RESUMEN
Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations that maximize these plasma cell metabolic properties might thus provide enduring antibody-mediated immunity.
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Células Productoras de Anticuerpos/inmunología , Glucosa/metabolismo , Mitocondrias/metabolismo , Células Plasmáticas/inmunología , Ácido Pirúvico/metabolismo , Animales , Transporte Biológico Activo , Respiración de la Célula , Células Cultivadas , Glicosilación , Humanos , Inmunoglobulinas/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proproteína Convertasa 2/genética , Proproteína Convertasa 2/metabolismo , Estrés Fisiológico/inmunologíaRESUMEN
Esophageal atresia and tracheoesophageal fistula (EA/TEF) are relatively common malformations of the human foregut. The etiology remains incompletely understood with genetic causes identified in a small minority of affected patients. We present the case of a newborn with type C EA/TEF along with proximal symphalangism found to have a de novo NOG nonsense mutation. Patients with chromosome 17q deletions including the NOG gene have previously been reported to have EA/TEF but mutations in the gene have not been identified in patients with this malformation. This case provides evidence that haploinsufficiency for NOG may be the cause for EA/TEF in the 17q deletion syndrome and suggests that the clinical spectrum of NOG-related symphalangism spectrum disorders may include EA/TEF.
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Atresia Esofágica , Artropatías , Fístula Traqueoesofágica , Codón sin Sentido , Atresia Esofágica/genética , Humanos , Recién Nacido , Mutación , Fístula Traqueoesofágica/diagnóstico , Fístula Traqueoesofágica/genéticaRESUMEN
While most blood lineages are assumed to mature through a single cellular and developmental route downstream of HSCs, dendritic cells (DCs) can be derived from both myeloid and lymphoid progenitors in vivo. To determine how distinct progenitors can generate similar downstream lineages, we examined the transcriptional changes that accompany loss of in vivo myeloid potential as common myeloid progenitors differentiate into common DC progenitors (CDPs), and as lymphoid-primed multipotent progenitors (LMPPs) differentiate into all lymphoid progenitors (ALPs). Microarray studies revealed that IFN regulatory factor 8 (IRF-8) expression increased during each of these transitions. Competitive reconstitutions using Irf8(-/-) BM demonstrated cell-intrinsic defects in the formation of CDPs and all splenic DC subsets. Irf8(-/-) common myeloid progenitors and, unexpectedly, Irf8(-/-) ALPs produced more neutrophils in vivo than their wild-type counterparts at the expense of DCs. Retroviral expression of IRF-8 in multiple progenitors led to reduced neutrophil production and increased numbers of DCs, even in the granulocyte-macrophage progenitor (GMP), which does not normally possess conventional DC potential. These data suggest that IRF-8 represses a neutrophil module of development and promotes convergent DC development from multiple lymphoid and myeloid progenitors autonomously of cellular context.
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Linaje de la Célula/genética , Células Dendríticas/citología , Células Madre Hematopoyéticas/citología , Factores Reguladores del Interferón/genética , Linfocitos/citología , Células Mieloides/citología , Neutrófilos/citología , Animales , Diferenciación Celular/genética , Células HEK293 , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Humanos , Factores Reguladores del Interferón/metabolismo , Linfocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/metabolismo , Transcripción GenéticaRESUMEN
BACKGROUND: Kidney disease is an important cause of morbidity and mortality in patients with sickle cell anemia (SCA). The factors that affect progression of renal disease are unknown, especially in children and adolescents. Alterations in blood pressure, including hypertension and lack of the normal nocturnal dip in blood pressure, are important determinants of diabetic nephropathy and other renal diseases and may play a role in sickle cell nephropathy. Our primary hypothesis was that children with SCA who have microalbuminuria will demonstrate less nocturnal dipping of blood pressure compared to patients without microalbuminuria. We also investigated other potential factors associated with microalbuminuria. PROCEDURE: This prospective study of 52 adolescents with SCA followed in the Children's Medical Center Dallas Comprehensive Sickle Cell Center characterized 24-hour ambulatory blood pressure profiles and presence of microalbuminuria. Stepwise logistic regression was performed to identify significant independent factors that are associated with microalbuminuria. RESULTS: Thirty-five percent of patients were identified as having previously unrecognized hypertension, and 17% had pre-hypertension (blood pressure greater than the 90th percentile but less than the 95th percentile). Fifty-six percent of patients lacked the normal nocturnal dip in blood pressure. In addition, 21% had microalbuminuria, and their percent nocturnal dip was significantly less than those without microalbuminuria (P = 0.01). CONCLUSIONS: Blood pressure abnormalities are common in adolescents with SCA and are a possible modifiable risk factor in the progression of sickle cell nephropathy.
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Anemia de Células Falciformes/complicaciones , Hipertensión/epidemiología , Adolescente , Albuminuria/epidemiología , Anemia de Células Falciformes/fisiopatología , Presión Sanguínea , Monitoreo Ambulatorio de la Presión Arterial , Niño , Femenino , Tasa de Filtración Glomerular , Humanos , Modelos Logísticos , Masculino , Estudios ProspectivosRESUMEN
Invariant NKT (iNKT) cells regulate early immune responses to infections, in part because of their rapid release of IFN-gamma and IL-4. iNKT cells are proposed to reduce the severity of Lyme disease following Borrelia burgdorferi infection. Unlike conventional T cells, iNKT cells express an invariant alphabeta TCR that recognizes lipids bound to the MHC class I-like molecule, CD1d. Furthermore, these cells are positively selected following TCR interactions with glycolipid/CD1d complexes expressed on CD4+CD8+ thymocytes. Whereas conventional T cell development can proceed with as few as 4/10 CD3 immunoreceptor tyrosine-based activation motifs (ITAMs), little is known about the ITAM requirements for iNKT cell selection and expansion. We analyzed iNKT cell development in CD3 zeta transgenic lines with various tyrosine-to-phenylalanine substitutions (YF) that eliminated the functions of the first (YF1,2), third (YF5,6), or all three (YF1-6) CD3 zeta ITAMs. iNKT cell numbers were significantly reduced in the thymus, spleen, and liver of all YF mice compared with wild type mice. The reduced numbers of iNKT cells resulted from significant reductions in the expression of the early growth response 2 and promyelocytic leukemia zinc finger transcription factors. In the mice with few to no iNKT cells, there was no difference in the severity of Lyme arthritis compared with wild type controls, following infections with the spirochete B. burgdorferi. These findings indicate that a full complement of functional CD3 zeta ITAMs is required for effective iNKT cell development.
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Complejo CD3/inmunología , Células T Asesinas Naturales/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Secuencias de Aminoácidos , Animales , Diferenciación Celular/inmunología , Separación Celular , Citometría de Flujo , Interleucina-4/inmunología , Interleucina-4/metabolismo , Enfermedad de Lyme/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Transgénicos , Células T Asesinas Naturales/citología , Receptores de Antígenos de Linfocitos T/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The CD3 epsilon subunit of the TCR complex contains two defined signaling domains, a proline-rich sequence and an ITAM. We identified a third signaling sequence in CD3 epsilon, termed the basic-rich stretch (BRS). Herein, we show that the positively charged residues of the BRS enable this region of CD3 epsilon to complex a subset of acidic phospholipids, including PI(3)P, PI(4)P, PI(5)P, PI(3,4,5)P(3), and PI(4,5)P(2). Transgenic mice containing mutations of the BRS exhibited varying developmental defects, ranging from reduced thymic cellularity to a complete block in T cell development. Peripheral T cells from BRS-modified mice also exhibited several defects, including decreased TCR surface expression, reduced TCR-mediated signaling responses to agonist peptide-loaded APCs, and delayed CD3 epsilon localization to the immunological synapse. Overall, these findings demonstrate a functional role for the CD3 epsilon lipid-binding domain in T cell biology.
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Complejo CD3/metabolismo , Fosfolípidos/metabolismo , Linfocitos T/inmunología , Secuencias de Aminoácidos , Aminoácidos Básicos , Animales , Sitios de Unión , Complejo CD3/genética , Complejo CD3/fisiología , Línea Celular , Citoplasma/química , ADN Complementario , Humanos , Ratones , Mutación , Receptores de Antígenos de Linfocitos T , Timo/citologíaRESUMEN
This review explores the current model of sickle cell nephropathy and the limitations of the model. Renal abnormalities are common complications of sickle cell disease (SCD). Beginning in childhood, patients with SCD develop a urinary concentrating defect resulting in polyuria and a predisposition to nocturnal enuresis and dehydration. The current model of sickle cell nephropathy suggests that destruction of the renal medulla induces production of renal vasodilating substances that feedback to the glomerulus causing hyperfiltration. Hyperfiltration leads to glomerulosclerosis and proteinuria, with eventual reduction in kidney function. The crucial steps of vasodilating substance production and hyperfiltration in children with SCD have not been proven. Treatment of sickle cell nephropathy is aimed at the reduction of proteinuria with angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Hydroxyurea and chronic transfusion therapy may also alter the progression of sickle cell nephropathy in children. Further studies are needed to identify an accurate model and effective treatments for sickle cell nephropathy.
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Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/fisiopatología , Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , HumanosRESUMEN
PURPOSE OF REVIEW: Antenatally detected renal abnormalities are frequently encountered. Recommended postnatal evaluation of these infants has evolved to minimize invasive testing while maximizing detection of significant abnormalities. RECENT FINDINGS: There is a low rate of detectable renal abnormalities in infants with a normal postnatal sonogram at 4-6 weeks of age. Routine prophylactic antibiotics are not indicated in infants with isolated antenatal hydronephrosis. Infants with a multicystic dysplastic kidney and a normal contralateral kidney on renal ultrasound do not require further evaluation. Parents of these children should be counseled on symptoms of urinary tract infections to allow prompt diagnosis. SUMMARY: All infants with abnormalities on antenatal sonogram should undergo postnatal evaluation with a sonogram after birth and at 4-6 weeks of age. Further evaluation can be safely limited when the postnatal sonogram is normal at 6 weeks of age.
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Hidronefrosis/diagnóstico por imagen , Riñón Displástico Multiquístico/diagnóstico por imagen , Atención Perinatal/métodos , Ultrasonografía Prenatal , Reflujo Vesicoureteral/diagnóstico por imagen , Factores de Edad , Humanos , Recién Nacido , Síndrome del Abdomen en Ciruela Pasa/diagnóstico por imagen , Ureterocele/diagnóstico por imagen , Sistema Urinario/anomalías , Sistema Urinario/diagnóstico por imagenRESUMEN
T cell receptor signaling processes are controlled by the integrated actions of families of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPases). Several distinct cytosolic protein tyrosine phosphatases have been described that are able to negatively regulate TCR signaling pathways, including SHP-1, SHP-2, PTPH1, and PEP. Using PTPase substrate-trapping mutants and wild type enzymes, we determined that PTPN4/PTP-MEG1, a PTPH1-family member, could complex and dephosphorylate the ITAMs of the TCR zeta subunit. In addition, the substrate-trapping derivative augmented basal and TCR-induced activation of NF-kappaB in T cells. To characterize the contribution of this PTPase in T cells, we developed PTPN4-deficient mice. T cell development and TCR signaling events were comparable between wild type and PTPN4-deficient animals. The magnitude and duration of TCR-regulated ITAM phosphorylation, as well as overall protein phosphorylation, was unaltered in the absence of PTPN4. Finally, Th1- and Th2-derived cytokines and in vivo immune responses to Listeria monocytogenes were equivalent between wild type and PTPN4-deficient mice. These findings suggest that additional PTPases are involved in controlling ITAM phosphorylations.
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FN-kappa B/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 4/fisiología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/fisiología , Animales , Células COS , Línea Celular , Chlorocebus aethiops , Humanos , Células Jurkat , Riñón/citología , Ratones , FN-kappa B/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 4/química , Proteína Tirosina Fosfatasa no Receptora Tipo 4/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 4/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , TransfecciónRESUMEN
INTRODUCTION: While extracorporeal membrane oxygenation (ECMO) is effective in preventing further hypoxemia and maintains blood flow in endotoxin-induced shock, ECMO alone does not reverse the hypotension. In this study, we tested whether concurrent vasopressor use with ECMO would provide increased circulatory support and blood flow, and characterized regional blood flow distribution to vital organs. METHODS: Endotoxic shock was induced in piglets to achieve a 30% decrease in mean arterial pressure (MAP). Measurements of untreated pigs were compared to pigs treated with ECMO alone or ECMO and vasopressors. RESULTS: ECMO provided cardiac support during vasodilatory endotoxic shock and improved oxygen delivery, but vasopressor therapy was required to return MAP to normotensive levels. Increased blood pressure with vasopressors did not alter oxygen consumption or extraction compared to ECMO alone. Regional microcirculatory blood flow (RBF) to the brain, kidney, and liver were maintained or increased during ECMO with and without vasopressors. CONCLUSION: ECMO support and concurrent vasopressor use improve regional blood flow and oxygen delivery even in the absence of full blood pressure restoration. Vasopressor-induced selective distribution of blood flow to vital organs is retained when vasopressors are administered with ECMO.
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Oxigenación por Membrana Extracorpórea , Microcirculación , Flujo Sanguíneo Regional , Choque Séptico/tratamiento farmacológico , Choque Séptico/fisiopatología , Vasoconstrictores/uso terapéutico , Animales , Hemodinámica/efectos de los fármacos , Microcirculación/efectos de los fármacos , Oxígeno/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacos , Pruebas de Función Respiratoria , Porcinos , Vasoconstrictores/farmacologíaRESUMEN
The incidence of mercury intoxication has decreased considerably because of stricter public health regulations. However, it has not been completely eliminated and should be considered in a child with unexplained tachycardia, hypertension, mood changes, weight loss, and acrodynia. Mercury intoxication can be difficult to differentiate from pheochromocytoma and Kawasaki's disease. Here, the authors report the case of an 8-year-old boy with history of mercury exposure, signs and symptoms suggestive of mercury intoxication, and good response to chelation therapy, but with only mild increase in urinary mercury levels. This case highlights the fact that urinary mercury levels do not necessarily correlate with the severity of clinical signs and symptoms of mercury intoxication.
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Intoxicación del Sistema Nervioso por Mercurio/fisiopatología , Quelantes/uso terapéutico , Niño , Humanos , Masculino , Intoxicación del Sistema Nervioso por Mercurio/clasificación , Intoxicación del Sistema Nervioso por Mercurio/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Succímero/uso terapéuticoRESUMEN
Interferon alpha and its surrogates, including IP-10 and SIGLEC1, paralleled changes of disease activity in systemic lupus erythematosus (SLE). However, the whole blood interferon signature (WBIFNS)-the current standard for type I IFN assessment in SLE-does not correlate with SLE disease activity in individual patients over time. The underlying causes for this apparent contradiction have not been convincingly demonstrated. Using a multicenter dataset of gene expression data from leukocyte subsets in SLE, we identify distinctive subset-specific contributions to the WBIFNS. In a subsequent analysis, the effects of type I interferon on cellular blood composition in patients with SLE and hepatitis B were also studied over time. We found that type I interferon mediates significant alterations in whole blood composition, including a neutropenia and relative lymphocytosis. Given different effects of type 1 interferon on different leukocyte subsets, these shifts confound measurement of a type 1 interferon signature in whole blood. To minimize and overcome these limitations of the WBIFNS, we suggest to measure IFN-induced transcripts or proteins in a specific leukocyte subset to improve clinical impact of interferon biomarkers. KEY MESSAGES: Myeloid cells contribute more to the WBIFNS in SLE than their lymphocytic counterpart. Very similar leukocyte subsets reveal distinctive IFN signatures. IFN alpha mixes up composition of blood and leads to a preferential neutropenia, yielding relative lymphocytosis.
Asunto(s)
Hepatitis B/genética , Hepatitis C/genética , Interferón Tipo I/genética , Leucocitos/patología , Lupus Eritematoso Sistémico/genética , Transcriptoma , Adulto , Biomarcadores/análisis , Biomarcadores/sangre , Femenino , Hepatitis B/sangre , Hepatitis B/patología , Hepatitis C/sangre , Hepatitis C/patología , Humanos , Interferón Tipo I/análisis , Interferón Tipo I/sangre , Leucocitos/metabolismo , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/patología , Linfocitosis/sangre , Linfocitosis/genética , Linfocitosis/patología , Masculino , Persona de Mediana EdadRESUMEN
All-lymphoid progenitors (ALPs) yield few myeloid cells in vivo, but readily generate such cells in vitro. The basis for this difference remains unknown. We hypothesized that ALPs limit responsiveness to in vivo concentrations of myeloid-promoting cytokines by reducing expression of the corresponding receptors, potentially through posttranscriptional mechanisms. Consistent with such a mechanism, ALPs express higher levels of CSF1R transcripts than their upstream precursors, yet show limited cell-surface protein expression of colony-stimulating factor 1 receptor (CSF1R). All-lymphoid progenitors and other hematopoietic progenitors deficient in A disintegrin and metalloproteinase domain 17 (ADAM17), display elevated cell surface CSF1R expression. ADAM17(-/-) ALPs, however, fail to yield myeloid cells upon transplantation into irradiated recipients. Moreover, ADAM17(-/-) ALPs yield fewer macrophages in vitro than control ALPs at high concentrations of macrophage colony stimulating factor. Mice with hematopoietic-specific deletion of ADAM17 have normal numbers of myeloid and lymphoid progenitors and mature cells in vivo. These data demonstrate that ADAM17 limits CSF1R protein expression on hematopoietic progenitors, but that compensatory mechanisms prevent elevated CSF1R levels from altering lymphoid progenitor potential.
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Proteínas ADAM/fisiología , Células Madre Hematopoyéticas/metabolismo , Linfocitos/metabolismo , Receptor de Factor Estimulante de Colonias de Macrófagos/biosíntesis , Proteínas ADAM/deficiencia , Proteínas ADAM/genética , Proteína ADAM17 , Animales , Trasplante de Médula Ósea , Linaje de la Célula , Membrana Celular/metabolismo , Regulación de la Expresión Génica , Linfopoyesis/efectos de los fármacos , Linfopoyesis/genética , Factor Estimulante de Colonias de Macrófagos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mielopoyesis/efectos de los fármacos , Mielopoyesis/genética , ARN Mensajero/biosíntesis , Quimera por Radiación , Receptor de Factor Estimulante de Colonias de Macrófagos/genéticaRESUMEN
Specific G protein coupled receptors (GPRs) regulate the proper positioning, function, and development of immune lineage subsets. Here, we demonstrate that GPR18 regulates the reconstitution of intraepithelial lymphocytes (IELs) of the small intestine following bone marrow transplantation. Through analysis of transcriptional microarray data, we find that GPR18 is highly expressed in IELs, lymphoid progenitors, and mature follicular B cells. To establish the physiological role of this largely uncharacterized GPR, we generated Gpr18-/- mice. Despite high levels of GPR18 expression in specific hematopoietic progenitors, Gpr18-/- mice have no defects in lymphopoiesis or myelopoiesis. Moreover, antibody responses following immunization with hapten-protein conjugates or infection with West Nile virus are normal in Gpr18-/- mice. Steady-state numbers of IELs are also normal in Gpr18-/- mice. However, competitive bone marrow reconstitution experiments demonstrate that GPR18 is cell-intrinsically required for the optimal restoration of small intestine TCRγδ+ and TCRαß+ CD8αα+ IELs. In contrast, GPR18 is dispensable for the reconstitution of large intestine IELs. Moreover, Gpr18-/- bone marrow reconstitutes small intestine IELs similarly to controls in athymic recipients. Gpr18-/- chimeras show no changes in susceptibility to intestinal insults such as Citrobacter rodentium infections or graft versus host disease. These data reveal highly specific requirements for GPR18 in the development and reconstitution of thymus-derived intestinal IEL subsets in the steady-state and after bone marrow transplantation.
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Trasplante de Médula Ósea , Intestino Delgado/metabolismo , Linfocitos/citología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Linfocitos B/citología , Células de la Médula Ósea/citología , Citrobacter , Femenino , Enfermedad Injerto contra Huésped , Células Madre Hematopoyéticas/citología , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mielopoyesis , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Timo/metabolismo , Trasplante Homólogo , Virus del Nilo OccidentalRESUMEN
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by defective immune tolerance combined with immune cell hyperactivity resulting in the production of pathogenic autoantibodies. Previous gene expression studies employing whole blood or peripheral blood mononuclear cells (PBMC) have demonstrated that a majority of patients with active disease have increased expression of type I interferon (IFN) inducible transcripts known as the IFN signature. The goal of the current study was to assess the gene expression profiles of isolated leukocyte subsets obtained from SLE patients. Subsets including CD19(+) B lymphocytes, CD3(+)CD4(+) T lymphocytes and CD33(+) myeloid cells were simultaneously sorted from PBMC. The SLE transcriptomes were assessed for differentially expressed genes as compared to healthy controls. SLE CD33(+) myeloid cells exhibited the greatest number of differentially expressed genes at 208 transcripts, SLE B cells expressed 174 transcripts and SLE CD3(+)CD4(+) T cells expressed 92 transcripts. Only 4.4% (21) of the 474 total transcripts, many associated with the IFN signature, were shared by all three subsets. Transcriptional profiles translated into increased protein expression for CD38, CD63, CD107a and CD169. Moreover, these studies demonstrated that both SLE lymphoid and myeloid subsets expressed elevated transcripts for cytosolic RNA and DNA sensors and downstream effectors mediating IFN and cytokine production. Prolonged upregulation of nucleic acid sensing pathways could modulate immune effector functions and initiate or contribute to the systemic inflammation observed in SLE.
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Linfocitos B/metabolismo , Interferones/genética , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/genética , Células Mieloides/metabolismo , Subgrupos de Linfocitos T/metabolismo , Transcriptoma/genética , Adulto , Linfocitos B/patología , ADN/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Interferones/metabolismo , Lupus Eritematoso Sistémico/inmunología , Persona de Mediana Edad , Células Mieloides/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Subgrupos de Linfocitos T/patología , Regulación hacia Arriba/genética , Adulto JovenRESUMEN
BACKGROUND: Physiological stress evokes rapid changes in both the innate and adaptive immune response. Immature αß T cells developing in the thymus are particularly sensitive to stress, with infections and/or exposure to lipopolysaccharide or glucocorticoids eliciting a rapid apoptotic program. MicroRNAs are a class of small, non-coding RNAs that regulate global gene expression by targeting diverse mRNAs for degradation. We hypothesized that a subset of thymically encoded microRNAs would be stress responsive and modulate thymopoiesis. We performed microRNA profiling of thymic microRNAs isolated from control or stressed thymic tissue obtained from mice. We identified 18 microRNAs that are dysregulated >1.5-fold in response to lipopolysaccharide or the synthetic corticosteroid dexamethasone. These included the miR-17-90 cluster, which have anti-apoptotic functions, and the miR-181 family, which contribute to T cell tolerance. The stress-induced changes in the thymic microRNAs are dynamically and distinctly regulated in the CD4(-)CD8(-), CD4(+)CD8(+), CD4(+)CD8(-), and CD4(-)CD8(+) thymocyte subsets. Several of the differentially regulated murine thymic miRs are also stress responsive in the heart, kidney, liver, brain, and/or spleen. The most dramatic thymic microRNA down modulated is miR-181d, exhibiting a 15-fold reduction following stress. This miR has both similar and distinct gene targets as miR-181a, another member of miR-181 family. Many of the differentially regulated microRNAs have known functions in thymopoiesis, indicating that their dysregulation will alter T cell repertoire selection and the formation of naïve T cells. This data has implications for clinical treatments involving anti-inflammatory steroids, ablation therapies, and provides mechanistic insights into the consequences of infections.
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MicroARNs/genética , MicroARNs/metabolismo , Estrés Fisiológico/genética , Timo/metabolismo , Animales , Apoptosis/efectos de los fármacos , Secuencia de Bases , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Antígenos CD8/metabolismo , Proliferación Celular/efectos de los fármacos , Dexametasona/farmacología , Regulación hacia Abajo/efectos de los fármacos , Genes Reporteros/genética , Humanos , Factor Inhibidor de Leucemia/genética , Lipopolisacáridos/farmacología , Luciferasas/genética , Masculino , Ratones , Especificidad de Órganos , Estrés Fisiológico/efectos de los fármacos , Timocitos/citología , Timocitos/efectos de los fármacos , Timocitos/metabolismo , Timo/citología , Timo/efectos de los fármacos , Timo/fisiología , Factores de Tiempo , Transcriptoma/efectos de los fármacosRESUMEN
Primary renal lymphoma (PRL) is a rare lymphoma which usually presents with hematuria, flank pain, abdominal mass, and weight loss. PRL is more diagnosed in adults than children. We describe an asymptomatic child who presented with hypertension and was subsequently diagnosed with primary renal lymphoma. This case represents an atypical presentation for PRL.
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Hipertensión/complicaciones , Neoplasias Renales/complicaciones , Riñón/patología , Linfoma de Células T/complicaciones , Preescolar , Resultado Fatal , Humanos , Hipertensión/diagnóstico , Hipertensión/terapia , Neoplasias Renales/diagnóstico , Neoplasias Renales/terapia , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Masculino , Obesidad/complicaciones , Diálisis RenalRESUMEN
The TCR complex, when isolated from thymocytes and peripheral T cells, contains a constitutively tyrosine-phosphorylated CD3zeta molecule termed p21. Previous investigations have shown that the constitutive phosphorylation of CD3zeta results from TCR interactions with MHC molecules occurring in both the thymus and the periphery. To determine what contribution the selection environment had on this constitutive phosphorylation, we analyzed CD3zeta from several distinct class I- and II-restricted TCR-transgenic mice where thymocyte development occurred in either a selecting or a nonselecting MHC environment. Herein, we report that constitutively phosphorylated CD3zeta (p21) was present in thymocytes that developed under nonselecting peptide-MHC conditions. These findings strongly support the model that the TCR has an inherent avidity for MHC molecules before repertoire selection. Biochemical analyses of the TCR complex before and after TCR stimulation suggested that the constitutively phosphorylated CD3zeta subunit did not contribute to de novo TCR signals. These findings may have important implications for T cell functions during self-MHC recognition under normal and autoimmune circumstances.
Asunto(s)
Complejo CD3/metabolismo , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Tirosina/metabolismo , Animales , Complejo CD3/genética , Supervivencia Celular , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase II/genética , Ratones , Ratones Transgénicos , Fosforilación , Transducción de Señal , Timo/citología , Timo/inmunología , Tirosina/genéticaRESUMEN
Proximal tubule bicarbonate reabsorption is primarily mediated via the Na(+)/H(+) exchanger, identified as NHE3 in adults. Previous studies have demonstrated a maturational increase in rat proximal tubule NHE3 expression, with a paucity of NHE3 expression in neonates, despite significant Na(+)-dependent proton secretion. Recently, a novel Na(+)/H(+) antiporter (NHE8) was identified and found to be expressed on the apical membrane of the proximal tubule. To determine whether NHE8 may be the antiporter responsible for proton secretion in neonates, the present study characterized the developmental expression of NHE8 in rat proximal tubules. RNA blots and real-time RT-PCR demonstrated no developmental difference in the mRNA of renal NHE8. Immunoblots, however, demonstrated peak protein abundance of NHE8 in brush border membrane vesicles of 7- and 14-day-old compared with adult rats. In contrast, the level of NHE8 expression in total cortical membrane protein was higher in adults than in neonates. Immunohistochemistry confirmed the presence of NHE8 on the apical membrane of the proximal tubules of neonatal and adult rats. These data demonstrate that NHE8 does undergo maturational changes on the apical membrane of the rat proximal tubule and may account for the Na(+)-dependent proton flux in neonatal proximal tubules.