CN116564499A - Auxiliary screening method and system for immune dysfunction autism - Google Patents
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Abstract
The invention provides an auxiliary screening method and an auxiliary screening system for immune dysfunction autism. The immune dysfunction autism auxiliary screening system of the invention comprises: (a) an input module; (b) The processing module is used for processing the T cell subgroup characteristic data or the original data so as to obtain a screening result; wherein the processing comprises: comparing the Teff/Treg ratio characteristic with a reference control value to obtain a criterion, wherein when the severity score is higher than the reference control value, the subject is prompted to be an immune dysfunction autism patient or a person at higher risk of suffering from immune dysfunction autism than a normal population; (c) an output module. The invention can carry out auxiliary screening on the immune dysfunction autism and has auxiliary effect on the analysis of the severity of the behavioral disorder of the immune dysfunction autism.
Description
Technical Field
The invention relates to the field of medical diagnosis, in particular to autism diagnosis and severity judgment based on the relationship between effector T cells and induced T cells.
Background
Autism Spectrum Disorder (ASD), also known as autism, is one of the most common neurological developmental disorders in children. ASD is a group of heterogeneous mental disorders characterized by varying degrees of social impairment, difficulty in communicating, repetitive inscribing and narrowly focused interests, and most patients are associated with significant mental retardation. Statistics in different countries show that the prevalence of ASD rises year by year, with ASD reaching up to 2% and even higher in the general population. ASD has become an important mental disability disease for children, and with the increasing incidence, autism will continue to place a tremendous burden on the home and society.
Currently, the severity of ASD assessment depends only on the clinical symptoms of the patient and the professional medical assessment of the patient, often lacking reliable biomarkers or physiological indicators.
Accordingly, there is an urgent need in the art to develop new methods and systems for effectively performing early diagnosis or assisting diagnosis of autism.
Disclosure of Invention
The invention aims to provide a novel method and a system for effectively performing early diagnosis or auxiliary diagnosis of autism, in particular to an auxiliary screening method and an auxiliary screening system for immune dysfunction autism.
In a first aspect of the invention, there is provided an immune dysfunction autism assisted screening system, the system comprising:
(a) The input module is used for inputting the characteristic data of the T cell subset in the peripheral blood mononuclear cells of a certain object or the original data for calculating the characteristic of the T cell subset; wherein said T cell subpopulation profile includes a Teff/Treg ratio profile, said Teff cells selected from the group consisting of: th1, th2, th17, or a combination thereof;
(b) The processing module is used for processing the T cell subgroup characteristic data or the original data so as to obtain a screening result;
wherein the processing comprises: comparing the Teff/Treg ratio characteristic with a reference control value to obtain a criterion, wherein when the severity score is higher than the reference control value, the subject is prompted to be an immune dysfunction autism patient or a person at higher risk of suffering from immune dysfunction autism than a normal population; and
(c) And the output module is used for outputting the diagnosis result.
In another preferred embodiment, the raw data for calculating characteristics of the T cell subpopulation includes: number of Treg cells and number of Teff cells.
In another preferred embodiment, the Teff/Treg ratio profile is selected from the group consisting of:
(Z1) Th1/Treg ratio;
(Z2) Th2/Treg ratio;
(Z3) Th17/Treg ratio;
(Z4) any combination of Z1 to Z3.
In another preferred embodiment, the Teff/Treg ratio feature is selected from the group consisting of a Th1/Treg ratio and/or a Th2/Treg ratio, more preferably a Th1/Treg ratio.
In another preferred embodiment, the subject comprises a child.
In another preferred embodiment, the subject is between 3 and 16 years old.
In another preferred example, when the Teff/Treg ratio profile includes ≡two different Teff/Treg ratios, the processing further includes: comparing each Teff/Treg ratio to a corresponding standard value, thereby obtaining an evaluation score, the evaluation score comprising: risk degree score and/or severity score.
In another preferred embodiment, the process further comprises: and comparing the risk degree score with a risk cut-off value, wherein when the risk degree score is higher than the risk cut-off value, the subject is prompted to be an immune dysfunction autism patient or a person suffering from immune dysfunction autism, and the risk is higher than that of a normal crowd.
In another preferred embodiment, the process further comprises: comparing the severity score to a severity cutoff value, wherein when the severity score is above the severity cutoff value, the subject is prompted to be a severe immune dysfunction autism patient or at a higher risk of suffering from severe immune dysfunction autism (i.e., than a normal population or general immune dysfunction autism patient).
In another preferred embodiment, the input module is further configured to input mental state-behavioral disorder assessment data for autism.
In another preferred embodiment, the mental state-behavioural disorder assessment data comprises obtaining assessment data using a quantitative table selected from the group consisting of: autism mental state examination scale, childhood autism scale, gram autism behavior scale, abnormal behavior scale, hospital anxiety depression scale, or combinations thereof.
In another preferred embodiment, the processing module further includes: during the treatment, comprehensively analyzing the mental state-behavioural disorder assessment data and the Teff/Treg ratio characteristics, so as to obtain a screening result.
In another preferred embodiment, the screening result comprises: screening the immune dysfunction autism for the type of the behavioral disorder, namely classifying the subject into the corresponding immune dysfunction autism behavioral disorder population.
In another preferred embodiment, when the Th1/Treg ratio is characterized as higher than the reference control value, the subject is prompted to be the patient suffering from or at higher risk of the immune dysfunction autism of the behavioral disorder than the normal population.
In another preferred embodiment, the treatment further comprises classifying the subject into a behavioural disorder population of the corresponding immune dysfunction autism based on Th1/Treg ratio profile.
In another preferred embodiment, the population of immune dysfunction autism is selected from the group consisting of: "disorder of the emotion response and autism population", "disorder of the anxiety response and autism population", "disorder of the adaptation and autism population to environmental changes", "disorder of the hearing response and autism population" and "disorder of the anxiety and depression and autism population",
in another preferred embodiment, when the Th2/Treg ratio is characterized as higher than the reference control value, the subject is prompted to be an immune dysfunction autism patient with the behavioral disorder, or the risk of immune dysfunction autism with the behavioral disorder is higher than that of the normal population.
In another preferred embodiment, the treatment further comprises classifying the subject into a behavioural disorder population of the corresponding immune dysfunction autism based on Th2/Treg ratio profile.
In another preferred embodiment, the population of immune dysfunction autism is selected from the group consisting of: "auditory reaction disorder autism population".
In another preferred embodiment, when the Th17/Treg signature is higher than the reference control value, the subject is prompted to be an immune dysfunction autism patient with the behavioral disorder, or the risk of immune dysfunction autism with the behavioral disorder is higher than that of the normal population.
In another preferred embodiment, the treatment further comprises classifying the subject into a behavioural disorder population of the corresponding immune dysfunction autism based on Th17/Treg ratio profile.
In another preferred embodiment, when the Th17/Treg signature is higher than the reference control value, the subject is prompted to be an immune dysfunction autism patient with the behavioral disorder, or the risk of immune dysfunction autism with the behavioral disorder is higher than that of the normal population.
In another preferred embodiment, the population of immune dysfunction autism is selected from the group consisting of: "adaptation disorder autism population to environmental changes" and "auditory reaction disorder autism population".
In another preferred embodiment, in the treatment module, the immune dysfunction autism severity score is performed as follows: when the Th1/Treg ratio >0.63, the subject is suggested to have immune dysfunction autism or to be at higher risk than normal.
In another preferred embodiment, the output module is configured to output the autism spectrum of different behavioral disorders, wherein the autism spectrum of different behavioral disorders includes the following groups:
a1, the population suffering from autism due to affective disorder;
a2 anxiety disorder autism population;
a3, the adaptive disorder autism crowd for environmental change;
a4, the population suffering from autism due to auditory reaction disorder;
a5 anxiety-depressive disorder autistic population;
a6 auditory reaction disorder autism population.
In another preferred embodiment, the system includes an input module, a processing module, and an output module.
In a second aspect of the invention there is provided the use of a Teff/Treg ratio characterization test agent for the preparation of a kit for (a) aiding in the diagnosis of immune dysfunction autism, (b) for assessing the severity of immune dysfunction autism, and/or (c) for determining populations of different behavioural disorders of immune dysfunction autism.
In another preferred embodiment, the Teff/Treg ratio characterization reagent comprises:
human Th1/Th2/Th17Phenotyping Kit, containing Human CD4-PerCP-Cy5.5 (clone number: SK 3) specific antibody; human IL-17A-PE (clone No.: N49-653); human IFN-gamma-FITC (clone number: B27); human IL-4-APC (clone number: MP4-25D 2);
treg was detected by human CD4-FITC (Agilent Technologies, clone number: SK 3), CD3-PE-CY7 (Agilent Technologies, clone number: UCHT 1), CD45-PerCP-Cy5.5 (Agilent Technologies, clone number: HI 30), CD25-APC (Agilent Technologies, clone number: M-A251) and CD127-PE (Agilent Technologies, clone number: A019D 5) containing specific antibodies;
wherein CD4 is used + IFN-γ + Represents Th1 cells; CD4 + IL-4 + Represents Th2 cells; CD4 + IL-17 + Represents Th17 cells; CD45 + CD3 + CD4 + CD25 + CD127 dim Represents Treg cells.
In a third aspect of the invention, there is provided a method of assisting in the diagnosis of an ASD comprising the steps of:
(a) Providing T cell subpopulation characteristic data in peripheral blood mononuclear cells of a subject or raw data for calculating said T cell subpopulation characteristics; wherein said T cell subpopulation profile includes a Teff/Treg ratio profile, said Teff cells selected from the group consisting of: th1, th2, th17, or a combination thereof;
(b) Processing the T cell subset characteristic data or the original data so as to obtain screening results;
wherein the processing comprises: comparing the Teff/Treg ratio characteristic with a reference control value to obtain a discriminant criterion, wherein when the severity score is higher than the reference control value, the subject is prompted to be an immune dysfunction autism patient or a person at higher risk of suffering from immune dysfunction autism than a normal population.
In another preferred embodiment, the subject comprises a child.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
Figure 1 shows a subject operating characteristic (ROC) curve.
FIG. 2 shows T cell CD4 between ASD children and healthy control group + IFN-γ + (Th 1) difference.
Figure 3 shows the difference in Treg cells between ASD children and healthy control.
FIG. 4 shows a TGF-beta correlation analysis of ASD infants with Th1/Treg ratios higher than median.
FIG. 5 shows the relationship between the cytokines of the ASD infant with higher Th1/Treg ratio than the median.
Detailed Description
Through intensive and extensive research, the inventor of the invention unexpectedly develops an auxiliary screening system for children with immune dysfunction autism for the first time. Specifically, the inventor conducts intensive research on the Teff/Treg ratio characteristics of the T cell subgroup, and discovers that the Teff/Treg ratio characteristics (such as Th1/Treg ratio and/or Th2/Treg ratio) are closely related to the disease risk, the severity of behavioral disorder and different behavioral disorders of the immune dysfunction autism children, so that a screening system and a screening method capable of assisting in diagnosing the immune dysfunction autism are established. The present invention has been completed on the basis of this finding.
Terminology
The study was approved by the China clinical trial registry (clinical trial registry number: chiCTR 1800018348) and approved by the second affiliated hospital agency Review board (IRB) of the Kunming medical university (Review-pj-2017-023). Study participants obtained informed consent from the parents. All participating patients were informed-about informed consent by serum sample collection and subsequent analysis. A copy of the written consent is available for review.
Autism mental state examination scale (AMSE)
Autism mental state examination is a mental state examination tool containing 8 items of content, recording social, communication and behavioral symptoms of ASD. AMSE records social interactions including eye contact, interest in others, finger ability, language, practicality of language, repetitive/clapping behavior, unusual or narrow interests, unusual sensitivity. One study in the united states found excellent sensitivity and reasonable specificity when using the autism diagnostic observation scale (Autism Diagnostic Observational Schedule, ADOS) as a standard for diagnosis of the "autism spectrum" with AMSE scores greater than or equal to a cut-off of 5. According to DSM-5 standard, chinese version AMSE has sensitivity of 0.98 and specificity of 0.87 when total score is equal to or more than 6 score (unpublished data).
Children autism scale (CARS)
The pediatric autism rating scale (Childhood Autism Rating Scale) (CARS) is a standardized scale of diagnostic interest, compiled by E.Schopler, R.J.Reichler and B.R.Renner in 1980 [15] The scoring criteria are as follows: the total score is lower than 30: preliminarily judging that the autism is absent; 30-60 minutes: autism; wherein the weight ratio is 30-36: is a mild to moderate autism; 37-60 points, and at least 5 points scored above 3 points: severe autism. (this scale is divided into 60). The autism rating scale (CARS) of children is one of the most widely used autism (autism) test rating scales at present, is suitable for children over 2 years old, has good credibility and effectiveness, can distinguish autism (autism) and intellectual disability, and can judge the degree of autism, so that the autism rating scale has great practicability.
In the present invention, it was unexpectedly found that there is a correlation between Th1/Treg ratio characteristics and anomalies in certain scoring terms of the CARS magnitude. In addition, it has been unexpectedly found that there is a correlation between Th2/Treg ratio characteristics and anomalies of certain scoring items in the CARS magnitude table, and that there is a correlation between Th17/Treg ratio characteristics and anomalies of certain scoring items in the CARS magnitude table.
For example, there is a correlation between Th1/Treg ratio characteristics and abnormalities in anxiety response terms of the CARS scale, etc. There is a correlation between Th2/Treg ratio characteristics and abnormalities in auditory response terms of the CARS scale, etc. There is a correlation between Th17/Treg ratio characteristics and anomalies in the CARS scale's adaptation to environmental changes.
In the present invention, abnormal autism of anxiety response items is defined as "anxiety disorder autism population" in the present invention. Similarly, autism with abnormal affective response items is defined herein as "autistic population with affective disorder"; autism to the adaptation abnormality of environmental changes is defined in the present invention as "adaptation disorder autism population to environmental changes"; autism with abnormal auditory response is defined in the present invention as "autism population with dysauditory response disorder"; autism with anxiety-depressive disorder is defined herein as "anxiety-depressive disorder autistic population".
Ke's autism behavior scale (CABS)
The gram autism behavior scale (Clancy Autism Behavior Scale, CABS) is compiled by the CLANCY and the like in 1969, belongs to an autism rapid screening scale, is widely used in epidemiological researches of autism, has good identification significance for autism and normal children or non-autism children accompanied by other disorders, is simple and convenient, is easy to understand and score, and is suitable for rapid screening.
Abnormal behavior table (ABC)
Abnormal behavior scale (Aberrant Behavior Checklist, ABC for short) is used for children aged 2-14, and is a scale for patients 'parents to evaluate child's problem behavior. Is compiled by Kluger et al (Krug et al 1978), introduced and revised by the university of Beijing medical science Yang Xiaoling professor 1989, and is mainly used for screening autistic children. The autistic child behavioral scale has 57 items describing abnormal manifestations in terms of sensation, behavior, emotion, language, etc. of the autistic child, and can be generalized to 5 factors: (1) feel; (2) communicating; (8) body movement, (4) language: (5) and (5) living self-care. Total score 158; the screening limit was divided into 53 minutes and the diagnosis was divided into 67 minutes. ABC can effectively evaluate the symptom improvement degree, has better credibility and effectiveness for each factor and total amount table of Chinese version, is suitable for evaluating children autism groups in China, and has certain popularization and use values.
Hospital Anxiety Depression Scale (HADS)
Hospital anxiety depression scale (Hospital Anxiety and Depression Scale, HADS) was created by Zigmond AS and Snaith RP in 1983. HAD consisted of 14 entries in total, 7 of which rated depression and 7 of which rated anxiety. There were a total of 6 reverse questioning entries, 5 on the depression scale and 1 on the anxiety scale. Scores of both anxiety and depression scores were divided into 0-7 score asymptomatic; 8-10 classification of symptoms suspicious; 11-21 are classified as positive symptoms. The main purpose of the HAD is to conduct screening tests for anxiety and depression, and it is therefore important to determine a well-established threshold. The thresholds used in each study were not identical. HADS is clearly only a screening scale for anxiety and depression, the best use being as a comprehensive hospital doctor screening patients suspected of having anxiety or depression symptoms.
Caretaker pressure questionnaire (CGSQ)
Caregivers' stress questionnaires (caregiver strain questionnaire, CGSQ) were compiled by brannen equal to 1997 and were introduced for domestic use by the university of beijing mental health institute in 2001, with better retesting reliability, homogeneity reliability and structural efficiency. Further studies have found that it has better confidence in assessing stress problems in autistic child caregivers. The scale uses 22 entries, each with a 5-level score, the higher the total score, indicating greater stress.
Diagnosis and observation of autism subjects
Researchers use two assessment scales to record ASD symptoms, namely, autism mental state test (AMSE) and Childhood Autism Rating Scale (CARS). All subjects were evaluated by a psychiatrist trained in the correlation of AMSE and CARS ratings. Then, subjects with AMSE score of 6 or more and CARS score of 30 or more were comprehensively evaluated by a child and adolescent psychiatrist. A best-assessment clinical diagnostic (BECD) protocol (David Grodberg et al., 2016) is employed to determine whether a patient meets ASD criteria in the DSM-5 criteria; in these cases, the psychiatrist carefully collects medical histories (main complaints, present medical histories, past medical histories, auxiliary examination results and developmental histories), reviews the results of both evaluations, and interviews with caregivers and patients.
The results of all the above tests were judged in aggregate and each subject was diagnosed by the psychiatrist as ASD and non-ASD. For subjects whose first round of diagnosis was not determinable, a study group (including 1-2 children and adolescent psychiatric specialists, and 1-2 psychiatric hospitalizers) reexamined all medical files and interviewed with the patient and their caretaker if necessary, and finally concluded one. Finally, the study panel also determined the subtype of the subjects into the group according to ICD-10 criteria (the International Classification of Mental and Behavioral Disorders, tenth edition) (F84).
The main advantages of the invention include:
(a) It is proposed for the first time that the characteristic of the ratio of Th1/Treg is related to ASD disease severity;
(b) The invention can screen the autism patients with abnormal immune function by using the quantitative index, so that the diagnosis result is more objective;
(c) The invention can utilize the quantitative index to assist in evaluating the severity of ASD diseases to a certain extent;
(d) The invention can screen the autism patient with abnormal immune function by using the quantitative index, and can carry out targeted immunotherapy for ASD patient with abnormal target point.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer.
Sample case
The study was carried over into 82 subjects untreated with drugs and clinically diagnosed with ASD, all from the psychiatric department of the second affiliated hospital at the university of kunming medical science.
Healthy control children were from Kunming and Yuxi. Researchers use mental Development Screening Tests (DST) to evaluate overall development levels in children under 6 years of age and under 6 years of age. The children over 6 years old were questionnaired using the Chinese-Welch children intellectual Meter (C-WISC). All subjects participating in the study were classified as having a normal range of developmental levels or intelligence. In addition, a pediatrician makes a consultation with the child and his/her caretaker to examine the detailed medical history. Any healthy subject diagnosed or suspected of having a diagnosis including psychotic disorders (schizophrenia, mood disorders, attention deficit hyperactivity disorder, tic disorders), major somatic disorders (acute or chronic infectious diseases, autoimmune diseases, etc.), and hematological disorders, are excluded from the study.
ASD children and control groups did not differ in social demographics of age, gender and race. Table 1 is subject social demographic information.
TABLE 1 subject social demographic information
Example 1, PBMC and serum separation
All participants, after informed consent, were collected peripheral blood using EDTA blood collection tubes (BD company) and serum separation tubes containing inert separation gel (SST II Advance, BD company). Separation of tube Sepmate with lymphocytes TM (STEM CELL tech) Peripheral Blood Mononuclear CELLs (PBMC) are isolated. The isolated mononuclear cells were washed twice in PBS for flow cytometry analysis. After centrifugation at 2000g for 5min, serum was collected and sub-packaged in EP tubes for storage at-80℃for further analysis.
Example 2T cell phenotype in PMBC in a subject
PBMC were washed in PBS, incubated in 1640 medium after washing, and then washed with PMA/ionomycin andthe Golgi apparatus blocking agent was cultured for 5 hours. Detection of T-cell subpopulations by flow cytometry using +.>Human TH1/TH2/TH17Phenotyping Kit, containing Human CD4-PerCP-Cy5.5 (clone number: SK 3) specific antibody; human IL-17A-PE (clone No.: N49-653); human IFN-gamma-FITC (clone number: B27); human IL-4-APC (clone number: MP4-25D 2); treg was detected by human CD4-FITC (Agilent Technologies, clone number: SK 3), CD3-PE-CY7 (Agilent Technologies, clone number: UCHT 1), CD45-PerCP-Cy5.5 (Agilent Technologies, clone number: HI 30), CD25-APC (Agilent Technologies, clone number: M-A251) and CD127-PE (Agilent Technologies, clone number: A019D 5) containing specific antibodies.
Example 3 Bead-based cytokine analysis
IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A, TNF-alpha and IFN-gamma levels in serum were determined using the Human air-plex kit (AimPlax, cat#C60011). Serum TGF-beta was quantitatively detected using human TGF-beta-plex kit (AimPlax, cat#B 111206). All experiments were performed according to the manufacturer's instructions.
Example 4 statistical analysis
Children with CARS score below 30 are healthy children, children with score between 30 and 36 are mild to moderate autism, and children with score between 37 and 60 are severe autism. The data were analyzed using SPSS21.0 (LEAD Technology inc., charlotte, NC, USA). The continuous variable is represented by a median ± Quartile Range (QR). The normalization of the distribution was measured with a K-S test (Kolmogorov-Smirnov test). The ratio of ASD groups Teff/Treg to CARS, CABS, ABC, AMSE, HADS, CGSQ scores was analyzed using Spearman rank correlation, with P values <0.05 considered statistically significant.
Results
1. Differences in effector T cells between ASD children and healthy controls
Since effector T cells (Teff) are involved in the immune inflammatory response of ASD, the present inventionThe role of Teff in ASD was studied in the open. PBMC from 82 ASD children and 50 healthy children were isolated, stimulated with PMA/ionomycin (P+I), and Teff cell levels in ASD patients were significantly higher than healthy controls, th1 cells (CD 4) + IFN-γ + ) (ASD group 3.27 (2.00,5.06)% VS Normal group 1.24 (0.60,1.79)%, p<0.001 Th2 cells (CD 4) + IL-4 + ) (ASD group 0.76 (0.38,1.28)% VS Normal group 0.28 (0.10,0.44)%, p<0.001 Th17 cells (CD 4) + IL-17A + ) (ASD group 0.69 (0.16,1.04)% VS normal group 0.23 (0.12,0.55)%, p=0.025) (table 2 and fig. 2).
TABLE 2 differentiation of T cell subsets between ASD children and healthy controls
The result data is represented by a median ± Quartile Range (QR). * p < 0.05.
2. Treg cytopenia in ASD patients
CD4 + FOXP3 + Treg cells play a central role in maintaining peripheral immune tolerance, with a marked decrease in peripheral tolerance in ASD patients compared to healthy children, suggesting that Treg cells may be decreased in ASD patients. Thus, two known Treg markers, CD127 (IL-7 Ra) and CD25 (IL-2 Ra), were decided to be used to compare Treg differences between ASD and healthy children. Although no difference in total CD4+ T and CD8+ T cell ratios was found between the two groups, CD127 was found in the ASD group - CD25 + The frequency of tregs was significantly reduced compared to healthy controls, ASD group 1.20 (0.84,1.70)% VS normal group 4.71 (3.03,7.19)%, p<0.001 (table 2 and fig. 3).
3. Teff/Treg ratio changes in ASD patients
Studies have demonstrated that Teff/Treg cell axis imbalance is closely related to biological abnormalities in many autoimmune diseases. According to the apparent difference between Th1, th2, th17 and Treg in ASD groups and healthy controls, whether Teff/Treg imbalance exists in ASD patients was studied, and the results show that the ratio of Th1/Treg (ASD group 3.07 (1.05-6.18) vs. normal group 0.26 (0.11-0.44), the ratio of Th2/Treg (ASD group 0.51 (0.30-1.07) vs. normal group 0.06 (0.02-0.12), and the ratio of Th17/Treg (ASD group 0.36 (0.09-0.95) vs. normal group 0.06 (0.03-0.13) was significantly higher than in normal control group (Table 3).
TABLE 3 difference in Teff/Treg between ASD children and healthy controls
The result data is represented by a median ± Quartile Range (QR). * p < 0.05.
4. ASD patients developed an inflammatory state compared to healthy controls
To investigate whether ASD patients had immune system dysfunction, the blood of subjects was collected to analyze the expression of various pro/anti inflammatory cytokines in serum ASD (n=82) and healthy children (n=50). Various cytokines including Th1 (IL-2), th2 (IL-4, IL-5), and ASD patients were significantly increased compared to healthy controls. In sharp contrast to pro-inflammatory cytokines, levels of cytokine TGF- β in serum of ASD patients with important immunomodulatory functions were significantly reduced (table 4). These results indicate that the immune system of ASD patients is in an inflammatory state compared to healthy children.
TABLE 4 comparison of peripheral blood serum cytokine concentrations (pg/ml) for autism group and healthy control group
The result data is represented by a median ± Quartile Range (QR). * p < 0.05.
5. Relationship between Teff/Treg ratio and behavioural characteristics of ASD patients
To determine the potential relationship of immune indicators to ASD behavior for various disorders in ASD children, the CARS, CABS, ABC, AMSE, HADS, CGSQ scale was used to conduct correlation analysis of ASD behavioral characteristics, clinical signs and symptoms with the Teff/Treg ratio of the ASD patient itself. Spearman correlation analysis showed that the Th1/Treg ratio was significantly positively correlated with the two component score of "adaptation to environmental changes" (rs=0.29, p < 0.001) and "anxiety response" (rs=0.30, p < 0.001), and significantly negatively correlated with the other two component score "language communication" (rs= -0.31, p < 0.001) and "intellectual function" (rs= -0.31, p < 0.001). (r= -0.48, p < 0.001). The Th2/Treg ratio correlated positively with the CARS sub-scale score "non-verbal communication" (rs=0.27, p=0.021). The Th17/Treg ratio was positively correlated with the three component tables of CARS for "adaptation to environmental changes" (rs=0.45, p < 0.001), "auditory response" (rs=0.25, p=0.043) and "anxiety response" (rs=0.21, p=0.041) (table 5).
Table 5 analysis of correlation between Teff/Treg and CARS total score and each component table score for ASD group of patients (n=82)
*p＜0.05.
The correlation analysis result of the Teff/Treg ratio and the cab score shows that the Th1/Treg ratio is in positive correlation with the cab "deafness" (rs=0.24, p=0.048), "face of undesired party" (rs=0.25, p=0.041) and "dislike hug of other person" (rs=0.24, p=0.048). The Th2/Treg ratio is positively correlated with the CABS component table "constantly moving, unsettled, too high activity" score (rs=0.25, p=0.038). The Th17/Treg ratio was inversely related to the component table "moleply smile" score (rs= -0.25, p=0.043) (table 6).
Table 6 correlation analysis between Teff/Treg and CABS total score and each component table for ASD group of patients (n=82)
*p＜0.05.
Interestingly, only Th1/Treg was associated with the correlation analysis of the Teff/Treg ratio with the ABC, CGSQ, HADS, AMSE score in ASD patientsHAD scores were positively correlated (r Anxiety of people ＝0.39,p＝0.028；r Depression of =0.37, p=0.043) (table 7).
Table 7 analysis of correlation between Teff/Treg and ABC, CGSQ, HAD, AMSE scores for ASD patients (n=82)
To some extent, these results indicate that high levels of effector T cells and reduced Treg populations may be associated with ASD severity.
6. Th1/Treg as a better diagnostic aid for autism childhood immune dysfunction or inflammation
Sensitivity and specificity are fundamental measures of the accuracy of diagnostic tests.
As shown in fig. 1, th1/Treg has higher sensitivity and specificity than Th2/Treg and Th17/Treg by subject work characteristic (ROC) curve analysis.
The area under the TH1/Treg curve (AUC) was 95.02%, the Youden index (Youden index) was 80.24, and the cut-off value (cut Point) was 0.63.
The AUC of Th2/Treg was 94.74%, the Johnson index was 80.68, and the cut-off value was 0.17.
The AUC of Th17/Treg was 76.33%, the Johnson index was 45.17, and the cutoff was 0.11.
The above results indicate that the autism disease severity score (CARS) of the patient is correlated with Th1/Treg when Th1/Treg > 0.63. This suggests that the patient is an autistic patient with immune dysfunction or is at higher risk of suffering from immune dysfunction autism than normal. Although the cut-off value of Th1/Treg is set to 0.63, it is still understood that a higher Th1/Treg suggests a higher risk of autism or a more severe autism in the patient.
When Th2/Treg >0.17, the patient is suggested to be an autistic patient with immune dysfunction or to be at higher risk of suffering from immune dysfunction autism than normal.
When Th17/Treg >0.11, the patient is suggested to be an autistic patient with immune dysfunction or to be at higher risk of suffering from immune dysfunction autism than normal.
7. High Teff/Treg ratio (Th 1/Treg) high ) Correlation of Th1/Treg with CARS Total score and component score in ASD patients
Based on ROC and AUC results, 72 out of 82 patients above Th1/Treg cut-off were screened and the socioeconomic profile of these patients is summarized in table 8. Again, this patient population Teff/Treg ratio was analyzed for correlation with the CARS total score and the component table score.
The correlation analysis results are shown in Table 9.
Spearman correlation analysis showed that Th1/Treg ratios correlated positively with the four component table scores, respectively, "affective response" (r=0.38, p < 0.001), "adaptation to environmental changes" (r=0.35, p=0.003), "auditory response" (r=0.32, p=0.007), "anxiety response" (r=0.36, p=0.002) and the total score with CARS (r=0.25, p=0.036) and the other component table "intellectual consistency" score correlated negatively "(rs= -0.42, p < 0.001). The Th2/Treg ratio correlated positively with the CARS's component table score "auditory response" (rs=0.25, p=0.035). The Th17/Treg ratio correlated positively with the two component scores of CARS (table 9) for "adaptation to environmental changes" (rs=0.41, p < 0.001), "auditory response" (rs=0.27, p=0.022).
Table 8: th1/Treg high ASD patient social demographic information table
TABLE 9 Th1/Treg high Correlation analysis of ASD patient Teff/Treg with CABS total score and each component table ASD child (n=72)
*p＜0.05.
8. Th1/Treg high ratio ASD infant cytokine correlation analysis:
the study results also show that some cytokines are correspondingly increased in the ASD infants with high Th1/Treg ratio. As shown in Table 10, IFN-gamma and IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A positive correlation.
Table 10 correlation analysis between serum cytokines for ASD patients with higher than median ratio of Th1/Treg (n=44)
*p＜0.05.
9. Comparing the serum cytokine concentration of the ASD infant with the control group with the Th1/Treg median
From the results of Table 3, 44 patients were selected from the patients with a median of 82 Th1/Treg or more and further analyzed.
As shown in Table 11, IFN-. Gamma., TNF-. Alpha., IL-4, IL-5, IL-6, IL-10, IL-17A were significantly elevated in the serum of 44 ASD patients and serum TGF-. Beta.levels were significantly reduced as compared to the normal control group.
Table 11 serum cytokine concentration comparison (n=44) for ASD patients with a ratio of Th1/Treg higher than the median (pg/ml)
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The result data is represented by a median ± Quartile Range (QR). * p < 0.05.
10. ASD infant TGF-beta correlation analysis with high Th1/Treg ratio
From the results of Table 3, 44 patients were selected from 82 Th1/Treg median patients and further analyzed for relationship between TGF-. Beta.levels and CARS scores.
The results are shown in FIG. 4, where TGF- β levels are inversely related to CARS scores in ASD infants with high Th1/Treg ratios.
11. Relation of cytokines of ASD infant with high Th1/Treg ratio
Based on the results in Table 3, 44 patients were selected from the patients with a median of 82 Th1/Treg or more, and the relationship between cytokines was further analyzed.
In ASD infants with higher Th1/Treg ratio than median, the correlation profile between peripheral blood cytokines IFN-gamma, TNF-alpha, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A is shown in FIG. 5. There is a certain correlation between some cytokines.
Discussion of the invention
For a long time, the assessment of the severity of autism (Autism Spectrum Disorder, ASD) has been largely dependent on clinical assessment, which is a long time and places a burden on the clinician's effort. In addition, many scale evaluations are too dependent on parental descriptive reports of patient condition, which may sometimes be inaccurate, e.g., exaggerated or hidden. Therefore, it is important to find a few relatively reliable biomarkers to assess the severity of ASD patients.
Although genetic factors are considered to be the primary cause of ASD, immune dysfunction plays an important role in ASD as well. The neuroimmune interactions occur early in embryonic development and last for a lifetime. Neural development is regulated by the interaction of neural cells and T cells, the development of the nervous system is affected by the change of the number and the activity of the T cells, and the damage of neural tissues can be caused by the overactivation of any T cell subgroup.
Although some ASD patients have T lymphocyte dysfunction, many of the findings are inconsistent. For example, studies have found that ASD patients have total lymphocyte count and CD4 + The number of T helper lymphocytes was significantly reduced compared to the healthy control group. Several important T helper cell subsets in ASD patients that may be involved in inflammatory lesions, such as T helper cells (Th 1), T helper cells 2 (Th 2), have also been reported to be inconsistent, e.g., ashwood et al found that the ASD infant Th1 immune response was suppressed and the Th2 immune response was enhanced. However, ahmad et al have found that up-regulation of the core transcription factor signals occurs in Th1 and Th2 in ASD patients. Regulatory T cells (Treg) water for ASD infantsThe flatness is low. Although partial immune abnormalities are observed in some ASDs, the potential value of Teff/Treg ratio features in ASD screening or assisted diagnosis has not been reported prior to the present invention due to the complexity of the immune system and individual variability.
In the study of the present invention, the inventors investigated various immune indicators of 82 ASD children and 50 healthy children. By "subject work profile" (Receiver Operating Characteristic, ROC) analysis, it was unexpectedly found that the ratio of Th1 cells to Treg cells was a potential diagnostic marker for immune dysfunction autism children. Through comprehensive correlation analysis of the childhood autism scale (Child Autism Rating Scale, CARS) and ASD severity, the inventors found that a population of high Th1/Treg ratios (Th 1/Treg high ) The TH1/Treg ratio is correlated with the disease severity of ASD. This suggests that Th1/Treg can be used as an autism childhood adjuvant diagnostic marker of immune dysfunction and can develop new ASD therapeutic targets.
In particular, the inventors found that among various different immune indicators, the ratio of Th1/Treg in the ASD group was significantly increased relative to the normal group. Meanwhile, through correlation analysis, the ratio of the Th1/Treg to the Th2/Treg and the Th17/Treg of the ASD group is found to be correlated with the score of the component table in CARS and CABS of the patient, and particularly the Th1/Treg shows more correlation with the component table. At the same time, the expression of various pro-inflammatory/anti-inflammatory cytokines in serum and healthy children was analyzed. Various cytokines including Th1 (IL-2), th2 (IL-4, IL-5), th17 (IL-17A), and ASD patients were significantly increased compared to healthy controls. In sharp contrast to pro-inflammatory cytokines, levels of cytokine TGF- β in serum of ASD patients with important immunomodulatory functions are significantly reduced. These results indicate that the immune system of ASD patients is in an inflammatory state compared to healthy children. In addition, th1/Treg was also positively correlated with anxiety scores of the HAD scale, with depression scores all positively correlated, suggesting that elevated ASD phenotypes of Th1/Treg may be associated with more severe behavioral disorders.
Based on ASD diagnostic criteria set by this study, the inventors found that Th1/Treg possessed higher sensitivity and specificity than Th2/Treg, th17/Treg, through "subject work profile" (Receiver Operating Characteristic, ROC) analysis, and Th1/Treg was likely a potential adjunct diagnostic marker for immune dysfunction autism children.
Then, according to the results of ROC and AUC, 72 patients above the Th1/Treg cut-off value are screened out from 82 patients, and the correlation of the Teff/Treg ratio of the patient group and the CARS total score and the component score is analyzed again. The results show that this fraction of patients Th1/Treg shows a correlation with the fraction of CARS and more importantly it also correlates with the total fraction of CARS, which further suggests that Th1/Treg can classify ASD phenotypes of a class of immune disorders and that ASD infants with such phenotypes develop more severe behavioural disorders with increasing ratios.
Finally, the inventors continue to analyze the cytokine status of patients with Th1/Treg ratio above the median, and screen 44 patients from 82 patients with Th1/Treg above the median, and compared with the normal control group, the serum of 44 ASD patients has significantly increased IFN-gamma, TNF-alpha, IL-4, IL-5, IL-6, IL-10, IL-17A, and significantly reduced serum TGF-beta levels. The TGF- β levels of the 44 patients selected were inversely correlated with the CARS score. These results demonstrate that, in addition to exhibiting different characteristics of T cell subpopulation phenotypes, high Th1/Treg ratio ASD patients, abnormalities in cytokines in these patients indicate that the patient's immunity has been abnormal at the level of cellular function, which may be one of the causes of exacerbation of this part of the patient's behavioral deterioration.
The research results of the invention provide new insights for the role of T cell subsets and their inflammatory factors in ASD patients, and provide the basis for exploring potential diagnostic and therapeutic strategies for autism.
For example, in some high Th1/Treg ratios (Th 1/Treg high ) The ratio of Th1/Treg is correlated with the disease severity of ASD, suggesting that Th1/Treg may be used as an autism pediatric aid diagnostic marker for immune dysfunction and may be used to develop new ASD therapeutic targets.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (10)
1. An immune dysfunction autism assisted screening system, the system comprising:
(a) The input module is used for inputting the characteristic data of the T cell subset in the peripheral blood mononuclear cells of a certain object or the original data for calculating the characteristic of the T cell subset; wherein said T cell subpopulation profile includes a Teff/Treg ratio profile, said Teff cells selected from the group consisting of: th1, th2, th17, or a combination thereof;
(b) The processing module is used for processing the T cell subgroup characteristic data or the original data so as to obtain a screening result;
wherein the processing comprises: comparing the Teff/Treg ratio characteristic with a reference control value to obtain a criterion, wherein when the severity score is higher than the reference control value, the subject is prompted to be an immune dysfunction autism patient or a person at higher risk of suffering from immune dysfunction autism than a normal population; and
(c) And the output module is used for outputting the diagnosis result.
2. The immune dysfunction autism assisted screening system according to claim 1, wherein the Teff/Treg ratio profile is selected from the group consisting of:
(Z1) Th1/Treg ratio;
(Z2) Th2/Treg ratio;
(Z3) Th17/Treg ratio;
(Z4) any combination of Z1 to Z3.
3. The immune dysfunction autism assisted screening system of claim 1, wherein the input module is further configured to input mental state-behavioral disorder assessment data for autism.
4. The immune dysfunction autism assisted screening system of claim 1, wherein the population of immune dysfunction autism different behavioral disorders is selected from the group consisting of: "population suffering from autism due to affective disorder", "population suffering from anxiety disorder", "population suffering from autism due to adaptation to environmental changes", "population suffering from hearing disorder" and "population suffering from anxiety and depression disorder".
5. The immune dysfunction autism assisted screening system of claim 1, wherein the population of immune dysfunction autism behavioural disorders is selected from the group consisting of: "auditory reaction disorder autism population".
6. The immune dysfunction autism assisted screening system of claim 1, wherein the population of immune dysfunction autism behavioural disorders is selected from the group consisting of: "adaptation disorder autism population to environmental changes" and "auditory reaction disorder autism population".
7. The immune dysfunction autism assisted screening system of claim 1, wherein in the processing module, immune dysfunction autism assessment is performed as follows: when the Th1/Treg ratio >0.63, the subject is prompted to suffer from immune dysfunction autism or a higher risk than normal population.
8. The immune dysfunction autism assisted screening system of claim 1, wherein the output module is configured to output autism populations of different behavioral disorders, wherein the autism populations of different behavioral disorders comprise the group of:
a1, the population suffering from autism due to affective disorder;
a2 anxiety disorder autism population;
a3, the adaptive disorder autism crowd for environmental change;
a4, the population suffering from autism due to auditory reaction disorder;
a5 anxiety-depressive disorder autistic population;
a6 auditory reaction disorder autism population.
9. The immune dysfunction autism assisted screening system of claim 1, wherein the system includes an input module, a processing module, and an output module.
10. Use of a Teff/Treg ratio characterization test agent for the preparation of a kit for (a) aiding in the diagnosis of immune dysfunction autism, (b) for assessing the severity of immune dysfunction autism, and/or (c) for determining the type of behavioral disorder of immune dysfunction autism.
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| CN202210108080.7A CN116564499A (en) | 2022-01-28 | 2022-01-28 | Auxiliary screening method and system for immune dysfunction autism |
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| CN202210108080.7A CN116564499A (en) | 2022-01-28 | 2022-01-28 | Auxiliary screening method and system for immune dysfunction autism |
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