, the evaluation of the pathological damage degree of the gland has higher guiding value in clinic and clinical treatment, so that there is an urgent need to find a non-invasive or low-invasive means for evaluating the damage degree of the salivary gland.
Unlike primary sjogren's syndrome. The secondary sicca syndrome refers to the sicca syndrome on the basis of rheumatism with positive diagnosis, such as systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue diseases, polymyositis and dermatomyositis, systemic sclerosis and the like. According to incomplete statistics, secondary sicca syndrome occurs in almost all autoimmune diseases, but most commonly in patients with rheumatoid arthritis. The rheumatoid arthritis is diagnosed definitely, has typical joint swelling and pain, morning stiffness, bone erosion, and symptoms such as dry mouth, dry eyes appear on the basis, accord with the diagnosis of sicca syndrome through oral department, ophthalmology examination and blood test, can diagnose as secondary sicca syndrome. Approximately half of the patients with rheumatoid arthritis will develop secondary sicca syndrome, especially the middle-aged and the elderly patients with rheumatoid arthritis. The diagnosis of the secondary sjogren's syndrome as a whole still lacks clear indications.
Therefore, there is an urgent need in the art to find a non-invasive index that can be used for early diagnosis and disease judgment of SS and is simple and convenient to operate. The research has important significance for the early discovery and early treatment of SS, the prevention of systemic injury and the reduction of patient death.
Disclosure of Invention
In view of the above, in order to overcome the defects of the prior art, the present invention provides an application of the chemokine CCL28 as a new diagnostic marker in the preparation of a sicca syndrome diagnostic reagent, so as to simply and conveniently diagnose SS and judge the disease condition.
The chemokine CCL28 provided by the invention is used as a marker in the preparation of a Sjogren syndrome diagnostic reagent, and a detection sample of the Sjogren syndrome diagnostic reagent is serum.
Further, the sjogren's syndrome diagnostic agent judges whether the subject has sjogren's syndrome by monitoring the concentration of CCL28 in the serum of the subject, and judges that the subject has sjogren's syndrome when the concentration of CCL28 in the serum of the subject is lower than 900-990 pg/ml.
Further, when the concentration of CCL28 in the serum of the subject is lower than 945pg/ml, the subject is judged to have sjogren syndrome, the sensitivity is 70.49%, and the specificity is 78.69%.
Further, the sjogren's syndrome diagnostic reagent judges the degree of salivary gland damage of the subjects with the sjogren's syndrome by monitoring the concentration of CCL28 in the serum of the subjects.
Further, the sicca syndrome is mild or more.
The invention also provides a sicca syndrome diagnostic reagent which judges whether the subject has sicca syndrome by monitoring the concentration of CCL28 in the serum of the subject.
Further, the reagent comprises a reagent for quantitatively detecting the concentration of CCL28 in the serum sample; the agent is selected from: an antibody with detection specificity for CCL 28.
Further, the reagent is used for quantitatively detecting the concentration of the CCL28 in the serum by adopting one of the following detection methods: U-PLEX electrochemiluminescence detection method, enzyme-linked immunosorbent assay, immunoblot-based protein Profiler (Proteome Profiler) human cytokine detection.
Further, the diagnostic reagent comprises CCL28 determination buffer solution, immunoadsorbent, enzyme-labeled conjugate, standard substance and standard serum, washing solution and stop solution.
CCL28 is a CC-class chemokine, also known as mucosa-associated epithelial chemokine (MEC), secreted by epithelial cells, with its mRNA distributed primarily in the salivary glands, parotid gland, mammary gland, trachea, gastrointestinal tract and prostate, and in small amounts in leukocytes and other mucosal tissues in the peripheral blood. In 2000 Wang et al isolated CCL28 from the kidney of mouse and cloned into its open reading frame, the sequence encoded 127 amino acids in total, of which 22 amino acids at the N-terminus were signal peptides, with high homology of CCL28 between different species in terms of sequence similarity. To date, there are no reports of detecting serum CCL28 levels for SS diagnosis and disease judgment.
The existing research shows that human salivary gland, mammary gland, colon and bronchial tissues highly express CCL28, and the receptor of CCL28 is CCR 10. CCL28 recruits IgA expressing CCR10 in the circulation by binding to the receptor+Antibody-secreting cells participate in mucosal immunity by secreting sIgA antibodies to saliva, milk, and the like. In addition, the CCL28 can directly play the role of antibiosis and bacteriostasis, participate in mucosal immunity and effectively kill candida albicans, pseudomonas aeruginosa, streptococcus mutans and the like. Sjogren's syndrome is a disorder in which lacrimal and salivary glands are destroyed by lymphocytes, and destruction of the glands may result in a decrease in CCL28 expression, and studies have shown that CCL28 expression is decreased in saliva of patients compared to normal persons. However, many patients with sjogren's syndrome have damaged their glands, resulting in the absence of saliva.
The inventor of the invention researches and discovers that the expression of CCL28 in the serum is reduced in both primary sicca syndrome and secondary sicca syndrome, but the expression of CCL28 in the serum of patients with simple rheumatoid arthritis and systemic lupus erythematosus is not obviously reduced.
Caries is a common complication of sicca syndrome, and research shows that the expression loss of CCL28 is closely related to caries. The inventors' studies also showed that dry integrated patients with caries had lower levels of CCL28 in serum.
The sicca syndrome is easy to cause blood system involvement such as leukopenia and thrombocytopenia, so the inventor analyzes the expression level of serum CCL28 in patients with or without blood system involvement, and the result indicates that the expression level of serum CCL28 in patients with blood system involvement is lower. The inventors further analyzed the relationship of the blood system trilineage to CCL28 and the results indicated lower CCL28 expression in sjogren's syndrome patients with thrombocytopenia. No research results suggest the relationship between CCL28 and platelet changes. And thrombocytopenia secondary to sjogren's syndrome is a complication difficult to treat clinically, and the relation between the two is explored, and the related mechanism is further researched, so that a new treatment target point can be found for thrombocytopenia.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention combines a large amount of clinical information to determine that the serum level of CCL28 has obvious diagnostic significance for SS. The CCL28 molecule can be used for preparing protein molecular markers for judging SS, can diagnose SS more specifically, and can carry out preliminary evaluation on the disease activity condition of SS. Based on the close relation between the serum CCL28 level and SS, the molecular is used as a diagnostic reagent of a biomarker to carry out serum enzyme-linked immunoassay on a patient, can be used for guiding the accurate diagnosis and disease judgment of SS, and has important guiding significance for the disease judgment and the sequential treatment of SS patients.
2. The diagnostic reagent can reflect the damage degree of salivary glands of patients with sjogren syndrome.
3. The discovery of detecting the correlation between the CCL28 molecules in serum and SS provides a brand-new way for early diagnosis of SS, and has important effects on diagnosis and treatment, treatment evaluation and SS condition estimation. When the concentration of CCL28 detected by ELISA method is lower than 900-990pg/ml, the patient is suggested to have SS, and the SS disease condition is gradually reduced.
4. The inventor obtains a large number of serum samples of patients with primary and secondary sicca syndrome from clinic, and provides powerful guarantee for the research of the invention. The invention utilizes the enzyme-linked immunoassay technology to detect the expression level of the CCL28 molecule in the serum of a patient, and has the characteristics of simple and convenient operation, sensitive detection, good specificity, high repeatability and the like.
5. The detection reagent is used for guiding accurate diagnosis and disease judgment of sicca syndrome, and has the advantages of simple and reliable method, short period, high specificity and easy clinical popularization.
Drawings
FIG. 1: comparison of CCL28 levels in serum (sjogren syndrome patients versus healthy controls);
FIG. 2: comparison of CCL28 levels in serum (healthy controls, patients with primary sjogren syndrome, patients with sjogren syndrome secondary to rheumatoid arthritis, patients with sjogren syndrome secondary to systemic lupus erythematosus, patients with simple rheumatoid arthritis and patients with systemic lupus erythematosus);
FIG. 3: ROC plot of serum CCL28 levels versus diagnostic value of SS in the present invention;
FIG. 4: comparison of the expression levels of CCL28 around acinus in labial glands of different sicca syndrome patients (0 point, 3 point and 12 points of lymphocyte focalization index score of labial glands);
FIG. 5: correlation of CCL28 levels in serum of sjogren's syndrome patients with labial foci index;
FIG. 6: the correlation of CCL28 in serum with clinical symptoms and indexes (A. no dry mouth group and dry mouth group; B. no dry eye group and dry eye group; C. no arthritis group and arthritis group; D. no caries group and caries group; E. ANA antibody positive group and negative group in serum; F. RF antibody positive group and negative group in serum; G. M2 antibody positive group and negative group in serum; H. SSB antibody positive group and negative group in serum; I. no systemic lupus erythematosus patient group and systemic lupus erythematosus patient group; J. leukopenia group and no leukopenia group; K. no thrombocytopenia group and thrombocytopenia group; L. no anemia group and anemia group).
The specific implementation mode is as follows:
hereinafter, specific embodiments of the present invention will be described in detail. Through the embodiment, scientific research personnel can clearly understand the invention, and can make certain changes and modifications on the basis of the embodiment to obtain different research effects. The experimental procedures in the following examples are conventional unless otherwise specified. The reagents involved in the experimental process are all conventional reagents, and the use of the reagents is all referred to the product use instruction.
Example 1 serum CCL28 assay
The study included 60 patients with sjogren's syndrome, 35 of which were patients with primary sjogren's syndrome and 25 with secondary sjogren's syndrome (11 patients with sjogren's syndrome secondary to rheumatoid arthritis, 14 patients with sjogren's syndrome secondary to systemic lupus erythematosus). In addition, 18 rheumatoid arthritis, 10 systemic lupus erythematosus and 24 healthy controls were included in the study. The diagnosis of sjogren's syndrome refers to the international standard in 2002, the diagnosis of rheumatoid arthritis refers to the standard established by ACR and ELUAR in 2009, and the diagnosis of systemic lupus erythematosus refers to the classification standard of international lupus research clinical cooperation group (SLICC) in 2012.
During the study, we drawn blood from the patient, centrifuged and immediately stored frozen at-70 ℃ after serum was obtained.
50ul serum was drawn from patients and healthy controls and serum CCL28(Mlbio, Shanghai, China, SU-B14397) was assayed by ELISA. Each sample was tested in triplicate.
Table 1 shows the sex and age of the patient records
Table 1 Gender and age of the enrolled patients
Data is usedStandard deviation (mean ± standard deviation) presented HC ═ health control volume healthy control;
syndrome sicca syndrome; pSS ═ primary
syndrome primary sicca syndrome; RA ═ rheumatoid arthritis; SLE (systemic lupus erythematous systemic lupus erythematosus. SS + RA standards for
synthetic secondary to rhematoid arthritis; sicca syndrome secondary to rheumatoid arthritis; SS + SLE standards for
syndrome second to system lupus erythematosis secondary to sjogren's syndrome of systemic lupus erythematosus, a, in comparison to healthy controls; b, comparing with a rheumatoid arthritis group; c, in comparison to systemic lupus erythematosus.
As shown in table 1, the mean age of patients with sjogren's syndrome was 50.88 ± 13.80 years, and the majority of patients with sjogren's syndrome were women (3/57). The mean course of disease was 51.87. + -. 55.60 months. The mean age of the healthy controls was 50.88 ± 13.80 years. The age and the sex of the patients with the sicca syndrome have no obvious difference from those of healthy control groups. The mean ages of rheumatoid arthritis and systemic lupus erythematosus are respectively 55.28 + -9.59 and 50.40 + -24.27 years, and the gender of the male and female are respectively as follows: 2/16, 1/9 were not significantly different from healthy controls in both gender and age.
As shown in fig. 1, levels of CCL28 in serum of sjogren's syndrome patients were significantly lower than those of healthy controls. We further divided sjogren's syndrome into primary and secondary, and compared it with simple rheumatoid arthritis and systemic lupus erythematosus, and the results are shown in fig. 2, the serum CCL28 level of the primary sjogren's syndrome patient is significantly lower than that of the healthy control group [1166 ± 173.9vs1844 ± 274.6pg/ml, p <0.001 ]; serum CCL28 levels in sjogren's syndrome patients secondary to rheumatoid arthritis and systemic lupus erythematosus were also significantly lower than healthy controls [776.9 ± 143.2p ═ 0.0159,682.9 ± 177.5p ═ 0.0048pg/ml ]; the serum CCL28 level of the patients with simple rheumatoid arthritis and systemic lupus erythematosus has no obvious difference from the healthy control group [1339 +/-189.5 p ═ 0.1660,1790 +/-382.0 p ═ 0.9133pg/ml ], but the level of the CCL28 in the serum of the patients with sjogren syndrome secondary to rheumatoid arthritis or systemic lupus erythematosus is obviously lower than that of the patients with simple rheumatoid arthritis and systemic lupus erythematosus.
And (4) conclusion: CCL28 expression was reduced in serum of patients with sjogren's syndrome.
Example 2: the invention relates to a sicca syndrome diagnostic reagent using CCL28 as a serum marker and an operation process thereof
The diagnostic reagent of the present invention comprises: CCL28 assay buffer, immunoadsorbent, enzyme-labeled conjugate, standard and standard serum, wash solution, and stop solution.
60 patients with Sjogren's syndrome (diagnosis standard: 2002 international classification diagnosis standard) and 60 patients with age-and sex-matched non-Sjogren's syndrome were tested by ELISA using the above diagnostic reagent, and ROC curve for diagnosis of Sjogren's syndrome was prepared.
FIG. 3 is a ROC curve of CCL28 in serum as a diagnostic index for the diagnosis of Sjogren's syndrome.
The results suggest that AUC value is 0.766, Cutoff value is 945pg/ml, and CCL28 in serum is used as a diagnostic index to diagnose sicca syndrome, and the sensitivity is 70.49% and the specificity is 78.69%.
And (4) conclusion: the level of CCL28 in serum can be used as a serum marker for diagnosing sjogren's syndrome disease.
Example 3: correlation between degree of labial gland injury and serum CCL28 of different patients with sjogren's syndrome
Histological and immunohistochemical studies of the labial glands:
after the patient's labial gland specimen was obtained, a 4mm labial gland specimen pathological section was prepared, and routine histological examination was performed by hematoxylin and eosin staining (H & E). The lesion scoring method is used for judging the lymphocyte infiltration degree of the specimen. The scoring method was to count the number of focal inflammatory cell aggregates containing 50 or more monocytes per 4mm2 area in salivary gland tissue.
After antigen recovery, salivary gland paraffin sections were cut with 3% H2O2Incubate for 10min, add 1:100 diluted rabbit anti-human CCL28 antibody (Abcam, Cambridge, UK), incubate overnight at 4 ℃. Goat anti-rabbit IgG antibody HRP multimers (Bioss, beijing, china) were added to DAB counterstain (Boster, wuhan, china) at a dilution of 1:200 and sealed with resin. Light brown or dark brown staining showed positive results.
Statistical analysis data are shown as mean ± SEM.
The non-parametric Mann-whtney U test was used to evaluate the differences between the two groups. P values <0.05 were statistically significant. The correlation of serum CCL28 content with LSG focus score and serum IgA level was investigated using spearman rank correlation coefficient. P <0.05 is a good correlation.
As shown in fig. 4, CCL28 molecules were expressed around acini in the labial glands of patients with sjogren's syndrome, and the expression of CCL28 was different in lymphocyte focalization index scores of different labial glands. The labial gland with 0 score of focal index has the highest CCL28 expression level, the second of 3 scores and the lowest CCL28 expression level of 12 scores. As shown in fig. 5, levels of CCL28 in serum of sjogren's syndrome patients correlated negatively with the focal index of the labial glands.
And (4) conclusion: the level of CCL28 in serum of patients with sjogren's syndrome is in negative correlation with pathological focus index of labial gland, and can be used for evaluating the damage degree of labial gland of SS patients.
Example 4: correlation of serum CCL28 with clinical symptoms
The study used standardized tables to record demographic data, length of disease course, oral symptoms, ocular symptoms, joint symptoms, Schirmer I test, presence or absence of caries, blood routine, labial gland pathology results and immunological indicators (ANA, ENA, IgA, RF, Anti-CCP).
The study was approved by the ethical committee of the institute of medicine in Chongqing, and according to the declaration of Helsinki, all patients and controls signed informed consent for study participation.
Table 2 shows the clinical and serological characteristics of patients with sjogren's syndrome.
Sjogren's syndrome patients were divided into two groups based on the presence or absence of dry mouth, dry eye, arthritis, dental caries, blood system involvement and positive serum presence of the relevant antibodies (RF, M2, SSB, ANA levels), and the levels of CCL28 levels in the sera of the two groups were compared.
To explore the relevance of serum CCL28 to serological indices, we looked at whether ANA titers in patient sera were greater than or equal to 1: 320. whether rheumatoid factor, SSB antibody and M2 antibody are positive or not and whether no blood system is affected are determined, and SS patients are divided into two groups to compare the level of CCL28 in serum.
Clinical and serological characteristics of patients with Table 2 sjogren's syndrome
Fig. 6 shows comparison of CCL28 levels in serum between the group a. non-dry mouth and the group oral stem, the group b. non-dry mouth and the group dry eye, the group c. non-arthritis and the group arthritis, the group d. non-caries and the group caries, the group e. ANA antibody positive and negative in serum, the group f. RF antibody positive and negative in serum, the group g. M2 antibody positive and negative in serum, the group h. SSB antibody positive and negative in serum, the group i. non-blood system affected patient and the group blood system affected, the group j. leukopenia and the group non-leukopenia, the group k. non-thrombocytopenia and the group thrombocytopenia, the group l. non-anemia and the group.
And (4) prompting by a result: patients with Sjogren's syndrome with a systemic involvement had lower levels of CCL28 in the serum than patients without Sjogren's syndrome. Patients with different indices have no obvious difference in the levels of CCL28 in the sera of the two groups. To further study the association of the three blood systems of sjogren's syndrome with CCL28 in serum, we further divided sjogren's syndrome into two groups based on the presence or absence of leukopenia, thrombocytopenia, and anemia in patients with sjogren's syndrome, and compared the level of CCL28 in serum. The results suggest that the serum level of CCL28 is lower in patients with sjogren syndrome with thrombocytopenia than in patients without thrombocytopenia. The level of CCL28 in serum was not significantly different in sjogren's syndrome patients with leukopenia and anemia.
And (4) conclusion: patients with sjogren's syndrome with caries have lower levels of CCL28, and patients with blood system-compromised sjogren's syndrome have lower serum CCL28 expression, with lower levels of CCL28 in patients with thrombocytopenic sjogren's syndrome. In patients with or without the remaining symptoms, the levels of CCL28 in the sera of the two groups did not differ much.
While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full range of equivalents. Finally, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.
Claims (10)
1. The application of the chemokine CCL28 as a marker in preparing a Sjogren syndrome diagnostic reagent.
2. The use of claim 1, wherein the test sample of the sjogren's syndrome diagnostic reagent is serum.
3. The use of claim 2, wherein the sjogren's syndrome diagnostic agent determines whether the subject has sjogren's syndrome by monitoring the concentration of CCL28 in the serum of the subject, and determines that the subject has sjogren's syndrome when the concentration of CCL28 in the serum of the subject is lower than 900-.
4. The use of claim 3, wherein the subject is judged to have Sjogren syndrome when the concentration of CCL28 in the subject's serum is less than 945 pg/ml.
5. The use of claim 3, wherein the sjogren's syndrome diagnostic reagent is used for determining the degree of salivary gland damage of sjogren's syndrome in the subject by monitoring the concentration of CCL28 in the serum of the subject.
6. The use according to any one of claims 1 to 5, wherein the Sjogren's syndrome is mild or above.
7. A sjogren's syndrome diagnostic agent, which is used for determining whether a subject has sjogren's syndrome by monitoring the concentration of CCL28 in the serum of the subject.
8. The Sjogren syndrome diagnostic reagent according to claim 7,
the reagent comprises a reagent for quantitatively detecting the concentration of CCL28 in a serum sample;
the reagent for quantitatively detecting the concentration of CCL28 in the serum sample is selected from the group consisting of: an antibody with detection specificity for CCL 28.
9. The Sjogren syndrome diagnostic reagent according to claim 7,
the reagent is used for quantitatively detecting the concentration of CCL28 in serum by adopting one of the following detection methods: U-PLEX electrochemical luminescence detection method, enzyme-linked immunosorbent assay, and immunoassay-based protein Profiler human cytokine detection.
10. The sjogren's syndrome diagnostic kit of claim 9, wherein the diagnostic reagents comprise CCL28 assay buffer, immunoadsorbent, enzyme-labeled conjugate, standard and standard serum, wash solution and stop solution.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117025745A (en) * | 2022-11-18 | 2023-11-10 | 中国医学科学院北京协和医院 | Use of molecular markers for diagnosing sjogren's syndrome |
| CN117025745B (en) * | 2022-11-18 | 2024-02-23 | 中国医学科学院北京协和医院 | Use of molecular markers for diagnosing sjogren's syndrome |
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