RESUMEN

Liver X receptors α and ß are members of the nuclear receptor family, which comprise a flexible N-terminal domain, a DNA binding domain, a hinge linker, and a ligand binding domain. Liver X receptors are important regulators of cholesterol and lipid homeostasis by controlling the transcription of numerous genes. Key to their transcriptional role is synergetic interaction among the domains. DNA binding domain binds on DNA; ligand binding domain is a crucial switch to control the transcription activity through conformational change caused by ligand binding. The Liver X receptors form heterodimers with retinoid X receptor and then the liganded heterodimer may recruit other necessary transcription components to form an active transcription complex.

Asunto(s)

Receptores X del Hígado , Humanos , Ligandos , Dominios Proteicos

RESUMEN

OBJECTIVES@#To investigate the clinical features of juvenile myelomonocytic leukemia (JMML) and their association with prognosis.@*METHODS@#Clinical and prognosis data were collected from the children with JMML who were admitted from January 2008 to December 2016, and the influencing factors for prognosis were analyzed.@*RESULTS@#A total of 63 children with JMML were included, with a median age of onset of 25 months and a male/female ratio of 3.2∶1. JMML genetic testing was performed for 54 children, and PTPN11 mutation was the most common mutation and was observed in 23 children (43%), among whom 19 had PTPN11 mutation alone and 4 had compound PTPN11 mutation, followed by NRAS mutation observed in 14 children (26%), among whom 12 had NRAS mutation alone and 2 had compound NRAS mutation. The 5-year overall survival (OS) rate was only 22%±10% in these children with JMML. Of the 63 children, 13 (21%) underwent hematopoietic stem cell transplantation (HSCT). The HSCT group had a significantly higher 5-year OS rate than the non-HSCT group (46%±14% vs 29%±7%, P<0.05). There was no significant difference in the 5-year OS rate between the children without PTPN11 gene mutation and those with PTPN11 gene mutation (30%±14% vs 27%±10%, P>0.05). The Cox proportional-hazards regression model analysis showed that platelet count <40×109/L at diagnosis was an influencing factor for 5-year OS rate in children with JMML (P<0.05).@*CONCLUSIONS@#The PTPN11 gene was the most common mutant gene in JMML. Platelet count at diagnosis is associated with the prognosis in children with JMML. HSCT can improve the prognosis of children with JMML.

Asunto(s)

Niño , Humanos , Masculino , Femenino , Preescolar , Leucemia Mielomonocítica Juvenil/terapia , Pronóstico , Pruebas Genéticas , Mutación , Trasplante de Células Madre Hematopoyéticas

RESUMEN

Objective: To analyze the clinical and molecular diagnostic status of Fanconi anemia (FA) in China. Methods: The General situation, clinical manifestations and chromosome breakage test and genetic test results of 107 pediatric FA cases registered in the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) and the Chinese Children Blood and Marrow Transplantation Registry Group (CCBMTRG) from August 2009 to January 2022 were analyzed retrospectively. Children with FANCA gene variants were divided into mild and severe groups based on the type of variant, and Wilcoxon-test was used to compare the phenotypic differences between groups. Results: Of the 176 registered FA patients, 69 (39.2%) cases were excluded due to lack of definitive genetic diagnosis results, and the remaining 107 children from 15 hospitals were included in the study, including 70 males and 37 females. The age at transplantation treatment were 6 (4, 9) years. The enrolled children were involved in 10 pathogenic genes, including 89 cases of FANCA gene, 7 cases of FANCG gene, 3 cases of FANCB gene, 2 cases of FANCE gene and 1 case each of FANCC, FANCD1, FANCD2, FANCF, FANCJ, and FANCN gene. Compound heterozygous or homozygous of loss-of-function variants account for 69.2% (72/104). Loss-of-function variants account for 79.2% (141/178) in FANCA gene variants, and 20.8% (37/178) were large exon deletions. Fifty-five children (51.4%) had chromosome breakage test records, with a positive rate of 81.8% (45/55). There were 172 congenital malformations in 80 children.Café-au-Lait spots (16.3%, 28/172), thumb deformities (16.3%,28/172), polydactyly (13.9%, 24/172), and short stature (12.2%, 21/172) were the most common congenital malformations in Chinese children with FA. No significant difference was found in the number of congenital malformations between children with severe (50 cases) and mild FANCA variants (26 cases) (Z=-1.33, P=0.185). Conclusions: FANCA gene is the main pathogenic gene in children with FA, where the detection of its exon deletion should be strengthened clinically. There were no phenotypic differences among children with different types of FANCA variants. Chromosome break test is helpful to determine the pathogenicity of variants, but its accuracy needs to be improved.

Asunto(s)

Masculino , Femenino , Humanos , Niño , Anemia de Fanconi/genética , Rotura Cromosómica , Estudios Retrospectivos , Exones , China/epidemiología

RESUMEN

BACKGROUND: Infections by viruses including severe acute respiratory syndrome coronavirus 2 could cause organ inflammations such as myocarditis, pneumonia and encephalitis. Innate immunity to viral nucleic acids mediates antiviral immunity as well as inflammatory organ injury. However, the innate immune mechanisms that control viral induced organ inflammations are unclear. METHODS: To understand the role of the E3 ligase TRIM18 in controlling viral myocarditis and organ inflammation, wild-type and Trim18 knockout mice were infected with coxsackievirus B3 for inducing viral myocarditis, influenza A virus PR8 strain and human adenovirus for inducing viral pneumonia, and herpes simplex virus type I for inducing herpes simplex encephalitis. Mice survivals were monitored, and heart, lung and brain were harvested for histology and immunohistochemistry analysis. Real-time PCR, co-immunoprecipitation, immunoblot, enzyme-linked immunosorbent assay, luciferase assay, flow cytometry, over-expression and knockdown techniques were used to understand the molecular mechanisms of TRIM18 in regulating type I interferon (IFN) production after virus infection in this study. RESULTS: We find that knockdown or deletion of TRIM18 in human or mouse macrophages enhances production of type I IFN in response to double strand (ds) RNA and dsDNA or RNA and DNA virus infection. Importantly, deletion of TRIM18 protects mice from viral myocarditis, viral pneumonia, and herpes simplex encephalitis due to enhanced type I IFN production in vivo. Mechanistically, we show that TRIM18 recruits protein phosphatase 1A (PPM1A) to dephosphorylate TANK binding kinase 1 (TBK1), which inactivates TBK1 to block TBK1 from interacting with its upstream adaptors, mitochondrial antiviral signaling (MAVS) and stimulator of interferon genes (STING), thereby dampening antiviral signaling during viral infections. Moreover, TRIM18 stabilizes PPM1A by inducing K63-linked ubiquitination of PPM1A. CONCLUSIONS: Our results indicate that TRIM18 serves as a negative regulator of viral myocarditis, lung inflammation and brain damage by downregulating innate immune activation induced by both RNA and DNA viruses. Our data reveal that TRIM18 is a critical regulator of innate immunity in viral induced diseases, thereby identifying a potential therapeutic target for treatment.

Asunto(s)

Encefalitis por Herpes Simple , Miocarditis , Ubiquitina-Proteína Ligasas , Virosis , Animales , Antivirales , Humanos , Inmunidad Innata , Inflamación/genética , Ratones , Miocarditis/genética , Miocarditis/virología , Proteína Fosfatasa 2C , ARN , Ubiquitina-Proteína Ligasas/genética

RESUMEN

Innate immune cells are critical in protective immunity against viral infections, involved in sensing foreign viral nucleic acids. Here we report that the poly(ADP-ribose) polymerase 9 (PARP9), a member of PARP family, serves as a non-canonical sensor for RNA virus to initiate and amplify type I interferon (IFN) production. We find knockdown or deletion of PARP9 in human or mouse dendritic cells and macrophages inhibits type I IFN production in response to double strand RNA stimulation or RNA virus infection. Furthermore, mice deficient for PARP9 show enhanced susceptibility to infections with RNA viruses because of the impaired type I IFN production. Mechanistically, we show that PARP9 recognizes and binds viral RNA, with resultant recruitment and activation of the phosphoinositide 3-kinase (PI3K) and AKT3 pathway, independent of mitochondrial antiviral-signaling (MAVS). PI3K/AKT3 then activates the IRF3 and IRF7 by phosphorylating IRF3 at Ser385 and IRF7 at Ser437/438 mediating type I IFN production. Together, we reveal a critical role for PARP9 as a non-canonical RNA sensor that depends on the PI3K/AKT3 pathway to produce type I IFN. These findings may have important clinical implications in controlling viral infections and viral-induced diseases by targeting PARP9.

Asunto(s)

Células Dendríticas/enzimología , Proteínas de Neoplasias/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Infecciones por Virus ARN/enzimología , ARN Viral/metabolismo , Animales , Chlorocebus aethiops , Células Dendríticas/virología , Humanos , Factor 3 Regulador del Interferón/metabolismo , Factor 7 Regulador del Interferón/metabolismo , Interferón Tipo I/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Poli(ADP-Ribosa) Polimerasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Infecciones por Virus ARN/virología , Virus ARN/genética , Virus ARN/fisiología , Transducción de Señal , Células THP-1 , Células Vero

RESUMEN

OBJECTIVE@#To study the pharmacokinetic characteristics, clinical effect, and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in children with acute lymphoblastic leukemia (ALL).@*METHODS@#A prospective study was performed on children with ALL who cyclophosphamide, cytarabine, and 6-mercaptopurine were used for consolidation therapy. PEG-rhG-CSF (PEG-rhG-CSF group) or rhG-CSF (rhG-CSF group) was injected after chemotherapy. The plasma concentration of PEG-rhG-CSF was measured, and clinical outcome and safety were observed for both groups.@*RESULTS@#A total of 17 children with ALL were enrolled, with 9 children in the PEG-rhG-CSF group and 8 children in the rhG-CSF group. In the PEG-rhG-CSF group, the peak concentration of PEG-rhG-CSF was 348.2 ng/mL (range 114.7-552.0 ng/mL), the time to peak was 48 hours (range 12-72 hours), and the half life was 14.1 hours (range 11.1-18.1 hours). The plasma concentration curve of PEG-rhG-CSF was consistent with the mechanism of neutrophil-mediated clearance. Compared with the rhG-CSF group, the PEG-rhG-CSF group had a significantly shorter median time to absolute neutrophil count (ANC) recovery (P0.05).@*CONCLUSIONS@#The pharmacokinetic characteristics of PEG-rhG-CSF in children with ALL receiving consolidation chemotherapy are consistent with the mechanism of neutrophil-mediated clearance, with a short half life and fast recovery of ANC, and there are no significant differences in safety between PEG-rhG-CSF and rhG-CSF.

Asunto(s)

Niño , Humanos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neutropenia , Polietilenglicoles , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estudios Prospectivos , Proteínas Recombinantes

RESUMEN

OBJECTIVE@#To study the clinical features and genetic mutations of children with Shwachman-Diamond syndrome (SDS) and malignant myeloid transformation.@*METHODS@#Next-generation sequencing was used to analyze the gene mutations in 11 SDS children with malignant myeloid transformation, and their clinical features and genetic mutations were analyzed.@*RESULTS@#Of the 11 children with SDS, 9 (82%) presented with refractory cytopenia of childhood (RCC), 1 (9%) had myelodysplastic syndrome with excess blasts (MDS-EB), and 1 (9%) had acute myeloid leukemia with myelodysplasia-related changes (AML-MRC). The median age of onset of malignant myeloid transformation was 48 months (ranged 7 months to 14 years). Of the 11 children, 45% had abnormalities in the hematological system alone. Mutations of the SBDS gene were detected in all 11 children, among whom 5 (45%) had c.258+2T>C homozygous mutation and 3 (27%) had c.184A>T+c.258+2T>C compound heterozygous mutation. The new mutations of the SBDS gene, c.634_635insAACATACCTGT+c.637_638delGA and c.8T>C, were rated as "pathogenic" and "possibly pathogenic" respectively. The 3-year predicted overall survival rates of children transformed to RCC and MDS-EB/AML-MRC were 100% and 0% respectively (P=0.001).@*CONCLUSIONS@#SDS children may have hematological system symptoms as the only manifestation, which needs to be taken seriously in clinical practice. The type of malignant transformation is associated with prognosis.

Asunto(s)

Adolescente , Niño , Preescolar , Humanos , Lactante , Insuficiencia Pancreática Exocrina , Leucemia Mieloide Aguda , Mutación , Síndromes Mielodisplásicos , Síndrome de Shwachman-Diamond

RESUMEN

OBJECTIVE@#To investigate the consistency between FCM and PCR on the detecting of MRD in TCF3-PBX1@*METHODS@#55 cases of paediatric TCF3-PBX1@*RESULTS@#Among the 55 children with TCF3-PBX1@*CONCLUSION@#The detection result of MRD in TCF3-PBX1 detect by FCM and PCR shows better consistency. MRD positivity detected by FCM at the end of induction therapy (day 33) predicts a high risk of relapse in TCF3-PBX1 ALL patients.

Asunto(s)

Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Médula Ósea , Neoplasia Residual , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Pronóstico , Recurrencia

RESUMEN

OBJECTIVE@#To study the clinical features of Wiskott-Aldrich syndrome (WAS) in children.@*METHODS@#A retrospective analysis was performed for the clinical data of 13 children with WAS.@*RESULTS@#All 13 children were boys, with a median age of onset of 3 months (range 1-48 months) and a median age of 24 months (range 1-60 months) at the time of diagnosis. Of the 13 children, only 3 had typical WAS and the remaining 10 children had X-linked thrombocytopenia (XLT). The mean WAS score was 2 (range 1-3), the mean platelet count was 20.5×10/L [range (13-46)×10/L], and the mean platelet volume was 8.1 fl (range 6.7-12.1 fl). Lymphocyte subsets and immunoglobulins were measured for 4 children, among whom 1 (25%) had a reduction in both the percentage of CD3T cells per lymphocyte and lymphocyte per nuclear cells, 1(25%) had a reduction in CD3CD56 NK cells. Among these 4 children, 1 (25%) had an increase in IgG, 2 (50%) had a reduction in IgM, 1 (25%) had a reduction in IgA, and 4 (100%) had an increase in IgE. A total of 14 gene mutations belonging to 13 types were found in 13 children, among which there were 9 missense mutations (65%), 2 splicing mutations (14%), 2 nonsense mutation (14%), and 1 frameshift mutation (7%). The median follow-up time was 39 months (range 3-62 months), and all 13 children survived.@*CONCLUSIONS@#Children with WAS often have a young age of onset, and most of them are boys. Major clinical features include thrombocytopenia with a reduction in platelet volume. Missense mutation is the main type of gene mutation.

Asunto(s)

Preescolar , Humanos , Lactante , Masculino , Mutación , Estudios Retrospectivos , Trombocitopenia , Síndrome de Wiskott-Aldrich , Proteína del Síndrome de Wiskott-Aldrich

RESUMEN

Objective: To enrich the gene mutation sites and accumulate treatment experience of congenital dyserythropoietic anemia (CDA) type Ⅱ by reporting one case of CDA patient with new mutation site of SEC23B and was successfully treated by homozygous allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: The mutation within SEC23B gene in a child case with the reduced hemoglobin for more than 3 months, and his family were analyzed in combination with literatures review. Results: A 3-day 5-month female child was admitted due to "decreasing hemoglobin for more than 3 months" , blood routine test showed HGB 44 g/L, positive for acid hemolysis test (Ham test) . Bone marrow showed that the proportion of erythroid line was 69%, mainly middle and late juvenile erythrocytes, binuclear and odd nucleated erythrocytes could be observed, and nuclear fragmentation and nuclear budding could be seen occasionally in nucleated erythrocytes, transmission electron microscopy disclosed that bone marrow harbored the typical double-layer membrane structure of nuclear erythrocytes. There were two unreported new mutation sites in the SEC23B gene, including 1504 G>C/wt and c. 2254-2255 insert A/wt. The two mutations were derived from the father and mother of the child respectively. At the late stage, the child was successfully treated with allo-HSCT, the original mutation turned negative. Conclusion: This study reported the mutation type of SEC23B gene insertion for the first time in China. Allo-HSCT could be utilized as a treatment for CDA.

Asunto(s)

Femenino , Humanos , Anemia Diseritropoyética Congénita/genética , China , Eritroblastos , Mutación , Proteínas de Transporte Vesicular/genética

RESUMEN

The innate immunity is critically important in protection against virus infections, and in the case of RNA viral infections, the signaling mechanisms that initiate robust protective innate immunity without triggering autoimmune inflammation remain incompletely defined. In this study, we found the E3 ligase TRIM29 was specifically expressed in poly I:C-stimulated human myeloid dendritic cells. The induced TRIM29 played a negative role in type I IFN production in response to poly I:C or dsRNA virus reovirus infection. Importantly, the challenge of wild-type mice with reovirus led to lethal infection. In contrast, deletion of TRIM29 protected the mice from this developing lethality. Additionally, TRIM29-/- mice have lower titers of reovirus in the heart, intestine, spleen, liver, and brain because of elevated production of type I IFN. Mechanistically, TRIM29 was shown to interact with MAVS and subsequently induce its K11-linked ubiquitination and degradation. Taken together, TRIM29 regulates negatively the host innate immune response to RNA virus, which could be employed by RNA viruses for viral pathogenesis.

Asunto(s)

Inmunidad Innata/inmunología , Interferón Tipo I/biosíntesis , Infecciones por Reoviridae/inmunología , Reoviridae/inmunología , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Células Cultivadas , Células Dendríticas/inmunología , Humanos , Interferón Tipo I/inmunología , Ratones , Ratones Noqueados , Poli I-C , Factores de Transcripción/genética , Ubiquitinación

RESUMEN

Th9 cells are prominently featured in allergic lung inflammation, but the mechanism that regulates IL-9 induction in T helper cells remains poorly defined. Here we demonstrate that formation of super-enhancers (SEs) is critical in robust induction of IL-9 and that assembly of the Il9 SEs in Th cells requires OX40-triggered chromatin acetylation. Mechanistically, we found that OX40 costimulation induces RelB expression, which recruits the histone acetyltransferase p300 to the Il9 locus to catalyze H3K27 acetylation. This allows binding of the SE factor Brd4 to organize assembly of the SE complex, which in turn drives robust IL-9 expression and Th9 cell induction. Thus, Th9 cells are strongly induced upon OX40 stimulation, and disruption of SEs abolished Th9 cell induction in vitro and inhibited Th9 cell-mediated allergic airway inflammation in vivo. Together, our data suggest that formation of SEs is essential in IL-9 expression and Th9 cell induction. These findings may have important clinical implications.

Asunto(s)

Inflamación/inmunología , Interleucina-9/biosíntesis , Interleucina-9/genética , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Acetilación , Animales , Asma/etiología , Asma/inmunología , Asma/metabolismo , Elementos de Facilitación Genéticos , Código de Histonas , Humanos , Inflamación/etiología , Inflamación/metabolismo , Ratones , Ratones Transgénicos , Familia de Multigenes , Neumonía/etiología , Neumonía/inmunología , Neumonía/metabolismo , Receptores OX40/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Factor de Transcripción ReIB/metabolismo

RESUMEN

Ischemia and reperfusion injury (IRI) is an inevitable event in conventional organ transplant procedure and is associated with significant mortality and morbidity post-transplantation. We hypothesize that IRI is avoidable if the blood supply for the organ is not stopped, thus resulting in optimal transplant outcomes. Here we described the first case of a novel procedure called ischemia-free organ transplantation (IFOT) for patients with end-stage liver disease. The liver graft with severe macrovesicular steatosis was donated from a 25-year-old man. The recipient was a 51-year-old man with decompensated liver cirrhosis and hepatocellular carcinoma. The graft was procured, preserved, and implanted under continuous normothermic machine perfusion. The recipient did not suffer post-reperfusion syndrome or vasoplegia after revascularization of the allograft. The liver function test and histological study revealed minimal hepatocyte, biliary epithelium and vascular endothelium injury during preservation and post-transplantation. The inflammatory cytokine levels were much lower in IFOT than those in conventional procedure. Key pathways involved in IRI were not activated after allograft revascularization. No rejection, or vascular or biliary complications occurred. The patient was discharged on day 18 post-transplantation. This marks the first case of IFOT in humans, offering opportunities to optimize transplant outcomes and maximize donor organ utilization.

Asunto(s)

Carcinoma Hepatocelular/cirugía , Isquemia , Cirrosis Hepática/cirugía , Trasplante de Hígado/métodos , Preservación de Órganos , Daño por Reperfusión/prevención & control , Obtención de Tejidos y Órganos/métodos , Adulto , Humanos , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Perfusión , Pronóstico , Donantes de Tejidos/provisión & distribución

RESUMEN

<p><b>OBJECTIVE</b>To explore the HER22 expression in children with ETV6/RUNX1 (E/R)-positive acute lymphoblastic leukemia(ALL) and to investigate the relationship between the HER2 expression and clinical features.</p><p><b>METHODS</b>Thirty-seven newly diagnosed E/R-positive ALL children and 6 controls (4 cases of ITP and 2 healthy children) were selected in Institute of hematology and blood disease hospital. The 37 patients were divided into standard risk (SR), intermediate risk(IR), high risk(HR) groups according to risk stratification; and they were divided into relapse and non-relapse groups according to follow-up result. The CD10CD19 cells were sorted by flow cytometry. The mRNA was extracted from these cells. Real-time fluorescent quantitative PCR was used to detect the expression level of HER2.</p><p><b>RESULTS</b>Among the 37 cases, 51.35% (n=19) were boys and 48.65% (n=18) were girls and their median age was 4.72 (1.72-11.99) years old. Among the 6 controls, 50% (n=3) were boys and 50% (n=3) were girls and the median age was 5.24 (1.53-13.17) years old. The expression level of HER2 in E/R-positive ALL patients were lower than that in controls (P<0.05). Although the difference of HER2 expression level between the 2 groups failed to achieve statistical significance, the expression level of HER2 in relapse patients were significantly lower than that in non-relapse patients, and the HER2 expression in HR group patients were lower than that in SR and IR groups. In addition, there was no significant correlation between the expression level of HER2 and the sex, age, initial white blood cell count, blast cell percentage and the level of LDH (P>0.05).</p><p><b>CONCLUSION</b>The expression level of HER2 in E/R ALL patients is lower than that in controls, and in relapse group lower than that in non-relapse patient. Thus, HER2 may play important roles in the pathogenesis and relapse mechanism of pediatric E/R-positive ALL patients.</p>

Asunto(s)

Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Citometría de Flujo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Pronóstico , Proteínas Proto-Oncogénicas c-ets , Receptor ErbB-2 , Recurrencia , Proteínas Represoras

RESUMEN

<p><b>OBJECTIVE</b>To investigate the value of multiparameter flow cytometry (MFC) and flow cytometric scoring system (FCSS) in the diagnosis and prognostic evaluation of childhood myelodysplastic syndrome (MDS).</p><p><b>METHODS</b>A retrospective analysis was performed for the clinical data of 42 children who were diagnosed with MDS. MFC was performed to investigate the phenotype and proportion of each lineage of bone marrow cells. The correlations of FCSS score with MDS type, International Prognostic Scoring System (IPSS) score, and revised IPSS (IPSS-R) score were analyzed.</p><p><b>RESULTS</b>Of all the 42 children, 20 (48%) had an increase in abnormal marrow blasts, 19 (45%) had a lymphoid/myeloid ratio of >1, 14 (33%) had abnormal cross-lineage expression of lymphoid antigens in myeloid cells, 8 (19%) had abnormal CD13/CD16 differentiation antigens, 5 (12%) had abnormal expression of CD56, 3 (7%) had reduced or increased side scatter of granulocytes, 3 (7%) had reduced expression of CD36 in nucleated red blood cells, 2 (5%) had reduced expression of CD71 in nucleated red blood cells, 1 (2%) had absent expression of CD33 in myeloid cells, 1 (2%) had reduced or absent expression of CD11b in granulocytes, and 1 (2%) had absent expression of CD56 and CD14 in monocytes. There were significant differences in the median overall survival time and event-free survival time among the low-, medium-, and high-risk FCSS groups (P<0.05). Among the low-, medium-, and high-risk FCSS groups, the low-risk FCSS group had the highest 2-year overall survival rate, while there was no significant difference between the medium- and high-risk FCSS groups (P>0.05). The three groups had a 2-year event-free survival rate of 95%, 60%, and 46% respectively (P<0.05). FCSS score was positively correlated with MDS type, IPSS score, and IPSS-R score (P<0.05).</p><p><b>CONCLUSIONS</b>MFC and FCSS help with the diagnosis and prognostic evaluation of childhood MDS.</p>

RESUMEN

Many double-stranded DNA viruses, such as Epstein-Barr virus, can establish persistent infection, but the underlying virus-host interactions remain poorly understood. Here we report that in human airway epithelial cells Epstein-Barr virus induces TRIM29, a member of the TRIM family of proteins, to inhibit innate immune activation. Knockdown of TRIM29 in airway epithelial cells enhances type I interferon production, and in human nasopharyngeal carcinoma cells results in almost complete Epstein-Barr virus clearance. TRIM29 is also highly induced by cytosolic double-stranded DNA in myeloid dendritic cells. TRIM29 -/- mice have lower adenovirus titers in the lung, and are resistant to lethal herpes simplex virus-1 infection due to enhanced production of type I interferon. Mechanistically, TRIM29 induces K48-linked ubiquitination of Stimulator of interferon genes, a key adaptor in double-stranded DNA-sensing pathway, followed by its rapid degradation. These data demonstrate that Epstein-Barr virus and possible other double-stranded DNA viruses use TRIM29 to suppress local innate immunity, leading to the persistence of DNA virus infections.Proteins of the TRIM family have regulatory functions in immune signaling, often via ubiquitination of target proteins. Here, the authors show that TRIM29 is induced upon infection with DNA viruses, resulting in degradation of STING, decreased interferon signaling and increased pathogenicity in mice.

Asunto(s)

Proteínas de Unión al ADN/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Inmunidad Innata/inmunología , Factores de Transcripción/inmunología , Animales , Línea Celular , Infecciones por Virus ADN/inmunología , Infecciones por Virus ADN/metabolismo , Infecciones por Virus ADN/virología , Virus ADN/inmunología , Virus ADN/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/virología , Infecciones por Virus de Epstein-Barr/virología , Silenciador del Gen , Herpesvirus Humano 4/fisiología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata/genética , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Ratones Noqueados , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/virología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo

RESUMEN

Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (Treg) cells in the thymus. Activation of NF-κB transcription factors is critically required for Treg cell development, partly via initiating Foxp3 expression. NF-κB activation is controlled by a negative feedback regulation through the ubiquitin editing enzyme A20, which reduces proinflammatory signaling in myeloid cells and B cells. In naive CD4+ T cells, A20 prevents kinase RIPK3-dependent necroptosis. Using mice deficient for A20 in T lineage cells, we show that thymic and peripheral Treg cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic Treg differentiation. A20-deficient thymic Treg cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-κB transcription factor RelA was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic Treg cells. Furthermore, we found that the increase in Treg cells in T cell-specific A20-deficient mice was already observed in CD4+ single-positive CD25+ GITR+ Foxp3- thymic Treg cell progenitors. Treg cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic Treg cell development. A20-deficient Treg cells efficiently suppressed effector T cell-mediated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, suggesting normal suppressive function. Holding thymic production of natural Treg cells in check, A20 thus integrates Treg cell activity and increased effector T cell survival into an efficient CD4+ T cell response.

Asunto(s)

Linfocitos T CD4-Positivos/inmunología , Linfocitos T Reguladores/fisiología , Timo/citología , Timo/fisiología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Animales , Apoptosis , Diferenciación Celular , Citometría de Flujo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Enfermedad Injerto contra Huésped/prevención & control , Interleucina-2/inmunología , Activación de Linfocitos , Ratones , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-rel/genética , Transducción de Señal , Trasplante de Células Madre , Timo/inmunología , Factor de Transcripción ReIA/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/deficiencia

RESUMEN

Tissue-resident immune cells play a key role in local and systemic immune responses. The liver, in particular, hosts a large number of invariant natural killer T (iNKT) cells, which are involved in diverse immune responses. However, the mechanisms that regulate survival and homeostasis of liver iNKT cells are poorly defined. Here we have found that liver iNKT cells constitutively express the costimulatory TNF superfamily receptor OX40 and that OX40 stimulation results in massive pyroptotic death of iNKT cells, characterized by the release of potent proinflammatory cytokines that induce liver injury. This OX40/NKT pyroptosis pathway also plays a key role in concanavalin A-induced murine hepatitis. Mechanistically, we demonstrated that liver iNKT cells express high levels of caspase 1 and that OX40 stimulation activates caspase 1 via TNF receptor-associated factor 6-mediated recruitment of the paracaspase MALT1. We also found that activation of caspase 1 in iNKT cells results in processing of pro-IL-1ß to mature IL-1ß as well as cleavage of the pyroptotic protein gasdermin D, which generates a membrane pore-forming fragment to produce pyroptotic cell death. Thus, our study has identified OX40 as a death receptor for iNKT cells and uncovered a molecular mechanism of pyroptotic cell death. These findings may have important clinical implications in the development of OX40-directed therapies.

Asunto(s)

Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Células T Asesinas Naturales/fisiología , Piroptosis , Receptores OX40/fisiología , Animales , Caspasa 1/metabolismo , Caspasas/metabolismo , Línea Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Activación Enzimática , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Proteínas de Neoplasias/metabolismo , Transporte de Proteínas

RESUMEN

Myeloid-derived suppressor cells (MDSCs), a population of immature myeloid cells expanded and accumulated in tumor-bearing mice and in patients with cancer, have been shown to mediate immune suppression and to promote tumor progression, thereby, posing a major hurdle to the success of immune-activating cancer therapies. MDSCs, like their healthy counterparts, such as monocytes/macrophages and granulocytes, express an array of costimulatory and coinhibitory molecules as well as myeloid activators and inhibitory receptors, such as leukocyte immunoglobulin-like receptors (LILR) A and B. This review summarizes current findings on the LILR family members in various diseases, their potential roles in the pathogenesis, and possible strategies to revert or enhance the suppressive function of MDSCs for the benefit of patients by targeting LILRs.

Asunto(s)

Células Supresoras de Origen Mieloide/inmunología , Receptores Inmunológicos/inmunología , Animales , Humanos , Inmunoterapia/métodos , Escape del Tumor/inmunología

RESUMEN

<p><b>OBJECTIVE</b>To evaluate the clinical characteristics and risk factors of clonal evolution after immunosuppressive therapy (IST) in children with severe/very severe aplastic anemia (SAA/VSAA).</p><p><b>METHODS</b>The clinical data of 231 children with newly-diagnosed SAA/VSAA who received IST were retrospectively studied. The incidence and risk factors of clonal evolution after IST were analyzed.</p><p><b>RESULTS</b>The 5-year overall survival rate of the 231 patients was 82.7%. Except for 18 cases of early deaths, 213 patients were evaluated for IST efficacy. Among the 231 patients, cytogenetic abnormalities for at least two chromosome metaphase were detectable in 14 (7.4%) patients, and PNH clones were detectable in either peripheral red blood cells or neutrophils for 95 patients. Among the 213 patients evaluated for IST efficacy, 15 patients experienced clonal evolution after IST. Five patients had PNH and trisomy 8 which were defined as favorable progressions, and ten patients experienced monosomy 7 and MDS/AML as unfavorable progressions. The 5-year accumulative incidence of favorable and unfavorable progression were (2.2±2.2)% and (4.8±3.3)%, respectively. Until the last follow-up, 100% (5/5) of patients with favorable progressions and 50% (5/10) of patients with unfavorable progressions survived. WBC>3.5×10/L, CD3T cell percentage>80%, dosage of antithymocyte globulin >3.0 mg/(kg·d) and no response to IST were related to unfavorable progressions by univariate analysis. Cox multivariate analysis revealed that an increased CD3T cell percentage (>80%) and no response to IST were independent risk factors for unfavorable progressions.</p><p><b>CONCLUSIONS</b>The children with SAA/VSAA who have an increased CD3T cell percentage at diagnosis or have no response to IST are in high risks of unfavorable progressions.</p>

Asunto(s)

Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Anemia Aplásica , Quimioterapia , Genética , Alergia e Inmunología , Mortalidad , Aberraciones Cromosómicas , Evolución Clonal , Inmunosupresores , Usos Terapéuticos , Modelos de Riesgos Proporcionales , Estudios Retrospectivos