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Objective: To evaluate the T-lymphocyte subset distribution and the diagnostic and prognosis value of double-negative T (DNT) cells in colorectal cancer (CRC). Methods: This retrospective study compared the T-lymphocyte subsets and DNT of 114 patients with CRC with those of 107 healthy controls (HC). The diagnostic potential of DNT and T-lymphocyte subsets was assessed using the receiver operating characteristic (ROC) curve, and prognostic values were evaluated using the Kaplan-Meier curve and the Cox regression model. Results: The percentages of CD8+ T cells and DNT cells, and value of carcinoembryonic antigen (CEA), were remarkably higher in patients with CRC than in those with HC, but the ratio of CD4+/CD8+ was decreased. Using ROC curve analysis, DNT cell percentage, CEA, and CD4+/CD8+ ratio all had good diagnostic efficacy, with areas under the curve (AUCs) of 0.865, 0.786 and 0.624, respectively. The combination of DNT cell percentage and CEA had an AUC of 0.905, which was significantly higher than that of any single biomarker (p < 0.05). In univariate analysis, the Tumor Node Metastasis (TNM) clinical stage, CD4+/CD8+ ratio, and DNT cell percentage were significantly associated with overall survival (OS) (p < 0.05). In multivariate analysis, TNM clinical staging (HR = 2.37, 95 % CI: 1.15-4.90), a decreased CD4+/CD8+ ratio (HR = 0.33, 95 % CI: 0.15-0.74), and an increased DNT cell percentage (HR = 2.29, 95 % CI: 1.11-4.73) were independent prognostic factors for CRC. Conclusion: The percentage of DNT cells may be useful as an evaluation index for CRC diagnosis and prognosis, which was even better when combined with serum CEA.
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BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by disturbance of pro-inflammatory and anti-inflammatory lymphocytes. Growing evidence shown that gut microbiota participated in the occurrence and development of SLE by affecting the differentiation and function of intestinal immune cells. The purpose of this study was to investigate the changes of gut microbiota in SLE and judge its associations with peripheral T lymphocytes. METHODS: A total of 19 SLE patients and 16 HCs were enrolled in this study. Flow cytometry was used to detect the number of peripheral T lymphocyte subsets, and 16 s rRNA was used to detect the relative abundance of gut microbiota. Analyzed the correlation between gut microbiota with SLEDAI, ESR, ds-DNA and complement. SPSS26.0 software was used to analyze the experimental data. Mann-Whitney U test was applied to compare T lymphocyte subsets. Spearman analysis was used for calculating correlation. RESULTS: Compared with HCs, the proportions of Tregs (P = 0.001), Tfh cells (P = 0.018) and Naïve CD4 + T cells (P = 0.004) significantly decreased in SLE patients, and proportions of Th17 cells (P = 0.020) and γδT cells (P = 0.018) increased in SLE. The diversity of SLE patients were significantly decreased. Addition, there were 11 species of flora were discovered to be distinctly different in SLE group (P < 0.05). In the correlation analysis of SLE, Tregs were positively correlated with Ruminococcus2 (P = 0.042), Th17 cells were positively correlated with Megamonas (P = 0.009), γδT cells were positively correlated with Megamonas (P = 0.003) and Streptococcus (P = 0.004), Tfh cells were positively correlated with Bacteroides (P = 0.040), and Th1 cells were negatively correlated with Bifidobacterium (P = 0.005). As for clinical indicators, the level of Tregs was negatively correlated with ESR (P = 0.031), but not with C3 and C4, and the remaining cells were not significantly correlated with ESR, C3 and C4. CONCLUSION: Gut microbiota and T lymphocyte subsets of SLE changed and related to each other, which may break the immune balance and affect the occurrence and development of SLE. Therefore, it is necessary to pay attention to the changes of gut microbiota and provide new ideas for the treatment of SLE.
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Microbioma Gastrointestinal , Lúpus Eritematoso Sistêmico , Subpopulações de Linfócitos T , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/microbiologia , Microbioma Gastrointestinal/imunologia , Feminino , Adulto , Masculino , Subpopulações de Linfócitos T/imunologia , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia , Adulto Jovem , Células Th17/imunologiaRESUMO
OBJECTIVE: This study aimed to investigate the impact of surgical intervention on peripheral blood T lymphocyte subsets and natural killer (NK) cell activity in pediatric patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: A total of 36 OSAHS children, 32 children with tonsillar hypertrophy, and 30 healthy children were enrolled. Clinical data and polysomnography (PSG) results were collected. Peripheral blood samples were analyzed for T lymphocyte subsets, NK cells, and cytokine levels including Th1 (IFN-γ, IL-2, TNF-α), Th2 (IL-4, IL-10), and Th17 (IL-17). RESULTS: At baseline, OSAHS children exhibited lower LSaO2 levels and higher AHI values compared to healthy children. They also showed decreased percentages of CD3 + T cells, CD4 + T cells, NK cells, and elevated CD8 + T cells and CD4+/CD8 + ratio. Levels of IFN-γ, IL-2, TNF-α, IL-4, and IL-17 were significantly lower in OSAHS children. Post-surgery improvements were observed in LSaO2, AHI, and immune markers at 3 months and 6 months. Pearson's correlation analysis revealed significant associations between LSaO2, AHI, and peripheral blood immune parameters at baseline and 6 months post-surgery. CONCLUSION: Surgical intervention in pediatric OSAHS influences peripheral blood T lymphocyte subsets and NK cell activity. Early intervention and monitoring of immune function are crucial for the recovery and healthy development of affected children.
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BACKGROUND: Currently, there is a lack of effective indicators for predicting the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to investigate the expression and prognostic value of peripheral T lymphocyte subsets in advanced HCC. METHODS: Patients with advanced HCC who were treated with immune checkpoint inhibitors (ICIs) from December 2021 to December 2023 were included in the study. Flow cytometry was used to detect lymphocyte subsets before treatment. The patients were divided into disease control (DC) and nondisease control (nDC) groups based on treatment efficacy. Relationships between the clinical characteristics/peripheral T lymphocytes and immunotherapy efficacy were analyzed. The effectiveness of peripheral T lymphocyte subsets in predicting immunotherapy efficacy for patients with advanced HCC was analyzed using receiver operating characteristic (ROC) curves. RESULTS: A total of 40 eligible patients were included in this study. Non-DC was significantly associated with higher albumin-bilirubin (ALBI) scores. The percentages of γδ+Vδ2+PD1+ T cells and γδ+Vδ2+Tim3+ T cells were greater in the nDC group than in the DC group. Multivariable regression analysis revealed that the ALBI score and T lymphocytes expressing γδ+Vδ2+PD1+ and γδ+Vδ2+Tim3+ were founded to be independent influencing factors. The area under the ROC curve (AUC) values for these combinations was 0.944 (95% CI, 0.882 ~ 1.000). CONCLUSIONS: The calculation of the ALBI score and determination of the percentages CD3+γδ+Vδ2+PD1+ T lymphocytes and CD3+γδ+Vδ2+Tim3+ T lymphocytes in the peripheral blood of patients with advanced HCC are helpful for predicting the patients' responses to ICIs, helping to screen patients who may clinically benefit from immunotherapy. RETROSPECTIVELY REGISTERED: number: ChiCTR2400080409, date of registration: 2024-01-29.
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Carcinoma Hepatocelular , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Idoso , Prognóstico , Complexo CD3/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologiaRESUMO
INTRODUCTION: The absence of predictive models for early latent tuberculosis infection (LTBI) progression persists. This study aimed to create a screening model to identify high-risk LTBI patients prome to active tuberculosis (ATB) reactivation. METHODOLOGY: Patients with confirmed ATB were enrolled alongside LTBI individuals as a reference, with relevant clinical data gathered. LASSO regression cross-validation reduced data dimensionality. A nomogram was developed using multiple logistic regression, internally validated with Bootstrap resampling. Evaluation included C-index, receiver operating characteristic (ROC) curve, and calibration curves, with clinical utility assessed through decision curve analysis. RESULTS: The final nomogram incorporated serum albumin (OR = 1.337, p = 0.046), CD4+ (OR = 1.010, p = 0.004), and CD64 index (OR = 0.009, p = 0.020). The model achieved a C-index of 0.964, an area under the ROC curve of 0.962 (95% CI: 0.926-0.997), sensitivity of 0.971, and specificity of 0.910. Internal validation showed a mean absolute error of 0.013 and 86.4% identification accuracy. The decision curve indicated substantial net benefit at a risk threshold exceeding 10% (1: 9). CONCLUSIONS: This study established a biologically-rooted nomogram for high-risk LTBI patients prone to ATB reactivation, offering strong predictability, concordance, and clinical value. It serves as a personalized risk assessment tool, accurately identifying patients necessitating priority prophylactic treatment, complementing existing host risk factors effectively.
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Tuberculose Latente , Nomogramas , Humanos , Tuberculose Latente/diagnóstico , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Medição de Risco/métodos , Curva ROC , Tuberculose/diagnóstico , Tuberculose/complicações , Fatores de RiscoRESUMO
OBJECTIVE: We analyzed the impact of different inhalant allergens on T-lymphocyte subsets in patients diagnosed with bronchial asthma. METHODS: The study included 57 bronchial asthma patients and 22 healthy controls. Asthma patients were categorized into dust mite, animal hair, pollen, and mold groups. Flow cytometry was used to measure the cells in the case group and control group. These T-lymphocyte subset markers were evaluated among patients with bronchial asthma caused by different allergens as well as between the case group and control group. RESULTS: Peripheral blood CD4+ T-cells, CD8+ T-cells, CD4/CD8 ratio, and Th17/Treg ratios were all higher in the case group than in the control group (p < 0.05). Peripheral blood T-lymphocyte subsets were compared among the four groups, and it was found that there were statistical differences in the Th17/Treg ratio among the four groups (p < 0.05). There were no significant differences observed among the four groups in terms of CD3+ cells, CD4+ cells, CD8+ cells, Th1 cells, Th2 cells, Th17 cells, Treg cells, Th9 cells, and Th22 cells. Further pairwise comparison was made, and the results suggested that the peripheral blood Th17/Treg ratio in the pollen mixed group was lower than that in the dust mite mixed group, animal hair mixed group, and mold mixed group (p < 0.05). CONCLUSION: Patients with bronchial asthma show varied T-lymphocyte subset responses to different inhalant allergens. Elevated CD4+ T cells and Th17 cells in peripheral blood could indicate asthma risk. However, small sample size may introduce bias to these findings.
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OBJECTIVE: Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren's syndrome (pSS). METHODS: In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration. RESULTS: Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8+CD103+CD69+ cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8+ CD103+ Trm contributed to the secretion of granzyme-B and interferon-γ, CD8+ Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of CD69, ITGAE, GZMB, GZMK and HLA-DRB1 among CD3+CD8+ SG T cells. In the SG of ESS, CD8+CD69+CD103+ Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow. CONCLUSIONS: CD103+CD8+Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.
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BACKGROUND: Diabetic retinopathy (DR) stands as a prominent complication of diabetes. Berberine (BBR) has reported to be effective to ameliorate the retinal damage of DR. Studying the potential immunological mechanisms of BBR on the streptozotocin (STZ) induced DR mouse model will explain the therapeutic mechanisms of BBR and provide theoretical basis for the clinical application of this drug. METHODS: C57BL/6 J mice were induced into a diabetic state using a 50 mg/(kg·d) dose of STZ over a 5-day period. Subsequently, they were subjected to a high-fat diet (HFD) for one month. Following a 5-week treatment with 100 mg/(kg·d) BBR, the concentrations of inflammatory factors in the mice's peripheral blood were determined using an enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin staining was employed to scrutinize pathological changes in the mice's retinas, while flow cytometry assessed the proportions of T-lymphocyte subsets and the activation status of dendritic cells (DCs) in the spleen and lymph nodes. CD4+T cells and DC2.4 cell lines were utilized to investigate the direct and indirect effects of BBR on T cells under high glucose conditions in vitro. RESULTS: Following 5 weeks of BBR treatment in the streptozotocin (STZ) mouse model of DR, we observed alleviation of retinal lesions and a down-regulation in the secretion of inflammatory cytokines, namely TNF-α, IL-1ß, and IL-6, in the serum of these mice. And in the spleen and lymph nodes of these mice, BBR inhibited the proportion of Th17 cells and promoted the proportion of Treg cells, thereby down-regulating the Th17/Treg ratio. Additionally, in vitro experiments, BBR directly inhibited the expression of the transcription factor RORγt and promoted the expression of the transcription factor Foxp3 in T cells, resulting in a down-regulation of the Th17/Treg ratio. Furthermore, BBR indirectly modulated the Th17/Treg ratio by suppressing the secretion of TNF-α, IL-1ß, and IL-6 by DCs and enhancing the secretion of indoleamine 2,3-dioxygenase (IDO) and transforming growth factor-beta (TGF-ß) by DCs. This dual action inhibited Th17 cell differentiation while promoting Treg cells. CONCLUSION: Our findings indicate that BBR regulate T cell subpopulation differentiation, reducing the Th17/Treg ratio by directly or indirectly pathway. This represents a potential therapeutic avenue of BBR for improving diabetic retinopathy.
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Berberina , Diabetes Mellitus Experimental , Retinopatia Diabética , Linfócitos T Reguladores , Células Th17 , Animais , Berberina/farmacologia , Berberina/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/imunologia , Retinopatia Diabética/etiologia , Células Th17/imunologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Camundongos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/imunologia , Masculino , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Retina/patologia , Retina/imunologia , Retina/efeitos dos fármacos , Retina/metabolismoRESUMO
BACKGROUND: Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. METHODS: This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. RESULTS: The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. CONCLUSION: In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice.
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Trióxido de Arsênio , Arsenicais , Modelos Animais de Doenças , Síndromes Mielodisplásicas , Animais , Trióxido de Arsênio/administração & dosagem , Trióxido de Arsênio/farmacologia , Arsenicais/farmacologia , Arsenicais/administração & dosagem , Camundongos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/imunologia , Sulfetos/farmacologia , Sulfetos/administração & dosagem , Dissulfetos/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2LD) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc. OBJECTIVE: We aimed to assess the safety and biological efficacy of IL-2LD in patients with SSc. METHODS: As part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6. RESULTS: At day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4+ T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2LD was well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period. CONCLUSION: IL-2LD at a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2LD therapeutic efficacy in SSc.
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Interleucina-2 , Escleroderma Sistêmico , Linfócitos T Reguladores , Humanos , Doenças Autoimunes/tratamento farmacológico , Interleucina-2/efeitos adversos , Interleucina-2/uso terapêutico , Qualidade de Vida , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/imunologia , Linfócitos T Reguladores/efeitos dos fármacosRESUMO
Anti-PD-(L)1 therapy has shown great efficacy in some patients with cancer. However, a significant proportion of patients with cancer do not respond to it. Another unmet clinical need for anti-PD-(L)1 therapy is the dynamic monitoring of treatment effects. Therefore, identifying biomarkers that can stratify potential responders before PD-(L)1 treatment and timely monitoring of the efficacy of PD-(L)1 treatment are crucial in the clinical setting. The identification of biomarkers by liquid biopsy has attracted considerable attention. Among the identified biomarkers, circulating T cells are one of the most promising because of their indispensable contribution to anti-PD-(L)1 therapy. The present review aimed to thoroughly explore the potential of circulating T cells as biomarkers of anti-PD-(L)1 therapy and its advantages and limitations.
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Neoplasias , Linfócitos T , Humanos , Biomarcadores , Imunoterapia , Neoplasias/tratamento farmacológicoRESUMO
OBJECTIVE: Diffuse central nervous system manifestations, referred to as neuropsychiatric lupus (NPSLE), are observed in 20-40% of lupus patients and involve complex mechanisms that have not yet been adequately elucidated. In murine NPSLE models, choroid plexus (ChP)-infiltrating T cells have not been fully evaluated as drivers of neuropsychiatric disease. METHOD: Droplet-based single-cell transcriptomic analysis (single-cell RNA sequencing) and immune T-cell receptor profiling were performed on ChP tissue from MRL/lpr mice, an NPSLE mouse model, at an 'early' and 'late' disease state, to investigate the infiltrating immune cells that accumulate with NPSLE disease progression. RESULTS: We found 19 unique clusters of stromal and infiltrating cells present in the ChP of NPSLE mice. Higher resolution of the T-cell clusters uncovered multiple T-cell subsets, with increased exhaustion and hypoxia expression profiles. Clonal analysis revealed that the clonal CD8+T cell CDR3 sequence, ASGDALGGYEQY, matched that of a published T-cell receptor sequence with specificity for myelin basic protein. Stromal fibroblasts are likely drivers of T-cell recruitment by upregulating the VCAM signalling pathway. Systemic blockade of VLA-4, the cognate ligand of VCAM, resulted in significant resolution of the ChP immune cell infiltration and attenuation of the depressive phenotype. CONCLUSION: Our analysis details the dynamic transcriptomic changes associated with murine NPSLE disease progression, and highlights its potential use in identifying prospective lupus brain therapeutic targets.
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Plexo Corióideo , Modelos Animais de Doenças , Vasculite Associada ao Lúpus do Sistema Nervoso Central , Animais , Plexo Corióideo/imunologia , Plexo Corióideo/patologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Camundongos , Camundongos Endogâmicos MRL lpr , Linfócitos T CD8-Positivos/imunologia , Feminino , Subpopulações de Linfócitos T/imunologia , Perfilação da Expressão Gênica/métodosRESUMO
BACKGROUND: The aim of this study was to investigate the effects and significance of rituximab (RTX) on the levels of T lymphocyte subsets in patients diagnosed with primary membranous nephropathy (PMN). METHODS: A total of 58 PMN patients and 25 healthy donors were chosen as the subjects. Among the PMN patients, 40 individuals received RTX treatment and completed at least 6 months of follow-up. All subjects underwent flow cytometry analysis to determine the peripheral blood lymphocyte subsets. The changes in anti-PLA2R antibody titers and 24-hour urinary protein levels were evaluated by ELISA and Biuret method before and after treatment. RESULTS: (1) The PMN group exhibited a significantly greater percentage of peripheral blood CD3-CD19+ B cells than the healthy group, which is consistent with the findings of previous reports. Additionally, compared with those in the peripheral blood of healthy individuals, the numbers of CD4+ central memory T cells, CD4+ effector memory T cells, CD4+/CD8+, and CD4+CD25+ T cells in the PMN peripheral blood were markedly greater. However, the number of peripheral blood Treg cells was reduced in the PMN group. (2) After 6 months of RTX treatment, PMN patients exhibited significant decreases in anti-PLA2R antibody titers, 24-hour urinary protein levels, and peripheral blood CD3-CD19+ B cells. Importantly, RTX administration decreased CD4+CD25+ T cells and CD4+/CD8+ in the peripheral blood of PMN patients and improved Treg cell levels. (3) RTX treatment induced alterations in the CD4+ T lymphocyte subsets in PMN patients, which did not correlate with B lymphocyte counts or anti-PLA2R antibody titers. CONCLUSIONS: RTX treatment might have a beneficial impact on cellular immunity by effectively restoring the balance of CD4+ T lymphocyte subsets in PMN patients, which is beyond its effects on B cells and antibody production. TRIAL REGISTRATION: The research was registered at the First Affiliated Hospital of Soochow University. REGISTRATION NUMBER: MR-32-23-016211. Registration Date: May 31, 2023.
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Glomerulonefrite Membranosa , Humanos , Rituximab/uso terapêutico , Glomerulonefrite Membranosa/tratamento farmacológico , Subpopulações de Linfócitos T , Linfócitos T Reguladores , Linfócitos B , Proteínas Adaptadoras de Transdução de Sinal , Antígenos CD19RESUMO
BACKGROUND: Tuberculosis (TB) is not only related to infection but also involves immune factors. This study explores the changes in T-lymphocyte subsets in children with TB who are human immunodeficiency virus (HIV)-negative and examines their relationship using chest computed tomography (CT) scans. Additionally, the study identifies risk factors for severe TB (STB) in children and establishes relevant risk prediction models. METHODS: We recruited 235 participants between 2018 and 2022, comprising 176 paediatric patients with TB who were HIV-negative and 59 age-matched children with bacterial community-acquired pneumonia (CAP). We quantitatively analysed and compared T-lymphocyte subsets between the two groups and among different types of TB infection. Both univariate and multivariate analyses of clinical and laboratory characteristics were conducted to identify independent risk factors for STB in children and to establish a risk prediction model. RESULTS: The absolute counts of CD3, CD4 and CD8 T-cells in children with TB infection decreased significantly compared with bacterial CAP. The percentage of CD8 T-cells increased, whereas the percentage of CD4 T-cells did not change significantly. The absolute count of CD3, CD4 and CD8 T-cells in extrapulmonary TB (EPTB) was significantly higher than in extra-respiratory TB, with unchanged subset percentages. According to chest CT lesion classification, CD4 T-cell counts decreased significantly in S3 compared with S1 or S2, with no significant change in CD3 and CD8 T-cell counts and percentages. No significant differences were observed in lymphocyte subset counts and percentages between S1 and S2. Univariate analyses indicated that factors such as age, symptom duration, white blood cell count, platelet count, neutrophil-to-lymphocyte ratio (NLR), erythrocyte sedimentation rate, prealbumin level, albumin level, globulin level, albumin/globulin (A/G) ratio, high-sensitivity C-reactive protein (Hs-CRP) level and CD4 and CD8 T-cell counts are associated with STB. Multivariate logistic regression analysis revealed that age, Hs-CRP level, NLR, symptom duration and A/G ratio are independent risk factors for STB in children. Increased age, Hs-CRP levels and NLR, along with decreased A/G, correlate with increased susceptibility to STB. A nomogram model, based on these independent risk factors, demonstrated an area under the receiver operating characteristics curve of 0.867 (95% CI: 0.813-0.921). Internal verification confirmed the model's accuracy, with the calibration curve approaching the ideal and the Hosmer-Lemeshow goodness-of-fit test showing consistent results (χ2 = 12.212, p = 0.142). CONCLUSION: In paediatric patients with TB, the absolute counts of all lymphocyte subsets were considerably reduced compared with those in patients with bacterial CAP. Clinicians should consider the possibility of EPTB infection in addition to respiratory infections in children with TB who have higher CD3, CD4 and CD8 T-cell counts than the ERTB group. Furthermore, CD4 T-cell counts correlated closely with the severity of chest CT lesions. Age, symptom duration, A/G ratio, Hs-CRP level and NLR were established as independent risk factors for STB. The nomogram model, based on these factors, offers effective discrimination and calibration in predicting STB in children.
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Globulinas , Infecções por HIV , Tuberculose Latente , Mycobacterium tuberculosis , Tuberculose , Humanos , Criança , Proteína C-Reativa , Subpopulações de Linfócitos T , Tuberculose/diagnóstico , Fatores de Risco , Subpopulações de Linfócitos , Contagem de LinfócitosRESUMO
OBJECTIVES: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease affecting mainly the axial skeleton. Peripheral involvement (arthritis, enthesitis and dactylitis) and extra-musculoskeletal manifestations, including uveitis, psoriasis and bowel inflammation, occur in a relevant proportion of patients. AS is responsible for chronic and severe back pain caused by local inflammation that can lead to osteoproliferation and ultimately spinal fusion. The association of AS with the human leucocyte antigen-B27 gene, together with elevated levels of chemokines, CCL17 and CCL22, in the sera of patients with AS, led us to study the role of CCR4+ T cells in the disease pathogenesis. METHODS: CD8+CCR4+ T cells isolated from the blood of patients with AS (n=76) or healthy donors were analysed by multiparameter flow cytometry, and gene expression was evaluated by RNA sequencing. Patients with AS were stratified according to the therapeutic regimen and current disease score. RESULTS: CD8+CCR4+ T cells display a distinct effector phenotype and upregulate the inflammatory chemokine receptors CCR1, CCR5, CX3CR1 and L-selectin CD62L, indicating an altered migration ability. CD8+CCR4+ T cells expressing CX3CR1 present an enhanced cytotoxic profile, expressing both perforin and granzyme B. RNA-sequencing pathway analysis revealed that CD8+CCR4+ T cells from patients with active disease significantly upregulate genes promoting osteogenesis, a core process in AS pathogenesis. CONCLUSIONS: Our results shed light on a new molecular mechanism by which T cells may selectively migrate to inflammatory loci, promote new bone formation and contribute to the pathological ossification process observed in AS.
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Espondilite Anquilosante , Humanos , Espondilite Anquilosante/genética , Espondilite Anquilosante/metabolismo , Osteogênese/genética , Subpopulações de Linfócitos T/metabolismo , Linfócitos T CD8-Positivos/metabolismo , InflamaçãoRESUMO
OBJECTIVES: Based on genetic associations, McGonagle and McDermott suggested a classification of autoimmune and autoinflammatory diseases as a continuum ranging from purely autoimmune to purely autoinflammatory diseases and comprising diseases with both components. We used deep immunophenotyping to identify immune cell populations and molecular targets characterising this continuum. METHODS: We collected blood from 443 patients with one of 15 autoimmune or autoinflammatory diseases and 71 healthy volunteers. Deep phenotyping was performed using 13 flow cytometry panels characterising over 600 innate and adaptive cell populations. Unsupervised and supervised analyses were conducted to identify disease clusters with their common and specific cell parameters. RESULTS: Unsupervised clustering categorised these diseases into five clusters. Principal component analysis deconvoluted this clustering into two immunological axes. The first axis was driven by the ratio of LAG3+ to ICOS+ in regulatory T lymphocytes (Tregs), and segregated diseases based on their inflammation levels. The second axis was driven by activated Tregs and type 3 innate lymphoid cells (ILC3s), and segregated diseases based on their types of affected tissues. We identified a signature of 23 cell populations that accurately characterised the five disease clusters. CONCLUSIONS: We have refined the monodimensional continuum of autoimmune and autoinflammatory diseases as a continuum characterised by both disease inflammation levels and targeted tissues. Such classification should be helpful for defining therapies. Our results call for further investigations into the role of the LAG3+/ICOS+ balance in Tregs and the contribution of ILC3s in autoimmune and autoinflammatory diseases. TRIAL REGISTRATION NUMBER: NCT02466217.
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Doenças Autoimunes , Doenças Hereditárias Autoinflamatórias , Humanos , Imunidade Inata , Imunofenotipagem , Linfócitos , InflamaçãoRESUMO
OBJECTIVES: Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are life-threatening systemic autoimmune diseases manifesting in the kidneys as necrotizing crescentic glomerulonephritis (NCGN). ANCA antigens are myeloperoxidase (MPO) or proteinase 3. Current treatments include steroids, cytotoxic drugs and B cell-depleting antibodies. The use of chimeric antigen receptor (CAR) T cells in autoimmune diseases is a promising new therapeutic approach. We tested the hypothesis that CAR T cells targeting CD19 deplete B cells, including MPO-ANCA-producing B cells, thereby protecting from ANCA-induced NCGN. METHODS: We tested this hypothesis in a preclinical MPO-AAV mouse model. NCGN was established by immunisation of MPO-/- mice with murine MPO, followed by irradiation and transplantation with haematopoietic cells from wild-type mice alone or together with either CD19-targeting CAR T cells or control CAR T cells. RESULTS: CD19 CAR T cells efficiently migrated to and persisted in bone marrow, spleen, peripheral blood and kidneys for up to 8 weeks. CD19 CAR T cells, but not control CAR T cells, depleted B cells and plasmablasts, enhanced the MPO-ANCA decline, and most importantly protected from NCGN. CONCLUSION: Our proof-of-principle study may encourage further exploration of CAR T cells as a treatment for ANCA-vasculitis patients with the goal of drug-free remission.
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Injúria Renal Aguda , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Glomerulonefrite , Humanos , Camundongos , Animais , Anticorpos Anticitoplasma de Neutrófilos , Linfócitos T , PeroxidaseRESUMO
OBJECTIVES: Understanding interpatient variation in CD4+T-cell responses is the bases for understanding the pathogenesis and management of rheumatoid arthritis (RA). We examined immune responses to SARS-CoV-2 vaccine in a cohort of patients with RA and determined factors associated with the responses. METHODS: Four hundred and thirty-one patients with RA having received two doses of BNT162b2, a messenger RNA-based vaccine for SARS-CoV-2, were included. Vaccine antigen-specific IgG was detected by ELISA, and antigen-specific CD4+T cells were detected by CD154 expression in response to antigenic stimulation. Expression of cytokines was concomitantly detected by intracellular staining. Associations among background variables, antigen-specific antibody production and the CD4+T-cell responses were analysed. Unsupervised hierarchical clustering was performed based on the profiles of antigen-specific cytokine production by CD4+T cells to stratify patients with RA. RESULTS: Multivariate analysis indicated that ageing negatively affects CD4+T-cell response as well as antibody production. No association was detected between the presence or the levels of rheumatoid factor/anti-cyclic citrullinated peptide antibody and anti-vaccine immune responses. Methotrexate and prednisolone reduced B cell but not T-cell responses. Conventional immunophenotyping by the expression of chemokine receptors was not associated with the actual CD4+T-cell response, except for T helper cells (Th1). Functional immunophenotyping based on the profiles of antigen-specific cytokine production of CD4+T cells stratified patients with RA into three clusters, among which Th1-dominant type less frequently underwent joint surgery. CONCLUSIONS: Clinical and immunological variables that are associated with antigen-specific CD4 T-cell responses in patients with RA were determined by analysing immune responses against SARS-CoV-2 vaccine.
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Artrite Reumatoide , Linfócitos T CD4-Positivos , Humanos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Vacina BNT162 , Vacinas contra COVID-19 , Citocinas/metabolismoRESUMO
BACKGROUND: Indeterminate readout of the quantitative interferon-γ release test (QFT) for Mycobacterium tuberculosis screening is a specific laboratory finding for systemic lupus erythematosus (SLE), which may be due to T-cell exhaustion and abnormal programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) signalling. METHODS: We enrolled 104 patients with SLE and 225 with other rheumatic musculoskeletal diseases (RMDs) who presented to the outpatient clinic between 2020 and 2023. Twenty healthy donors served as the controls. The QFT was performed in all participants, and those with indeterminate results were compared among the groups. Immunophenotyping and functional assays were performed using blood mononuclear cells. Interferon (IFN)-γ was detected in vitro and ex vivo in patients with SLE with indeterminate or negative QFT results, before or after rituximab therapy. RESULTS: 104 patients with SLE had a significantly higher rate of indeterminate QFT results was significantly higher (17.31%) than that of 225 patients with RMD (3.56%). Patients with SLE with indeterminate QFT had more active disease (SLEDAI-2K, mean 10.94 vs 4.02, p<0.0001), including a higher incidence of active nephritis (55.56% vs 29.07%). Indeterminate QFT in SLE is mainly caused by an insufficient IFN-γ response in CD8+T cells with exhausted immunophenotypes. The abnormal interaction between exhausted PD-1 high CD8+ T cells and activated PD-L1 low memory B cells in SLE can be reversed with a PD-1 agonist or increased PD-L1 expression. Rituximab treatment indirectly reversed this IFN-γ response. CONCLUSION: The PD-1/PD-L1 signalling pathway, which governs the crosstalk between exhausted CD8+ T cells and activated memory B cells, is a mechanistic explanation for insufficient interferon-γ response in patients with SLE.
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Linfócitos T CD8-Positivos , Lúpus Eritematoso Sistêmico , Humanos , Linfócitos T CD8-Positivos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Células B de Memória , Antígeno B7-H1/fisiologia , Ligantes , Rituximab , Lúpus Eritematoso Sistêmico/complicaçõesRESUMO
OBJECTIVE: Polymorphisms in the antifungal signalling molecule CARD9 are associated with ankylosing spondylitis (AS). Here, we investigated the cellular mechanism by which CARD9 controls pathogenic Th17 responses and the onset of disease in both experimental murine AS and patients. METHODS: Experiments in SKG, Card9-/-SKG, neutrophil-deplete SKG mice along with in vitro murine, neutrophil and CD4+ T cell cocultures examined Card9 function in neutrophil activation, Th17 induction and arthritis in experimental AS. In AS patients the neutrophil: Bath Ankylosing Spondylitis Functional Index relationship was analysed. In vitro studies with autologous neutrophil: T cell cocultures examined endogenous CARD9 versus the AS-associated variant (rs4075515) of CARD9 in T cellular production of IL-17A. RESULTS: Card9 functioned downstream of Dectin-1 and was essential for induction of Th17 cells, arthritis and spondylitis in SKG mice. Card9 expression within T cells was dispensable for arthritis onset in SKG mice. Rather, Card9 expression controlled neutrophil function; and neutrophils in turn, were responsible for triggering Th17 expansion and disease in SKG mice. Mechanistically, cocultures of zymosan prestimulated neutrophils and SKG T cells revealed a direct cellular function for Card9 within neutrophils in the potentiation of IL-17 production by CD4+ T cells on TCR-ligation. The clinical relevance of the neutrophil-Card9-coupled mechanism in Th17-mediated disease is supported by a similar observation in AS patients. Neutrophils from HLA-B27+ AS patients expanded autologous Th17 cells in vitro, and the AS-associated CARD9S12N variant increased IL-17A. CONCLUSIONS: These data reveal a novel neutrophil-intrinsic role for Card9 in arthritogenic Th17 responses and AS pathogenesis. These data provide valuable utility in our future understanding of CARD9-specific mechanisms in spondyloarthritis .