Interleukin 18 maintains a long-standing inflammation in coeliac disease patients

Producción CientíficaDietary gluten induces an early response in the intestine of coeliac disease patients (CD), within a few hours, and this is driven by high levels of proinflammatory cytokines, including IFNg and IL-15, as has been thoroughly shown by gluten stimulation of biopsy explants. Our aim was to identify the immune mediators involved in the long-standing inflammation in untreated CD patients at diagnosis. mRNA and protein levels of TNFa, IL-12(p35), IL-12(p40), IL-15, IL-18 and IL-23(p19) were quantified in biopsies from active CD patients, CD patients on a gluten-free diet (GFD), healthy controls, and patients with non-CD inflammation and mild histological changes in the intestine. Biopsies from CD patients on a GFD were also stimulated in vitro with gliadin, and protein expression of IL-15 and IL-18 was analysed. Levels of IL-12 and IL-23 mRNA are nearly absent, and TNFa levels remain unchanged among different groups. Both the active and inactive forms of IL-18 protein have been found in all samples from active CD, and protein expression was only localized within the crypts. Levels of IL-15 mRNA remain unchanged, and protein expression, localized within the lamina propria, is found in a small number of samples. In vitro stimulation with gluten induces the expression of IL-15 and IL-18. In active CD, the early response following gluten intake characterized by high IFNg levels is driven by IL-18, and probably IL-15, and this alternates with periods of long-standing inflammation with moderate IFNg levels, maintained by IL-18 alone

Tachyphylaxis to β2-agonists in Spanish asthmatic patients could be modulated by β2-adrenoceptor gene polymorphisms

Producción CientíficaThe study of determinants of asthma is a subject of much interest currently, especially the pharmacogenetic aspects of asthma management. Genetic polymorphisms affecting amino-acids at positions 16 and 27 within β2-adrenoceptor (β2AR) gene have been implicated in the asthma phenotypes and influence on the variability observed in response to use of bronchodilator agents used in the treatment of asthma. Whether these polymorphisms alter the bronchoprotection response to -agonist treatment in Spanish asthmatic population is unknown. The aim of this study was to investigate whether genetic polymorphisms within β2AR gene modulate the clinical outcomes of the individual response to β2-agonist therapy and the development of desensitization in Spanish asthmatic patients.Fondo de Investigación Sanitaria y Ministerio de Sanidad, Consumo y Bienestar Social (FIS00648 and 02/3068)Junta de Castilla y León (VA032/04

Interleukin 18 maintains a long-standing inflammation in coeliac disease patients

Producción CientíficaDietary gluten induces an early response in the intestine of coeliac disease patients (CD), within a few hours, and this is driven by high levels of proinflammatory cytokines, including IFNg and IL-15, as has been thoroughly shown by gluten stimulation of biopsy explants. Our aim was to identify the immune mediators involved in the long-standing inflammation in untreated CD patients at diagnosis. mRNA and protein levels of TNFa, IL-12(p35), IL-12(p40), IL-15, IL-18 and IL-23(p19) were quantified in biopsies from active CD patients, CD patients on a gluten-free diet (GFD), healthy controls, and patients with non-CD inflammation and mild histological changes in the intestine. Biopsies from CD patients on a GFD were also stimulated in vitro with gliadin, and protein expression of IL-15 and IL-18 was analysed. Levels of IL-12 and IL-23 mRNA are nearly absent, and TNFa levels remain unchanged among different groups. Both the active and inactive forms of IL-18 protein have been found in all samples from active CD, and protein expression was only localized within the crypts. Levels of IL-15 mRNA remain unchanged, and protein expression, localized within the lamina propria, is found in a small number of samples. In vitro stimulation with gluten induces the expression of IL-15 and IL-18. In active CD, the early response following gluten intake characterized by high IFNg levels is driven by IL-18, and probably IL-15, and this alternates with periods of long-standing inflammation with moderate IFNg levels, maintained by IL-18 alone

Human corneal fibroblast migration and ECM synthesis during stromal repair: Role played by PDGF-BB, bFGF, and TGFβ1 (HCFs migration and ECM synthesis during stromal repair: GFs effects)

Producción CientíficaThe development of treatments that modulate corneal wound healing to avoid fibrosis during tissue repair is important for the restoration of corneal transparency after an injury. To date, few studies have studied the influence of growth factors (GFs) on human corneal fibroblast (HCF) expression of extracellular matrix (ECM) proteins such as collagen types I and III, proteoglycans such as perlecan, or proteins implicated in cellular migration such as α5β1-integrin and syndecan-4. Using in vitro HCFs, we developed a mechanical wound model to study the influence of the GFs basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF-BB), and transforming growth factor beta 1 (TGFβ1) on ECM protein production and cellular migration. Our results show that mechanical wounding provokes the autocrine release of bFGF and TGFβ1 at different time points during the wound closure. The HCF response to PDGF-BB was a rapid closure due to fast cellular migration associated with a high focal adhesion replacement and a high expression of collagen and proteoglycans, producing a non-fibrotic healing. bFGF stimulated non-fibrotic ECM production and limited the migration process. Finally, TGFβ1 induced expression of the fibrotic markers collagen type III and α5β1 integrin, and it inhibited cellular migration due to the formation of focal adhesions with a low turnover rate. The novel in vitro HCF mechanical wound model can be used to understand the role played by GFs in human corneal repair. The model can also be used to test the effects of different treatments aimed at improving the healing process

Is it true coeliacs do not digest gliadin ?. Degradation pattern of gliadin in coeliac disease small intestinal mucosa

Prolyl-endopeptidase supplementation has been proposed to favour gliadin degradation as an alternative treatment for coeliac disease (CD), although the real usefulness of this therapy in vivo is still under discussion. 1 However, our data point to alternative treatments aiming to modify the intestinal microbiota in patients with CD by the use of probiotics and/or prebiotics. We propose that the induction of gliadin proteolysis in the human gut might not be the solution but the origin of CD

Expression and potential role of apolipoprotein D on the death–survival balance of human colorectal cancer cells under oxidative stress conditions

Producción CientíficaPurpose Inverse correlations of apolipoprotein D (ApoD) expression with tumor growth have been shown, therefore proposing ApoD as a good prognostic marker for diverse cancer types, including colorectal cancer (CRC). Besides, ApoD expression is boosted upon oxidative stress (OS) in many pathological situations. This study aims at understanding the role of ApoD in the progression of human CRC. Methods Samples of CRC and distant normal tissue (n051) were assayed for levels of lipid peroxidation, expression profile of OS-dependent genes, and protein expression. Three single-nucleotide polymorphisms in the ApoD gene were analyzed (n0139), with no significant associations found. Finally, we assayed the effect of ApoD in proliferation and apoptosis in the CRC HT-29 cell line

Genes and populations in susceptibility to celiac disease

Producción CientíficaFue en 1996 cuando Zhong (1) publicó el primer estudio pangenómico de asociación relacionado con la enfermedad celiaca (EC). Desde entonces, como escribiría el Profesor Ludwig Sollid en un editorial del año 2008 (2), se abrió la veda para la caza del gen en la EC. La asociación entre esta enfermedad y los genes del CMH era conocida, pero sólo unos pocos años antes se habían definido específicamente los alelos de riesgo en los genes del HLA-DQB1 y DQA1 (3). Sin embargo, siendo el HLA una región fundamental en la susceptibilidad a la EC, solo aportaba alrededor de un 40% del componente genético de la enfermedad. Casi diez años después del trabajo de Zhong, Monsuur y cols. encontraron una asociación entre la EC y variantes del gen de una miosina no convencional, MYO9B (4), en un área caliente del cromosoma 19 (19p13.1) que había sido definido anteriormente por el mismo grupo (5). Pero no se trata de un hallazgo más en esa carrera por conocer los genes de susceptibilidad a esta enfermedad, sino que, además de ser uno de los primeros frutos del uso de las modernas plataformas de genómica en el estudio de las enfermedades de herencia compleja, pone de manifiesto la participación de genes no directamente relacionados con el sistema inmunológico en la patogenia de la EC, al asociar la enfermedad con un gen de posible implicación en la permeabilidad del epitelio

Cytokines in the pathogeny of celiac disease

Producción CientíficaLa Enfermedad celíaca se manifiesta por una enteropatía causada por la intolerancia al gluten, una familia de las proteinas presente en el trigo y otros cereales. Tras la activación de los linfocitos T del intestino delgado en individuos predispuestos, se ponen en marcha mecanismos inflamatorios regulados por el balance entre citocinas inflamatorias de perfil Th1, como el interferón gamma (IFNy), el factor de necrosis tumoral alfa (TNFa), la interleucina (IL)-15 e IL-18 y otras reguladoras como el factor transformados del crecimiento beta (TGFb) e IL-10. Estas citocinas, además de incrementar el número de células del sistema inmunitario en la mucosa intestinal y el grado de activación, regulan la actividad de los factores de crecimiento epitelial y de las metaproteinasas, moléculas encargadas de mantener y renovar la estructura de la mucosa, que en situaciones de inflamación provocan la lesión intestinal que conduce al síndrome de malabsorción

Enfermedad celíaca. Nuevas perspectivas terapeúticas basadas en un mejor conocimiento de su patogenia molecular

Producción CientíficaLa enfermedad celíaca (EC) es una patología gastrointestinal crónica de tipo autoinmune desencadenada por un antígeno exógeno conocido (el gluten). Está fuertemente asociada al sistema HLA, aunque otros factores genéticos, ambientales e inmunológicos, aún no completamente identificados, determinarían el momento y forma de presentación. La respuesta inmune en la mucosa intestinal frente a ciertos péptidos derivados de gliadinas es caracterizada por una fuerte respuesta de tipo TH1 (con predominio de IFNγ secretado por linfocitos T específicos), la que es probablemente precedida por una respuesta inmune innata, mediada fundamentalmente por IL-15. La dieta estricta libre de gluten es la forma más eficaz de revertir las alteraciones de la mucosa intestinal y la sintomatología. Sin embargo, las transgresiones y el bajo cumplimiento de la dieta han conducido a formular nuevas estrategias terapéuticas que se discuten en esta revisión