Differences in the thoracic aorta by region and sex in a murine model of Marfan Syndrome

Marfan syndrome (MFS) is a hereditary disorder of the connective tissue that causes life-threatening aortic aneurysm, which initiates at the aortic root and can progress into the ascending portion. However, analysis of ascending aorta reactivity in animal models of MFS has remained elusive. Epidemiologic evidence suggests that although MFS is equally prevalent in men and women, men are at a higher risk of aortic complications than non-pregnant women. Nevertheless, there is no experimental evidence to support this hypothesis. The aim of this study was to explore whether there are regional and sex differences in the thoracic aorta function of mice heterozygous for the fibrillin 1 (Fbn1) allele encoding a missense mutation (Fbn1C1039G/+), the most common class of mutation in MFS. Ascending and descending thoracic aorta reactivity was evaluated by wire myography. Ascending aorta mRNA and protein levels, and elastic fiber integrity were assessed by qRT-PCR, Western blotting, and Verhoeff-Van Gieson histological staining, respectively. MFS differently altered reactivity in the ascending and descending thoracic aorta by either increasing or decreasing phenylephrine contractions, respectively. When mice were separated by sex, contractions to phenylephrine increased progressively from 3 to 6 months of age in MFS ascending aortas of males, whereas contractions in females were unchanged. Endothelium-dependent relaxation was unaltered in the MFS ascending aorta of either sex; an effect related to augmented endothelium-dependent hyperpolarization-type dilations. In MFS males, the non-selective cyclooxygenase (COX) inhibitor indomethacin prevented the MFS-induced enhancement of phenylephrine contractions linked to increased COX-2 expression. In MFS mice of both sexes, the non-selective nitric oxide synthase inhibitor L-NAME revealed negative feedback of nitric oxide on phenylephrine contractions, which was associated with upregulation of eNOS in females. Finally, MFS ascending aortas showed a greater number of elastic fiber breaks than the wild-types, and males exhibited more breaks than females. These results show regional and sex differences in Fbn1C1039G/+ mice thoracic aorta contractility and aortic media injuries. The presence of more pronounced aortic alterations in male mice provides experimental evidence to support that male MFS patients are at increased risk of suffering aortic complications

Features and distribution of CD8 T cells with human leukocyte antigen class I-specific receptor expression in chronic hepatitis C.: NKRs+ CD8 T cells in chronic Hepatitis C.

CD8(+) T cells represent a sizable component of the liver inflammatory infiltrate in chronic hepatitis C and are thought to contribute to immune-mediated tissue injury. Because chronic stimulation may promote the expression by CD8(+) T cells of distinct human leukocyte antigen class I-specific natural killer cell receptors (NKRs) susceptible to both inhibiting effector functions and promoting cell survival, we examined the distribution and characteristics of CD8(+) T cells with such receptors in chronic hepatitis C patients. NKR CD8(+) T cells were detectable in liver and peripheral blood from hepatitis C virus (HCV)-infected patients but were not major subsets. However, the frequency of NKG2A(+) CD8(+) in the liver and in a lesser extent in the peripheral blood was positively correlated to histological activity in HCV-infected patients. No such correlation was found with KIR(+) T cells in liver in HCV-infected patients and with the both NKR CD8(+) T cells in hepatitis B virus (HBV) infected patients. Circulating CD8(+) T cells expressing KIRs exhibited phenotypic features of memory T cells with exacerbated expression of the senescence marker CD57 in patients. NKG2A(+)CD8(+) T cells were committed T cells that appeared less differentiated than KIR(+)CD8(+) T cells. In HCV-infected patients, their content in perforin was low and similar to that observed in NKG2A(-)CD8(+) T cells; this scenario was not observed in healthy subjects and HBV-infected patients. Both NKG2A and KIRs could inhibit the response of HCV-specific CD8(+) T cells ex vivo. CONCLUSION: These results support the concept that an accumulation in the liver parenchyma of NKR(+)CD8(+) T cells that have functional alterations could be responsible for liver lesions. They provide novel insights into the complexity of liver-infiltrating CD8(+) T cells in chronic hepatitis C and reveal that distinct subsets of antigen-experienced CD8(+) T cells are differentially sensitive to the pervasive influence of HCV

March1-dependent modulation of donor MHC II on CD103+ dendritic cells mitigates alloimmunity.

In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs

Extracellular mycobacterial DnaK polarizes macrophages to the M2-like phenotype

Macrophages are myeloid cells that play an essential role in inflammation and host defense, regulating immune responses and maintaining tissue homeostasis. Depending on the microenvironment, macrophages can polarize to two distinct phenotypes. The M1 phenotype is activated by IFN-c and bacterial products, and displays an inflammatory profile, while M2 macrophages are activated by IL-4 and tend to be anti-inflammatory or immunosupressive. It was observed that DnaK from Mycobacterium tuberculosis has immunosuppressive properties, inducing a tolerogenic phenotype in dendritic cells and MDSCs, contributing to graft acceptance and tumor growth. However, its role in macrophage polarization remains to be elucidated. We asked whether DnaK was able to modulate macrophage phenotype. Murine macrophages, derived from bone marrow, or from the peritoneum, were incubated with DnaK and their phenotype compared to M1 or M2 polarized macrophages. Treatment with DnaK leads macrophages to present higher arginase I activity, IL-10 production and FIZZ1 and Ym1 expression. Furthermore, DnaK increased surface levels of CD206. Importantly, DnaK-treated macrophages were able to promote tumor growth in an allogeneic melanoma model. Our results suggest that DnaK polarizes macrophages to the M2-like phenotype and could constitute a virulence factor and is an important immunomodulator of macrophage responses

Prolonged Survival of Allografts Induced by Mycobacterial Hsp70 Is Dependent on CD4+CD25+ Regulatory T Cells

Background: Heat shock proteins (Hsps) are stress induced proteins with immunomodulatory properties. The Hsp70 of Mycobacterium tuberculosis (TBHsp70) has been shown to have an anti-inflammatory role on rodent autoimmune arthritis models, and the protective effects were demonstrated to be dependent on interleukin-10 (IL-10). We have previously observed that TBHsp70 inhibited maturation of dendritic cells (DCs) and induced IL-10 production by these cells, as well as in synovial fluid cells. Methodology/Principal Findings: We investigated if TBHsp70 could inhibit allograft rejection in two murine allograft systems, a transplanted allogeneic melanoma and a regular skin allograft. In both systems, treatment with TBHsp70 significantly inhibited rejection of the graft, and correlated with regulatory T cells (Tregs) recruitment. This effect was not tumor mediated because injection of TBHsp70 in tumor-free mice induced an increase of Tregs in the draining lymph nodes as well as inhibition of proliferation of lymph node T cells and an increase in IL-10 production. Finally, TBHsp70 inhibited skin allograft acute rejection, and depletion of Tregs using a monoclonal antibody completely abolished this effect. Conclusions/Significance: We present the first evidence for an immunosuppressive role for this protein in a graft rejection system, using an innovative approach - immersion of the graft tissue in TBHsp70 solution instead of protein injection. Also, this is the first study that demonstrates dependence on Treg cells for the immunosuppressive role of TBHsp70. This finding is relevant for the elucidation of the immunomodulatory mechanism of TBHsp70. We propose that this protein can be used not only for chronic inflammatory diseases, but is also useful for organ transplantation management.Pontificia Universidade Catolica do Rio Grande do Sul (PUCRS)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Financiadora de Estudos e Projetos (FINEP

La renovación de la palabra en el bicentenario de la Argentina : los colores de la mirada lingüística

El libro reúne trabajos en los que se exponen resultados de investigaciones presentadas por investigadores de Argentina, Chile, Brasil, España, Italia y Alemania en el XII Congreso de la Sociedad Argentina de Lingüística (SAL), Bicentenario: la renovación de la palabra, realizado en Mendoza, Argentina, entre el 6 y el 9 de abril de 2010. Las temáticas abordadas en los 167 capítulos muestran las grandes líneas de investigación que se desarrollan fundamentalmente en nuestro país, pero también en los otros países mencionados arriba, y señalan además las áreas que recién se inician, con poca tradición en nuestro país y que deberían fomentarse. Los trabajos aquí publicados se enmarcan dentro de las siguientes disciplinas y/o campos de investigación: Fonología, Sintaxis, Semántica y Pragmática, Lingüística Cognitiva, Análisis del Discurso, Psicolingüística, Adquisición de la Lengua, Sociolingüística y Dialectología, Didáctica de la lengua, Lingüística Aplicada, Lingüística Computacional, Historia de la Lengua y la Lingüística, Lenguas Aborígenes, Filosofía del Lenguaje, Lexicología y Terminología

Etude des Populations Lymphocytaires Exprimant des Récepteurs Spécifiques de Molécules HLA de Classe I au cours de l'Hépatite Virale C Chronique.

We have analyzed the distribution and features of lymphocytes populations expressing HLA class I specific receptors (NKG2A and the KIRs CD158a,b and CD158b,j) in patients with persistent hepatitis C virus (HCV) infection. Such receptors are central for the regulation of natural killer (NK) cell responses and are found also on CD8+ T cells with activated/memory phenotype. We did not detect substantial accumulation of KIRs+CD8+ T cells in the blood or liver of chronic hepatitis C (cHC) patients. Of interest was the fact that the frequency of intrahepatic NKG2A+CD8+ T cells correlated positively with the severity of liver lesions. Finally, we found that KIRs+CD8+ and NKG2A+CD8+ T cells were differentially sensitive to the known pervasive influence that HCV can exert on CD8+ T cell phenotype. Altogether the results show that the analysis of HLA class I specific receptors expression reveal multiple alterations in the distribution of lymphocytes subsets in cHC patients.Nous avons analysé, chez les patients atteints d'hépatite virale C chronique, les lymphocytes exprimant des récepteurs de molécules HLA de classe I (NKG2A et les membres CD158a,b et CD158b,j du groupe KIRs) qui sont important pour réguler les cellules NK et qui peuvent aussi être exprimés par les cellules T (LT)CD8+ activés/mémoires. Nous n'avons pas détecté de phénomènes d'accumulation généralisée de ces cellules dans le foie ou le sang des patients. Nonobstant, l'infection VHC semble influencer le phénotype des LT CD8+. Par rapport aux paramètres cliniques, nous avons observé une corrélation positive entre la fréquence intra-hépatiques de cellules T CD8+ NKG2A+ et le degré de sévérité des lésions. Ces résultats montrent de multiples altérations de la représentation de sous populations lymphocytaires T au cours de l'hépatite virale C chronique et révèle des associations positives de certaines de ces sous populations avec des paramètres cliniques majeurs de la maladie

Etude des Populations Lymphocytaires Exprimant des Récepteurs Spécifiques de Molécules HLA de Classe I au cours de l'Hépatite Virale C Chronique.

We have analyzed the distribution and features of lymphocytes populations expressing HLA class I specific receptors (NKG2A and the KIRs CD158a,b and CD158b,j) in patients with persistent hepatitis C virus (HCV) infection. Such receptors are central for the regulation of natural killer (NK) cell responses and are found also on CD8+ T cells with activated/memory phenotype. We did not detect substantial accumulation of KIRs+CD8+ T cells in the blood or liver of chronic hepatitis C (cHC) patients. Of interest was the fact that the frequency of intrahepatic NKG2A+CD8+ T cells correlated positively with the severity of liver lesions. Finally, we found that KIRs+CD8+ and NKG2A+CD8+ T cells were differentially sensitive to the known pervasive influence that HCV can exert on CD8+ T cell phenotype. Altogether the results show that the analysis of HLA class I specific receptors expression reveal multiple alterations in the distribution of lymphocytes subsets in cHC patients.Nous avons analysé, chez les patients atteints d'hépatite virale C chronique, les lymphocytes exprimant des récepteurs de molécules HLA de classe I (NKG2A et les membres CD158a,b et CD158b,j du groupe KIRs) qui sont important pour réguler les cellules NK et qui peuvent aussi être exprimés par les cellules T (LT)CD8+ activés/mémoires. Nous n'avons pas détecté de phénomènes d'accumulation généralisée de ces cellules dans le foie ou le sang des patients. Nonobstant, l'infection VHC semble influencer le phénotype des LT CD8+. Par rapport aux paramètres cliniques, nous avons observé une corrélation positive entre la fréquence intra-hépatiques de cellules T CD8+ NKG2A+ et le degré de sévérité des lésions. Ces résultats montrent de multiples altérations de la représentation de sous populations lymphocytaires T au cours de l'hépatite virale C chronique et révèle des associations positives de certaines de ces sous populations avec des paramètres cliniques majeurs de la maladie

El uso de las relaciones léxicas como recurso lingüístico en la definición

Definition is frequently used in scientific and academic texts to explain objects and phenomena of the real world. When you define a word, of a natural language, you try to determine its meaning. So that every definition, besides being a structured procedure in binary form, states the relationship between two terms semantically equivalent, that in question and the one which tries to define it. At the same time, when you define something, a series of semantic relations is set in motion, which relates the word in question to others. Accordingly, semantic relations, such as synonymy, antonymy, and hyperonymy, are fundamental semantic resources through which speakers construct a definition. During school, we are faced with situations in which either we read the definition of a particular concept or we are required to produce it. We hereby consider how students in the last year of Polimodal and fi rst year of ESB construct a definition. The analysis of the collected data made it possible for us to assess to what extent semantic relationships are used by students to formulate definitions required for their school work.Tanto en el discurso escolar como en el científico y el académico, la definición es un procedimiento frecuente que se utiliza para explicar los objetos y fenómenos del mundo circundante. A la hora de definir una palabra, dentro de una lengua natural, se intenta determinar su significado. Así es que toda definición, además de ser un procedimiento estructurado en forma binaria, pone en relación dos términos semánticamente equivalentes: el definido y el que (lo) define. A su vez, cuando se define, se ponen en funcionamiento una serie de relaciones semánticas que vinculan la palabra en cuestión con otras. En esta perspectiva, las relaciones semánticas, tales como la sinonimia, la antonimia y la hiperonimia, constituyen recursos lingüísticos fundamentales de los que nos valemos los hablantes para producir definiciones. Durante la escolarización, nos encontramos con situaciones en las cuales o bien se lee la definición de un concepto determinado o resulta necesario producirla. En este trabajo nos ocupamos de cómo construyen definiciones los alumnos del último año del Polimodal y primer año de ESB. El análisis del corpus recogido nos condujo a considerar en qué medida y de qué manera(s) específica(s) las relaciones léxicas son utilizadas por los estudiantes en la formulación de las definiciones que les demanda su desempeño escolar