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The 30 Doradus star-forming region in the Large Magellanic Cloud is a nearby analog of large star-formation events in the distant universe. We determined the recent formation history and the initial mass function (IMF) of massive stars in 30 Doradus on the basis of spectroscopic observations of 247 stars more massive than 15 solar masses ([Formula: see text]). The main episode of massive star formation began about 8 million years (My) ago, and the star-formation rate seems to have declined in the last 1 My. The IMF is densely sampled up to 200 [Formula: see text] and contains 32 ± 12% more stars above 30 [Formula: see text] than predicted by a standard Salpeter IMF. In the mass range of 15 to 200 [Formula: see text], the IMF power-law exponent is [Formula: see text], shallower than the Salpeter value of 2.35.
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Following the detection of methicillin-resistant Staphylococcus aureus (MRSA) ST398 in food-producing animals, both livestock and wildlife, and derived products, are considered potential sources of MRSA in humans. There is a paucity of data on MRSA in foods in Italy, and the data regarding wild animals are particularly scarce. A total of 2162 food samples collected during official monitoring activities in 2008 were analyzed for the detection of S. aureus. Also, samples from 1365 wild animals collected by the National Reference Center for Wild Animal Diseases in 2003-2009 were subjected to anatomopathological examination. S. aureus isolates were processed for phenotypic and molecular methicillin resistance determinations. S. aureus was found in 2.0% of wild animal carcasses and in 3.2% of wild boar lymph nodes: none showed methicillin resistance. The prevalence of S. aureus in food was 17.1%. Two MRSA strains, both from bulk tank milk (prevalence 0.77%) were isolated: the strains were resistant to tetracycline, had spa-type t899, and were negative for the Panton-Valentine leukocidin gene. The low prevalence of MRSA suggests that the risk of transmission to humans via food is limited. However, attention should be paid to the cattle food chain, which may be a potential route of transmission of LA-MRSA.
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Animales Salvajes/microbiología , Microbiología de Alimentos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Infecciones Estafilocócicas/veterinaria , Animales , Antibacterianos/farmacología , Bovinos , Cabras , Caballos , Italia/epidemiología , Carne/microbiología , Resistencia a la Meticilina , Staphylococcus aureus Resistente a Meticilina/clasificación , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/genética , Leche/microbiología , Prevalencia , Conejos , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/microbiología , PorcinosRESUMEN
We demonstrate that a seismic analysis of stars in their earliest evolutionary phases is a powerful method with which to identify young stars and distinguish their evolutionary states. The early star that is born from the gravitational collapse of a molecular cloud reaches at some point sufficient temperature, mass, and luminosity to be detected. Accretion stops, and the pre-main sequence star that emerges is nearly fully convective and chemically homogeneous. It will continue to contract gravitationally until the density and temperature in the core are high enough to start nuclear burning of hydrogen. We show that there is a relationship for a sample of young stars between detected pulsation properties and their evolutionary status, illustrating the potential of asteroseismology for the early evolutionary phases.
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OBJECTIVE: To describe the impact of empiric appropriate treatment and the risk factors associated with mortality in patients with bacteremia by E. coli, K. pneumoniae and P. mirabilis producing ESBL. METHODS: Data were reviewed in an 8-year retrospective study, and 128 bacteremias were found: 80 caused by E. coli (62.5%), 28 by K. pneumoniae (21.9%) and 20 by P. mirabilis (18.6%). RESULTS: The initial antibiotic treatment, administered within 72 h after the first positive blood culture, was appropriate with carbapenems or other antimicrobial agents with documented in vitro sensitivity in 53.8 and 16% of patients, respectively. The overall mortality 21 days after diagnosis was 17.2%, and it was 14.9 and 35.2% for patients adequately and inadequately treated, respectively. At univariate analysis the p value for mortality with and without appropriate treatment was 0.05, and significant differences were found only for previous positive blood cultures (p = 0.004) and presence of septic shock at diagnosis (p = 0.006). CONCLUSION: In this case series there was a high rate of initial appropriate empiric treatment, and only a marginal impact on mortality was found with regard to appropriate and inappropriate treatment. This report shows that the knowledge of ESBL-producing characteristics varies widely among the different case series for reasons that still have to be clarified.
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Antibacterianos/administración & dosificación , Bacteriemia/tratamiento farmacológico , Infecciones por Enterobacteriaceae/tratamiento farmacológico , beta-Lactamasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Bacteriemia/microbiología , Bacteriemia/mortalidad , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/mortalidad , Escherichia coli/enzimología , Escherichia coli/aislamiento & purificación , Femenino , Humanos , Klebsiella pneumoniae/enzimología , Klebsiella pneumoniae/aislamiento & purificación , Masculino , Persona de Mediana Edad , Proteus mirabilis/enzimología , Proteus mirabilis/aislamiento & purificación , Estudios Retrospectivos , Análisis de Supervivencia , Insuficiencia del Tratamiento , Resultado del TratamientoAsunto(s)
Portador Sano/transmisión , Infección Hospitalaria/microbiología , Infección Hospitalaria/transmisión , Personal de Salud , Resistencia a la Meticilina , Infecciones Estafilocócicas/transmisión , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Portador Sano/microbiología , Dermatoglifia del ADN , ADN Bacteriano/genética , Brotes de Enfermedades , Electroforesis en Gel de Campo Pulsado , Genotipo , Humanos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Italia/epidemiología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/clasificaciónRESUMEN
AIM: Postoperative wound infections generally cause considerable extra morbidity, mortality and costs. The prevalence of total wound infections after cardiac surgery, including both sternal wound and donor site infections, ranges from 1.3 to 12.8%. The present study was conducted to identify the incidence of wound infections following cardiac surgery, to identify the risk factors and evaluate the efficacy of present modes of management. METHODS: From September 2004 to May 2005, 493 consecutive patients undergoing cardiac surgery were included in the study and were followed for the prevalence of surgical site infection (SSI) up to 60 days postoperatively. The wound infections were defined according to the Centers for Disease Control and Prevention (CDC) and U.S. National Nosocomial Infections Surveillance (NNIS) system criteria. RESULTS: The total incidence of SSI was 3.9%. Sternal wound infection (SWI) occurred in 17 patients (3.4%). Superficial wound infection was diagnosed in 10 patients (2%) and deep wound infection in 7 patients (1.4%). Donor site infection (DSI) occurred in 2 patients (0.4%). Early reoperation for bleeding, postoperative dialysis and the use of one internal mammary artery were independently associated with an increased risk of SWI. CONCLUSION: Preventing SSI in the operating room is the primary goal of the surgical team. Attention should be paid to antibiotic prophylaxis and Methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage treatment. The identification of risk factors will help to further reduce the incidence of wound infection.
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Procedimientos Quirúrgicos Cardíacos/efectos adversos , Diabetes Mellitus Tipo 1/complicaciones , Diálisis/efectos adversos , Técnicas Hemostáticas/efectos adversos , Obesidad/complicaciones , Infección de la Herida Quirúrgica/etiología , Adulto , Anciano , Anciano de 80 o más Años , Profilaxis Antibiótica , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Anastomosis Interna Mamario-Coronaria/efectos adversos , Tiempo de Internación , Modelos Logísticos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/prevención & control , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: In the Italian general population, prevalence of C282Y is lower than in Northern European countries. We hypothesised a higher prevalence of C282Y in Northern than in Central and Southern Italy. We previously identified a nonsense mutation (W169X) in haemochromatosis probands originating from a Northern Italian region (Brianza). AIM: To define the prevalence of HFE mutations in that region. Subjects and methods. A total of 1132 unrelated blood donors from the Blood Banks of Monza and Merate were investigated for C282Y, H63D, S65C and W169X mutations by PCR-restriction assays. A total of 300 were also tested for rare HFE and TFR2 mutations by reverse-hybridization test strips. RESULTS: Two C282Y homozygotes, eight C282Y/H63D compound heterozygotes, 27 H63D homozygotes and one W169X heterozygote were found. The allele frequencies of C282Y, H63D, S65C, and W169X were 3.2, 13.4, 1.3, and 0.04%, respectively. CONCLUSIONS: Our results confirm the existence of a decreasing frequency of C282Y allele from upper to lower Northern Italy. This difference is probably related to the larger Celtic component of upper Northern Italian populations in which screening studies for haemochromatosis may even be cost effective. W169X, due to its severity, should be looked for in all haemochromatosis patients of Northern ancestry with an incomplete HFE genotype.
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Etnicidad/genética , Frecuencia de los Genes , Genética de Población , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Mutación , Adulto , Anciano , Genotipo , Proteína de la Hemocromatosis , Humanos , Italia/epidemiología , Persona de Mediana Edad , PrevalenciaRESUMEN
BACKGROUND & AIMS: Most hemochromatosis patients of Northern European descent are homozygous for the C282Y mutation of HFE gene. In Italy, many patients with iron overload are not homozygous for C282Y, and the presence of other mutations or other genetic determinant has been suggested. METHODS: Five unrelated Italian patients heterozygous for C282Y with the classic hemochromatosis phenotype were studied. The entire coding sequence and the exon-intron boundaries of the HFE gene were analyzed. Chromosome 6p haplotypes were defined in each patient by analysis of D6S265, D6S105, and D6S1281 microsatellites. RESULTS: Two novel nonsense HFE mutations were identified in exon 3 in the C282Y negative chromosome. The first one, a G-to-T transition at codon 168, was detected in 3 probands; the second, a G-to-A transition at codon 169, was detected in the others. CONCLUSIONS: The 2 nonsense mutations in the compound heterozygous state with C282Y result in the classic hemochromatosis phenotype in several unrelated Italian patients. This confirms that hemochromatosis in Italy is not as homogeneous as in northern Europe and suggests that other mutations can exist in C282Y or H63D heterozygotes with iron overload. These findings have practical implications for diagnostic and screening strategies for hemochromatosis.
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Hemocromatosis/genética , Mutación Puntual , Adulto , Codón sin Sentido , Análisis Mutacional de ADN , Exones/genética , Ligamiento Genético , Haplotipos , Humanos , Italia , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Linaje , FenotipoRESUMEN
The generation of autoantibodies and deposition of immune complexes (ICs) in tissue play a primary role in autoimmune diseases. However, the IC-triggered response consists of complex mechanisms that make it difficult to identify the pathogenesis and develop specific therapy. We clarified here a sequential mechanism for the induction of hypersensitivity angiitis by analyzing the responsible Fc receptor (FcR), effector cells, and mediators in an animal model using FcR-deficient mice. In this model, rheumatoid factor-mediated skin vasculitis was induced in wild-type mice, whereas FcRgamma-deficient mice did not develop the vasculitis. Adoptive transfer of various FcR(+) cells into FcRgamma-deficient mice showed that mast cells but not macrophages derived from wild-type mice triggered skin vasculitis. Mast cells derived from either FcgammaRIII-deficient or tumor necrosis factor (TNF)-deficient mice did not possess the inducibility of skin vasculitis. These results indicate that triggering of vascular inflammation was induced by mast cells through IC binding on FcgammaRIII. TNF produced by such activated mast cells was mainly responsible for the pathogenesis of autoantibody-mediated vasculitis. These findings illustrate the clinical significance of mast cells, Fcgamma receptors, and TNF in IC-induced vasculitis syndrome.
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Autoanticuerpos/inmunología , Mastocitos/inmunología , Receptores Fc/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Vasculitis/inmunología , Animales , Mastocitos/patología , Ratones , Transducción de Señal/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Vasculitis/etiología , Vasculitis/patologíaRESUMEN
BACKGROUND: Hepatic iron overload is a common but still poorly characterized finding in patients with chronic viral hepatitis. AIM: To evaluate lobular and cellular distribution of iron in patients with chronic viral hepatitis, the relation between hepatic iron distribution, grading and staging, and the frequency of haemochromatosis gene mutations. PATIENTS: Thirty-four patients with chronic viral hepatitis and iron overload; 34 matched chronic viral hepatitis controls without iron overload; 139 healthy controls. METHODS: Hepatic iron was assessed by hepatic iron concentration and Deugnier's score, histological grading and staging by Ishak's score, and frequency of haemochromatosis gene mutations by polymerase chain reaction-restriction assays. RESULTS AND CONCLUSIONS: Iron deposits were found in hepatocytes (94% of the patients), sinusoidal tracts (88%) and portal cells (59%). In 41%, iron deposits were homogeneously distributed in the hepatic specimen. Hepatocytic iron showed a decreasing gradient from Rappaport's zone 1 to 3. Heavy alcohol intake influenced the distribution rather than the amount of hepatic iron by increasing sinusoidal iron. Haemochromatosis gene mutations were more frequent in chronic viral hepatitis patients with iron overload than in those without iron overload and in healthy controls suggesting they contribute to pathogenesis of hepatic iron accumulation. The correlation between hepatic fibrosis and portal iron supports the fibrogenetic role of iron in chronic viral hepatitis.
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Hemocromatosis/metabolismo , Hepatitis B Crónica/metabolismo , Hepatitis C Crónica/metabolismo , Hierro/metabolismo , Hígado/metabolismo , Proteínas de la Membrana , Mutación , Adulto , Anciano , Biopsia , Femenino , Genes MHC Clase I/genética , Antígenos HLA/genética , Hemocromatosis/clasificación , Hemocromatosis/genética , Hemocromatosis/patología , Proteína de la Hemocromatosis , Hepatitis B Crónica/clasificación , Hepatitis B Crónica/genética , Hepatitis B Crónica/patología , Hepatitis C Crónica/clasificación , Hepatitis C Crónica/genética , Hepatitis C Crónica/patología , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Hierro/análisis , Sobrecarga de Hierro/clasificación , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Hígado/química , Hígado/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Reacción en Cadena de la PolimerasaRESUMEN
Mild to moderate hepatic iron overload is frequent in patients with chronic viral hepatitis (CH). We evaluated the role of hemochromatosis (HFE) gene mutations and other acquired factors in the development of iron overload in these patients. We studied 110 patients with chronic B or C viral hepatitis (31 women, 79 men), including 20 with cirrhosis, and 139 controls. Hepatic iron was evaluated by semiquantitative analysis in all the patients, and hepatic iron concentration (HIC) was determined in 97 of them (26 women, 71 men). C282Y and H63D mutations were sought in all the subjects by a polymerase chain reaction-restriction assay. The frequency of HFE genotypes and alleles did not differ in patients and controls. No relation was detected between hepatic iron stores and HFE gene mutations in women. In men, all C282Y heterozygotes had iron overload, and the H63D mutation was significantly more frequent in patients with more marked hepatic siderosis than in those with mild or no siderosis (P = .0039) and in controls (P = .0008). Heavy alcohol intake and hepatic cirrhosis were also associated with increased hepatic iron stores in the men. In the 71 men in whom HIC was measured, multiple regression analysis showed that this variable was related independently only to alcohol intake and HFE gene mutations. We suggest that in patients with CH, iron accumulates in the liver as the result of an interplay between genetic and acquired factors, and that increased liver iron stores may influence progression toward liver fibrosis.
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Antígenos HLA/genética , Hepatitis B Crónica/genética , Hepatitis B Crónica/metabolismo , Hepatitis C Crónica/genética , Hepatitis C Crónica/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Hierro/metabolismo , Hígado/metabolismo , Proteínas de la Membrana , Siderosis/metabolismo , Adulto , Anciano , Consumo de Bebidas Alcohólicas , Femenino , Ferritinas/sangre , Genotipo , Hemocromatosis/genética , Proteína de la Hemocromatosis , Humanos , Hierro/sangre , Cirrosis Hepática/etiología , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Complejo Mayor de Histocompatibilidad , Masculino , Persona de Mediana Edad , Análisis de Regresión , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Caracteres Sexuales , Siderosis/complicaciones , Espectrofotometría Atómica , Transferrina/metabolismoRESUMEN
Interleukin-4 (IL-4) provides support for humoral immune responses through upregulation of T helper (Th) type 2 cell differentiation, but it is not known whether IL-4 promotes antibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we show that the constitutive expression of an IL-4 transgene by B cells completely prevents the development of lethal lupus-like glomerulonephritis in the (NZW x C57BL/6.Yaa)F1 murine model of SLE. This was associated with marked changes in the serum levels of IgG subclasses, rather than in the total levels of anti-DNA antibodies, with a lack of IgG3, a decrease of IgG2a, and an increase in IgG1 subclasses, and by a strong reduction in the serum levels of gp70-anti-gp70 immune complexes. This effect of the transgene appears to result from a modulation of the Th1 versus Th2 autoimmune response, since the protected mice displayed comparably modified IgG2a and IgG3 antibody response against exogenous T cell-dependent antigen, but not against T cell-independent antigens. Thus, IL-4 prevents the development of this lupus-like autoimmune disease, most likely by downregulating the appearance of Th1-mediated IgG subclasses of autoantibodies such as the IgG3 autoantibodies which have been shown to be especially nephritogenic.
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Linfocitos B/inmunología , Interleucina-4/biosíntesis , Nefritis Lúpica/genética , Nefritis Lúpica/prevención & control , Animales , Anticuerpos Antinucleares/biosíntesis , Anticuerpos Antinucleares/sangre , Formación de Anticuerpos , Diferenciación Celular , Elementos de Facilitación Genéticos , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunoglobulina G/sangre , Cadenas Pesadas de Inmunoglobulina/genética , Interleucina-4/genética , Nefritis Lúpica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Transgénicos , Regiones Promotoras Genéticas , Linfocitos T/inmunología , Células Th2/citología , Células Th2/inmunologíaRESUMEN
The gene(s) encoded within major histocompatibility complex (MHC) act as one of the major genetic elements contributing to the susceptibility of murine systemic lupus erythematosus (SLE). We have recently demonstrated that lupus susceptibility is more closely linked to the I-E- H-2(b) haplotype than to the I-E+ H-2(d) haplotype in lupus-prone BXSB and (NZB x BXSB)F1 hybrid mice. To investigate whether the reduced susceptibility to SLE in H-2(d) mice is related to the expression of the MHC class II Ea gene (absent in H-2(b) mice), we determined the possible role of the Ea gene as a lupus protective gene in mice. Our results showed that (i) the development of SLE was almost completely prevented in BXSB (H-2(b)) mice expressing two copies of the Ead transgene at the homozygous level as well as in BXSB H-2(k) (I-E+) congenic mice as for H-2(d) BXSB mice, and (ii) the expression of two functional Ea (transgenic and endogenous) genes in either H-2(d/b) (NZB x BXSB)F1 or H-2(k/b) (MRL x BXSB)F1 mice provided protection from SLE at levels comparable to those conferred by the H-2(d/d) or H-2(k/k) haplotype. In addition, the level of the Ea gene-mediated protection appeared to be dependent on the genetic susceptibility to SLE in individual lupus-prone mice. Our results indicate that the reduced susceptibility associated with the I-E+ H-2(d) and H-2(k) haplotypes (versus the I-E- H-2(b) haplotype) is largely, if not all, contributed by the apparent autoimmune suppressive effect of the Ea gene, independently of the expression of the I-A or other MHC-linked genes.
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Antígenos de Histocompatibilidad Clase II/genética , Lupus Eritematoso Sistémico/inmunología , Animales , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Ratones , Ratones TransgénicosRESUMEN
INTRODUCTION: The usefulness of posatirelin (L-pyro-2-aminoadipyl-L-leucyl-L-prolinamide), a synthetic peptide having modulatory activity on the monoaminergic and cholinergic systems and neurotrophic effects, was evaluated in vascular dementia. PATIENTS AND METHODS: A multicentre, parallel groups, double-blind clinical study vs placebo was carried out with patients suffering from probable vascular dementia according to the NINDS-AIREN criteria. The study consisted of a two-week run-in of a once daily, orally administered, placebo phase, followed by 12 weeks of intramuscular treatment with posatirelin 10 mg/ml or placebo given once a day and a follow-up after one month's withdrawal. Efficacy was assessed using the Gottfries-Bråne-Steen (GBS) Rating Scale for dementia, the Randt Memory Test and the Toulouse-Piéron Attention Test. Data were evaluated using analysis of variance and covariance. RESULTS: As regards GBS scores, patients treated with posatirelin showed a significant improvement in intellectual performance, in orientation, motivation and memory as compared to controls. The improvement of memory performance was also confirmed by the acquisition score and memory index of the Randt Memory Test. At the end of the follow-up period the differences between treatments were still maintained. Tolerability was good. CONCLUSIONS: The significant improvement observed in cognitive functions, attention and motivation of demented patients treated with posatirelin suggests the potential usefulness of this drug in vascular dementia. Furthermore, the presence of a long-lasting effect after drug withdrawal suggests the possibility of administering the drug cyclically.
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Demencia Vascular/tratamiento farmacológico , Hormona Liberadora de Tirotropina/análogos & derivados , Anciano , Demencia Vascular/psicología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Hormona Liberadora de Tirotropina/uso terapéuticoRESUMEN
To investigate the respective roles of Th1 and Th2 cells in the pathogenesis of lupus-like autoimmune disease, we have analyzed the spontaneous and antigen-induced productions of IgG1 vs IgG2a and IgG3 subclasses in relation to the mRNA expression of INF-gamma (Th1 cytokine promoting IgG2a and IgG3 production), IL-4 (Th2 cytokine promoting IgG1 production), and IL-10 (Th2 cytokine) in CD4+ T cells from lupus-prone MRL mice. For this purpose, two paired sets of MRL mice were chosen for the comparison of these parameters: (a) MRL-lpr/lpr (lpr for lymphoproliferation) and its recently described substrain with a prolonged survival, termed MRL-lpr/lpr.ll (ll for long lived) and (b) MRL male mice bearing the Yaa (Y-linked autoimmune acceleration) gene (MRL.Yaa) with an accelerated disease and their male counterparts lacking the Yaa gene. We demonstrate herein that the accelerated development of lupus-like autoimmune disease in MRL-lpr/lpr and MRL.Yaa mice, as compared with MRL-lpr/lpr.ll and MRL-+/+ mice, respectively, was correlated with an enhanced expression of IFN-gamma vs IL-4 and IL-10 mRNA in CD4+ T cells, which paralleled with an increase of spontaneous and foreign T cell-dependent antigen-induced productions of IgG2a and IgG3 vs IgG1 antibodies. These data suggest that an imbalance towards Th1 predominance may play a significant role in the acceleration of lupus-like autoimmune disease in MRL mice.
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Enfermedades Autoinmunes/inmunología , Lupus Eritematoso Sistémico/inmunología , Células TH1/inmunología , Animales , Antígenos/administración & dosificación , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/genética , Secuencia de Bases , Cartilla de ADN/genética , Femenino , Expresión Génica , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/sangre , Inmunoglobulina G/clasificación , Interferón gamma/genética , Interleucina-10/genética , Interleucina-4/genética , Lupus Eritematoso Sistémico/etiología , Lupus Eritematoso Sistémico/genética , Masculino , Ratones , Ratones Mutantes , Datos de Secuencia Molecular , ARN Mensajero/genética , ARN Mensajero/metabolismo , Células Th2/inmunologíaRESUMEN
It has been established that CD4+ T cells play an essential role in the development of systemic lupus erythematosus (SLE). Since CD4+ T cells differentiate upon activation into two defined subsets, TH1 and TH2, differing in their capacities of cytokine production with distinct immunopathological consequences, it becomes important to understand the respective roles of TH subsets in the pathogenesis of SLE. Our analysis on 4 different substrains of autoimmune-prone MRL mice revealed that the progression of SLE in these mice is correlated with an enhanced expression of interferon-gamma (a TH1 type cytokine regulating the production of IgG2a and IgG3) vs interleukin-4 (IL-4; a TH2 type cytokine regulating the production of IgG1), in parallel with an increased production of IgG2a and IgG3 autoantibodies over IgG1. In addition, studies on lupus-prone mice expressing an IL-4 transgene have shown that the constitutive expression of IL-4, biasing autoimmune responses towards a TH2 phenotype, inhibits the development of lupus nephritis. These results suggest that the development and progression of murine lupus is determined by the type of TH responses (either acceleration by TH1 responses or protection by TH2 responses) inducing the generation of more or less pathogenic autoantibodies. In fact, murine IgG3 has been shown to be extremely nephritogenic, generating "wire-loop" lupus-like glomerular lesions, because of their cryoglobulin activity associated with a unique physicochemical property of IgG3 constant region. Our results underline the importance in the pathogenesis of SLE of the qualitative aspects of autoantibody responses controlled by subpopulations of TH cells.
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Lupus Eritematoso Sistémico/fisiopatología , Subgrupos de Linfocitos T/fisiología , Linfocitos T Colaboradores-Inductores/fisiología , Animales , Autoanticuerpos/clasificación , Autoanticuerpos/inmunología , Citocinas/inmunología , Citocinas/fisiología , Humanos , Inmunoglobulina G/clasificación , Inmunoglobulina G/inmunología , Interferón gamma/inmunología , Interferón gamma/fisiología , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Nefritis Lúpica/fisiopatología , Ratones , Ratones Endogámicos MRL lpr , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
The BXSB Y chromosome-linked mutant gene, Yaa, promotes autoimmune responses in mice predisposed to a lupus-like autoimmune disease. We have previously shown that a cognate interaction of T cells with B cells expressing the Yaa gene appears to be responsible for the accelerated production of autoantibodies. To investigate whether T cells that provide help for autoantibody production by Yaa+ B cells need to express the Yaa gene, we have made radiation bone marrow chimeras containing two sets of T and B cells from mice with or without the Yaa gene and differing by the Thy-1 and Igh allotypes. We then determined autoantibody production following the selective elimination of T cells of Yaa+ origin by treating mice with allele-specific anti-Thy-1 monoclonal antibody. Our results demonstrated that the selective production of autoantibodies by Yaa+ B cells in Yaa(+)-Yaa- double bone marrow chimeras can be mediated as efficiently by T cells from non-autoimmune mice lacking the Yaa gene as by T cells from autoimmune mice bearing the Yaa gene. This indicates that T cells from non-autoimmune Yaa- mice are capable of providing help for autoimmune responses by collaborating with Yaa+ B cells. These data thus strongly suggest that the Yaa gene defect is not functionally expressed in T cells, but only in B cells, and contrast with parallel experiments in the lpr model, in which defects of the Fas antigen in both T and B cells are crucial for the lpr gene-mediated promotion of autoantibody production.
Asunto(s)
Autoanticuerpos/biosíntesis , Linfocitos B/inmunología , Lupus Eritematoso Sistémico/etiología , Lupus Eritematoso Sistémico/genética , Cooperación Linfocítica/genética , Linfocitos T/inmunología , Cromosoma Y/genética , Cromosoma Y/inmunología , Animales , Linfocitos B/metabolismo , Secuencia de Bases , Médula Ósea/inmunología , Femenino , Isoanticuerpos/farmacología , Depleción Linfocítica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Datos de Secuencia Molecular , Quimera por Radiación , Síndrome , Antígenos Thy-1/inmunologíaRESUMEN
Three major components of the plasminogen activators (PA)/plasmin system are synthesized physiologically in glomeruli, and can be involved in glomerular proteolysis and extracellular matrix metabolism: tissue-type PA (tPA), urokinase (uPA) and PA inhibitor type 1 (PAI-1). To explore the possible role of a dysregulation of the plasmin protease system in the development and progression of lupus-like glomerulonephritis, we studied the expression of the renal plasmin protease components during the course of the disease, either acute, induced by IgG3 monoclonal cryoglobulins, or chronic, occurring spontaneously in three different lupus-prone mice: (NZBxNZW)F1, BXSB and MRL-lpr/lpr. RNase protection assays and in situ hybridizations revealed a marked glomerular induction of PAI-1 mRNA abundance without any significant changes in renal tPA and uPA mRNA levels in the two different types of lupus-like glomerulonephritis. The overexpression of PAI-1 mRNA occurred in parallel with a significant decrease in glomerular tPA-catalyzed enzymatic activity as determined by zymographic analysis. In addition, a concomitant increase in glomerular expression of transforming growth factor beta 1 (TGF-beta 1) mRNA was observed. The demonstration of a close correlation between the PAI-1 and TGF-beta 1 mRNA levels and the severity of lupus-like glomerular lesions suggests that a pertubation of the glomerular PA/PAI balance, resulting from a marked TGF-beta 1-mediated induction of PAI-1 gene expression, plays an important role in the progression of lupus-like glomerular lesions, leading to glomerulosclerosis.