RESUMEN
BACKGROUND: Immune thrombocytopenia (ITP) is a prevalent autoimmune bleeding disorder, with the primary objective of treatment being the prevention of bleeding. Clinical investigations have indicated that individuals with ITP face an elevated risk of thrombosis, and the occurrence of thromboembolic events in ITP patients can be attributed to a multitude of factors. However, establishing a definitive causal relationship between ITP and thrombosis remains challenging. METHODS: A two-sample Mendelian randomization (MR) study utilizing summary data from FinnGen consortium and UK Biobank was undertaken to investigate the causal association between ITP and thrombosis. The primary analysis employed the inverse-variance weighted (IVW) method, while supplementary analyses were conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. RESULTS: Based on IVW method, there was a statistically significant but small positive correlation between ITP and thrombosis. Specifically, ITP patients exhibited a suggestive positive correlation with myocardial infarction and deep-vein thrombosis. However, our investigation did not identify any causal relationship between ITP and cerebral infarction, arterial embolism, other arterial embolisms, pulmonary embolism, thrombophlebitis, or portal vein thrombosis. Sensitivity analyses further confirmed the accuracy and robustness of these findings. CONCLUSIONS: This study presents empirical support for the causal relationship between ITP and thrombosis. It is important to note that a diminished platelet count does not serve as a preventive measure against thrombus formation. Consequently, when managing a newly diagnosed ITP patient, clinicians need to be aware that there is a slight elevation in the risk of thrombosis during treatment.
Asunto(s)
Análisis de la Aleatorización Mendeliana , Púrpura Trombocitopénica Idiopática , Trombosis , Humanos , Púrpura Trombocitopénica Idiopática/epidemiología , Púrpura Trombocitopénica Idiopática/complicaciones , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/sangre , Trombosis/epidemiología , Trombosis/etiología , Trombosis/diagnóstico , Trombosis/genética , Factores de RiesgoRESUMEN
BACKGROUND: Immune thrombocytopenia (ITP) and Evans syndrome (ES) are manifestations of immune dysregulation. Genetic variants in immune-related genes have been identified in patients with ITP and especially ES. We aimed to explore familial autoimmunity in patients with ITP and ES to understand possible contributions to chronicity. PROCEDURE: We assessed family history in two ways: via patient report for ITP and ES and by population-based analysis using the Utah Population Database (UPDB) for ITP. A total of 266 patients with ITP and 21 patients with ES were identified via chart review, and 252 of the 266 patients with ITP were also identified in the UPDB. RESULTS: Chart review showed familial autoimmunity in 29/182 (15.9%) and 25/84 (29.8%) of patients with newly diagnosed+persistent (nd+p) ITP and chronic ITP (cITP), respectively, (p = .009). The UPDB analysis revealed that autoimmunity in relatives of patients with nd+pITP was higher than in relatives of controls (odds ratio [OR]: 1.69 [1.19-2.41], p = .004), but was not significantly increased in relatives of patients with cITP (OR 1.10 [0.63-1.92], p = .734). Incomplete family history in medical records likely contributed to the observed discrepancy. CONCLUSIONS: The findings suggest that familial autoimmunity may have a stronger association with the development of ITP rather than its duration. Twelve (57.1%) patients with ES reported autoimmunity in their relatives. UPDB analysis was omitted due to the small number of patients with ES. The use of population databases offers a unique opportunity to assess familial health and may provide clues about contributors to immune dysregulation features within families.
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Anemia Hemolítica Autoinmune , Autoinmunidad , Púrpura Trombocitopénica Idiopática , Trombocitopenia , Humanos , Anemia Hemolítica Autoinmune/inmunología , Anemia Hemolítica Autoinmune/epidemiología , Anemia Hemolítica Autoinmune/genética , Femenino , Masculino , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/epidemiología , Niño , Preescolar , Trombocitopenia/inmunología , Trombocitopenia/genética , Adolescente , Lactante , Adulto , Adulto Joven , Factores de Riesgo , Persona de Mediana EdadRESUMEN
BACKGROUND: Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by a breakdown of immune tolerance; in ITP, the body's immune system mistakenly attacks and destroys platelets. This study aims to investigate the role and underlying mechanisms of FOXP3 in chronic ITP. METHODS: Flow cytometry was used to detect the proportion of CD4+CD25+FOXP3+ regulatory T cells (Tregs) in CD4+CD25+ T lymphocytes from 20 patients with chronic ITP (CITP), 20 acute ITP (AITP) controls, and 20 healthy individuals.CD4+CD25+ Treg cells were isolated from peripheral blood of patients with CITP using magnetic beads and then treated with phosphate-buffered saline solution or decitabine (a methylation inhibitor) for 48 h. The levels of interleukin-2 (IL-2), IL-10, and transforming growth factor-beta1 (TGF-ß1) in the plasma and CD4+CD25+ Treg cells were assessed by Enzyme-linked-immunosorbent serologic assay and quantitative real-time polymerase chain reaction (qRT-PCR). FOXP3 level was measured by qRT-PCR and Western blot analysis. Methylation-specific PCR (MS-PCR) was adopted to detect the status of FOXP3 methylation. RESULTS: The number of Treg cells and the contents of IL-2, IL-10, and TGF-ß1 decreased in patients with CITP, compared to the AITP control group and normal group. FOXP3 expression was reduced and FOXP3 methylation increased in patients with CITP, compared to the AITP control group and normal group. Hypermethylation of FOXP3 promoter led to decrease in FOXP3 level in Treg cells. Inhibition of FOXP3 promoter hypermethylation promoted the secretion of IL-2, IL-10, and TGF-ß1 in Treg cells. CONCLUSION: The number of Treg cells in CITP patients decreased, and the hypermethylation of FOXP3 promoter led to reduction of its expression in Treg cells, thus affecting the immune functioning of Treg cells.
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Metilación de ADN , Factores de Transcripción Forkhead , Púrpura Trombocitopénica Idiopática , Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , Enfermedad Crónica , Interleucina-2 , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/sangre , Adulto Joven , Decitabina/farmacología , Células Cultivadas , Interleucina-10/genética , Interleucina-10/metabolismo , AncianoRESUMEN
Immune thrombocytopenia (ITP) is an autoimmune disease caused by T-cell dysfunction. Recently, several studies have shown that a disturbed Th17/Treg balance contributes to the development of ITP. MicroRNAs (miRNAs) are small noncoding RNA moleculesthat posttranscriptionally regulate gene expression. Emerging evidences have demonstrated that miRNAs play an important role in regulating the Th17/Treg balance. In the present study, we found that miR-641 was upregulated in ITP patients. In primary T cells, overexpression of miR-641 could cause downregulation of its target genes STIM1 and SATB1, thus inducing a Th17 (upregulated)/Treg (downregulated) imbalance. Inhibition of miR-641 by a miR-641 sponge in primary T cells of ITP patients or by antagomiR-641 in an ITP murine model could cause upregulation of STIM1 and SATB1, thus restoring Th17/Treg homeostasis. These results suggested that the miR-641-STIM/SATB1 axis plays an important role in regulating the Th17/Treg balance in ITP.
Asunto(s)
Proteínas de Unión a la Región de Fijación a la Matriz , MicroARNs , Púrpura Trombocitopénica Idiopática , Molécula de Interacción Estromal 1 , Linfocitos T Reguladores , Células Th17 , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/metabolismo , Molécula de Interacción Estromal 1/genética , Molécula de Interacción Estromal 1/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
BACKGROUND: Chronic Granulomatous Disease (CGD) is a rare immunodeficiency disorder characterized by impaired phagocytic function, leading to recurrent infections and granuloma formation. Genetic mutations in NADPH oxidase complex components, such as CYBB, NCF1, NCF2, and CYBA genes, contribute to the pathogenesis. This case report explores the possible ocular and hematologic complications associated with CGD. CASE PRESENTATION: A 6-year-old girl with a history of vitrectomy, membranotomy, and laser therapy due to congenital blindness (diagnosed with chorioretinopathy) was referred to the hospital with generalized ecchymosis and thrombocytopenia. Diagnostic workup initially suggested chronic immune thrombocytopenic purpura (ITP). Subsequent admissions revealed necrotic wounds, urinary tract infections, and recurrent thrombocytopenia. Suspecting immunodeficiency, tests for CGD, Nitroblue tetrazolium (NBT) and dihydrorhodamine (DHR) were performed. She had a low DHR (6.7), and her NBT test was negative (0.0%). Her whole exome sequencing results confirmed autosomal recessive CGD with a homozygous NCF1 mutation. CONCLUSION: This case underscores the diverse clinical manifestations of CGD, including recurrent thrombocytopenia and possible early-onset ocular involvement. The diagnostic challenges highlight the importance of a multidisciplinary approach involving hematologists, immunologists, and ophthalmologists for accurate diagnosis and management. The rare coexistence of ITP in CGD emphasizes the intricate link between immunodeficiency and autoimmunity, requiring tailored therapeutic strategies.
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Enfermedad Granulomatosa Crónica , Púrpura Trombocitopénica Idiopática , Humanos , Femenino , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/complicaciones , Niño , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/complicaciones , NADPH Oxidasas/genética , Mutación , Secuenciación del ExomaRESUMEN
Immune thrombocytopenia (ITP) is a highly heterogeneous autoimmune bleeding disorder characterized by low platelet counts due to an immune-mediated platelet destruction and impaired platelet production. The pathophysiology is multifactorial and remains to be fully unravelled. Consequently, disease trajectories and responses to therapeutics, despite the availability of multiple agents, can be unpredictable and differing between patients. There is an urgent need for the identification of diagnostic and therapeutic biomarkers, but this has proven to be challenging to achieve. To shed light on this, two studies in this issue of the British Journal of Haematology have recognized the opportunity of using high-throughput Omics technologies in ITP. Sun et al. performed proteomics, and Li et al. metabolomics, on bone marrow biopsy samples of patients with ITP. This was conducted using mass spectrometry and, due to the generation of large datasets, in combination with machine learning. These studies set the stage for further investigations exploring the high potential of multi-omics technologies in order to shed light on the heterogeneity in ITP, accelerating the path towards a much needed personalized medicine approach. Commentary on: Li et al. Metabolomics profile and machine learning prediction of treatment responses in immune thrombocytopenia: A prospective cohort study. Br J Haematol 2024;204:2405-2417. Commentary on: Sun et al. Proteomics landscape and machine learning prediction of long-term response to splenectomy in primary immune thrombocytopenia. Br J Haematol 2024;204:2418-2428.
Asunto(s)
Metabolómica , Proteómica , Púrpura Trombocitopénica Idiopática , Humanos , Púrpura Trombocitopénica Idiopática/terapia , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/sangre , Proteómica/métodos , Metabolómica/métodos , Biomarcadores , Aprendizaje AutomáticoRESUMEN
Immune thrombocytopenia (ITP), an acquired autoimmune disease, is characterized by immune-mediated platelet destruction. A biomarker is a biological entity that contributes to disease pathogenesis and reflects disease activity. Metabolic alterations are reported to be associated with the occurrence of various diseases. As metabolic biomarkers for ITP have not been identified. This study aimed to identify metabolism-related differentially expressed genes as potential biomarkers for pathogenesis of ITP using bioinformatic analyses.The microarray expression data of the peripheral blood mononuclear cells were downloaded from the Gene Expression Omnibus database (GSE112278 download link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112278 ). Key module genes were intersected with metabolism-related genes to obtain the metabolism-related key candidate genes. The hub genes were screened based on the degree function in the coytoscape sofware. The key ITP-related genes were subjected to functional enrichment analysis. Immune infiltration analysis was performed using a single-sample gene set enrichment analysis algorithm to evaluate the differential infiltration levels of immune cell types between ITP patient and control. Molecular subtypes were identified based on the expression of hub genes. The expression of hub genes in the ITP patients was validated using quantitative real-time polymerase chain reaction analysis. This study identified five hub genes (ADH4, CYP7A1, CYP1A2, CYP8B1, and NR1H4), which were be associated with the pathogenesis of ITP, and two molecular subtypes of ITP. Among these hub genes, CYP7A1 and CYP8B1 involved in cholesterol metabolism,were further verified in clinical samples.
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Púrpura Trombocitopénica Idiopática , Trombocitopenia , Humanos , Púrpura Trombocitopénica Idiopática/genética , Leucocitos Mononucleares , Esteroide 12-alfa-Hidroxilasa , Biomarcadores , Biología ComputacionalRESUMEN
Gut microbiota have been linked to immune thrombocytopenia (ITP) and Henoch-Schönlein purpura (HSP) in recent studies, but a cause-and-effect relationship is unclear. We used Mendelian randomization (MR) to assess causal relationships between gut microbiota and HSP/ITP using summary statistics from the GWAS dataset of the international MiBioGen and FinnGen consortium. The IVW method was used as the main evaluation indicator. MR analysis of 196 intestinal flora and HSP/ITP/sTP phenotypes showed that 12 flora were potentially causally associated with ITP, 6 with HSP, and 9 with sTP. The genes predicted that genus Coprococcus3 (p = 0.0264, OR = 2.05, 95% CI 1.09-3.88)and genus Gordonibacter (p = 0.0073, OR = 1.38; 95% CI 1.09-1.75) were linked to a higher likelihood of developing ITP. Additionally, family Actinomycetaceae (p = 0.02, OR = 0.51, 95% CI 0.28-0.90) and order Actinomycetales (p = 0.0199, OR = 0.50, 95% CI 0.28-0.90) linked to reduced HSP risk. Genus Ruminococcaceae UCG013 (p = 0.0426, OR = 0.44, 95% CI 0.20-0.97) negatively correlated with sTP risk. Our MR analyses offer evidence of a possible cause-and-effect connection between certain gut microbiota species and the likelihood of HSP/ITP.
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Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Vasculitis por IgA , Análisis de la Aleatorización Mendeliana , Púrpura Trombocitopénica Idiopática , Humanos , Vasculitis por IgA/genética , Vasculitis por IgA/microbiología , Microbioma Gastrointestinal/genética , Púrpura Trombocitopénica Idiopática/microbiología , Púrpura Trombocitopénica Idiopática/genéticaRESUMEN
Primary immune thrombocytopenia (ITP) is linked to specific pathogenic mechanisms, yet its relationship with mitophagy and ferroptosis is poorly understood. This study aimed to identify new biomarkers and explore the role of mitophagy and ferroptosis in ITP pathogenesis. Techniques such as differential analysis, Mfuzz expression pattern clustering, machine learning, gene set enrichment analysis, single-cell RNA sequencing (scRNA-seq) and immune infiltration analysis were employed to investigate the molecular pathways of pivotal genes. Two-sample Mendelian randomization (TSMR) assessed the causal effects in ITP. Key genes identified in the training set included GABARAPL1, S100A8, LIN28A, and GDF9, which demonstrated diagnostic potential in validation sets. Functional analysis indicated these genes' involvement in ubiquitin phosphorylation, PPAR signalling pathway and T-cell differentiation. Immune infiltration analysis revealed increased macrophage presence in ITP, related to the critical genes. scRNA-seq indicated reduced GABARAPL1 expression in ITP bone marrow macrophages. TSMR linked S100A8 with ITP diagnosis, presenting an OR of 0.856 (95% CI = 0.736-0.997, p = 0.045). The study pinpointed four central genes, GABARAPL1, S100A8, LIN28A, and GDF9, tied to mitophagy and ferroptosis in ITP. It posits that diminished GABARAPL1 expression may disrupts ubiquitin phosphorylation and PPAR signalling, impairing mitophagy and inhibiting ferroptosis, leading to immune imbalance.
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Ferroptosis , Mitofagia , Púrpura Trombocitopénica Idiopática , Humanos , Ferroptosis/genética , Púrpura Trombocitopénica Idiopática/genética , Masculino , Femenino , Biomarcadores , Persona de Mediana EdadRESUMEN
Immune thrombocytopenia (ITP) is an autoimmune-mediated hemorrhagic disease. Emerging evidence indicates that FOXO1 SNPs are related to the immune dysregulation of several autoimmune diseases suggesting that FOXO1 may be involved in inflammation and pathologic activities in patients with ITP. This study aimed to evaluate whether FOXO1 gene single-nucleotide polymorphisms (SNPs) are associated with susceptibility to ITP and clinical priorities of concern include bleeding severity and sensitivity of glucocorticoid treatment. This study recruited 327 newly diagnosed ITP and 220 healthy controls. Four SNPs (rs17446593, rs17446614, rs2721068, and rs2721068) of the FOXO1 gene were detected using the Sequenom MassArray system. Bleeding severity were classified into the mild and severe groups based on the bleeding scores. ITP patients were classified as sensitive and insensitive to glucocorticoid treatment according to the practice guideline for ITP (2019 version). The frequencies of the four SNPs did not show any significant differences between the ITP and healthy control groups. Patients with AA genotype at rs17446593 (p = 0.009) and GG genotype at rs17446614 (p = 0.009) suffered more severe bleeding than patients without them. Carriers of haplotype Grs17446593Ars17446614Crs2721068Trs2755213 were protective to severe bleeding (p = 0.002). The AA genotype at rs17446593 was significantly higher in ITP patients sensitive to glucocorticoid treatment than in those insensitive to glucocorticoid treatment (p = 0.03). Haplotype Grs17446593Grs17446614Trs2721068Trs2755213 increases the risk of glucocorticoid resistance (p = 0.007). Although FOXO1 gene polymorphisms were not associated with susceptibility to ITP, the AA genotype at rs17446593 and GG genotype at rs17446614 were associated with bleeding severity. Haplotype GACT have a protective effect against severe bleeding. Patients with AA genotype at rs17446593 may tend to have good responds to glucocorticoid treatment. However, the FOXO1 gene haplotype GGTT increases the risk of glucocorticoid-resistant. Trial registration: ChiCTR1900022419.
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Proteína Forkhead Box O1 , Glucocorticoides , Hemorragia , Polimorfismo de Nucleótido Simple , Púrpura Trombocitopénica Idiopática , Humanos , Glucocorticoides/uso terapéutico , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Masculino , Femenino , Niño , Proteína Forkhead Box O1/genética , Preescolar , Hemorragia/genética , Haplotipos , Predisposición Genética a la Enfermedad , Estudios de Casos y Controles , Adolescente , Lactante , Índice de Severidad de la Enfermedad , GenotipoAsunto(s)
Cara , Enfermedades Hematológicas , Mutación , Púrpura Trombocitopénica Idiopática , Tiroiditis Autoinmune , Enfermedades Vestibulares , Humanos , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/complicaciones , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/complicaciones , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/complicaciones , Cara/anomalías , Cara/patología , Tiroiditis Autoinmune/complicaciones , Tiroiditis Autoinmune/genética , Femenino , Anomalías Múltiples/genética , MasculinoRESUMEN
Kabuki syndrome (KS) is now listed in the Human Inborn Errors of Immunity (IEI) Classification. It is a rare disease caused by KMT2D and KDM6A variants, dominated by intellectual disability and characteristic facial features. Recurrently, pathogenic variants are identified in those genes in patients examined for autoimmune cytopenia (AIC), but interpretation remains challenging. This study aims to describe the genetic diagnosis and the clinical management of patients with paediatric-onset AIC and KS. Among 11 patients with AIC and KS, all had chronic immune thrombocytopenic purpura, and seven had Evans syndrome. All had other associated immunopathological manifestations, mainly symptomatic hypogammaglobinaemia. They had a median of 8 (5-10) KS-associated manifestations. Pathogenic variants were detected in KMT2D gene without clustering, during the immunological work-up of AIC in three cases, and the clinical strategy to validate them is emphasized. Eight patients received second-line treatments, mainly rituximab and mycophenolate mofetil. With a median follow-up of 17 (2-31) years, 8/10 alive patients still needed treatment for AIC. First-line paediatricians should be able to recognize and confirm KS in children with ITP or multiple AIC, to provide early appropriate clinical management and specific long-term follow-up. The epigenetic immune dysregulation in KS opens exciting new perspectives.
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Anomalías Múltiples , Proteínas de Unión al ADN , Cara , Enfermedades Hematológicas , Histona Demetilasas , Proteínas de Neoplasias , Enfermedades Vestibulares , Humanos , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/diagnóstico , Niño , Cara/anomalías , Femenino , Masculino , Preescolar , Anomalías Múltiples/genética , Adolescente , Histona Demetilasas/genética , Proteínas de Neoplasias/genética , Enfermedades Hematológicas/genética , Proteínas de Unión al ADN/genética , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/terapia , Púrpura Trombocitopénica Idiopática/diagnóstico , Lactante , Trombocitopenia/genética , Trombocitopenia/diagnóstico , Trombocitopenia/etiología , Trombocitopenia/terapia , Anemia Hemolítica Autoinmune/genética , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/terapia , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/diagnóstico , Rituximab/uso terapéutico , Mutación , CitopeniaRESUMEN
This study aimed to identify key proteomic analytes correlated with response to splenectomy in primary immune thrombocytopenia (ITP). Thirty-four patients were retrospectively collected in the training cohort and 26 were prospectively enrolled as validation cohort. Bone marrow biopsy samples of all participants were collected prior to the splenectomy. A total of 12 modules of proteins were identified by weighted gene co-expression network analysis (WGCNA) method in the developed cohort. The tan module positively correlated with megakaryocyte counts before splenectomy (r = 0.38, p = 0.027), and time to peak platelet level after splenectomy (r = 0.47, p = 0.005). The blue module significantly correlated with response to splenectomy (r = 0.37, p = 0.0031). KEGG pathways analysis found that the PI3K-Akt signalling pathway was predominantly enriched in the tan module, while ribosomal and spliceosome pathways were enriched in the blue module. Machine learning algorithm identified the optimal combination of biomarkers from the blue module in the training cohort, and importantly, cofilin-1 (CFL1) was independently confirmed in the validation cohort. The C-index of CFL1 was >0.7 in both cohorts. Our results highlight the use of bone marrow proteomics analysis for deriving key analytes that predict the response to splenectomy, warranting further exploration of plasma proteomics in this patient population.
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Aprendizaje Automático , Proteómica , Púrpura Trombocitopénica Idiopática , Esplenectomía , Humanos , Masculino , Femenino , Proteómica/métodos , Púrpura Trombocitopénica Idiopática/cirugía , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/genética , Adulto , Persona de Mediana Edad , Biomarcadores/sangre , Anciano , Estudios RetrospectivosRESUMEN
BACKGROUND: Relation between the emergence of ITP and the presence of TNFα 308G/A polymorphism in the involved individuals has been studied by previous researchers in different ethnicity, but a definite result was not gained. So, this meta-analysis was performed to find an absolute answer to the question whether TNF-α-308G/A polymorphism is a susceptibility factor for ITP or not? METHODS: Electronic databases including PubMed, Google scholar, and Science Direct were searched and case control studies compatible to the defined inclusion criteria were selected; their references were also evaluated manually. Pooled OR with 95 % confidence intervals (CIs) as a strength of association between TNF-α-308G/A polymorphism and risk of ITP were calculated using a random-effect model. Funnel plot and Egger's linear regression test were conducted to examine the risk of publication bias. RESULTS: Totally, 16 eligible articles were found involving 1470 ITP cases and 2324 healthy controls. The Meta-results revealed that TNFα 308G/A polymorphism is associated with increased risk of ITP under the genetic models of recessive (OR: 1.54, 95 % CI: 1.03-2.29), dominant (OR: 2.29, 95 % CI: 1.44-3.64), and the heterozygote (OR: 2.46, 95 % CI:1.49-4.6). Subgroup analysis suggested a remarkable role for this SNP as a risk factor in the Caucasian ethnicity and the chronic subtype. CONCLUSION: TNFα 308G/A polymorphism can be an ITP susceptibility factor in the Caucasian population and the chronic subtype. Although more studies in large scale are needed for clinical decision but this finding can be used in the clinical trials to prevent the ITP consequences in the involved individuals.
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Púrpura Trombocitopénica Idiopática , Factor de Necrosis Tumoral alfa , Humanos , Factor de Necrosis Tumoral alfa/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Púrpura Trombocitopénica Idiopática/genética , HeterocigotoRESUMEN
OBJECTIVE: To explore the expression of microRNA-3162-3p in different clinical stages of childhood primary immune thrombocytopenia (ITP) and its significance. METHODS: Ninety-six children with ITP were enrolled and divided into new diagnosis group (n=40), persistent group (n=30) and chronic group (n=26) according to the course of disease. 80 healthy children were selected as the control group. Peripheral blood mononuclear cells (PBMNC) of ITP children and healthy children were isolated and cultured, and the expression of microRNA-3162-3p in PBMNC of subjects was detected by real-time fluorescence quantitative PCR. The contents of IL-17, IL-23, IL-10 and TGF-ß in PBMNC of subjects were determined by ELISA. The correlation between microRNA-3162-3p and platelet count, IL-17, IL-23, IL-10 and TGF-ß was analyzed. RESULTS: Compared with the control group, the expression of microRNA-3162-3p and IL-10 in PBMNC and platelet count of ITP children were significantly decreasedï¼P < 0.05ï¼, while IL-17, IL-23 and TGF-ß were significantly increased (P < 0.05). With the prolongation of the disease course, the expressions of microRNA-3162-3p and IL-10 in PBMNC and platelet count were significantly decreasedï¼P < 0.05ï¼, while the expressions of IL-17, IL-23 and TGF-ß were significantly increased (P < 0.05). The expression of microRNA-3162-3p in PBMNC was positively correlated with platelet count and IL-10 (r =0.716, 0.667), and negatively correlated with IL-17, IL-23, and TGF-ß (r =-0.540, -0.641, -0.560). CONCLUSION: MicroRNA-3162-3p expression is significantly reduced in PBMNC of children with ITP, and is involved in the regulation of Th17/Treg imbalance, which can be used as a potential therapeutic target of ITP.
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MicroARNs , Púrpura Trombocitopénica Idiopática , Niño , Humanos , Púrpura Trombocitopénica Idiopática/genética , Interleucina-10 , Interleucina-17 , Leucocitos Mononucleares , Factor de Crecimiento Transformador beta , Interleucina-23RESUMEN
BACKGROUND: The E3 ubiquitin ligase casitas B-lineage lymphoma-b (CBLB) is a newly identified component of the ubiquitin-dependent protein degradation system and is considered an important negative regulator of immune cells. CBLB is essential for establishing a threshold of T-cell activation and regulating peripheral T-cell tolerance through various mechanisms. However, the involvement of CBLB in the pathogenesis of immune thrombocytopenia (ITP) is unknown. OBJECTIVES: We aimed to investigate the expression and role of CBLB in CD4+ T cells obtained from patients with ITP through quantitative proteomics analyses. METHODS: CD4+ T cells were transfected with adenoviral vectors overexpressing CBLB to clarify the effect of CBLB on anergic induction of T cells in patients with ITP. DNA methylation levels of the CBLB promoter and 5' untranslated region (UTR) in patient-derived CD4+ T cells were detected via MassARRAY EpiTYPER assay (Agena Bioscience). RESULTS: CD4+ T cells from patients with ITP showed resistance to anergic induction, highly activated phosphoinositide 3-kinase-protein kinase B (AKT) signaling, decreased CBLB expression, and 5' UTR hypermethylation of CBLB. CBLB overexpression in T cells effectively attenuated the elevated phosphorylated protein kinase B level and resistance to anergy. Low-dose decitabine treatment led to significantly elevated levels of CBLB expression in CD4+ T cells from 7 patients showing a partial or complete response. CONCLUSION: These results indicate that the 5' UTR hypermethylation of CBLB in CD4+ T cells induces resistance to T-cell anergy in ITP. Thus, the upregulation of CBLB expression by low-dose decitabine treatment may represent a potential therapeutic approach to ITP.
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Linfoma , Púrpura Trombocitopénica Idiopática , Humanos , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/genética , Regiones no Traducidas 5' , Decitabina , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Proto-Oncogénicas c-cbl/genética , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Linfoma/genéticaRESUMEN
BACKGROUND: Emerging clinical evidence has been discovered associating Inflammatory bowel disease (IBD) with Henoch-Schönlein purpura (HSP) and immune thrombocytopenia (ITP). However, it is unclear whether a cause-effect relationship exists between them. We aimed to examine the casual effect of IBD on the risk of HSP and ITP. METHODS: Based on summary statistics from International IBD Genetics (IIBDG) Consortium and FinnGen study, a two-sample Mendelian randomization study was carried out to determine whether IBD including ulcerative colitis (UC) and Crohn's disease (CD) is causally related to HSP, ITP or secondary thrombocytopenia. To support the results, a variety of sensitivity analyses were performed. RESULTS: Significant causal relationships between IBD and HSP (odds ratios = 1.20, 95% confidence interval: 1.07-1.36, adjusted P = 0.006) and ITP (odds ratios =1.22, 95% confidence interval: 1.08-1.38, adjusted P = 0.006) were found. Both genetically predicted UC and CD were positively related with ITP, while CD alone may be responsible for the higher risk of HSP. Besides, no significant association was observed between IBD and secondary thrombocytopenia. CONCLUSIONS: The results of this Mendelian randomization study supported the causal association of IBD with HSP and ITP. Taken together, our findings may present implications for management of IBD.
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Colitis Ulcerosa , Enfermedad de Crohn , Vasculitis por IgA , Enfermedades Inflamatorias del Intestino , Púrpura Trombocitopénica Idiopática , Trombocitopenia , Humanos , Púrpura Trombocitopénica Idiopática/genética , Análisis de la Aleatorización Mendeliana , Vasculitis por IgA/complicaciones , Vasculitis por IgA/genética , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/genética , Enfermedad de Crohn/genética , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/genéticaRESUMEN
Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease. Cellular and systemic lipid metabolism plays a significant role in the regulation of immune cell activities. However, the role of lipoprotein lipids and apolipoproteins in ITP remains elusive. The automatic biochemistry analyser was used to measure the levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA-I), apoB, apoE and lipoprotein a [LP(a)]. Genetic variants strongly associated with circulating lipoprotein lipids and apolipoproteins (LDL-C, apoB, TG, HDL-C and apoA-I) were extracted to perform Mendelian randomization (MR) analyses. Finally, drug-target MR and passive ITP mice model was used to investigate the potential druggable targets of ITP. Levels of HDL-C, apoA-I, decreased and LP(a) increased in ITP patients compared with healthy controls. Low HDL-C was causally associated with ITP susceptibility. Through drug-target MR and animal modelling, ABCA1 was identified as a potential target to design drugs for ITP. Our study found that lipid metabolism is related to ITP. The causative association between HDL-C and the risk of ITP was also established. The study provided new evidence of the aetiology of ITP. ABCA1 might be a potential drug target for ITP.
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Apolipoproteína A-I , Púrpura Trombocitopénica Idiopática , Animales , Ratones , Humanos , Apolipoproteína A-I/genética , LDL-Colesterol , Lípidos , Análisis de la Aleatorización Mendeliana , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/genética , Apolipoproteínas/genética , Triglicéridos , HDL-ColesterolRESUMEN
OBJECTIVE: High-throughput sequencing was used to screen expressing differences of miRNA, lncRNA, and mRNA in CD19+ B peripheral blood samples of newly diagnosed immune thrombocytopenia (ITP) patients and healthy controls. The study aimed to explore the regulatory role of ceRNA network in the pathogenesis of dysfunctional CD19 + B lymphocytes of ITP patients. METHODS: CD19+ B lymphocytes were isolated from peripheral blood samples of ITP patients and their healthy counterparts. High-throughput sequencing was used to screen for the expression of miRNA, lncRNA, and mRNA of ITP patients and healthy controls, which were analysed by the ceRNA network. Moreover, qPCR was used to verify the differential expression of miRNA, lncRNA, and mRNA in ITP patients and healthy controls. The correlation between differentially expressed miRNA, lncRNA, mRNA, and B lymphocyte subsets was also analysed. RESULTS: The CD19+ B lymphocytes of 4 newly diagnosed ITP patients and 4 healthy controls were sequenced and analysed. There were 65 differentially expressed lncRNA and 149 mRNA forming a ceRNA network showed that 12 lncRNA and 136 differentially expressed mRNA were closely associated. Similarly, miR-144-3p, miR-374c-3p, and miR-451a were highly expressed in ITP patients, as confirmed by qPCR, which was consistent with the high-throughput sequence results. LOC102724852 and CCL20 were highly expressed in ITP patients, while LOC105378901, LOC112268311, ALAS2, and TBC1D3F were not as compared to healthy controls, which was consistent with the high-throughput sequence results. In addition, the expression of miR-374c-3p, LOC112268311, LOC105378901, and CXCL3 were correlated with the percentage of B lymphocyte subsets. CONCLUSIONS: The ceRNA network of miRNA, lncRNA, and mRNA in peripheral CD19 + B lymphocytes plays an essential role in the pathogenesis of ITP.
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MicroARNs , Púrpura Trombocitopénica Idiopática , ARN Largo no Codificante , Trombocitopenia , Humanos , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/genética , ARN Largo no Codificante/genética , MicroARNs/genética , Linfocitos B , ARN Mensajero/genética , Antígenos CD19/genética , Redes Reguladoras de Genes , 5-Aminolevulinato Sintetasa/genéticaRESUMEN
ANKRD26-related thrombocytopenia (ANKRD26-RT or THC2, MIM 188 000), an autosomal dominant thrombocytopenia, is unresponsive to immunosuppressive therapy and susceptible to hematological malignancies. A large number of pediatric patients are diagnosed with immune thrombocytopenia (ITP) every year; however, thrombocytopenia of genetic origin is often missed. Extensive characterization of ANKRD26-RT will help prevent missed diagnosis and misdiagnosis. Furthermore, identification of ANKRD26-RT will help in the formulation of an accurate diagnosis and a treatment plan. In our study, we report cases of two Chinese pediatric patients with ANKRD26-RT and analyze their clinical characteristics, gene mutations, and treatment modalities. Both patients were 1-year-old and presented with mild bleeding (World Health Organization(WHO) score grade 1), different degrees of platelet reduction, normal mean platelet volume, and megakaryocyte maturation impairment not obvious. Genetic tests revealed that both patients had ANKRD26 gene mutations.Patient 1 had a mutation c.-140C>G of the 5' untranslated region (UTR), and patient 2 had a mutation of c.-127A>T of 5'UTR. Both patients were treated with eltrombopag, and the treatment was no response, with no adverse reactions.
What is the background? ANKRD26-RT is an autosomal dominant thrombocytopenia which is unresponsive to immunosuppressive therapy and susceptible to hematological malignancies.It is rare and lacks specific clinical features, making misdiagnosis easy.Some studies report that eltrombopag is safe and effective for short-term treatment of the disease; however, these reports are limited.What we did and summary of findings. We retrospectively studied the clinical manifestations and diagnosis process of ANKRD26-RT and discussed the treatment efficacy of immunosuppressants and eltrombopag for its management.We found two pediatric cases of patients with ANKRD26-RT with varying degrees of thrombocytopenia, mild bleeding, normal mean platelet volume, and megakaryocyte maturation impairment that was not obvious. Immunosuppressant treatment wasunresponsiveor temporarily responsivebut not sustained , and short-term administration of eltrombopag (25 mg/day) was safe, but it did not effectively improve the patients' platelet counts.What is the impact? If patients clinically diagnosed with immune thrombocytopenia do not respond to immunosuppressive agents, genetic testing should be conducted to exclude hereditary thrombocytopenia, and a normal mean platelet volume should not exclude the possibility of the disease.For patients with ANKRD26-RT, eltrombopag is safe for short-term use;however, 25 mg/day treatment is unresponsive.Ourreport complements data on the diagnosis and management of ANKRD26-RT disease in children.