CN115372625A - Complement pathway-associated plasma protein marker and diagnostic kit - Google Patents

Complement pathway-associated plasma protein marker and diagnostic kit Download PDF

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CN115372625A
CN115372625A CN202210798739.6A CN202210798739A CN115372625A CN 115372625 A CN115372625 A CN 115372625A CN 202210798739 A CN202210798739 A CN 202210798739A CN 115372625 A CN115372625 A CN 115372625A
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ighv3
complement pathway
plasma protein
myocarditis
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程蕾蕾
沈毅辉
汪雪君
陈怡帆
张卉
许宇辰
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Shanghai Dunhui Medical Technology Development Co ltd
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Abstract

The invention belongs to the technical field of biomedicine, and particularly relates to a complement pathway-related plasma protein marker and a diagnostic kit. The invention provides application of a reagent for detecting the content or expression quantity of complement pathway-associated plasma proteins in preparing a kit for detecting myocarditis induced by an immune checkpoint inhibitor, wherein the complement pathway-associated plasma proteins are selected from one or a combination of more of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 proteins. Compared with the prior art, the invention carries out next GO clustering analysis on plasma proteins with statistical significance, enriches the paths with the most obvious change, and further carries out logistic regression analysis on the enriched paths, namely the related targets in the activation of the classical complement paths, so as to obtain 6 biomarkers. The invention is helpful to solve the difficult problems of the diagnosis and the prognosis detection of myocarditis induced by the immunodetection inhibitor, and has important clinical significance for the diagnosis and the prognosis evaluation of myocarditis induced by the immunodetection inhibitor.

Description

Complement pathway-associated plasma protein marker and diagnostic kit
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to a complement pathway-related plasma protein marker and a diagnostic kit.
Background
The rise and development of immunotherapy has brought new treatment options for many patients with advanced tumors. Immune Checkpoint Inhibitors (ICIs) achieve the anti-tumor purpose by activating the Immune system and preventing the Immune escape of tumor cells. With the widespread clinical use of ICIs, the immune-related Adverse reactions (IRAEs) of ICIs gradually attract attention. Cardiotoxicity caused by ICIs is mainly manifested by myocarditis occurring after ICIs are used, and the fatality rate is at the leaders of iraES. The results of multicenter clinical studies have shown an incidence of ici-related myocarditis of 1.14%. Moreover, the disease course of ICIs-related myocarditis is rapidly progressed after the onset, the prognosis is extremely violent, the median time from symptom occurrence to death of a patient is only 32 days, and the final mortality rate is even up to 46%.
At present, experts at home and abroad still commonly know that a diagnosis and treatment method of ICIs (inter-inflammatory syndromes) related myocarditis is explored according to a treatment mode of conventional myocarditis, and the possible ICIs related myocarditis is monitored mainly through troponin, but in a diagnosis section, the cardiac troponin I (cTnI) is used as a regulatory protein for muscle tissue contraction, and the elevation in serum can reflect myocardial injury, but the occurrence of the cardiac troponin I usually prompts that the myocardial is injured and has certain hysteresis, and the specificity and the sensitivity of the cardiac troponin I are mainly used for acute myocardial infarction, and cannot completely meet the requirement for evaluating the severity of the myocarditis. Therefore, the finding of the biomarker with high specificity for the ICIs-related myocarditis is an urgent problem to be solved clinically.
The complement system is an important component of innate immunity and also an important link between innate immunity and acquired immunity, and has been found to play a key role in autoimmune inflammatory diseases such as inflammatory myopathy, SARS-CoV-2-associated myocarditis, and hyper-inflammatory multisystem inflammatory syndrome.
The family of autoimmune-associated immunoglobulin heavy chain variable region genes (IGHV genes) are often highly expressed in some B cell malignancies and autoimmune diseases, often exhibit high degrees of polymorphism, and also exhibit bias in infection and protective antibody responses. However, no correlation between the IGHV gene and the myocarditis induced by the immunodetection inhibitor has been found in the prior art.
Disclosure of Invention
In order to solve the current situation that an immune checkpoint inhibitor is lacked in the prior art to induce a biomarker with high specificity to myocarditis, the invention provides a complement pathway-related plasma protein marker and a diagnostic kit.
The purpose of the invention can be realized by the following technical scheme:
the invention firstly provides the application of a complement pathway associated plasma protein as a biomarker for detecting myocarditis induced by an immune checkpoint inhibitor in a sample of a non-disease diagnosis method, wherein the complement pathway associated plasma protein is selected from one or a combination of more of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 proteins.
In one embodiment of the invention, the sample is plasma of a subject.
The invention also provides the use of complement pathway associated plasma proteins as biomarkers for predicting the prognosis of immune checkpoint inhibitors induced myocarditis.
The invention further provides application of the complement pathway related plasma protein in preparing a kit for detecting myocarditis induced by immune checkpoint inhibitor, wherein the complement pathway related plasma protein is selected from one or more of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 protein.
The invention further provides application of a reagent for detecting the content or expression quantity of the complement pathway-associated plasma protein in preparing a kit for detecting myocarditis induced by an immune checkpoint inhibitor, wherein the complement pathway-associated plasma protein is selected from one or a combination of more of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 proteins.
In one embodiment of the invention, the detection method of the reagent for detecting the content or expression level of the complement pathway-associated plasma protein is enzyme-linked immunosorbent assay, immunochromatography, immunohistochemistry, western blotting or protein chip method.
The invention further provides application of a reagent for detecting the content or expression amount of the complement pathway related plasma protein in preparing a kit for monitoring or evaluating the acute phase and/or the recovery phase of myocarditis induced by the immune checkpoint inhibitor, wherein the complement pathway related plasma protein is selected from one or more of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 protein.
The invention further provides a kit for detecting myocarditis induced by the immune checkpoint inhibitor, which comprises a reagent for detecting the content or expression amount of a complement pathway related plasma protein in a sample, wherein the complement pathway related plasma protein is selected from one or more of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 protein.
In one embodiment of the present invention, the detection of the content or expression level of the complement pathway-associated plasma protein in the sample can be achieved by conventional immunological detection or genetic detection methods, and the principle of the immunological detection method is based on antigen-antibody binding reaction, such as enzyme-linked immunosorbent assay or immunochromatography in the immunological detection method, immunohistochemistry, or western blotting, immunodiafiltration, protein chip method, and the like.
The invention further provides a kit for monitoring or evaluating the acute phase and/or recovery phase of myocarditis induced by immune checkpoint inhibitors, which comprises a reagent for detecting the content or expression amount of complement pathway related plasma proteins in a sample, wherein the complement pathway related plasma proteins are selected from one or more of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1 proteins.
The invention further provides a method for detecting myocarditis induced by immune checkpoint inhibitors, which is not used for disease diagnosis, and the content or the expression amount of complement pathway related plasma proteins in a sample to be detected is detected, wherein the complement pathway related plasma proteins are selected from one or more of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 proteins, and the IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 proteins are known proteins.
In one embodiment of the present invention, the subject is human and the biological sample is derived from the plasma of the subject by a method for quantitatively determining the expression level of human peripheral blood plasma protein by DIA.
In one embodiment of the invention, the Log is used 2 FOT calculation, setting the standard values of the expression quantities of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1 proteins in peripheral blood plasma as 23.0, 22.8, 24.5, 32.0 and 34.0 respectively, and indicating that the ICIs-related myocarditis is suffered when the detection value of at least one of the IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1 proteins is higher than the standard value.
The invention proves that the classical complement pathway in the peripheral blood plasma protein of the myocarditis patients related to the ICIs is obviously activated by the related research of the plasma protein, and is obviously higher than that of the tumor patients who have not developed the myocarditis by using the ICIs. Furthermore, multiple subtypes of the IGHV gene are significantly elevated in the activated complement pathway. Furthermore, the expression level of plasma proteins in peripheral blood and Gene Ontology hierarchical clustering analysis show that the classical complement pathway related plasma proteins of myocarditis patients induced by an immunodetection inhibitor are obviously increased, and when the classical complement pathway is obviously activated, the probability of occurrence of the myocarditis related to the ICIs is obviously improved.
Meanwhile, the expression level of plasma protein in peripheral blood is used as a biomarker for detection, and the biomarker is IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1. When the expression level of the 6 plasma proteins is increased beyond the cut-off value, the probability of generating the myocarditis related to the ICIs is obviously improved.
Based on the above, the invention is provided.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. when DIA quantitative proteomics analysis is carried out on peripheral blood plasma protein, the fact that the classical complement pathway in peripheral blood plasma protein of a patient with myocarditis related to ICIs is obviously activated is found, and according to the fact that the level of the plasma protein related to the classical complement pathway is obviously higher than that of a tumor patient who uses the ICIs and does not develop the myocarditis, a risk assessment model is constructed on the basis of a logistic regression model, and the occurrence of the myocarditis related to ICIS can be effectively predicted.
2. According to the invention, the plasma protein with statistical significance is subjected to next GO cluster analysis, and is enriched to a path with the most obvious change, namely: activation of the classical complement pathway. Further, the enrichment pathway, namely the relevant target point in the activation of the classical complement pathway, is subjected to logistic regression analysis, the value of the area under the curve (AUC) is taken out, and the value is larger than 0.8, and then the subsequent detection and analysis are carried out, so that 6 biomarkers, namely IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1, are obtained, and the 6 biomarkers have better distinguishing capability.
3. The invention is helpful to solve the difficult problems of the diagnosis and the prognosis detection of myocarditis induced by the immunodetection inhibitor, and has important clinical significance for the diagnosis and the prognosis evaluation of myocarditis induced by the immunodetection inhibitor.
Drawings
FIG. 1 is a schematic and flow diagram of a complement pathway-associated plasma protein marker kit for the diagnosis of myocarditis induced by an immunodetection inhibitor.
FIG. 2 is a GO hierarchical clustering analysis of complement pathway associated plasma proteins for immunodetection inhibitor induced myocarditis diagnosis.
FIG. 3 is a ROC curve for a classical complement pathway-associated plasma protein.
Fig. 4 summarizes the t-test (two-tailed) results and the scatter plot.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments.
Example 1
This example provides a screening method for distinguishing potential plasma protein markers between ICIs-associated myocarditis patients and normal persons.
The principle and the flow of the complement pathway-associated plasma protein marker kit for diagnosing myocarditis induced by the immunodetection inhibitor are shown in figure 1, and the method specifically comprises the following steps:
1. extraction of peripheral blood plasma protein
1.1 draw 2-3ml of peripheral venous blood into a yellow biochemical tube, temporarily store, place on ice or in a refrigerator at 4 ℃ and then put into an ultracentrifuge, centrifuge at 2000rpm for 20min at 4 ℃.
1.2 the supernatant, i.e. plasma, is then transferred to a 1.5ml sterile EP tube using a pipette, and if not immediately processed, the EP tube is placed in a freezer at-80 ℃ for long term storage.
2. Plasma proteome detection
The method is as described by Agilent technologies: mainly comprises the preparation and separation of a sample generated by a DDA library; filter assisted sample preparation (FASP digestion); data-dependent mass spectrometry analysis; these methods are conventional methods for plasma proteome detection, the procedures established by Agilent, all operating according to the official instructions.
3. Bioinformatics analysis
Statistical analysis of the data was performed to screen for plasma proteins with high association with myocarditis associated with the ici. The analytical logic is as follows: and (3) performing data processing and analysis by adopting SPSS 23 software, selecting, analyzing, comparing average values, performing parameter inspection, performing independent sample T inspection, and detecting according to a non-myocarditis group and a myocarditis group, wherein finally, the p-value is less than 0.05, namely that the two groups are considered to have significant difference. The differential proteins are then subjected to a next step of bioinformatic analysis, here mainly by Gene Ontology (GO) hierarchical clustering analysis, which is a standardized functional classification system describing the properties of genes and Gene products in an organism mainly by three aspects: the Biological processes involved (Biological processes), the Molecular functions (Molecular functions) and the Cellular components (Cellular components). Subsequently, in the Biological processes involved (BP), these differential proteins were classified, potential activation pathways were found, and the pathways were located in relation to one another, and Gene Ontology (GO) hierarchical clustering analysis of the immunodetection inhibitors induced myocarditis diagnosis, as shown in fig. 2, found to be enriched in the most variable pathways among the samples studied, namely: activation of the classical complement pathway.
4. Screening of proteomic markers useful for accurate diagnosis of ICIs-associated myocarditis
Finally, the differential potential targets in the classical complement pathway are included in Logistic Regression, the input analysis method is selected, the potential diagnosis target of AUC (area under curve > 0.8) is found by Logistic Regression, and then the potential diagnosis target, the scatter diagram and the t-test result are listed, and the t-test (double-tailed) result and the scatter diagram are summarized as shown in fig. 4. And finally, selecting a cutoff value with the specificity higher than 90%, thereby ensuring that the cutoff value has higher specificity, reducing the occurrence of false positive and being more suitable for clinical use.
Among them, 6 candidate complement pathway-associated plasma proteins with good differentiation efficacy are summarized in table 1.
TABLE 1 summary of candidate complement pathway-associated plasma proteins with good differential potency
Figure BDA0003733196780000061
The 6 biomarkers IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3, IGHG1 were included as state variables by analysis of SPSS-ROC curve according to inclusion in non-myocarditis and myocarditis groups, and subsequently analyzed to obtain ROC curve of classical complement pathway-associated plasma protein as shown in fig. 3.
In addition, in the embodiment, log is used 2 FOT calculation, setting the expression levels of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1 proteins in peripheral plasma at 23.0, 22.8, 24.5, respectively,24.5, 32.0 and 34.0, when at least one of the IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1 proteins is detected to be higher than the standard value, the myocarditis related to the ICIs is suggested to be suffered.
In this example, for 6 biomarkers, when selecting the cut-off value, the cut-off value with Specificity higher than 90% is taken for better clinical use, so as shown in table 1, when the corresponding cut-off value (cut off), the Specificity (Specificity) is the occurrence probability, for example: the patient's IGHV3-13 >.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (10)

1. Use of a complement pathway associated plasma protein as a biomarker for immune checkpoint inhibitor induced myocarditis in a test sample for a non-disease diagnostic method, wherein the complement pathway associated plasma protein is selected from the group consisting of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or a combination of IGHG1 proteins.
2. Use of a complement pathway-associated plasma protein as a biomarker for predicting the prognosis of myocarditis induced by an immune checkpoint inhibitor, wherein the complement pathway-associated plasma protein is selected from the group consisting of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 proteins, or a combination thereof.
3. Use of a complement pathway associated plasma protein in the preparation of a kit for detecting immune checkpoint inhibitor induced myocarditis, wherein the complement pathway associated plasma protein is selected from one or a combination of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 proteins.
4. The application of a reagent for detecting the content or the expression quantity of the complement pathway-associated plasma protein in the preparation of a kit for detecting the myocarditis induced by the immune checkpoint inhibitor is characterized in that the complement pathway-associated plasma protein is selected from one or the combination of more of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 protein.
5. Use of a reagent for detecting the content or expression level of a complement pathway-associated plasma protein in the preparation of a kit for monitoring or evaluating the acute phase and/or recovery phase of myocarditis induced by an immune checkpoint inhibitor, wherein the complement pathway-associated plasma protein is selected from one or more of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1 proteins.
6. The use of claim 4 or 5, wherein the detection method of the reagent for detecting the content or expression level of the plasma protein associated with the complement pathway is enzyme-linked immunosorbent assay, immunochromatography, immunohistochemistry, western blotting or protein chip method.
7. A kit for detecting myocarditis induced by immune checkpoint inhibitors, which comprises a reagent for detecting the content or expression amount of a complement pathway-associated plasma protein in a sample, wherein the complement pathway-associated plasma protein is selected from one or a combination of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1 proteins.
8. A kit for monitoring or assessing the acute and/or convalescent phase of myocarditis induced by an immune checkpoint inhibitor, comprising reagents for detecting the amount or expression of a complement pathway-associated plasma protein in a sample, wherein the complement pathway-associated plasma protein is selected from the group consisting of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1 protein.
9. A method for detecting myocarditis induced by an immune checkpoint inhibitor for non-disease diagnostic purposes, comprising detecting the amount or expression level of a complement pathway-associated plasma protein selected from one or a combination of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 or IGHG1 protein in a sample to be tested.
10. The method of claim 9, wherein the Log is used 2 FOT calculation, wherein the standard values of the expression levels of IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1 proteins in peripheral blood plasma are respectively set to be 23.0, 22.8, 24.5, 32.0 and 34.0, and when the detection value of at least one of the IGHV3-13, IGHV3-43, IGHV3-30, IGHV3-33, IGHG3 and IGHG1 proteins is higher than the standard value, the occurrence of ICIs-related myocarditis is indicated.
CN202210798739.6A 2022-07-06 2022-07-06 Complement pathway-associated plasma protein marker and diagnostic kit Pending CN115372625A (en)

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