RESUMEN
The C-type lectin-like receptor CD161 is expressed by lymphocytes found in human gut and liver, as well as blood, especially natural killer (NK) cells, T helper 17 (Th17) cells, and a population of unconventional T cells known as mucosal-associated invariant T (MAIT) cells. The association of high CD161 expression with innate T-cell populations including MAIT cells is established. Here we show that CD161 is also expressed, at intermediate levels, on a prominent subset of polyclonal CD8+ T cells, including antiviral populations that display a memory phenotype. These memory CD161(int)CD8+ T cells are enriched within the colon and express both CD103 and CD69, markers associated with tissue residence. Furthermore, this population was characterized by enhanced polyfunctionality, increased levels of cytotoxic mediators, and high expression of the transcription factors T-bet and eomesodermin (EOMES). Such populations were induced by novel vaccine strategies based on adenoviral vectors, currently in trial against hepatitis C virus. Thus, intermediate CD161 expression marks potent polyclonal, polyfunctional tissue-homing CD8+ T-cell populations in humans. As induction of such responses represents a major aim of T-cell prophylactic and therapeutic vaccines in viral disease and cancer, analysis of these populations could be of value in the future.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Memoria Inmunológica , Mucosa Intestinal/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Células Th17/inmunología , Adenoviridae/inmunología , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/patología , Ensayos Clínicos como Asunto , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Colon/inmunología , Colon/patología , Enfermedad de Crohn/genética , Enfermedad de Crohn/patología , Regulación de la Expresión Génica , Hepacivirus/inmunología , Hepatitis C/inmunología , Hepatitis C/prevención & control , Hepatitis C/virología , Humanos , Cadenas alfa de Integrinas/genética , Cadenas alfa de Integrinas/inmunología , Mucosa Intestinal/patología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Activación de Linfocitos , Subfamilia B de Receptores Similares a Lectina de Células NK/genética , Cultivo Primario de Células , Transducción de Señal , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología , Acetato de Tetradecanoilforbol/farmacología , Células Th17/efectos de los fármacos , Células Th17/patologíaAsunto(s)
Ceftriaxona/administración & dosificación , Bloqueo Cardíaco , Enfermedad de Lyme , Miocarditis , Antibacterianos/administración & dosificación , Electrocardiografía , Bloqueo Cardíaco/diagnóstico , Bloqueo Cardíaco/etiología , Humanos , Enfermedad de Lyme/complicaciones , Enfermedad de Lyme/tratamiento farmacológico , Enfermedad de Lyme/fisiopatología , Masculino , Miocarditis/tratamiento farmacológico , Miocarditis/etiología , Miocarditis/fisiopatología , Síncope/etiología , Resultado del Tratamiento , Adulto JovenAsunto(s)
Estenosis de la Válvula Mitral/diagnóstico , Edema Pulmonar/diagnóstico , Cardiopatía Reumática/diagnóstico , Adulto , Diuréticos/uso terapéutico , Femenino , Humanos , Válvula Mitral/cirugía , Estenosis de la Válvula Mitral/tratamiento farmacológico , Embarazo , Edema Pulmonar/tratamiento farmacológico , Cardiopatía Reumática/tratamiento farmacológicoRESUMEN
A pool of immature T cells with a seemingly unrestricted repertoire of antigen specificities is generated life-long in the thymus. Amongst these cells are, however, thymocytes that express a strongly self-reactive antigen receptor and hence hold the potential to trigger autoimmunity. To prevent such an outcome, the thymus employs several independent but functionally related strategies that act in parallel to enforce self-tolerance. The deletion of strongly self-reactive thymocytes and the generation of regulatory T cells constitute the two most efficient mechanisms to induce and maintain immunological tolerance. Thymic epithelial cells of the medulla express for this purpose tissue-restricted self-antigens. This review will focus on the cellular and molecular mechanisms operative in the thymus to shape a repertoire of mature T cells tolerant to self-antigens.
Asunto(s)
Modelos Inmunológicos , Subgrupos de Linfocitos T/inmunología , Timo/inmunología , Autoinmunidad/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunidad Celular , Mutación , Autotolerancia/inmunología , Linfocitos T Reguladores/inmunología , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Proteína AIRERESUMEN
Acute arrhythmia is a condition covering a wide variety of rhythm disturbances. The aim of the article is to give practical recommendations for the approach and the treatment of the patient presenting with an acute arrhythmia. We discuss bradycardia and tachycardia. Tachycardias are divided into the small QRS complex tachycardias and the wide QRS complex tachycardias. Another important distinction with immediate therapeutic consequences is that between the hemodynamic stable and unstable patient. Flowcharts with diagnostic means and therapeutic schemes are added and a table with practical considerations for electrical cardioversion.
Asunto(s)
Arritmias Cardíacas/terapia , Enfermedad Aguda , Arritmias Cardíacas/fisiopatología , Bradicardia/fisiopatología , Bradicardia/terapia , Árboles de Decisión , Humanos , Taquicardia/fisiopatología , Taquicardia/terapiaRESUMEN
The role of cholesteryl ester transfer protein (CETP) in atherogenesis remains ambiguous, as both pro and antiatherogenic effects have been described. Expression of CETP increases HDL-cholesteryl ester turnover, but there is no direct evidence whether CETP mobilizes cholesterol in vivo. The rate of cholesterol removal injected into a leg muscle as cationized low density lipoprotein (cat-LDL) was compared in CETP transgenic and control mice. Four days after injection the exogenous cholesterol mass retained in muscle was 65% in CETP transgenic and 70% of injected dose in controls; it decreased to 52-54% by day 8 and negligible amounts remained on day 28. The cat-LDL was labeled with either 3H-cholesterol oleate (3H-CE) or 3H-cholesteryl oleoyl ether (3H-COE), a nonhydrolyzable analog of 3H-CE. After injection of 3H-CE cat-LDL, clearance of 3H-cholesterol had a t(1/2) of 4 days between day 4 and 8 but there was little loss of 3H-COE between day 4 and 51. Liver radioactivity on day 4 was 1.7% in controls and 3.4% in CETP transgenics; it was 2.8 and 4.6%, respectively, on day 8. 3H-COE in liver accounted for 60% of label in CETP transgenics. In conclusion, high levels of plasma CETP in mice do not enhance reverse cholesterol transport in vivo but may act on extracellularly located cholesteryl ester.
Asunto(s)
Proteínas Portadoras/metabolismo , Ésteres del Colesterol/metabolismo , Colesterol/metabolismo , Glicoproteínas , Metabolismo de los Lípidos , Animales , Proteínas de Transferencia de Ésteres de Colesterol , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Músculo Esquelético/metabolismoRESUMEN
Mice susceptible (C57BL/6) or resistant (C3H) to atherosclerosis induced by a high cholesterol-cholate containing diet (A-diet) were used to study reverse cholesterol transport (RCT) in vivo as measured by loss of cholesterol from a depot created by injection of cationized LDL into the rectus femoris muscle. Plasma total and HDL-cholesterol (HDL-C), total and HDL phospholipid (HDL-PL) levels in chow fed C3H male and female mice were higher than in C57BL/6 mice. After one month on A-diet, plasma cholesterol more than doubled in both strains and genders. The decrease in HDL-C and HDL-PL was twice as great in C57BL/6 as in C3H female mice, while in male C3H mice there was no decrease. The loss of exogenous cholesterol mass (ECM) after injection of cationized LDL was more rapid in C3H than in C57BL/6 mice. In chow fed mice, ECM retained in muscle on day 12 was 37% in C57BL/6 and 20% in C3H females; in males it was 39% and 18% in C57BL/6 and C3H, respectively. On A-diet, 76% were retained in C57BL/6 and 28% in C3H females; these values were 59% and 28% in C57BL/6 and C3H males. Thus, the slow clearance of ECM (which represents RCT) in C57BL/6 mice on A-diet, that could be related to a marked decrease of HDL-PL, might contribute towards their susceptibility to atherosclerosis.
Asunto(s)
Arteriosclerosis/dietoterapia , Arteriosclerosis/metabolismo , Colesterol en la Dieta/administración & dosificación , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Colesterol/metabolismo , Animales , Transporte Biológico Activo/fisiología , Colesterol/análisis , HDL-Colesterol/análisis , LDL-Colesterol/análisis , Modelos Animales de Enfermedad , Femenino , Modelos Lineales , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Probabilidad , Medición de Riesgo , Sensibilidad y Especificidad , Especificidad de la EspecieRESUMEN
Spontaneous coronary dissection is a rare event occurring particularly in women during the peripartum and postpartum period. Two cases related to the early postpartum period with a successful outcome are described, together with a comprehensive review of all the previously published cases. Diagnostic and therapeutic considerations of this unique clinical entity are discussed and reviewed.
Asunto(s)
Disección Aórtica/cirugía , Aneurisma Coronario/cirugía , Infarto del Miocardio/terapia , Trastornos Puerperales/terapia , Adulto , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/etiología , Aneurisma Coronario/diagnóstico por imagen , Aneurisma Coronario/etiología , Angiografía Coronaria , Femenino , Estudios de Seguimiento , Humanos , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico , Embarazo , Complicaciones Cardiovasculares del Embarazo/terapia , Resultado del Tratamiento , Procedimientos Quirúrgicos Vasculares/métodosRESUMEN
Female mice known to be susceptible (C57BL) and resistant (C3H and BALB/c) to diet-induced atherosclerosis were studied. Feeding of a cholate-containing atherogenic diet for 1 month resulted in an increase in plasma total cholesterol, little or no change in total phospholipids and high density lipoprotein (HDL) cholesterol, and a fall in HDL phospholipid, which was most pronounced in the C57BL strain. In elicited macrophages, cholesterol esterification was lower with acetylated low density lipoprotein (acLDL) and higher with beta-very low density lipoprotein (beta-VLDL) in C57BL than in C3H or BALB/C strains. In resident macrophages, acLDL enhanced cholesterol esterification more than did rabbit beta-VLDL. With acLDL, more apolipoprotein E (apoE) was recovered in all macrophage cultures. In macrophages from chow-fed mice, most apoE was in the medium, whereas in mice fed an atherogenic diet, half of the apoE was in the cells. ApoE protein was highest in macrophages from BALB/c mice fed an atherogenic diet; an increase in apoE mRNA occurred in BALB/c and C3H macrophages. Scavenger receptor AI/II mRNA was significantly higher in macrophages from atherosclerosis-resistant mice. Thus, higher HDL phospholipid and plasma apoE levels (reported by others), together with high macrophage scavenger receptor AI/II mRNA, could inhibit accretion of cholesterol in the vessel wall in the 2 resistant strains.
Asunto(s)
Apolipoproteínas E/genética , Arteriosclerosis/etiología , Arteriosclerosis/metabolismo , Colesterol/metabolismo , Macrófagos Peritoneales/metabolismo , ARN Mensajero/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Apolipoproteínas E/biosíntesis , Arteriosclerosis/patología , Células Cultivadas , Colesterol/sangre , Ésteres del Colesterol/metabolismo , Dieta Aterogénica , Susceptibilidad a Enfermedades , Femenino , Lípidos/sangre , Macrófagos Peritoneales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , ARN Mensajero/biosíntesis , Conejos , Receptores DepuradoresRESUMEN
T cell development is tightly controlled by thymic stromal cells. Alterations in stromal architecture affect T cell maturation and the development of self-tolerance. The monogenic autoimmune syndrome APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy) is characterized by the loss of self-tolerance to multiple organs. Although mutations in the autoimmune regulator (AIRE) gene are responsible for this disease, the function of AIRE is not known. Here we report on the spatial and temporal pattern of murine Aire expression during thymic ontogeny and T cell selection. Early during development, thymic Aire transcription is critically dependent on RelB and occurs in epithelial cells in response to lymphocyte-mediated signals. In adult tissue, Aire expression is confined to the medulla and the corticomedullary junction, where it is modulated by thymocytes undergoing negative selection. Aire may determine thymic stromal organization and with it the induction of self-tolerance.
Asunto(s)
Regulación de la Expresión Génica/inmunología , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/inmunología , Timo/citología , Timo/inmunología , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Animales , Comunicación Celular/genética , Comunicación Celular/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Desarrollo Embrionario y Fetal/genética , Desarrollo Embrionario y Fetal/inmunología , Células Epiteliales/citología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Tolerancia Inmunológica/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Poliendocrinopatías Autoinmunes/patología , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/fisiología , ARN Mensajero/biosíntesis , Células del Estroma/citología , Células del Estroma/inmunología , Células del Estroma/metabolismo , Timo/anatomía & histología , Timo/crecimiento & desarrollo , Factor de Transcripción ReIB , Factores de Transcripción/deficiencia , Factores de Transcripción/fisiología , Transcripción Genética/inmunología , Proteína AIRERESUMEN
To evaluate the spectrum and regulation of matrix metalloproteinases (MMPs) in bacterial meningitis (BM), concentrations of MMP-2, MMP-3, MMP-8, and MMP-9 and endogenous inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were measured in the cerebrospinal fluid (CSF) of 27 children with BM. MMP-8 and MMP-9 were detected in 91% and 97%, respectively, of CSF specimens from patients but were not detected in control patients. CSF levels of MMP-9 were higher (P<.05) in 5 patients who developed hearing impairment or secondary epilepsy than in those who recovered without neurological deficits. Levels of MMP-9 correlated with concentrations of TIMP-1 (P<.001) and tumor necrosis factor-alpha (P=.03). Repeated lumbar punctures showed that levels of MMP-8 and MMP-9 were regulated independently and did not correlate with the CSF cell count. Therefore, MMPs may derive not only from granulocytes infiltrating the CSF space but also from parenchymal cells of the meninges and brain. High concentrations of MMP-9 are a risk factor for the development of postmeningitidal neurological sequelae.
Asunto(s)
Barrera Hematoencefálica , Daño Encefálico Crónico/líquido cefalorraquídeo , Infecciones por Haemophilus/líquido cefalorraquídeo , Haemophilus influenzae , Metaloproteinasa 8 de la Matriz/líquido cefalorraquídeo , Metaloproteinasa 9 de la Matriz/líquido cefalorraquídeo , Meningitis Bacterianas/líquido cefalorraquídeo , Meningitis Meningocócica/líquido cefalorraquídeo , Meningitis Neumocócica/líquido cefalorraquídeo , Daño Encefálico Crónico/patología , Niño , Preescolar , Estudios de Seguimiento , Infecciones por Haemophilus/patología , Humanos , Lactante , Metaloproteinasa 2 de la Matriz/líquido cefalorraquídeo , Metaloproteinasa 3 de la Matriz/líquido cefalorraquídeo , Meningitis Bacterianas/patología , Meningitis Meningocócica/patología , Meningitis Neumocócica/patología , Neisseria meningitidis , Estudios Retrospectivos , Punción Espinal , Streptococcus pneumoniae , Factores de Tiempo , Inhibidor Tisular de Metaloproteinasa-1/líquido cefalorraquídeo , Inhibidor Tisular de Metaloproteinasa-2/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone marrow transplantation and is also dependent on the reestablishment of normal thymic structure and function. Graft-versus-host disease (GVHD), however, exacerbates posttransplant immunodeficiency through a deleterious effect on thymic function. To investigate the mechanisms of GVHD-mediated thymic disease, 2 murine parent-->F(1 )transplantation models of acute and chronic GVHD, respectively, were studied. Acute GVHD was associated with changes in thymic architecture and a reduction in cellularity mainly because of the decrease in CD4(+)CD8(+), or double-positive (DP) thymocytes, to less than 15% of values found in mice without GVHD. Simultaneously, mature donor-derived T cells expanded in the confines of the allogeneic thymic microenvironment, leading to local inflammation. Through analysis of in vivo cell proliferation, we demonstrated that the ensuing depletion of DP thymocytes was secondary to a decreased commitment of resident pro-T and pre-T cells to enter the cell cycle. Moreover, DP cells themselves showed altered proliferative capacities in the presence of acute GVHD. These findings suggested that thymic atrophy in acute GVHD is effected by impaired cellular proliferation of immature host thymocytes and that the failure of these cells to enter the cell cycle is dependent on an interferon (IFN)-gamma-driven immune response. In contrast, interleukin-4-driven chronic GVHD was not accompanied by a sustained thymic infiltration of donor T cells. Consequently, there was a lack of apparent structural changes, a restricted in situ transcription of inflammatory cytokines, and a virtually unchanged cell cycle progression in vivo.
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Transfusión de Linfocitos , Linfocitos T/inmunología , Timo/patología , Timo/trasplante , Trasplante Homólogo/inmunología , Animales , Atrofia , Ciclo Celular/inmunología , Cruzamientos Genéticos , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos , Linfocitos T/clasificación , Linfocitos T/patología , Timo/inmunología , Quimera por Trasplante , Trasplante HeterotópicoRESUMEN
BACKGROUND: Elimination of immature thymocytes resulting in thymic atrophy is characteristic of acute graft-versus-host disease (aGVHD). Because aGVHD has been associated with elevated glucocorticoid (GC) production, and CD4,CD8 double-positive thymocytes undergo rapid apoptosis in response to GCs, we hypothesized that administration of the GC receptor antagonist RU486 (mifepristone) should alter aGVHD-mediated thymocyte apoptosis. METHODS: Thymic development in the presence of aGVHD was studied in a haploidentical nonirradiated murine transplantation model (C57BL/6-->B6D2F1). Recipients were treated with RU486 or vehicle alone. Thymic development was analyzed by flow cytometry at different times post transplant. RESULTS: Acute thymic GVHD was characterized (1) by infiltration of mature donor-derived T cells and (2) by increased apoptosis of immature CD4+CD8+ thymocytes between 1 and 2 weeks after allogeneic transplantation. Contrary to expectations, administration of RU486 had no effect on these two parameters. CONCLUSIONS: Our data suggest that thymic pathology during aGVHD is mediated via a glucocorticoid-independent mechanism of apoptosis as blockade of glucocorticoid receptors did not alter the GVHD-induced thymic phenotype.
Asunto(s)
Apoptosis , Enfermedad Injerto contra Huésped/inmunología , Transfusión de Linfocitos , Mifepristona/farmacología , Linfocitos T/inmunología , Timo/patología , Trasplante Homólogo/inmunología , Trasplante Isogénico/inmunología , Animales , Apoptosis/efectos de los fármacos , Atrofia , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Citometría de Flujo , Enfermedad Injerto contra Huésped/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Receptores de Glucocorticoides/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Linfocitos T/patologíaRESUMEN
T-cell development is under the tight control of thymic microenvironments. Conversely, the integrity of thymic microenvironments depends on the physical presence of developing thymocytes, a phenomenon designated as 'thymic crosstalk'. We now show, using three types of immunodeficient mice, i.e. CD3(epsilon) transgenic mice, RAG(null) mice and RAG(null)-bone-marrow-transplanted CD3(epsilon) transgenic mice, that the control point in lymphoid development where triple negative (CD3(-),CD4(-),CD8(-)) thymocytes progress from CD44(+)CD25(-) towards CD44(-)CD25(+), influences the development of epithelial cells, critically inducing the extra, third dimension in the organization of the epithelial cells in the cortex. This tertiary configuration of the thymic epithelium is a typical feature for the thymus, enabling lymphostromal interaction during T-cell development. Crosstalk signals at this control point also induce the formation of thymic nurse cells. Moreover, our data indicate that establishment of a thymic cortex is a prerequisite for the development of the thymic medulla. Thus, differentiating thymocytes regulate the morphogenesis of thymic microenvironments in a stepwise fashion.
Asunto(s)
Subgrupos de Linfocitos T/fisiología , Timo/fisiología , Animales , Células de la Médula Ósea/fisiología , Trasplante de Médula Ósea , Complejo CD3/genética , Complejo CD3/fisiología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/fisiología , Ratones , Ratones Transgénicos , Fenotipo , Subgrupos de Linfocitos T/citología , Timo/citologíaRESUMEN
After primary infection in childhood, varicella zoster virus (VZV) remains latent in the dorsal route ganglia. Its reactivation later in life can lead to a zoster episode. VZV-specific, T-cell-mediated immunity (VZV-CMI) is likely to be important in preventing symptomatic reactivation. As CMI declines with age, a vaccine enhancing VZV-CMI might be effective in decreasing the incidence or severity of zoster in elderly subjects. A randomized, double blind controlled trial assessing CMI responses of elderly subjects immunized with a live attenuated, VZV-Oka vaccine was conducted. Two hundred healthy volunteers (55-75 years of age) received either a single injection of the VZV vaccine (PMC), containing 3200 (Oka 3200), 8500 (Oka 8500), or 41,650 (Oka 41650) PFU of live VZV, or a pneumococcus vaccine control group (Pneumo 23((R)). The immune response to VZV was assessed by measuring the T-cell response to VZV antigens, i.e. proliferation (stimulation index, SI), precursor cell frequency (PCF), cytokine secretion, and antibody titers. Six weeks post-vaccination, VZV-specific SI (adjusted mean values) was significantly greater (P<0.0001) in the 3 vaccine groups (with SI=5. 6 for Oka 3200; SI=5.0 for Oka 8500, and SI=7.2 for Oka 41,650) than in the control group (SI=2.9). The increase in PCF was striking, with 72.4, 91.2 and 85.1 precursors per million cells respectively in these 3 vaccine groups, vs 26.3 in the control group. No significant IL-4 secretion was observed in any subject, whereas the presence of IFN-gamma secretion was found to correlate with good responder status. The increase of these CMI parameters did not depend upon the titer of virus injected. Geometric mean titers of VZV antibodies increased in all vaccine groups and remained unchanged in the control group. Nevertheless, no correlation between the antibody response and the cell-mediated response was found. Live attenuated VZV vaccine caused a significant increase in VZV-CMI in a healthy, elderly population. No relationship between vaccine dose and the intensity of the specific response was found.