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1.
Medicine (Baltimore) ; 98(44): e17766, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31689837

RESUMEN

RATIONALE: Although essential thrombocythemia (ET) and immune thrombocytopenia (ITP) have different etiologies, 3 previous reports have described ET development in ITP patients, all of whom were positive for the JAK2 V617F mutation. Here, we report the first published case of ITP following ET in the absence of other platelet disorders. PATIENT CONCERNS: A 70-year-old woman with a five-year history of ET with JAK2 V617F mutation treated with hydroxycarbamide for five months presented with petechiae on her limbs. DIAGNOSIS: Her platelet count was 3 × 10/L, with the immature platelet fraction being 29%. White blood cell count and hemoglobin level were normal. Bone marrow examination showed increased number of megakaryocytes, but no morphologic dysplasia in any lineage. G-band analysis revealed no abnormalities. Platelet transfusion and cessation of hydroxycarbamide did not affect the platelet count. Thrombocytopenia was unlikely to have been induced by drugs, heparin, systemic lupus erythematosus, or human immunodeficiency virus. Hence, a diagnosis of ITP was made. INTERVENTIONS: The patient received oral prednisolone combined with intravenous immunoglobulin. OUTCOMES: Her platelet count rose to 310 × 10/L and remained stable, while her steroid dose was reduced. Further blood tests revealed the presence of antibodies against Helicobacter pylori, and appropriate treatment was administered. Resumption of hydroxycarbamide did not induce thrombocytopenia. LESSONS: Although ET and ITP have different etiologies, chronic inflammation and immune deregulation underlie both and may play an important role in the progression from one to the other. Further research is warranted to understand the relationship between ET and ITP.


Asunto(s)
Janus Quinasa 2/sangre , Púrpura Trombocitopénica Idiopática/genética , Trombocitemia Esencial/genética , Anciano , Plaquetas , Femenino , Humanos , Recuento de Leucocitos , Mutación , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/etiología , Trombocitemia Esencial/sangre , Trombocitemia Esencial/complicaciones
2.
Ann Hematol ; 98(11): 2497-2506, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31595308

RESUMEN

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by a low platelet count and consequent increased risk of bleeding. The etiology underlying this condition remains poorly understood. The aim of this study is to evaluate the association of a single nucleotide polymorphism (SNP) rs4077515 in the caspase recruitment domain-containing protein 9 (CARD9) gene with the pathogenesis and therapy of ITP. Two hundred ninety-four patients with ITP and 324 age-matched healthy participants were recruited in this case-control study. Genotyping of CARD9 rs4077515 polymorphism was performed by Sanger sequencing. Our results revealed that a polymorphism rs4077515 in CARD9 gene is associated with decreased risk of susceptibility to and severity of ITP (susceptibility: codominant, AA vs. GG, OR = 0.175, 95% CI = 0.054-0.776, p = 0.001; recessive, GG + AG vs. AA, OR = 6.183, 95% CI = 2.287-16.715, p < 0.001; severity: allele, A vs. G, OR = 0.685, 95% CI = 0.476-0.985, p = 0.041; codominant, AG vs. GG, OR = 0.571, 95% CI = 0.350-0.931, p = 0.025; dominant, AA + AG vs. GG, OR = 0.558, 95% CI = 0.343-0.907, p = 0.019). The existence of the allele A, the mutant AA genotype and the heterozygous AG genotype of CARD9 rs4077515, plays a protective role in ITP. However, CARD9 rs4077515 polymorphism had no effect on corticosteroid sensitivity or refractoriness of ITP.


Asunto(s)
Proteínas Adaptadoras de Señalización CARD/genética , Polimorfismo de Nucleótido Simple , Púrpura Trombocitopénica Idiopática/genética , Corticoesteroides/uso terapéutico , Adulto , Alelos , Proteínas Adaptadoras de Señalización CARD/fisiología , Estudios de Casos y Controles , Resistencia a Medicamentos , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Riesgo
3.
Biomed Res Int ; 2019: 1050285, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31380412

RESUMEN

Background: Th17/Treg balance skews towards Th17 in ITP patient. IRF4 has been highlighted for its close relationship to the immunosuppressive function of Treg cells and the IL-17 synthesis in CD4+ T cells. This study was aimed at examining the effects of IRF4 to the Th17/Treg cells in patients with ITP. Methods: Treg and Teff cells were isolated from PBMCs of newly diagnosed ITP patients. The percentages of CD4+CD25hiFoxp3+Treg cells and the CD3+CD4+IL-17+Th17 cells were detected by flow cytometry. After being cultured, the supernatants of Tregs were collected for IL-10 concentration test. The IRF4 levels of Tregs were measured. Teffs were cultured alone or with Tregs for 24 hours. Then the supernatants were collected for IL-17 concentration test. The binding intensity of IRF4 to the gene IL-10 in Treg cells was detected by ChIP-qPCR. Metabolic assays for Teffs and Tregs were performed with Agilent Seahorse XF96 Analyzer. Results: The secretion of IL-10 by Tregs was decreased in ITP patients. The intensity of IRF4 binding to IL-10 DNA of Tregs in patients was higher than that of normal controls and Teffs in ITP patients. The expressions of IRF4 of Tregs in ITP patients were remarkably lower than that of healthy controls. The percentage of Th17 cells in healthy controls was significantly increased after IRF4 mRNA silencing. Abnormal metabolism of Treg and Teff cells was found in ITP patients. Conclusion: The skewed ratio of Th17/Treg cells and dysfunction of Treg cells in newly diagnosed ITP patients was at least partly caused by IRF4 dysfunction. The underlying mechanism might be the impact of IRF4 on the metabolism of Treg and Teff cells.


Asunto(s)
Factores Reguladores del Interferón/genética , Interleucina-10/genética , Púrpura Trombocitopénica Idiopática/genética , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/inmunología , Femenino , Regulación de la Expresión Génica , Humanos , Inmunosupresión/métodos , Factores Reguladores del Interferón/inmunología , Masculino , Persona de Mediana Edad , Unión Proteica/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/patología , Linfocitos T Reguladores/metabolismo , Células Th17/inmunología , Células Th17/metabolismo
4.
Ann Hematol ; 98(8): 1845-1854, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31154474

RESUMEN

Primary immune thrombocytopenia is an autoimmune disease, characterized with decreased platelet and increased risk of bleeding. Recent studies have shown the reduction and dysfunction of regulatory T (Treg) cells in ITP patients. CD39 is highly expressed on the surface of Treg cells. It degrades ATP to AMP and CD73 dephosphorylates AMP into adenosine. Then adenosine binds with adenosine receptor and suppresses immune response by activating Treg cells and inhibiting the release of inflammatory cytokines from effector T (Teff) cells. Adenosine receptor has several subtypes and adenosine A2A receptor (A2AR) plays a crucial role especially within lymphocytes. The CD39+ Treg cells and the expression of A2AR showed abnormality in some autoimmune disease. But knowledge of CD39+ Treg cells and A2AR which are crucial in the adenosine immunosuppressive pathway is still limited in ITP. Thirty-one adult patients with newly diagnosed ITP were enrolled in this study. CD39 and A2AR expression was measured by flow cytometry and RT-PCR. The function of CD39 was reflected by the change of ATP concentration detected by CellTiter-Glo Luminescent Cell Viability Assay. CD39 expression within CD4+CD25+ Treg cells in ITP patients was decreased compared to normal controls. After high-dose dexamethasone therapy, response (R) group showed increased CD39 expression within Treg cells while non-response (NR) group did not show any difference in contrast to those before treatment. The expression of A2AR in CD4+CD25- Teff and CD4+CD25+ Treg cells was both lower in ITP patients than that of normal controls. After therapy, CD4+CD25- Teff cells had higher A2AR expression while CD4+CD25+ Treg cells did not show any difference in comparison to that before treatment. The enzymatic activity of CD39 was damaged in ITP patients and improved after high-dose dexamethasone therapy. In ITP, there was not only numerical decrease but also impaired enzymatic activity in CD39+ Treg cells. After high-dose dexamethasone treatment, these two defects could be reversed. Our results also suggested that ITP patients had reduced A2AR expression in both CD4+CD25+ Treg cells and CD4+CD25- Teff cells. CD4+CD25- Teff cells had increased A2AR expression after treatment.


Asunto(s)
Apirasa/genética , Dexametasona/uso terapéutico , Inmunosupresores/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Receptor de Adenosina A2A/genética , Linfocitos T Reguladores/efectos de los fármacos , Adenosina/inmunología , Adenosina/metabolismo , Adenosina Trifosfato/inmunología , Adenosina Trifosfato/metabolismo , Adulto , Anciano , Apirasa/inmunología , Estudios de Casos y Controles , Femenino , Expresión Génica , Humanos , Inmunofenotipificación , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/enzimología , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/inmunología , Receptor de Adenosina A2A/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/enzimología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/enzimología , Linfocitos T Reguladores/inmunología
5.
Pediatr Blood Cancer ; 66(9): e27874, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31207059

RESUMEN

Growth factor-independent 1B (GFI1B) variants are a rare cause of thrombocytopenia. We report on a male child who was initially diagnosed with immune thrombocytopenia. However, subtle clinical signs led to suspicion of a genetic cause of thrombocytopenia. Gene panel sequencing revealed a rare variant in GFI1B (C168F), which has recently been reported in several families with thrombocytopenia. We demonstrate that this variant significantly alters platelet parameters in population studies. This case highlights how diagnoses of exclusion, such as immune thrombocytopenia, can be confounded by genetic variation. Our understanding of blood disorders will undoubtedly evolve from an increased knowledge of human genetic variation.


Asunto(s)
Plaquetas/metabolismo , Enfermedades Genéticas Congénitas , Mutación Missense , Proteínas Proto-Oncogénicas/genética , Púrpura Trombocitopénica Idiopática , Proteínas Represoras/genética , Preescolar , Enfermedades Genéticas Congénitas/sangre , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Humanos , Masculino , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/genética
6.
Int Immunopharmacol ; 72: 437-444, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31030100

RESUMEN

BACKGROUND: Immune thrombocytopenia (ITP) is an immune-mediated acquired autoimmune hemorrhagic disease. About one-third of patients are unresponsive to first-line therapies. Thalidomide (THD) as an immunomodulatory agent is now used to treat several autoimmune disorders. Therefore, we assessed the safety and efficacy of THD in corticosteroid-resistant or relapsed ITP patients, and preliminarily explore its mechanism. METHODS: 50 newly-diagnosed ITP patients and 47 healthy volunteers were enrolled in this study. Additionally, 17 corticosteroid-resistant or relapsed ITP patients were recruited, with 7 cases in the rhTPO + THD group and 10 cases in the THD monotherapy group. Overall response rate at 6, 12, and 24 months were assessed. Levels of Neuropilin-1(NRP-1), regulatory T cells (Tregs) and regulatory B cells (Bregs) were detected. RESULTS: Expression of NRP-1, Tregs and Bregs were reduced in newly-diagnosed ITP patients. In vitro, THD treatment upregulated expression of NRP-1and Tregs only in ITP patients. As for corticosteroid-resistant or relapsed ITP patients, overall response rate at 6, 12, and 24 months was 85.7%, 57.1% and 100% in the rhTPO + THD group and 60%, 75% and 83.3% in the THD group, respectively. Additionally, rhTPO plus THD or THD therapy significantly increased the levels of NRP-1, Tregs and Bregs in responders. CONCLUSIONS: Our study shows for the first time that NRP-1 is involved in the pathogenesis of ITP, THD could induce response in ITP patients by upregulating NRP-1 expression and restoring the proportion of Tregs and Bregs. THD might be served as a novel therapeutic agent in corticosteroid-resistant or relapsed ITP patients.


Asunto(s)
Inmunosupresores/uso terapéutico , Neuropilina-1/inmunología , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Talidomida/uso terapéutico , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Linfocitos B Reguladores/efectos de los fármacos , Linfocitos B Reguladores/inmunología , Resistencia a Medicamentos , Femenino , Humanos , Inmunosupresores/farmacología , Masculino , Persona de Mediana Edad , Neuropilina-1/genética , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Talidomida/farmacología , Regulación hacia Arriba/efectos de los fármacos , Adulto Joven
7.
Lab Med ; 50(3): e42-e49, 2019 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-30955035

RESUMEN

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by symptoms of thrombocytopenia and bleeding due to production of autoantibodies against platelets. Recently, the occurrence of polymorphisms has been identified as one of the main causes of disease onset. METHODS: To conduct this study, we recruited 140 patients and control individuals with no history of platelet loss. After collection of specimens, the prevalence of interferon-γ polymorphism was evaluated using the allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) technique and confirmed by sequencing techniques. RESULTS: The results showed that the frequency of the AA genotype was higher in the control group, compared with patients with ITP; however, in the acute and chronic groups, the frequency of the AT genotype was higher than that of the AA genotype. We also discovered that there was no significant correlation between platelet counts before and after treatment, nor in its related parameters with interferon (IFN)-γ polymorphism. CONCLUSION: rs2430561 does not seem to have any role in ITP pathogenesis and treatment response.


Asunto(s)
Predisposición Genética a la Enfermedad , Interferón gamma/genética , Mutación Puntual , Púrpura Trombocitopénica Idiopática/genética , Adolescente , Adulto , Anciano , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven
8.
Thromb Res ; 177: 70-78, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30856381

RESUMEN

INTRODUCTION: Imbalance of T helper 17 (Th17) cells and regulatory T (Treg) cells occurs in primary immune thrombocytopenia (ITP), but the mechanism remains unclear. We investigated whether expression of microRNAs (miRNAs) related to helper T or Treg cells regulate the Th17/Treg ratio in CD4+ T cells. MATERIALS AND METHODS: Peripheral blood was obtained from 52 active ITP patients and 56 healthy controls. We detected miRNA expression using RT-PCR with stem-loop primers and U6 as control.Th17 and Treg percentages were analyzed by flow cytometry. CD4+ cells were transfected with miRNA (miR-99a, miR-182-5p, miR-183-5p) mimics or inhibitors to investigate their function. RESULTS: miR-99a expression in CD4+ cells in ITP patients was lower than in controls, while expression of miR-182-5p and miR-183-5p were higher in ITP patients. Moreover, Treg percentage correlated positively with miR-99a expression in ITP patients. We found no significant correlation between Th17 percentage and miR-182-5p or miR-183-5p expression. miR-183-5p expression correlated negatively with platelet count, while we found no significant difference between platelet count and miR-99a or miR-182-5p. miR-183-5p expression in CD4+ T cells from severe patients was significantly higher than in those from non-severe patients. Furthermore, down-regulating miR-183-5p expression repressed Th17 differentiation, while up-regulating miR-99a increased Tregs detected in CD4+ cells from ITP patients. In addition, up-regulated miR-99a repressed mTOR and p-mTOR expression. CONCLUSIONS: miR-99a, miR-182-5p, and miR-183-5p expression levels in CD4+ cells were abnormal in ITP patients. Aberrant expression of miRNAs may contribute to the Th17/Treg imbalance in ITP patients and may represent a novel therapeutic target.


Asunto(s)
Linfocitos T CD4-Positivos/patología , MicroARNs/genética , Púrpura Trombocitopénica Idiopática/genética , Adolescente , Adulto , Anciano , Linfocitos T CD4-Positivos/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/patología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Células Th17/metabolismo , Células Th17/patología , Adulto Joven
10.
Scand J Immunol ; 89(5): e12758, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30786049

RESUMEN

Several studies already explored associations between Fc gamma receptor (FCGR) polymorphisms and immune thrombocytopenia (ITP), but the results of these studies were not consistent. Consequently, we conducted a meta-analysis of relevant studies to better analyse the effects of FCGR polymorphisms on individual susceptibility to ITP. PubMed, Web of Science, Embase and CNKI were searched for eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Totally 17 studies were eligible for analyses (1200 cases and 1723 controls). Significant associations with ITP were observed for FCGR3A F158V polymorphism in dominant (P < 0.0001, OR = 0.47, 95% CI 0.39-0.57), recessive (P < 0.0001, OR = 2.03, 95% CI 1.58-2.61), overdominant (P < 0.0001, OR = 1.42, 95% CI 1.19-1.69) and allele (P < 0.0001, OR = 0.58, 95% CI 0.51-0.65) models in overall analyses. But we did not observe any significant associations with ITP for FCGR2A H131R and FCGR2B I232T polymorphisms in overall analyses. Subgroup analyses by ethnicity yielded similar positive results for FCGR3A F158V polymorphism in both Asians and Caucasians. Furthermore, subgroup analyses by type of disease revealed that FCGR2A H131R polymorphism was significantly associated with childhood-onset ITP, and FCGR3A F158V polymorphism was significantly associated with both childhood-onset and adult-onset ITP. In summary, our findings suggested that FCGR2A H131R polymorphism may serve as a potential genetic biomarker of childhood-onset ITP, while FCGR3A F158V polymorphism may serve as a potential genetic biomarker of both childhood-onset and adult-onset ITP.


Asunto(s)
Marcadores Genéticos/genética , Púrpura Trombocitopénica Idiopática/genética , Receptores de IgG/genética , Adulto , Edad de Inicio , Biomarcadores/metabolismo , Niño , China , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Fenotipo , Polimorfismo Genético
11.
Thromb Haemost ; 119(3): 377-383, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30630213

RESUMEN

Immune thrombocytopaenia (ITP) is the most common autoimmune bleeding disorder, where platelets are destroyed by auto-antibodies and/or cell-mediated mechanisms. To understand the pathogenesis of ITP and explore novel therapeutics, three types of animal models have been used: passive ITP, secondary ITP and platelet-induced ITP. However, the first two are not ideal for chronic ITP pathophysiology where both T cell and B cell play important roles in platelet destruction. The most efficient model to mimic chronic ITP is developed by Chow et al through transferring splenocytes from platelet-immune CD61-knockout (KO) mice into mice with severe combined immunodeficiency (SCID). However, placental defects are evident in 25% of CD61-KO females and post-natal haemorrhage does occur, reducing the survival rate of embryos and pups. Compared with CD61-KO mice, CD41-KO ones do not present such problems. In our study, we employ CD41-KO mice as another source of immunized spleen cells. We evaluated our model with existing standards. Transferred SCID mice presented typical features of ITP, such as reduced platelet counts in the peripheral blood, increased anti-platelet antibody levels in the serum and reduced mature megakaryocytes in the bone marrow. What is more, lymphocyte-depletion experiments showed the role of CD8+ T cells in mature megakaryocyte decrease and thrombocytopaenia. And we confirmed the antibody-mediated platelet destruction by phagocytosis in the spleen. Our study develops another efficient murine ITP model through immunized CD41-KO mice.


Asunto(s)
Traslado Adoptivo , Plaquetas/inmunología , Glicoproteína IIb de Membrana Plaquetaria/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Bazo/inmunología , Animales , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Plaquetas/metabolismo , Plaquetas/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Megacariocitos/inmunología , Megacariocitos/metabolismo , Megacariocitos/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Fagocitosis , Fenotipo , Glicoproteína IIb de Membrana Plaquetaria/genética , Glicoproteína IIb de Membrana Plaquetaria/metabolismo , Transfusión de Plaquetas , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/metabolismo , Bazo/metabolismo , Factores de Tiempo
12.
J Pediatr Hematol Oncol ; 41(2): e114-e115, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-29683950
13.
Hematology ; 24(1): 123-128, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30319055

RESUMEN

OBJECTIVES: To investigate the association of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) with immune thrombocytopenia (ITP). METHODS: A case-control association analysis of 277 Chinese Han children was performed. The tagging variants rs11571315 and rs3087243 in the CTLA4 gene were detected using polymerase chain reaction-restriction fragment length polymorphism method. The expression quantitative trait loci (eQTL) analysis and quantitative real-time polymerase chain reaction were performed to determine the relationship of CTLA4 with ITP. RESULTS: Neither SNP was significantly different between case and control groups in either the genotypic or allelic distribution. The eQTL analysis results indicated that in the spleen, the rs3087243 was significant with the expression of CTLA4. The rs11571315 has similar results. Interestingly, the transcript level of CTLA4 was found to significantly decrease in patients with ITP. DISCUSSION: The autoimmune and gene etiology is implicated in the pathogen of ITP. The CTLA4 is important for negative regulation of T-cell activation, and CTLA-4 gene has been identified as a risk factor for some autoimmune diseases. However, association studies of ITP and CTLA4 gene have obtained conflicting results. This is the first study to systematically investigate the association of CTLA4 with ITP in Chinese Han children. CONCLUSIONS: The CTLA4 gene is suggested to correlate with ITP through its abnormal expression level instead of gene site mutation.


Asunto(s)
Antígeno CTLA-4/genética , Polimorfismo de Nucleótido Simple , Púrpura Trombocitopénica Idiopática/genética , Sitios de Carácter Cuantitativo , Grupo de Ascendencia Continental Asiática , Antígeno CTLA-4/inmunología , Niño , Preescolar , China , Femenino , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Humanos , Masculino , Púrpura Trombocitopénica Idiopática/epidemiología , Púrpura Trombocitopénica Idiopática/inmunología
14.
Blood Cells Mol Dis ; 75: 20-25, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30594845

RESUMEN

Interleukin-17F rs763780 (7488A/G) gene polymorphism obviously affecting the expression and activity of IL17F and may affect primary immune thrombocytopenia (PIT) susceptibility and its clinical features in Egyptian children and adults. 105 ITP patients divided into (63 pediatric and 42 adult patient) and 112 age and sex matched healthy controls were enrolled in this case control study. All patients were subjected to history taking; clinical examination, CBC, bone marrow aspiration and genotyping of IL17F rs763780 polymorphism by (PCR-RFLP) technique. Our results revealed significant decrease in the mutant heterozygous genotype AG and also in IL-17F mutant allele G frequency in ITP patient group and associated with increased risk for ITP compared with the control group (P = 0.04 and P = 0.005 respectively). Furthermore, the mutant allele G frequency was significantly decreased in childhood onset than adult onset ITP (OR = 0.31, P = 0.02) and also was significantly lower in chronic ITP when compared with newly diagnosed and persistent ITP (P = 0.005). Patients with the AA genotype showed severe thrombocytopenic state at diagnosis than those with the AG genotype (P = 0.04). We concluded from our results that interleukin-17F rs763780 (7488A/G) polymorphism is strongly correlated with susceptibility and severity of ITP.


Asunto(s)
Interleucina-17/genética , Polimorfismo de Nucleótido Simple , Púrpura Trombocitopénica Idiopática/genética , Adulto , Edad de Inicio , Estudios de Casos y Controles , Niño , Egipto , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos
15.
Clin Immunol ; 197: 186-188, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30326257
16.
J Pediatr Hematol Oncol ; 40(8): e516-e518, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30080751

RESUMEN

Recently, a new disease of lymphocyte homeostasis caused by somatic mosaicism for the RAS mutation has been discovered (known as RALD, RAS-associated leukoproliferative disorder). Since few cases have been reported in literature, the prognosis and standard treatment for autoimmune diseases associated with RALD remain poorly understood. Standard rituximab therapy (375 mg/m for 4 wk) is effective in patients with autoimmune diseases, but early recurrences are common. We highlight the potential for monthly administration of rituximab in a patient with autoimmune thrombocytopenia and hemolytic anemia associated with RALD. RALD was diagnosed in an 11-year-old girl following a 9-year history of severe hepatosplenomegaly and autoimmune cytopenias. Genetic analyses confirmed somatic mosaicism for the G13C KRAS mutation without an autoimmune lymphoproliferative syndrome-related gene mutation. Rituximab therapy was used because of the refractory character of the autoimmune cytopenias which failed to respond to steroids and other immunosuppressive agents. Her treatment consisted of weekly infusions of rituximab for 4 weeks followed by monthly rituximab for 11 months. She maintained her response in hematologic parameters for 2 years after monthly rituximab was ceased and her scores representing quality of life were improved. Rituximab could improve clinical responses and quality of life of the patients with RALD.


Asunto(s)
Anemia Hemolítica/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Rituximab/administración & dosificación , Anemia Hemolítica/diagnóstico , Anemia Hemolítica/genética , Niño , Femenino , Humanos , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/genética
17.
J Immunol Res ; 2018: 8170436, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30140708

RESUMEN

Background: The NLRP3 inflammasome plays important roles in the pathogenesis of autoimmune diseases. However, the role of the NLRP3 inflammasome in the pathophysiology of immune thrombocytopenia (ITP) remains unclear. Methods: RT-PCR was used to examine the polymorphism and expression of genes involved in the NLRP3 inflammasome in ITP patients. T helper cells and apoptosis of PBMC from ITP patients were analyzed by flow cytometry. The antiplatelet autoantibodies in plasma were determined by modified monoclonal antibody-specific immobilization of platelet antigens (MAIPA). Results: We found that the NF-κB-94ins/del ATTG genotype contributed to the susceptibility of ITP. Furthermore, the platelet counts of ITP patients with the WW genotype or WD genotype were lower than those with the DD genotype of NF-κB-94ins/del ATTG. Compared with controls, NF-κB gene expression was significantly decreased and WW or WD genotype ITP patients displayed higher mRNA expression than DD individuals. Similarly, the mRNA expression of NLRP3 was also increased in the WW genotype. There was a significant gene dose effect of the percentage of Th17 cells for the WW, WD, and DD genotypes (WW < WD < DD) in the unstimulated group and no significant difference was found after being stimulated. The activation of the NLRP3 inflammasome could upregulate Th17 in ITP patients. Conclusion: The NF-κB-94ins/del ATTG genotype might serve as a novel biomarker and potential target for ITP.


Asunto(s)
Genotipo , Mutación INDEL/genética , Inflamasomas/fisiología , FN-kappa B/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Púrpura Trombocitopénica Idiopática/genética , Células Th17/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/metabolismo , Biomarcadores/metabolismo , Femenino , Dosificación de Gen , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Inhibidores de Agregación Plaquetaria/metabolismo , Polimorfismo Genético , Adulto Joven
18.
Cell Physiol Biochem ; 48(2): 618-632, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30021206

RESUMEN

BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) are important regulators of biological processes and they contribute to the pathological developments of various diseases, including autoimmune diseases. To gain the further understanding, we estimate the expression of lncRNAs in primary immune thrombocytopenia (ITP). METHODS: In this study, microarray studies were performed to characterize expression profiles of various lncRNAs and mRNAs in blood samples collected from ITP patients. Quantitative real-time PCR (qRT-PCR) was performed to confirm the results, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and gene ontology analysis were used to provide functional annotations, co-expression network construction (CNC) analysis was made to reveal the relations between lncRNAs and their targeted genes. RESULTS: A total of 1177 and 632 lncRNAs were significantly up-regulated or down-regulated, respectively, in "newly diagnosed ITP" patients versus healthy individuals. In addition, 1182 genes and 737 genes were up-regulated or down-regulated, respectively, in "chronic recurrent ITP" patients versus healthy individuals. In a KEGG analysis, "TNF signaling pathway-Homo sapiens (human)" was a key result. In a gene ontology analysis, "Granulocyte macrophage colony-stimulating factor production (GO: 0032604, ontology: Biological process, P = 1.69577E-05)" and "coreceptor activity (GO: 0015026, ontology: molecular function, P = 4.67594E-06)" were the two most critical results. Data from qRT-PCR and receiver operating characteristic curves further demonstrated that ENST00000440492, ENST00000528366, NR_038920, and ENST00000552576 can efficiently distinguish different stages of ITP, especially NR_038920 and ENST00000528366. In a CNC analysis, four lncRNAs were emphasized, and NR_038920 and ENST00000528366 were both associated with proteins with important roles in autoimmune diseases. CONCLUSIONS: These results suggest that lncRNAs act through targeted genes to mediate their functions and to mediate their functions and affect the pathogenesis of ITP.


Asunto(s)
Púrpura Trombocitopénica Idiopática/patología , ARN Largo no Codificante/metabolismo , Adulto , Área Bajo la Curva , Análisis por Conglomerados , Bases de Datos Genéticas , Regulación hacia Abajo , Femenino , Redes Reguladoras de Genes , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Púrpura Trombocitopénica Idiopática/genética , ARN Largo no Codificante/genética , Curva ROC , Regulación hacia Arriba , Adulto Joven
19.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 40(2): 225-232, 2018 Apr 28.
Artículo en Chino | MEDLINE | ID: mdl-29724313

RESUMEN

Objective To analyze the differentially expressed genes and key proteins in T cells between acute and chronic idiopathic thrombocytopenic purpura (ITP) in children and provide the basis for the prevention and therapies of this disease. Methods Microarray gene chip data from T cells of children with acute or chronic ITP were downloaded from the GEO Database. The gene expression profiles,gene function,and protein interaction network were analyzed by R,QOE,Networkanalyst,GCBI,and GenClip. Results The gene expression profiles between these two groups were significantly different. Among the 54 675 genes analyzed,there were 457 (0.84%) differentially expressed genes between these two groups. In the protein interaction networks among top 20 differentially expressed genes,the core was JUN(down-regulated) and ITCH(up-regulated),which were both related to the tumor necrosis factor signaling pathway;differentially expressed genes were mainly related to the activation and tolerance of T cell. Conclusions The gene expression profiles differ between acute and chronic ITP patients,suggesting that the gene transcription profile plays a regulatory role in the different stages of ITP. JUN and ITCH may play a role in predict the progression of ITP and may exert their biological functions by regulating the tumor necrosis factor signaling pathway.


Asunto(s)
Púrpura Trombocitopénica Idiopática/genética , Transcriptoma , Enfermedad Aguda , Niño , Enfermedad Crónica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Púrpura Trombocitopénica Idiopática/clasificación , Linfocitos T
20.
Blood Coagul Fibrinolysis ; 29(5): 458-464, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29846275

RESUMEN

: Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by decreased platelet count of which dysfunctional cellular immunity in its pathogenesis. Signal transducer and activator of transcription 3 (STAT3) is critical for the differentiation of T cells. The present study was aimed to investigate the STAT3 protein phosphorylation of CD4 T cells in ITP patients. Fourteen patients of newly diagnosed ITP with complete remission (R group) and other 15 newly diagnosed ITP patients with nonresponse (N group) after corticosteroids therapy were included. Sixteen healthy human volunteers were served as normal controls (C group). Blood samples were collected before and after the therapy. Serum levels of IL-6 were measured by ELISA. The phosphorylation of STAT3 protein (pSTAT3) and the percentage of Th17 cells of the CD4 T cells were analyzed by flow cytometry. The STAT3 mRNA expression was examined by Real-time PCR. The level of IL-6 in the R group was higher than that in the C group (P = 0.02) whereas no difference was found between groups of N and C. The basal level of pSTAT3 in the R group was significantly higher when compared with N group (P = 0.002). The percentage of Th17 cells of the CD4 T cells in the ITP patients was numerically higher than that in the controls (P = 0.03). Our results indicate that ITP patient with higher basal level of pSTAT3 might have more favorite response to the corticosteroid therapy, which warrants further investigation on the prognostic role of pSTAT3 in ITP.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Púrpura Trombocitopénica Idiopática/genética , Factor de Transcripción STAT3/genética , Adulto , Anciano , Linfocitos T CD4-Positivos/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Púrpura Trombocitopénica Idiopática/patología , Transducción de Señal
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