Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression

T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. In this study, we examine the role and mechanism of Th17 cells in the pathogenesis of autoimmune hepatitis (AIH). The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. The hepatic expressions of IL-17, IL-23, ROR-γt, IL-6 and IL-1β in patients with AIH were also significantly increased and were associated with increased inflammation and fibrosis. IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis

Modelización acústica de la expresión emocional en el español

En esta comunicación se exponen los resultados del proyecto "Modelización Acústica de la Expresión Emocional en el Español" que ha sido financiado por la DGICYT (PB94-0732). Se parte de la construcción inicial de un corpus con 336 discursos en los que 8 actores simularon 7 emociones básicas (alegría, deseo, rabia, miedo, sorpresa, tristeza y asco), que fueron juzgados mediante tests de recepción por 1.054 sujetos experimentales. De esta primera etapa se seleccionaron los 34 discursos mejor valorados en el test para ser analizados y modelizados acústicamente. En el desarrollo del análisis acústico se manejaron 17 parámetros numéricos asociados a una perspectiva suprasegmental (análisis comparativo del contorno de F0 y de la presión acústica inter-locutor e intra-locutor). Se consiguió modelizar 6 de las 7 emociones estudiadas

Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis

Background and Aims The “gut homing” hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut‐derived T cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here, we examine “the gut homing theory” in patients with PSC with associated inflammatory bowel disease (PSC‐IBD) and across multiple inflammatory liver diseases. Approach and Results Expression of MAdCAM‐1, CCL25, and E‐Cadherin were assessed histologically and using RT‐PCR on explanted liver tissue from patients with CLD undergoing OLT and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut‐derived T cells was assessed using flow cytometry. Hepatic expression of MAdCAM‐1, CCL25 and E‐Cadherin was up‐regulated in all CLDs compared with normal liver. There were no differences between disease groups. Frequencies of α4β7, αEβ7, CCR9, and GPR15 expressing hepatic T cells was increased in PSC‐IBD, but also in CLD controls, compared with normal liver. β7 expressing hepatic T cells displayed an increased inflammatory phenotype compared with β7 negative cells, although this inflammatory cytokine profile was present in both the inflamed and normal liver. Conclusions These findings refute the widely accepted “gut homing” hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut‐derived T cells is not unique to PSC, but is a panetiological feature of CLD

Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry

Background and Aims Genetic predisposition to autoimmune hepatitis (AIH) in adults is associated with possession of human leukocyte antigen (HLA) class I (A*01, B*08) and class II (DRB1*03, ‐04, ‐07, or ‐13) alleles, depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH‐1, AIH‐2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD. Approach and Results We studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8‐17), including 100 with AIH‐1, 59 with AIH‐2, and 77 with ASC. The follow‐up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence‐specific primers. HLA B*08, ‐DRB1*03, and the A1‐B8‐DR3 haplotype impart predisposition to all three forms of AILD. Homozygosity for DRB1*03 represented the strongest risk factor (8.8). HLA DRB1*04, which independently confers susceptibility to AIH in adults, was infrequent in AIH‐1 and ASC, suggesting protection; and DRB1*15 (DR15) was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD: DRB1*03 to AIH‐1, DRB1*13 to ASC, and DRB1*07 to AIH‐2. Possession of homozygous DRB1*03 or of DRB1*13 is associated with fibrosis at disease onset, and possession of these two genes in addition to DRB1*07 is associated with a more severe disease in all three subgroups. Conclusions Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predicting responsiveness to immunosuppressive treatment and course

The Interaction between Regulatory T Cells and NKT Cells in the Liver: A CD1d Bridge Links Innate and Adaptive Immunity

Regulatory T cells (Tregs) and natural killer T (NKT) cells are two distinct lymphocyte subsets that independently regulate hepatic adaptive and innate immunity, respectively. In the current study, we examine the interaction between Tregs and NKT cells to understand the mechanisms of cross immune regulation by these cells.The frequency and function of Tregs were evaluated in wild type and NKT cell deficient (CD1dko) mice. In vitro lymphocyte proliferation and apoptosis assays were performed with NKT cells co-cultured with Tregs. The ability of Tregs to inhibit NKT cells in vivo was examined by adoptive transfer of Tregs in a model of NKT cell mediated hepatitis.CD1dko mice have a significant reduction in hepatic Tregs. Although, the Tregs from CD1dko mice remain functional and can suppress conventional T cells, their ability to suppress activation induced NKT cell proliferation and to promote NKT cell apoptosis is greatly diminished. These effects are CD1d dependent and require cell to cell contact. Adoptive transfer of Tregs inhibits NKT cell-mediated liver injury.NKT cells promote Tregs, and Tregs inhibit NKT cells in a CD1d dependent manner requiring cell to cell contact. These cross-talk immune regulations provide a linkage between innate and adaptive immunity

El Control objetivo de la implicación de los informantes en el estudio del habla emocionada

En las investigaciones sobre la influencia de las emociones en el habla aparece sistemáticamente el problema de cómo objetivar el estado emocional de los informantes (locutores). Así, para construir los córpora (o bases de datos) se suele solicitar a uno o varios actores una serie de interpretaciones, proporcionándoles los textos y una serie de indicaciones más o menos completas sobre el tipo de estado emocional que han de interpretar. Luego, se asume ya, normalmente sin más control, que la interpretación del actor o actores contienen la "verdad" sonora. Si para cualquier buen aficionado al teatro o al cine no es ningún secreto que la interpretación de los actores con frecuencia dista mucho de ser creíble, no parece lógico que se asuma como válida para ser analizada acústicamente la interpretación de cualquier actor sin ningún otro tipo de control objetivo

Identificación perceptiva de locutores para la acústica forense : las RRV

En este artículo se exponen los resultados obtenidos hasta este momento en el proyceto de investigación "Identificación percepctiva de locutores para la acústica forense" financiado por el Minsterio de Ciencia y Tecnología (DGCYT PB98-0862). El objetivo de esta investigación es experimentar y validar un protocolo sistemátcio para realizar tests de discriminación auditiva en procedimientos de Ruedas de Reconocimiento de Voz (RRV). La investigación se ha desarrollado en 3 etapas: 1) búsqueda y formalización de las variabels fundamentales que actúan en la memoria auditiva para el reconocimiento de una voz; 2) definición de las condiciones óptimas para las variables /duración del discurso/, /dependencia del texto/ y /estado emocional del hablante/ para estimular la memoria auditiva y 3) estudio de la influencia de un periodo de latencia y del estrés emocional en el reconocimiento de voces. Para el desarrollo del estudio se han aplicado diversos métodos de investigación cualitativa y dos procedimientos experimentales.In this article we expose the results obtained up to now in the investigation project "Perceptive speaker identification for the forensic acoustics" funded by the Science and Technology Department (DGCYT PB98-0862). The aim of this investigation is to experiment and validate a systematic protocol to elaborate acoustics discrimination tests in a voice identity parade. The investigation has been carried out in 3 stages: 1) search and settle down of the fundamental variables that work in the acoustics memory to recognize a voice; 2)definition of the peak conditions for the variables/lenght of the speech/ dependence on the text/ and /emotional condition of the speaker/ to stimulate the acoustics memory and 3)Study of the influence of a latent period and of the emotional stress in the recognition of voices. To develop this study, sundries qualitative investigation methods have been applied and two experimental procedures

Desarrollo y validación de un protocolo para la identificación perceptiva forense en ruedas de reconocimiento de voz

En este informe científico se exponen completos los resultados finales obtenidos en el proyecto de investigación "IDENTIFICACIÓN PERCEPTIVA DE LOCUTORES PARA LA ACÚSTICA FORENSE" financiado por el Ministerio de Ciencia y Tecnología (DGCYT PB98-0862). Estos resultados fueron publicados parcialmente en Actas del II Congreso de la Sociedad Española de Acústica Forense1 El objetivo de esta investigación es experimentar y validar un protocolo sistemático para realizar tests de discriminación auditiva en procedimientos de Ruedas de Reconocimiento de Voz (RRV). La investigación se ha realizado siguiendo el método de análisis instrumental2 y se ha desarrollado en 3 etapas: 1) búsqueda y formalización de las variables fundamentales que actúan en la memoria auditiva para el reconocimiento de una voz; 2) definición de las condiciones óptimas para las variables /duración del discurso/, /dependencia del texto/ y /estado emocional del hablante/ para estimular la memoria auditiva y 3) estudio de la influencia de un periodo de latencia y del estrés emocional en el reconocimiento de voces. Para el desarrollo del estudio se han aplicado diversos métodos de investigación cualitativa y dos procedimientos experimentales.In this scientific report we expose the final results obtained in the research project "PERCEPTIVE SPEAKER IDENTIFICATION FOR THE FORENSIC ACOUSTICS" funded by the Science and Technology Department (DGCYT PB98-0862). The aim of this investigation is to experiment and validate a systematic protocol to elaborate acoustics discrimination tests in a voice identity parade. The investigation has been carried out in 3 stages: 1) search and settle down of the fundamental variables that work in the acoustics memory to recognize a voice; 2) definition of the peak conditions for the variables/ length of the speech/ dependence on the text/ and/ emotional condition of the speaker/ to stimulate the acoustics memory and 3) Study of the influence of a latent period and of the emotional stress in the recognition of voices. To develop this study, sundries qualitative investigation methods have been applied and two experimental procedures