RESUMO
Regulatory T cells (Treg) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25+Foxp3- and CD25-Foxp3lo precursors. However, the mechanisms regulating the recently identified Foxp3lo precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin α1ß2 (LTα1ß2) heterocomplex is upregulated during Treg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of Treg from Foxp3lo precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTα1ß2-lymphotoxin ß receptor-mediated interactions with mTEC limit Treg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic Treg development that fine-tunes the Foxp3lo Treg precursor pathway by limiting IL-4 availability.
Assuntos
Fatores de Transcrição Forkhead , Interleucina-4 , Receptor beta de Linfotoxina , Linfotoxina-alfa , Transdução de Sinais , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Interleucina-4/metabolismo , Camundongos , Linfotoxina-alfa/metabolismo , Linfotoxina-alfa/genética , Receptor beta de Linfotoxina/metabolismo , Receptor beta de Linfotoxina/genética , Timo/imunologia , Timo/citologia , Timo/metabolismo , Células Epiteliais/metabolismo , Camundongos Endogâmicos C57BL , Diferenciação Celular , Camundongos Transgênicos , Interleucina-2/metabolismo , Proliferação de Células , Heterotrímero de Linfotoxina alfa1 e beta2/metabolismo , Heterotrímero de Linfotoxina alfa1 e beta2/genéticaRESUMO
OBJECTIVES: The mechanism that leads to disseminated tuberculosis in HIV-negative patients is still largely unknown. T cell subsets and signaling pathways that were associated with disseminated tuberculosis were investigated. METHODS: Single-cell profiling of whole T cells was performed to identify T cell subsets and enriched signaling pathways that were associated with disseminated tuberculosis. Flow cytometric analysis and blocking experiment were used to investigate the findings obtained by transcriptome sequencing. RESULTS: Patients with disseminated tuberculosis had depleted Th1, Tc1 and Tc17 cell subsets, and IFNG was the most down-regulated gene in both CD4 and CD8 T cells. Gene Ontology analysis showed that non-canonical NF-κB signaling pathway, including NFKB2 and RELB genes, was significantly down-regulated and was probably associated with disseminated tuberculosis. Expression of several TNF superfamily ligands and receptors, such as LTA and TNF genes, were suppressed in patients with disseminated tuberculosis. Blocking of TNF-α and soluble LTα showed that TNF-α was involved in IFN-γ production and LTα influenced TNF-α expression in T cells. CONCLUSIONS: Impaired T cell IFN-γ response mediated by suppression of TNF and non-canonical NF-κB signaling pathways might be responsible for disseminated tuberculosis.
Assuntos
Interferon gama , NF-kappa B , Transdução de Sinais , Fator de Necrose Tumoral alfa , Humanos , Masculino , Feminino , Adulto , NF-kappa B/metabolismo , Pessoa de Meia-Idade , Interferon gama/metabolismo , Interferon gama/genética , Interferon gama/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tuberculose/imunologia , Fator de Transcrição RelB/metabolismo , Fator de Transcrição RelB/genética , Subunidade p52 de NF-kappa B/metabolismo , Subunidade p52 de NF-kappa B/genética , Análise de Célula Única , Linfócitos T CD8-Positivos/imunologia , Linfotoxina-alfa/genética , Linfotoxina-alfa/metabolismo , Adulto Jovem , Idoso , Perfilação da Expressão Gênica , Mycobacterium tuberculosis/imunologiaRESUMO
Introduction: Circulating cytokines were considered to play a critical role in the initiation and propagation of sarcopenia and frailty from observational studies. This study aimed to find the casual association between circulating cytokines and sarcopenia and frailty from a genetic perspective by two-sample Mendelian randomization (MR) analysis. Methods: Data for 41 circulating cytokines were extracted from the genome-wide association study dataset of 8,293 European participants. Inverse-variance weighted (IVW) method, MR-Egger, and weighted median method were applied to assess the relationship of circulating cytokines with the risk of aging-related syndromes and frailty. Furthermore, MR-Egger regression was used to indicate the directional pleiotropy, and Cochran's Q test was used to verify the potential heterogeneity. The "leave-one-out" method was applied to visualize whether there was a causal relationship affected by only one anomalous single-nucleotide polymorphisms. Results: Genetic predisposition to increasing levels of interleukin-10 (IL-10), IL-12, and vascular endothelial growth factor (VEGF) was associated with the higher risk of low hand grip strength according to the IVW method [R = 1.05, 95% CI = 1.01-1.10, P = 0.028, false discovery rate (FDR)-adjusted P = 1.000; OR = 1.03, 95% CI = 1.00-1.07, P = 0.042, FDR-adjusted P = 0.784; OR = 1.02, 95% CI = 1.00-1.05, P = 0.038, FDR-adjusted P = 0.567]. Furthermore, genetically determined higher macrophage colony-stimulating factors (M-CSFs) were associated with a lower presence of appendicular lean mass (OR = 1.01, 95% CI = 1.00-1.02, P = 0.003, FDR-adjusted P = 0.103). Monokine induced by interferon-γ (MIG) and tumor necrosis factor-beta (TNF-ß) were associated with a higher risk of frailty (OR = 1.03, 95% CI = 1.01-1.05, P < 0.0001, FDR-adjusted P = 0.012; OR = 1.01, 95% CI = 1.00-1.03, P = 0.013, FDR-adjusted P = 0.259). In this study, we did not find heterogeneity and horizontal pleiotropy between the circulating cytokines and the risk of frailty and sarcopenia. Conclusion: Genetic predisposition to assess IL-10, IL-12, and VEGF levels was associated with a higher risk of low hand grip strength and M-CSF with the presence of appendicular lean mass. The high levels of TNF-ß and MIG were associated with a higher risk of frailty. More studies will be required to explore the molecular biological mechanisms underlying the action of inflammatory factors.
Assuntos
Fragilidade , Sarcopenia , Humanos , Citocinas/genética , Interleucina-10 , Fator A de Crescimento do Endotélio Vascular , Linfotoxina-alfa , Sarcopenia/genética , Fragilidade/genética , Gerociência , Estudo de Associação Genômica Ampla , Força da Mão , Interleucina-12 , Interferon gama , Predisposição Genética para DoençaRESUMO
Lymphotoxin α (LTα) is a soluble factor produced by activated lymphocytes which is cytotoxic to tumor cells. Although a promising candidate in cancer therapy, the application of recombinant LTα has been limited by its instability and toxicity by systemic administration. Secreted LTα interacts with several distinct receptors for its biological activities. Here, we report a TNFR1-selective human LTα mutant (LTα Q107E) with potent antitumor activity. Recombinant LTα Q107E with N-terminal 23 and 27 aa deletion (named LTα Q1 and Q2, respectively) showed selectivity to TNFR1 in both binding and NF-κB pathway activation assays. To test the therapeutic potential, we constructed an oncolytic adenovirus (oAd) harboring LTα Q107E Q2 mutant (named oAdQ2) and assessed the antitumor effect in mouse xenograft models. Intratumoral delivery of oAdQ2 inhibited tumor growth. In addition, oAdQ2 treatment enhanced T cell and IFNγ-positive CD8 T lymphocyte infiltration in a human PBMC reconstituted-SCID mouse xenograft model. This study provides evidence that reengineering of bioactive cytokines with tissue or cell specific properties may potentiate their therapeutic potential of cytokines with multiple receptors.
Assuntos
Adenoviridae , Imunoterapia , Linfotoxina-alfa , Camundongos SCID , Terapia Viral Oncolítica , Receptores Tipo I de Fatores de Necrose Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Animais , Camundongos , Linfotoxina-alfa/genética , Adenoviridae/genética , Terapia Viral Oncolítica/métodos , Imunoterapia/métodos , Vírus Oncolíticos/genética , Linhagem Celular Tumoral , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/genética , Mutação , Linfócitos T CD8-Positivos/imunologia , NF-kappa B/metabolismoRESUMO
Osteoporosis is caused by the imbalance of osteoblasts and osteoclasts. The regulatory mechanisms of differentially expressed genes (DEGs) in pathogenesis of osteoporosis are of significant and needed to be further investigated. GSE100609 dataset downloaded from Gene Expression Omnibus (GEO) database was used to identified DEGs in osteoporosis patients. KEGG analysis was conducted to demonstrate signaling pathways related to enriched genes. Osteoporosis patients and the human mesenchymal stem cells (hMSCs) were obtained for in vivo and in vitro resaerch. Lentivirus construction and viral infection was used to knockdown genes. mRNA expression and protein expression were detected via qRT-PCR and western blot assay separately. Alkaline phosphatase (ALP) activity detection, alizarin Red S (ARS) staining, and expression of bone morphogenetic protein 2 (BMP2), osteocalcin (OCN) and Osterix were evaluated to determine osteoblast differentiation capacity. UL-16 binding protein 1 (ULBP1) gene was upregulated in osteoporosis and downregulated in differentiated hMSCs. Knockdown of ULBP1 increased ALP activity, mineralization ability evaluated by ARS staining, expression of BMP2, OCN and Osterix in differentiated hMSCs. Furthermore, rescue experiment demonstrated that suppressed ULBP1 boosted osteoblast differentiation by activating TNF-ß signaling pathway. Knockdown of ULBP1 gene could promoted osteoblast differentiation by activating TNF-ß signaling pathway in differentiated hMSCs. ULBP1 may be a the Achilles' heel of osteoporosis, and suppression of ULBP1 could be a promising treatment for osteoporosis.
Assuntos
Células-Tronco Mesenquimais , Osteoporose , Humanos , Proteínas de Transporte/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Linfotoxina-alfa/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteogênese/genética , Osteoporose/genética , Proteína Smad2/metabolismoRESUMO
The rate of caesarean section (CS) is increasing worldwide. Defects in uterine healing have a major gynaecological and obstetric impact (uterine rupture, caesarean scar defect, caesarean scar pregnancy, placenta accreta spectrum). The complex process of cellular uterine healing after surgery, and specifically after CS, remains poorly understood in contrast to skin wound healing. This literature review on uterine wound healing was mainly based on histological observations, particularly after CS. The primary objective of the review was to examine the effects of CS on uterine tissue at the cellular level, based on histological observations. The secondary objectives were to describe the biomechanical characteristics and the therapies used to improve scar tissue after CS. This review was performed using PRISMA criteria, and PubMed was the data source. The study included all clinical and animal model studies with CS and histological analysis of the uterine scar area (macroscopic, microscopic, immunohistochemical and biomechanical). Twenty studies were included: 10 human and 10 animal models. In total, 533 female humans and 511 female animals were included. Review articles, meeting abstracts, case series, case reports, and abstracts without access to full-text were excluded. The search was limited to studies published in English. No correlation was found between cutaneous and uterine healing. The histology of uterine scars is characterized by disorganized smooth muscle, fibrosis with collagen fibres and fewer endometrial glands. As for skin healing, the initial inflammation phase and mediation of some growth factors (particularly connective tissue growth factor, vascular endothelial growth factor, platelet-derived growth factor, tumour necrosis factor α and tumour necrosis factor ß) seem to be essential. This initial phase has an impact on the subsequent phases of proliferation and maturation. Collagen appears to play a key role in the initial granulation tissue to replace the loss of substance. Subsequent maturation of the scar tissue is essential, with a decrease in collagen and smooth muscle restoration. Unlike skin, the glandular structure of uterine tissue could be responsible for the relatively high incidence of healing defects. Uterine scar defects after CS are characterized by an atrophic disorganized endometrium with atypia and a fibroblastic highly collagenic stromal reaction. Concerning immunohistochemistry, one study found a decrease in tumour necrosis factor ß in uterine scar defects. No correlation was found between biomechanical characteristics (particularly uterine strength) and the presence of a collagenous scar after CS. Based on the findings of this review, an illustration of current understanding about uterine healing is provided. There is currently no validated prevention of caesarean scar defects. Various treatments to improve uterine healing after CS have been tested, and appeared to have good efficacy in animal studies: alpha lipoic acid, growth factors, collagen scaffolds and mesenchymal stem cells. Further prospective studies are needed.
Assuntos
Cesárea , Doenças Uterinas , Animais , Feminino , Humanos , Gravidez , Cesárea/efeitos adversos , Cicatriz/etiologia , Colágeno , Linfotoxina-alfa/farmacologia , Doenças Uterinas/complicações , Fator A de Crescimento do Endotélio Vascular , CicatrizaçãoRESUMO
This study aimed to investigate the effects of adding Nano-Selenium (NSe) and Nano-clay (NC) as feed supplements on European Sea Bass (Dicentrarchus labrax). Two separate experiments were conducted, one with NC and the other with NSe. Each experiment consisted of four sub-groups with varying concentrations of NC or NSe. The expression levels of five immune-related genes (TNF-α, TNF-ß, IL-2, IL-6 and IL-12) were measured using Real-time Quantitative PCR (Rt-PCR) Assay. The results showed an increase in the expression of interleukins (IL-2, IL-6 and IL-12) and pro-inflammatory cytokines (TNF-α and TNF-ß) after exposure to NC and NSe. TNF-α gene expression was significantly higher with both 1 mg and 10 mg concentrations of NC and NSe. TNF-ß gene expression was highest with the 5 mg concentration of NC. The concentrations of 1 mg and 10 mg for NC, and 1 mg, 5 mg, and 10 mg for NSe, led to the highest (p < 0.05) levels of IL-2 expression compared to the control. Similar trends were observed for IL-6 and IL-12 gene expression. Understanding the impact of these concentrations on gene expression, growth rate, biochemical indices, and antioxidant status can provide valuable insights into the potential applications of NC and NSe supplements on European Sea Bass.
Assuntos
Bass , Animais , Bass/metabolismo , Linfotoxina-alfa/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Interleucina-12/metabolismoRESUMO
The pathogenesis of appendicitis is not understood fully, and the diagnosis can be challenging. Previous research has suggested an association between a T helper (Th) 1-dependent immune response and complicated appendicitis. This prospective cohort study aimed to evaluate the association between serum concentrations of the Th1-associated cytokines interleukin (IL)-1α, IL-1ß, IL-2, IL-6, IL-10, IL-17A and tumor necrosis factor beta (TNF-ß) and the risk of complicated appendicitis in children. Appendicitis severity was determined through histopathological examination. A total of 137 children < 15 years with appendicitis were included with a median age of 10 years (IQR 8-12); 86 (63%) were boys, and 58 (42%) had complicated appendicitis. Children with complicated appendicitis had significantly higher concentrations of serum IL-6 and IL-10, and lower of TNF-ß. After adjustment for age, symptom duration, and presence of appendicolith in a multivariable logistic regression, a higher concentration of IL-6 remained associated with an increased risk of complicated appendicitis (aOR 1.001 [95% CI 1.000-1.002], p = 0.02). Serum concentrations of IL-1α, IL-1ß, IL-2, IL-10, IL-17A and TNF-ß were not significantly associated with the risk of complicated appendicitis. In conclusion, our results suggests that the systemic inflammatory response in complicated appendicitis is complex and not solely Th1-dependent.
Assuntos
Apendicite , Citocinas , Masculino , Humanos , Criança , Feminino , Interleucina-10 , Interleucina-17 , Apendicite/complicações , Interleucina-6 , Interleucina-2 , Linfotoxina-alfa , Estudos Prospectivos , Interleucina-1betaRESUMO
OBJECTIVES: There is a paucity of available biomarkers of disease activity in idiopathic inflammatory myopathies (IIM), and serum cytokines/chemokines hold potential as candidate biomarkers. We aimed to determine serum cytokine profiles of IIM patients with active disease as compared to patients in remission and healthy controls. METHODS: The IIM patients with active disease (included patients enrolled in repository corticotropin injection trial), in remission, and healthy controls were enrolled in this cross-sectional observational study. Serum concentrations of 51 cytokines/chemokines were obtained by utilising a bead-based multiplex cytokine assay (Luminex®). The myositis core set measures were obtained for all the patients. Cytokines with the best predictive ability to differentiate these clinical groups were assessed with three methods: 1) Least Absolute Shrinkage and Selection Operator modelling, 2) stepwise approach, and 3) logistic regression model. RESULTS: Twenty-one IIM patients with active disease, 11 IIM patients in remission and 10 healthy controls were enrolled. Myositis patients had elevated levels of chemokines that attract eosinophils (eotaxin) and dendritic cells, NK cells, cytotoxic T-cells and monocytes/macrophages (CXCL-9, IP-10), cytokines that drive T-helper 1 responses (TNF-a, lymphotoxin-a), matrix degrading enzymes (MMP-3 and -9), and IGFBP-2 compared to healthy controls. Myositis patients with active disease had higher levels of lymphotoxin-a, CXCL-9, MIP-1a, MIP-1b and MMP-3 than patients in remission. CONCLUSIONS: This study demonstrated differences in cytokine profiles of IIM patients (active and inactive disease) compared to healthy controls and identified some cytokines that could potentially be used as biomarkers. Larger longitudinal studies are needed to validate our findings.
Assuntos
Metaloproteinase 3 da Matriz , Miosite , Adulto , Humanos , Linfotoxina-alfa , Estudos Transversais , Citocinas , Quimiocinas , Miosite/diagnóstico , BiomarcadoresRESUMO
To explore the correlation between tear LT-a, pterygium status, and dry eye indicators. We established a diagnostic model to evaluate active pterygium. A retrospective study was conducted between June 2021 and June 2023 on 172 patients, comprising 108 men and 64 women. The study analyzed LT-a and various ocular parameters in all participants. The data was collected using Excel software and analyzed using SPSS 25.0 statistical software and Medcalc. We made a nomogram diagnostic model to different diagnosed the state of pterygium. This study found that pterygium has progressive eye surface damage during the active state. There was no significant difference in dry eye indicators between the two groups. However, the concentration of LT-a in the active group was significantly lower than that in the inactive group (P < 0.001). We observed that increased pterygium grade corresponded to a worse ocular surface condition. In addition, LT-a was significantly positively correlated with disease duration, but negatively correlated with age, pterygium size, active pterygium state, and LLT value. The optimal intercept value for evaluating active pterygium in Lt-a was ≤ 0.49 dg/ml. We screened three variables for evaluating active pterygium through Single and Multiple regression analysis: LT-a grading, pterygium size, and congestion score. Finally, we made a reliable diagnostic nomogram model. Pterygium development triggers immune inflammation. Our model based on LT-a identifies active pterygium for personalized treatment options and new research directions.
Assuntos
Túnica Conjuntiva/anormalidades , Síndromes do Olho Seco , Pterígio , Masculino , Humanos , Feminino , Pterígio/diagnóstico , Linfotoxina-alfa , Estudos RetrospectivosRESUMO
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Studies indicated that inflammatory cytokines involved in the occurrence and progression of DLBCL and it is challenging to discern causality from the effects due to the presence of feedback loops. We conducted a bidirectional Mendelian randomization (MR) study to investigate the potential causal relationship between DLBCL and inflammatory cytokines. The genetic variants associated with inflammatory cytokines were obtained from a genome-wide association study (GWAS) involving 8293 European participants, and the data on 1010 individuals with DLBCL were sourced from the FinnGen consortium. The primary method employed in this study was the inverse-variance weighted (IVW) method, with supplementary analyses conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. Based on the IVW method, genetically predicted that increasing level of Monokine induced by interferon gamma (MIG/CXC chemokine ligand 9, CXCL9) [OR: 1.31; 95% CI: 1.05-1.62; P = 0.01] and interferon gamma-induced protein 10(IP-10/CXC chemokine ligand 10, CXCL10) [OR: 1.30; 95% CI: 1.02-1.66; P = 0.03] showed suggestive associations with DLBCL risk. DLBCL may increase the level of macrophage colony-stimulating factor (M-CSF) [OR: 1.12; 95% CI: 1.01-1.2; P = 0.03], tumor necrosis factor beta (TNF-ß) [OR: 1.16; 95% CI: 1.02-1.31; P = 0.02] and TNF-related apoptosis-inducing ligand (TRAIL) [OR: 1.07; 95% CI: 1.01-1.13; P = 0.02]. This study presents evidence supporting a causal relationship between inflammation cytokines and DLBCL. Specifically, MIG/CXCL9 and IP-10/CXCL10 were identified as indicators of upstream causes of DLBCL; while, DLBCL itself was found to elevate the levels of M-CSF, TNF-ß, and TRAIL. These findings suggest that targeting specific inflammatory factors through regulation and intervention could serve as a potential approach for the treatment and prevention of DLBCL.
Assuntos
Citocinas , Linfoma Difuso de Grandes Células B , Humanos , Fator Estimulador de Colônias de Macrófagos , Linfotoxina-alfa , Interferon gama , Quimiocina CXCL10 , Estudo de Associação Genômica Ampla , Ligantes , Análise da Randomização Mendeliana , Linfoma Difuso de Grandes Células B/genéticaRESUMO
Objective: To analyze the risk factors of thrombosis in patients with JAK2V617F mutation positive myeloproliferative neoplasms (MPN). Methods: A total of 223 MPN patients with JAK2V617F mutation in the Second Hospital of Tianjin Medical University from September 2017 to May 2023 were retrospectively enrolled, including 111 males and 112 females, aged [M(Q1,Q3)] 57(21,66) years. According to the presence or absence of thromboembolism during follow-up, the patients were divided into thrombosis group (n=102) and non-thrombosis group (n=121). The clinical characteristics, laboratory characteristics, cytogenetics and other disease progression and survival of the two groups of patients were analyzed. As of March 31, 2023, the follow-up period [M (Q1, Q3)] was 6 (3, 10) years. The influencing factors of thrombosis in JAK2V617F positive MPN patients were analyzed by using the Cox risk model. Results: Among 223 JAK2V617F positive MPN patients, 144 were polycythemia vera (PV), 51 were essential thrombocythemia (ET) and 28 were primary myelofibrosis (PMF). The mutation rates of ASXL1 and BCORL1 genes in the thrombosis group were 19.6% (20/102) and 6.9% (7/102), respectively, which were higher than those in the non-thrombosis group [9.1% (11/121) and 0.8% (1/121)] (both P<0.05). The proportion of monocytes, C-reactive protein (CRP), interleukin-1ß (IL)-1ß, IL-8 and tumor necrosis factor-ß (TNF-ß) increased in the thrombosis group were higher than those in the non-thrombosis group (all P<0.05). Multivariate analysis showed that age≥60 years (HR=2.132, 95%CI: 1.376-3.303, P=0.001), history of thrombosis (HR=3.636, 95%CI: 2.121-6.202, P<0.001), ASXL1 mutation positive (HR=2.245, 95%CI: 1.093-3.231, P=0.022) and elevated TNF-ß (HR=2.009, 95%CI: 1.113-3.624, P=0.021) were risk factors for thrombosis in JAK2V617F positive MPN patients. Conclusions: In addition to age, history of thrombosis and positive ASXL1 mutation, elevated TNF-ß is also an influencing factor of thrombosis in JAK2V617F positive MPN patients. Intervention of inflammation may have a certain effect on the prevention and treatment of thrombosis.
Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Tromboembolia , Trombose , Masculino , Feminino , Humanos , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfotoxina-alfa/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/complicações , Policitemia Vera/complicações , Policitemia Vera/genética , Tromboembolia/complicações , Trombose/genética , Mutação , Fatores de Risco , Janus Quinase 2/genéticaRESUMO
MIS-C is a systemic inflammation disorder with poorly characterised immunopathological mechanisms. We compared changes in the systemic immune response in children with MIS-C (n = 12, 5-13 years) to healthy controls (n = 14, 5-15 years). Analysis was done in whole blood treated with LPS. Expression of CD11b and Toll-like receptor-4 (TLR4) in neutrophils and monocytes were analysed by flow cytometry. Serum cytokines (IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-Ira, TNF-α, TNF-ß, IFN-Υ, VEGF, EPO and GM-CSF) and mRNA levels of inflammasome molecules (NLRP3, ASC and IL-1ß) were evaluated. Subpopulations of lymphocytes (CD3+, CD19+, CD56+, CD4+, CD8+, TCR Vδ1+, TCR Vδ2+) were assessed at basal levels. Absolute counts of neutrophils and NLR were high in children with MIS-C while absolute counts of lymphocytes were low. Children with MIS-C had increased levels of IL-6, IL-10, TNF-ß and VEGF serum cytokines at the basal level, and significantly increased TNF-ß post-LPS, compared to controls. IL-1RA and EPO decreased at baseline and post-LPS in MIS-C patients compared to controls. The percentage of CD3+ cells, NK cells and Vδ1 was lower while B cells were higher in children with MIS-C than in controls. Dysregulated immune response in children with MIS-C was evident and may be amenable to immunomodulation.
Assuntos
Interleucina-10 , Linfotoxina-alfa , Criança , Humanos , Interleucina-10/metabolismo , Lipopolissacarídeos , Interleucina-6 , Fator A de Crescimento do Endotélio Vascular , Citocinas/metabolismo , Imunidade Inata , Receptores de Antígenos de Linfócitos TRESUMO
Introduction: Human Granzyme B (GZMB) regulatory B cells (Bregs) have suppressive properties on CD4+ effector T cells by a mechanism partially dependent on GZMB. Moreover, these cells may be easily induced in vitro making them interesting for cell therapy. Methods: We characterized this population of in vitro induced GZMB+Bregs using single cell transcriptomics. To investigate their regulatory properties, Bregs or total B cells were also co-cultured with T cells and scRNAseq was used to identify receptor ligand interactions and to reveal gene expression changes in the T cells. Results: We find that Bregs exhibit a unique set of 149 genes differentially expressed and which are implicated in proliferation, apoptosis, metabolism, and altered antigen presentation capacity consistent with their differentiated B cells profile. Notably, Bregs induced a strong inhibition of T cell genes associated to proliferation, activation, inflammation and apoptosis compared to total B cells. We identified and validated 5 receptor/ligand interactions between Bregs and T cells. Functional analysis using specific inhibitors was used to test their suppressive properties and we identified Lymphotoxin alpha (LTA) as a new and potent Breg ligand implicated in Breg suppressive properties. Discussion: We report for the first time for a role of LTA in GZMB+Bregs as an enhancer of GZMB expression, and involved in the suppressive properties of GZMB+Bregs in human. The exact mechanism of LTA/GZMB function in this specific subset of Bregs remains to be determined.
Assuntos
Linfócitos B Reguladores , Linfotoxina-alfa , Humanos , Granzimas , Ligantes , Linfócitos T CD4-Positivos , Proliferação de CélulasRESUMO
Correct development and maturation of the enteric nervous system (ENS) is critical for survival1. At birth, the ENS is immature and requires considerable refinement to exert its functions in adulthood2. Here we demonstrate that resident macrophages of the muscularis externa (MMÏ) refine the ENS early in life by pruning synapses and phagocytosing enteric neurons. Depletion of MMÏ before weaning disrupts this process and results in abnormal intestinal transit. After weaning, MMÏ continue to interact closely with the ENS and acquire a neurosupportive phenotype. The latter is instructed by transforming growth factor-ß produced by the ENS; depletion of the ENS and disruption of transforming growth factor-ß signalling result in a decrease in neuron-associated MMÏ associated with loss of enteric neurons and altered intestinal transit. These findings introduce a new reciprocal cell-cell communication responsible for maintenance of the ENS and indicate that the ENS, similarly to the brain, is shaped and maintained by a dedicated population of resident macrophages that adapts its phenotype and transcriptome to the timely needs of the ENS niche.
Assuntos
Sistema Nervoso Entérico , Intestinos , Macrófagos , Sistema Nervoso Entérico/citologia , Sistema Nervoso Entérico/crescimento & desenvolvimento , Sistema Nervoso Entérico/fisiologia , Intestinos/inervação , Linfotoxina-alfa/metabolismo , Macrófagos/metabolismo , Macrófagos/fisiologia , Neurônios/fisiologia , Desmame , Comunicação Celular , Transcriptoma , Fenótipo , Fagocitose , Sinapses , Plasticidade Neuronal , Trânsito GastrointestinalRESUMO
The inflammatory cytokines TNF-ß and IFN-γ are important mediators of the vertebrate inflammatory response and coordinators of the immune system in regard to NF-κB signalling pathways. In this study, the TNF-ß and IFN-γ genes of yellowfin seabream, Acanthopagrus latus were identified, and the multiple sequence alignments, evolutionary relationships and gene expressions of the two genes were also determined. AlTNF-ß contained a 762 bp open reading frame (ORF) encoding 253 amino acids, while AlIFN-γ contained a 582 bp ORF encoding 193 amino acids. An amino-acid sequence alignment analysis showed that these proteins have highly conserved transmembrane structural domains among teleosts. Moreover, AlTNF-ß has a close affinity with TNF-ß of yellowfin seabream while AlIFN-γ has a high evolutionary correlation with A. regius and Sparus aurata. In addition, the mRNAs of AlTNF-ß and AlIFN-γ are widely expressed in various tissues. AlTNF-ß is highly expressed in gill and intestinal tissues, and the mRNA levels of AlIFN-γ are higher in spleen, skin, and gill tissues than in other tissues. Under transportation density stress, the mRNA level of AlTNF-ß was significantly elevated in the intestine of the high-density group, while AlTNF-ß transcription in the gills did not vary significantly among the density groups. Furthermore, AlIFN-γ expression was increased in liver, intestinal, and gill tissues under high transportation density. The results of this study show that TNF-ß and IFN-γ expression in yellowfin seabream is greatly affected by density stress. The density of 125 per bag for 4-5 cm fry or 1200 per bag for 1-2 cm fry is most suitable for the transportation of live fish. These results might provide a reference for further studies on the immunomodulatory response process and auxiliary function of immune stress of TNF and IFN genes in fish under density stress.
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Perciformes , Dourada , Animais , Linfotoxina-alfa/metabolismo , Perciformes/genética , Interferon gama/genética , Interferon gama/metabolismo , Imunidade , RNA Mensageiro/metabolismoRESUMO
Objectives: Inflammatory mediators are associated with many chronic diseases; however, their role in metabolic syndrome (Met-S) is not well documented. We therefore aimed to compare the serum markers of inflammation including C-reactive protein (CRP), myeloperoxidase (MPO), interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), and TNF-ß in young military recruits with and without Met-S. We hypothesized that any significant change in inflammatory markers between the two groups would indicate the role of inflammation in Met-S that would help in future directions for screening and treatment of Met-S. Design and Methods. A total of 2010 adult men, aged 18-30 years, were divided into two groups: with Met-S (N = 488) and without Met-S (N = 1522), according to the International Diabetes Federation definition. We compared the serum levels of inflammatory biomarkers between the two groups. We also studied the correlations between the inflammatory markers and the components of Met-S to explore the biomarker potential of inflammatory markers for screening of Met-S. Logistic regression analysis was performed to test the association between inflammatory markers and Met-S. Results: A large number of subjects in the Met-S group were suffering from obesity. Out of the 2010 total subjects, only 731 (36.4%) had normal fasting blood sugar (FBS), while the prevalence of prediabetes and diabetes was significantly higher in subjects with Met-S. We observed significant increases in serum levels of CRP, MPO, IL-6, and TNF-ß but not TNF-α in subjects with Met-S as compared to subjects without Met-S. All the markers of inflammation showed significant correlations with Met-S, triglycerides (TG), blood pressure, body mass index (BMI), and age; however, none of these markers were correlated with HDL. Logistic regression analysis showed a significant association between Met-S and inflammatory markers. Conclusions: Serum levels of CRP, MPO, IL-6, and TNF-ß are significantly increased in young adults with Met-S. This is probably the first study reporting TNF-ß levels in Met-S. Since a proinflammatory cascade precedes many years before the onset of cardiovascular disease, these inflammatory biomarkers could help in the monitoring of high-risk individuals with Met-S who will be requiring therapeutic intervention.
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Síndrome Metabólica , Militares , Masculino , Adulto Jovem , Humanos , Interleucina-6 , Linfotoxina-alfa , Biomarcadores , Proteína C-Reativa/metabolismo , Inflamação , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Introduction: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with a better prognosis. But early death (ED) rate remains high. APL patients are simultaneously accompanied by coagulopathy and hyperinflammation at the onset. It is not known what effects cytokines have on ED and coagulopathy in these patients. Therefore, the purposes of this study are to explore the clinical differences between APL and other types of AML, the link between cytokines and coagulopathy in newly diagnosed APL, and their roles in the ED for APL. Methods: This study retrospectively collected the information of 496 adult patients with AML (age ≥14 years at admission) newly diagnosed in the First People's Hospital of Yunnan Province between January 2017 to February 2022, including 115 APL patients. The difference of clinical manifestations between two groups [APL and AML (non-APL)] was statistically analyzed. Then, the factors affecting ED in APL patients were screened, and the possible pathways of their influence on ED were further analyzed. Results: The results indicate APL at the onset have a younger age and higher incidence of ED and DIC than other types of AML. Intracranial hemorrhage (ICH), age, and PLT count are found to be independent factors for ED in newly APL, among which ICH is the main cause of ED, accounting for 61.54% (8/13). The levels of cytokines in newly APL are generally higher than that in AML (non-APL), and those in the group of ED for APL were widely more than the control group. IL-17A and TNF-ß are directly related to the ED in newly APL, especially IL-17A, which also affects ICH in these patients. Moreover, the increase of IL-17A and TNF-ß cause the prolongation of PT in APL patients, which reflected the exogenous coagulation pathway. However, they have no effect on APTT prolongation and FIB reduction. Thus, it is speculated that IL-17A leads to early cerebral hemorrhage death in newly APL by inducing tissue factor (TF) overexpression to initiate exogenous coagulation and further leading to excessive depletion of clotting factors and prolongation of PT. Conclusions: In conclusion, compared with other types of AML, APL patients have a younger age of onset and high inflammatory state, and are more likely to develop into DIC and die early. Age, and PLT count at diagnosis are independent factors for ED of APL, especially ICH. IL-17A is confirmed to be an independent risk factor for ED and ICH of newly APL. Hence, IL-17A may serve as a predictor of ED in newly diagnosed APL patients, and controlling its expression probably reduce ED in these patients.
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Transtornos da Coagulação Sanguínea , Leucemia Mieloide Aguda , Leucemia Promielocítica Aguda , Adulto , Humanos , Adolescente , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/diagnóstico , Interleucina-17 , Citocinas , Estudos Retrospectivos , Linfotoxina-alfa , China/epidemiologia , Leucemia Mieloide Aguda/complicações , Transtornos da Coagulação Sanguínea/complicações , Hemorragia Cerebral/complicaçõesRESUMO
BACKGROUND: Several lines of evidence have suggested that cytokines are implicated in the pathophysiology of depression and antidepressant treatment outcome. However, the results are not always congruent and partly contradictory. We therefore examined the serum levels of multiple cytokines in patients with major depressive disorder (MDD), with the aim to identify serum cytokines-based biomarkers for MDD diagnosis and antidepressant response. METHODS: Fifty-nine patients with MDD and 61 healthy controls were included. The baseline levels of serum cytokines between MDD group and control group were compared, and the discriminative ability of different cytokines in predicting MDD patients from healthy controls was investigated using the receiver operating characteristic (ROC) curve method. The baseline levels of serum cytokines between antidepressant nonresponders and responders were compared, and the discriminative ability of different cytokines in predicting nonresponders from responders was evaluated using the ROC curve method. RESULTS: Compared to controls, 15 of the 37 serum cytokines were increased, while 8 cytokines were decreased in MDD patients (all P < 0.05). The results of ROC curve showed that the Area Under Curve (AUC) values of 15 cytokines including IL-2, IL-5, IL-6, IL-8, IL-12, IL-13, IL-16, CCL3, CCL4, CCL17, CXCL10, TNF-α, TNF-ß, VEGF-C, and FGF basic were greater than 0.7 in discriminating MDD patients from healthy control. Moreover, after 4-week treatment, levels of the 2 cytokines (IL-12 and TSLP) elevated at baseline significantly down-regulated, and levels of the 6 cytokines (IL-5, IL-16, CCL17, CXCL10, TNF-ß, and PIGF) decreased at baseline significantly up-regulated (all P < 0.05). Furthermore, a positive relationship was found between TNF-α levels and Hamilton Depression Rating Scale-24 (HAMD-24) scores in patients with MDD at baseline (r = 0.302, P = 0.019). Additionally, compared to responders, nonresponders exhibited decreased levels of IL-1α, IL-5, IL-13, IL-15, VEGF, and ICAM-1 (all P < 0.05). The ROC curve analysis demonstrated that a combined panel of IL-1α, IL-5, and ICAM-1 achieved a high accuracy in discriminating antidepressant nonresponders from responders (AUC = 0.850, sensitivity = 83.3%, specificity = 81.8%). CONCLUSIONS: These results suggested that alterations in peripheral cytokines levels hold significant promise as biomarkers for MDD diagnosis and antidepressant response.
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Transtorno Depressivo Maior , Humanos , Feminino , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Citocinas , Molécula 1 de Adesão Intercelular , Interleucina-13 , Fator de Necrose Tumoral alfa , Linfotoxina-alfa , Interleucina-16/uso terapêutico , Interleucina-5 , Fator de Crescimento Placentário/uso terapêutico , Antidepressivos/uso terapêutico , Biomarcadores , Interleucina-12RESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide in terms of mortality, and susceptibility is attributed to genetic, lifestyle, and environmental factors. Lymphotoxin alpha (LTA) has a crucial role in communicating the lymphocytes with stromal cells and provoking cytotoxic effects on the cancer cells. There are no reports on the contribution of the LTA (c.179 C>A; p.Thr60Asn; rs1041981) gene polymorphism to HCC susceptibility. The main aim of this study is to investigate the association of LTA (c.179 C>A; p.Thr60Asn; rs1041981) variant with the HCC risk in the Egyptian population. METHODS: This case-control study included 317 participants (111 HCC patients, and 206 healthy controls). The LTA (c.179 C>A; p.Thr60Asn; rs1041981) polymorphism was assessed by tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) technique. RESULTS: The frequencies of the dominant and recessive models (CA + AA; AA) of the LTA (c.179 C>A; p.Thr60Asn; rs1041981) variant were statistically significant among HCC patients in comparison to controls (p = 0.01; p = 0.007; respectively). The A-allele of LTA (c.179 C>A; p.Thr60Asn; rs1041981) variant was statistically significant in HCC patients in comparison to controls (p Ë 0.001). CONCLUSION: The LTA (c.179 C>A; p.Thr60Asn; rs1041981) polymorphism was independently associated with an increased risk for hepatocellular carcinoma in the Egyptian population.