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Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1+effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.
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Atresia Biliar/inmunología , Atresia Biliar/terapia , Hígado/inmunología , Animales , Antígenos CD20/metabolismo , Linfocitos B/inmunología , Atresia Biliar/sangre , Atresia Biliar/tratamiento farmacológico , Biopsia , Receptor 1 de Quimiocinas CX3C/metabolismo , Muerte Celular , Línea Celular , Proliferación Celular , Transdiferenciación Celular , Niño , Preescolar , Estudios de Cohortes , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoglobulina G/metabolismo , Lactante , Inflamación/patología , Células Asesinas Naturales/inmunología , Macrófagos del Hígado/patología , Hígado/patología , Cirrosis Hepática/sangre , Cirrosis Hepática/complicaciones , Cirrosis Hepática/inmunología , Cirrosis Hepática/patología , Depleción Linfocítica , Linfopoyesis , Masculino , Ratones Endogámicos BALB C , Fagocitosis , ARN/metabolismo , Rituximab/administración & dosificación , Rituximab/farmacología , Rituximab/uso terapéutico , Rotavirus/fisiología , Análisis de la Célula Individual , Células TH1/inmunología , Células Th17/inmunologíaRESUMEN
Chondrocyte ferroptosis induces the occurrence of osteoarthritis (OA). As a key gene of OA, C5a receptor 1 (C5AR1) is related to ferroptosis. Here, we investigated whether C5AR1 interferes with chondrocyte ferroptosis during OA occurrence. C5AR1 was downregulated in PA-treated chondrocytes. Overexpression of C5AR1 increased the cell viability and decreased ferroptosis in chondrocytes. Moreover, Tumor necrosis factor superfamily member 13B (TNFSF13B) was downregulated in PA-treated chondrocytes, and knockdown of TNFSF13B eliminated the inhibitory effect of C5AR1 on ferroptosis in chondrocytes. More importantly, the PI3K/Akt/GSK3ß/Nrf2/HO-1 pathway inhibitor LY294002 reversed the inhibition of C5AR1 or TNFSF13B on ferroptosis in chondrocytes. Finally, we found that C5AR1 alleviated joint tissue lesions and ferroptosis in rats and inhibited the progression of OA in the rat OA model constructed by anterior cruciate ligament transection (ACLT), which was reversed by interfering with TNFSF13B. This study shows that C5AR1 reduces the progression of OA by upregulating TNFSF13B to activate the PI3K/Akt/GSK3ß/Nrf2/HO-1 pathway and thereby inhibiting chondrocyte sensitivity to ferroptosis, indicating that C5AR1 may be a potential therapeutic target for ferroptosis-related diseases.
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Condrocitos , Ferroptosis , Glucógeno Sintasa Quinasa 3 beta , Factor 2 Relacionado con NF-E2 , Osteoartritis , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Receptor de Anafilatoxina C5a , Animales , Ferroptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Condrocitos/metabolismo , Condrocitos/patología , Condrocitos/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Ratas , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Masculino , Receptor de Anafilatoxina C5a/metabolismo , Receptor de Anafilatoxina C5a/genética , Transducción de Señal , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Hemo Oxigenasa (Desciclizante)RESUMEN
BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by painful inflamed nodules, abscesses, and pus-draining tunnels appearing in axillary, inguinal, and perianal skin areas. HS lesions contain various types of immigrated immune cells. OBJECTIVE: This study aimed to characterize mediators that support lesional B/plasma cell persistence in HS. METHODS: Skin samples from several cohorts of HS patients and control cohorts were assessed by mRNA sequencing, quantitative PCR on reverse-transcribed RNA, flow cytometry, and immunohistofluorescence. Blood plasma and cultured skin biopsy samples, keratinocytes, dermal fibroblasts, neutrophilic granulocytes (neutrophils), monocytes, and B cells were analyzed. Complex systems biology approaches were used to evaluate bulk and single-cell RNA sequencing data. RESULTS: Proportions of B/plasma cells, neutrophils, CD8+ T cells, and M0 and M1 macrophages were elevated in HS lesions compared to skin of healthy and perilesional intertriginous areas. There was an association between B/plasma cells, neutrophils, and B-cell activating factor (BAFF, aka TNFSF13B). BAFF was abundant in HS lesions, particularly in nodules and abscesses. Among the cell types present in HS lesions, myeloid cells were the main BAFF producers. Mechanistically, granulocyte colony-stimulating factor in the presence of bacterial products was the major stimulus for neutrophils' BAFF secretion. Lesional upregulation of BAFF receptors was attributed to B cells (TNFRSF13C/BAFFR and TNFRSF13B/TACI) and plasma cells (TNFRSF17/BCMA). Characterization of the lesional BAFF pathway revealed molecules involved in migration/adhesion (eg, CXCR4, CD37, CD53, SELL), proliferation/survival (eg, BST2), activation (eg, KLF2, PRKCB), and reactive oxygen species production (eg, NCF1, CYBC1) of B/plasma cells. CONCLUSION: Neutrophil-derived BAFF supports B/plasma cell persistence and function in HS lesions.
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Factor Activador de Células B , Hidradenitis Supurativa , Neutrófilos , Hidradenitis Supurativa/inmunología , Hidradenitis Supurativa/metabolismo , Hidradenitis Supurativa/patología , Humanos , Linfocitos B/patología , Estudios de Casos y Controles , Masculino , Femenino , Adulto , Persona de Mediana Edad , Neutrófilos/metabolismo , Neutrófilos/patología , Factor Activador de Células B/metabolismo , Piel/metabolismo , Piel/patologíaRESUMEN
Glioblastoma (GBM) is the most lethal primary tumor in the human brain and lacks favorable treatment options. Sex differences in the outcome of GBM are broadly acknowledged, but the underlying molecular mechanisms remain largely unknown. To identify the sex-dependent critical genes in the progression of GBM, raw data from several microarray datasets with the same array platform were downloaded from the Gene Expression Omnibus (GEO) database. These datasets included tumorous and normal tissue from patients with GBM and crucial sex features. Then, the differentially expressed genes (DEGs) in female and male tumors were identified via bioinformatics analysis, respectively. Functional signatures of the identified DEGs were further annotated by Gene Ontology (GO) and pathway enrichment analyses. Venn diagram and functional protein-protein interaction (PPI) network analyses were performed to screen out the sex-specific DEGs. Survival analysis of patients with differences in the expression level of selected genes was then carried out using the data from The Cancer Genome Atlas (TCGA). Here, we showed that ECT2, AURKA, TYMS, CDK1, NCAPH, CENPU, OIP5, KIF14, ASPM, FBXO5, SGOL2, CASC5, SHCBP1, FN1, LOX, IGFBP3, CSPG4, and CD44 were enriched in female tumor samples, whereas TNFSF13B, CXCL10, CXCL8, CXCR4, TLR2, CCL2, and FCGR2A were enriched in male tumor samples. Among these key genes, interestingly, ECT2 was associated with increased an survival rate for female patients, whileTNFSF13B could be regarded as a potential marker of poor prognosis in male patients. These results suggested that sex differences in patients may be attributed to the heterogeneous gene activity, which might influence the oncogenesis and the outcomes of GBM.
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Glioblastoma , Transcriptoma , Humanos , Femenino , Masculino , Glioblastoma/patología , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Pronóstico , Proteínas Nucleares/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Adaptadoras de la Señalización Shc/genética , Proteínas Adaptadoras de la Señalización Shc/metabolismoRESUMEN
AIM: The aim of this case-control study was to evaluate the association between the TNFSF13B rs9514828 (-871 C > T) polymorphism and soluble BAFF (sBAFF) in apical periodontitis (AP) patients. METHODOLOGY: Two hundred and sixty one healthy subjects (HS) and 158 patients with AP classified as: 46 acute apical abscess (AAA), 81 primary AP (pAP) and 31 secondary AP (sAP) patients were included. Genomic DNA (gDNA) was extracted from peripheral blood cells according to the salting out method. The TNFSF13B rs9514828 (NC_000013.11:g.108269025C > T) were identified using polymerase chain reaction (PCR) followed by restriction fragment length polymorphisms (RFLP). Serum sBAFF levels were measured by ELISA test. The chi-squared or Fisher's exact test was performed. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the risk of AP associated with the rs9514828. The Mann-Whitney U test and Kruskal-Wallis analysis were used for non-normally distributed data. Differences were considered significant with a p-value <.05. RESULTS: No differences in the genotype/allele frequencies were shown between HS and patients with AAA. However, the TT genotype (OR = 2.68, 95% CI: 1.10-6.53; p = .025) and T allele (OR = 1.46, 95% CI: 1.00-2.12; p = .045) were associated with increased risk of pAP. In contrast, the minor allele T significantly decreased the risk of sAP (OR = 0.49, 95% CI: 0.024-0.99; p = .043). sBAFF serum levels were increased in AAA and pAP compared with HS (p < .01 and p = .021, respectively). The AAA patients had higher sBAFF serum levels than pAP (p = .034) and sAP (p < .01). CONCLUSIONS: These results suggest that the TNFSF13B rs9514828 (-871 C > T) polymorphism is associated with pAP susceptibility and that BAFF is a cytokine that might be involved in acute and chronic AP. The future exploration of the rs9514828 polymorphism in other AP cohorts is recommended.
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Factor Activador de Células B , Periodontitis Periapical , Humanos , Factor Activador de Células B/genética , Estudios de Casos y Controles , Polimorfismo de Nucleótido Simple , Frecuencia de los Genes , Genotipo , Periodontitis Periapical/genética , Polimorfismo de Longitud del Fragmento de Restricción , Interleucina-4/genética , Predisposición Genética a la Enfermedad , AlelosRESUMEN
BACKGROUND: Dysregulation of the B-cell activating factor (BAFF) system is involved in the pathogenesis of systemic lupus erythematosus (SLE). Increased serum concentrations of BAFF are related to lupus nephritis and disease activity among SLE patients. Recently, a variant of the BAFF-encoding gene, BAFF-var, was identified to be associated with autoimmune diseases, in particular SLE, and to promote the production of soluble BAFF. The present study aimed to assess the prevalence of BAFF-var in a cohort of 195 SLE patients and to analyze the association of the BAFF-var genotype (TNSF13B) with various manifestations of SLE. METHODS: A cohort of 195 SLE patients from Central Europe, including 153 patients from the Swiss SLE Cohort Study and 42 patients from the University Hospital Essen, Germany, underwent genotyping for detection of BAFF-var allele. RESULTS: Of the 195 patients, 18 (9.2%) tested positive for BAFF-var variant according to the minor allele frequency of 4.6%. The presence of BAFF-var was associated with the occurrence of lupus nephritis (p = 0.038) (p = 0.03 and p = 0.003). Among various organ manifestations of SLE, the presence of BAFF-var was associated with the occurrence of lupus nephritis (p = 0.038; odds ratio [OR], 2.4; 95% confidence interval [CI], 0.89-6.34) and renal activity markers such as proteinuria and hematuria (p = 0.03; OR, 2.4; 95% CI, 0.9-6.4 for proteinuria; p = 0.003; OR, 3.9; 95% CI, 1.43-10.76 for hematuria). SLE patients carrying the BAFF-var allele exhibited increased disease activity at study entry, as determined by the physician's global assessment (PGA: p = 0.002; OR, 4.8; 95% CI, 1.54-14.93) and the SLE Disease Activity Index (p = 0.012; OR, 3.5; 95% CI, 1.12-11.18). Consistent with that, the percentage of patients treated with immunosuppressive agents at study entry was higher among those carrying the BAFF-var allele than among those tested negative for BAFF-var (p = 0.006; OR, 3.7; 95% CI, 1.27-10.84). CONCLUSIONS: Our results indicate an association between the BAFF-var genotype and increased severity of SLE. Determining the BAFF-var status of SLE patients may improve the risk stratification of patients for whom the development of lupus nephritis is more likely and thus may be helpful in the follow-up care and treatment of SLE patients.
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Alelos , Factor Activador de Células B/genética , Variación Genética , Lupus Eritematoso Sistémico/genética , Nefritis Lúpica/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Factor Activador de Células B/sangre , Intervalos de Confianza , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Técnicas de Genotipaje , Alemania , Hematuria , Humanos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Nefritis Lúpica/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Proteinuria , Suiza , Adulto JovenRESUMEN
Glucocorticoid excess escalates osteoclastic resorption, accelerating bone mass loss and microarchitecture damage, which ramps up osteoporosis development. MicroRNA-29a (miR-29a) regulates osteoblast and chondrocyte function; however, the action of miR-29a to osteoclastic activity in the glucocorticoid-induced osteoporotic bone remains elusive. In this study, we showed that transgenic mice overexpressing an miR-29a precursor driven by phosphoglycerate kinase exhibited a minor response to glucocorticoid-mediated bone mineral density loss, cortical bone porosity and overproduction of serum resorption markers C-teleopeptide of type I collagen and tartrate-resistant acid phosphatase 5b levels. miR-29a overexpression compromised trabecular bone erosion and excessive osteoclast number histopathology in glucocorticoid-treated skeletal tissue. Ex vivo, the glucocorticoid-provoked osteoblast formation and osteoclastogenic markers (NFATc1, MMP9, V-ATPase, carbonic anhydrase II and cathepsin K) along with F-actin ring development and pit formation of primary bone-marrow macrophages were downregulated in miR-29a transgenic mice. Mechanistically, tumor necrosis factor superfamily member 13b (TNFSF13b) participated in the glucocorticoid-induced osteoclast formation. miR-29a decreased the suppressor of cytokine signaling 2 (SOCS2) enrichment in the TNFSF13b promoter and downregulated the cytokine production. In vitro, forced miR-29a expression and SOCS2 knockdown attenuated the glucocorticoid-induced TNFSF13b expression in osteoblasts. miR-29a wards off glucocorticoid-mediated excessive bone resorption by repressing the TNFSF13b modulation of osteoclastic activity. This study sheds new light onto the immune-regulatory actions of miR-29a protection against glucocorticoid-mediated osteoporosis.
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Factor Activador de Células B/metabolismo , Resorción Ósea/genética , MicroARNs/fisiología , Osteogénesis/genética , Animales , Factor Activador de Células B/genética , Hueso Esponjoso/patología , Diferenciación Celular , Inmunohistoquímica , Ratones Transgénicos , MicroARNs/genética , MicroARNs/metabolismo , Osteoclastos/patología , Transducción de SeñalRESUMEN
Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with numerous clinical manifestations. Organ involvement can aggravate patients with SLE and cause comorbidities such as atherosclerosis. Recently, the TNFSF13B gene has been found to be linked with SLE events. This study aimed to analyze the association between single nucleotide polymorphisms of the TNFSF13B rs9514828 with incidence of atherosclerosis and therapeutic outcomes in patients with SLE. Patients and Methods: This case-control study included 84 SLE patients, of whom 21 patients with SLE with atherosclerosis and 63 patients with SLE without atherosclerosis. Using enzyme-linked immunosorbent assay method, interleukin-6 and interferon gamma levels were quantified. The TNFSF13B gene polymorphism was evaluated using polymerase chain reaction followed by sequencing. The lupus low disease activity state (LLDAS) criteria were used to measure the therapeutic outcomes. Statistical analysis was conducted using binary logistic regression. Results: The genetic variations of TNFSF13B rs9514828 were CC = 35, CT = 41, and TT = 8. There was an association between TNFSF13B rs9514828 C>T polymorphism in patients with SLE with and without atherosclerosis (p = 0.03; odds ratio (OR) 4.72, 95% confidence interval [CI] 1.22-18.37). Furthermore, the TNFSF13B rs9514828 C>T polymorphism had association with the therapeutic outcomes of patients with SLE who manifested with LLDAS (p = 0.00; OR 7.58, 95% CI 2.61-21.99). Conclusion: The association of TNFSF13B rs9514828 C>T polymorphism and incidence of atherosclerosis as well as the therapeutic outcomes in patients with SLE indicate the potential utility of the gene variation as screening tool to employ personalized medicine to undertake preventive measures in order to prevent atherosclerosis and to predict a poor prognosis in SLE patient.
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BACKGROUND: Establishment of a reliable prognostic model and identification of novel biomarkers are urgently needed to develop precise therapy strategies for clear cell renal cell carcinoma (ccRCC). Stress response stated T cells (Tstr) are a new T-cell subtype, which are related to poor disease stage and immunotherapy response in various cancers. METHODS: 10 machine-learning algorithms and their combinations were applied in this work. A stable Tstr-related score (TCs) was constructed to predict the outcomes and PD-1 blockade treatment response in ccRCC patients. A nomogram based on TCs for personalized prediction of patient prognosis was constructed. Functional enrichment analysis and TimiGP algorithm were used to explore the underlying role of Tstr in ccRCC. The key TCs-related gene was identified by comprehensive analysis, and the bioinformatics results were verified by immunohistochemistry using a tissue microarray. RESULTS: A robust TCs was constructed and validated in four independent cohorts. TCs accurately predicted the prognosis and PD-1 blockade treatment response in ccRCC patients. The novel nomogram was able to precisely predict the outcomes of ccRCC patients. The underlying biological process of Tstr was related to acute inflammatory response and acute-phase response. Mast cells were identified to be involved in the role of Tstr as a protective factor in ccRCC. TNFS13B was shown to be the key TCs-related gene, which was an independent predictor of unfavorable prognosis. The protein expression analysis of TNFSF13B was consistent with the mRNA analysis results. High expression of TNFSF13B was associated with poor response to PD-1 blockade treatment. CONCLUSIONS: This study provides a Tstr cell-related score for predicting outcomes and PD-1 blockade therapy response in ccRCC. Tstr cells may exert their pro-tumoral role in ccRCC, acting against mast cells, in the acute inflammatory tumor microenvironment. TNFSF13B could serve as a key biomarker related to TCs.
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Carcinoma de Células Renales , Neoplasias Renales , Aprendizaje Automático , Carcinoma de Células Renales/inmunología , Humanos , Neoplasias Renales/inmunología , Pronóstico , Masculino , Femenino , Nomogramas , Biomarcadores de Tumor/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Linfocitos T/inmunologíaAsunto(s)
Factor Activador de Células B/análisis , Receptor del Factor Activador de Células B/análisis , Crisis Blástica/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Enfermedad Aguda , Factor Activador de Células B/metabolismo , Receptor del Factor Activador de Células B/metabolismo , Niño , Femenino , Humanos , Masculino , RecurrenciaRESUMEN
OBJECTIVE: B-cell activating factor (BAFF) is a key regulator of primary Sjögren's syndrome (pSS), which is characterized by B-lymphocyte hyperactivity. BAFF, also known as tumor necrosis factor ligand superfamily member 13B, is encoded by TNFSF13B. This study aimed to explore the possible relationships between five single-nucleotide polymorphisms (SNPs) of TNFSF13B (rs9514827, rs1041569, rs9514828, rs1224141, and rs12583006) and pSS susceptibility. METHODS: We searched the following databases for articles on TNFSF13B polymorphism and pSS published up to January 2023: PubMed, Cochrane, Elsevier, Web of Science, CNKI, CQVIP, and WanFang. The odds ratios (with 95% confidence intervals) of genotypes and SNP alleles of TNFSF13B were investigated in patients with pSS to determine their relationships with pSS. RESULTS: This meta-analysis employing the fixed-effect model comprised three studies of pSS patients and randomly selected healthy controls (HCs), revealing statistically significant relationships between pSS susceptibility and two SNPs: rs1041569 and rs12583006. Because rs1041569 was not in Hardy-Weinberg equilibrium in the HC group, it was eliminated from the analysis. CONCLUSIONS: Polymorphisms in the BAFF (TNFSF13B) gene were related to vulnerability to pSS among pSS patients and HCs alike. The SNP rs12583006 was significantly related to pSS susceptibility in pSS patients.
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Factor Activador de Células B , Síndrome de Sjögren , Humanos , Factor Activador de Células B/genética , Síndrome de Sjögren/genética , Genotipo , Polimorfismo de Nucleótido Simple , AlelosRESUMEN
Accumulating evidence shows HOOK1 disordered in human malignancies. However, the clinicopathological and biological significance of HOOK1 in renal cell carcinoma (RCC) remains rarely studied. In this study, the authors demonstrate that HOOK1 is downregulated in RCC samples with predicted poorer clinical prognosis. Mechanistically, HOOK1 inhibits tumor growth and metastasis via canonical TGF-ß/ALK5/p-Smad3 and non-canonical TGF-ß/MEK/ERK/c-Myc pathway. At the same time, HOOK1 inhibits RCC angiogenesis and sunitinib resistance by promoting degradation of TNFSF13B through the ubiquitin-proteasome pathway. In addition, HOOK1 is transcriptionally regulated by nuclear factor E2F3 in VHL dependent manner. Notably, an agonist of HOOK1, meletin, is screened and it shows antitumor activity more effectively when combined with sunitinib or nivolumab than it is used alone. The findings reveal a pivotal role of HOOK1 in anti-cancer treatment, and identify a novel therapeutic strategy for renal cell carcinoma.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Factor A de Crecimiento Endotelial Vascular , Sunitinib , Factor de Crecimiento Transformador beta , Neoplasias Renales/tratamiento farmacológico , Factor Activador de Células B/uso terapéuticoRESUMEN
BACKGROUND: The increased expression of B cell-activating factor (BAFF) has been linked to autoantibody production in autoimmune diseases (ADs). The aim of this study was to investigate the association among TNFSF13B gene (OMIM: 603969) single nucleotide polymorphisms (SNPs), TNFSF13B mRNA, and soluble BAFF (sBAFF) expression in patients with rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS). The diagnostic value of sBAFF also was evaluated by the area under the curve (AUC) of receiver operating characteristic or receptor (ROC) curves. METHODS: Genotypes of the TNFSF13B rs9514827 (-2841 T > C), rs1041569 (-2701 A > T) and rs9514828 (-871 C > T) SNPs were determined by PCR-RFLP assay. TNFSF13B mRNA and sBAFF expression were performed by RT-qPCR and ELISA, respectively. The study included 320 RA patients, 101 pSS patients, and 309 healthy subjects (HS). RESULTS: The rs9514828 T allele and the TAT haplotype were associated with an increased risk to develop RA. In both ADs, the TNFSF13B mRNA levels were increased in comparison with HS. The rs9514828 (-871 C > T) polymorphism was associated with increased gene expression in RA patients. Also, sBAFF levels were higher in both ADs, however pSS patients showed the highest sBAFF levels. sBAFF showed higher diagnostic performance for pSS with an AUC of 0.968, with a similar accuracy of anti-SSA/Ro antibody diagnosis (AUC = 0.974). CONCLUSIONS: Our findings demonstrate that the TNFSF13B rs9514828 (-871 C > T) polymorphism is a risk factor for RA in the western Mexican population. sBAFF levels may be a potential diagnosis biomarker in pSS.
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Artritis Reumatoide , Síndrome de Sjögren , Artritis Reumatoide/genética , Factor Activador de Células B/genética , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , ARN Mensajero/genética , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/genéticaRESUMEN
Multiple myeloma (MM) is a lethal hematological malignancy characterized by abundant myeloid cells in the microenvironment that fuel tumor progression. But the mechanism by which myeloid cells support myeloma cells has not been fully explored. We aimed to examine their effect on bone marrow cells of MM patients by scRNA-seq transcriptome analysis and reveal a high-resolution gene profile of myeloma cells and myeloma-associated myeloid cells. Based on correlation analysis of integrated scRNA-seq and bulk RNA-seq datasets from patients, we confirmed that myeloid-derived S100A9 was involved in TNFSF13B-dependent myeloma cell proliferation and survival. In the animal experiments, S100A9 was found to be critical for MM cell proliferation and survival via TNFSF13B production by myeloid cells, neutrophils, and macrophages. In-vitro analysis of patient primary myeloma cells further demonstrated that enhanced TNFSF13B signaling triggered the canonical NF-κB pathway to boost tumor cell proliferation. All these results suggest that myeloid-derived S100A9 is required for TNFSF13B/TNFRSF13B-dependent cell-fate specification, which provides fresh insights into MM progression.
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Growing evidence suggests that the tumor microenvironment (TME) plays crucial roles in tumor progression and treatment efficacy in clear cell renal cell carcinoma (ccRCC), which typically has a poor prognosis due to high relapse and metastasis rates. We comprehensively analyzed ccRCC RNA-sequencing data from The Cancer Genome Atlas (TCGA) database to identify candidate prognostic TME-related genes involved in ccRCC. We used the ESTIMATE and CIBERSORT algorithms to estimate the proportions of immune cells, stromal cells, and tumor-infiltrating immune cells (TICs) in the TME in ccRCC samples from 539 patients. By examining the intersection of the differentially expressed genes (DEGs) obtained by Cox regression analysis and protein-protein interaction network, we identified five overlapping DEGs (IGLL5, MZB1, HSD11B1, TNFSF13B, and PPARGC1A). Further analysis revealed that TNFSF13B expression was elevated in ccRCC tumor tissues and negatively associated with overall survival. PPARGC1A expression exhibited the opposite patterns. Immunohistochemical analysis of 35 paired ccRCC and adjacent normal tissues confirmed the in-silico results. Gene set enrichment analysis revealed that genes in the groups with high TNFSF13B and PPARGC1A expression were enriched mainly in immune-related activities. In the group with low PPARGC1A expression, genes were enriched in metabolic pathways. CIBERSORT analysis of TIC proportions revealed that Tregs and CD8 T-cell abundance correlated positively with TNFSF13B expression, but negatively with PPARGC1A expression. These findings demonstrate that TNFSF13B and PPARGC1A are prognostic predictors and possible therapeutic targets in ccRCC.
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Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe are disorders with amyotrophic lateral sclerosis-like features, usually with recessive inheritance. We aimed to identify causative mutations in 10 probands. Neurological examinations, genetic analysis, audiometry, magnetic resonance imaging, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in 7 probands. More importantly, only 1 mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in 3 probands. Two of the genes, WDFY4 and TNFSF13B, have immune-related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time. Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and amyotrophic lateral sclerosis.
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Factor Activador de Células B/genética , Parálisis Bulbar Progresiva/genética , Estudios de Asociación Genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de Transporte de Membrana/genética , Mutación , Esclerosis Amiotrófica Lateral/genética , Audiometría , Parálisis Bulbar Progresiva/diagnóstico , Parálisis Bulbar Progresiva/patología , Femenino , Pruebas Genéticas , Humanos , Pruebas Inmunológicas , Imagen por Resonancia Magnética , Masculino , Músculos/patología , Examen NeurológicoRESUMEN
BACKGROUND: Adrenocortical carcinoma (ACC) is an extremely rare malignant tumor with poor prognosis. Existing treatment options have limited effects, and new therapeutic targets urgently need to be discovered. TNFSF13B has been reported to be associated with the prognosis of clear cell renal cell carcinoma, but it has not been studied in ACC. METHODS: TNFSF13B expression was analyzed and compared between ACC tumors and normal tissues by using public datasets from TCGA and GTEx. Kaplan-Meier analysis was employed to evaluate survival, and Cox regression was employed to evaluate clinicopathologic features. The upstream and downstream regulatory mechanisms of TNFSF13B were also analyzed. GSEA was performed to explore the mechanisms of TNFSF13B in ACC. Finally, 14 ACC clinical samples were used to verify the relationships between TNFSF13B expression and disease-free survival (DFS) and overall survival (OS). RESULTS: TNFSF13B expression was significantly higher in ACC tissues than in normal tissues. The prognosis of ACC patients with high TNFSF13B expression was worse than that of patients with low TNFSF13B expression. High TNFSF13B expression was strongly correlated with poor prognosis, and TNFSF13B was a prognostic factor. TNFSF13B expression is modified by upstream miRNAs, methylation and ubiquitination, and downstream, it interacts with other proteins. GSEA showed that regulation of cholesterol biosynthesis by SREBP and SREBF, downstream signaling events of the B cell receptor (BCR) and activation of gene expression by SREBF and SREBP were significantly enriched in the TNFSF13B high-expression phenotype. Clinical samples confirmed that TNFSF13B expression was significantly associated with DFS but not with OS. CONCLUSIONS: TNFSF13B may be a potential prognostic molecular marker of poor survival in ACC patients, offering a new therapeutic target.
RESUMEN
Bronchiolitis associated with the respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants aged < 1 year. The main objective of this work was to assess the nasal and fecal microbiota and immune profiles in infants with RSV bronchiolitis, and to compare them with those of healthy infants. For this purpose, a total of 58 infants with RSV-positive bronchiolitis and 17 healthy infants (aged < 18 months) were recruited in this case-control study, which was approved by the Ethics Committee of the Hospital Gregorio Marañón. Nasal and fecal samples were obtained and submitted to bacterial microbiota analysis by 16S rDNA sequencing and to analysis of several immune factors related to inflammatory processes. Nasal samples in which Haemophilus and/or Moraxella accounted for > 20% of the total sequences were exclusively detected among infants of the bronchiolitis group. In this group, the relative abundances of Staphylococcus and Corynebacterium were significantly lower than in nasal samples from the control group while the opposite was observed for those of Haemophilus and Mannheimia. Fecal bacterial microbiota of infants with bronchiolitis was similar to that of healthy infants. Significant differences were obtained between bronchiolitis and control groups for both the frequency of detection and concentration of BAFF/TNFSF13B and sTNF.R1 in nasal samples. The concentration of BAFF/TNFSF13B was also significantly higher in fecal samples from the bronchiolitis group. In conclusion, signatures of RSV-associated bronchiolitis have been found in this study, including dominance of Haemophilus and a high concentration of BAFF/TNFSF13B, IL-8 and sTNF.R1 in nasal samples, and a high fecal concentration of BAFF/TNFSF13B.
RESUMEN
Human B cell activating factor (TNFSF13B, BAFF) is a tumor necrosis factor superfamily member. Binding its unique receptor (TNFRSF13C, BAFF-R) mediates gene expression and cell survival in B cells via activation of NFκB pathway. Furthermore, there is data indicating a role in T cell function. A functionally inhibitory isoform (ΔBAFF) resulting from the deletion of exon 3 in the TNFSF13B pre-RNA has already been reported. However, data on the complexity of post-transcriptional regulation is scarce. Here, we report molecular cloning of nine TNFSF13B transcript variants resulting from alternative splicing of the TNFSF13B pre-mRNA including BAFFX1. This variant is characterized by a partial retention of intron 3 of the TNFSF13B gene causing the appearance of a premature stop codon. We demonstrate the expression of the corresponding BAFFX1 protein in Jurkat T cells, in ex vivo human immune cells and in human tonsillar tissue. Thereby we contribute to the understanding of TNFSF13B gene regulation and reveal that BAFF is regulated through a post-transcriptional mechanism to a greater extent than reported to date.
Asunto(s)
Factor Activador de Células B/genética , Factor Activador de Células B/inmunología , Empalme Alternativo/genética , Factor Activador de Células B/metabolismo , Linfocitos B/metabolismo , Exones , Expresión Génica , Humanos , FN-kappa B/metabolismo , Isoformas de Proteínas/genética , Precursores del ARN/metabolismo , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Tumor necrosis factor (TNF) superfamily consists of 19 ligands and 29 receptors and is related to multiple cellular events from proliferation and differentiation to apoptosis and tumor reduction. In this review, we overview the whole system, and we focus on A proliferation-inducing ligand (APRIL, TNFSF13) and B cell-activating factor (BAFF, TNFSF13B) and their receptors transmembrane activator and Ca2+ modulator (CAML) interactor (TACI, TNFRSF13B), B cell maturation antigen (BCMA, TNFRSF17), and BAFF receptor (BAFFR, TNFRSF13C). We explore their role in cancer and novel biological therapies introduced for multiple myeloma and further focus on breast cancer, in which the modulation of this system seems to be of potential interest, as a novel therapeutic target. Finally, we discuss some precautions which should be taken into consideration, while targeting the APRIL-BAFF system.