{"id":113237,"date":"2018-03-11T10:40:35","date_gmt":"2018-03-11T10:40:35","guid":{"rendered":"https:\/\/www.deberes.net\/tesis\/sin-categoria\/mecanismos-moleculares-implicados-en-las-alteraciones-inmunologicas-de-los-ratones-deficientes-ae2ab\/"},"modified":"2018-03-11T10:40:35","modified_gmt":"2018-03-11T10:40:35","slug":"mecanismos-moleculares-implicados-en-las-alteraciones-inmunologicas-de-los-ratones-deficientes-ae2ab","status":"publish","type":"post","link":"https:\/\/www.deberes.net\/tesis\/bioquimica-molecular\/mecanismos-moleculares-implicados-en-las-alteraciones-inmunologicas-de-los-ratones-deficientes-ae2ab\/","title":{"rendered":"Mecanismos moleculares implicados en las alteraciones inmunol\u00f3gicas de los ratones deficientes ae2a,b"},"content":{"rendered":"<h2>Tesis doctoral de <strong> Axel Rolando Concepci\u00f3n Gonz\u00e1lez <\/strong><\/h2>\n<p>Molecular mechanisms involved in the immunological abnormalities in ae2a,b-deficient mice  axel r. Concepcion school of science. Division of gene therapy, cima, clinic and school of medicine university of navarra, spain. 2012.  primary biliary cirrhosis (pbc) is a chronic and progressive cholestatic liver disease of unknown etiopathogenesis that mainly affects middle-aged women. Patients show non-suppurative cholangitis with damage and destruction of the small- and medium-sized intrahepatic bile ducts. Characteristically, the disease in strongly associated with autoimmune phenomena such as the appearance of serum antimitochondrial autoantibodies (ama) and portal infiltrating t cells against the inner lipoyl domain in the e2 subunit of the pyruvate dehydrogenase complex (pdc-e2). We had previously reported a diminished expression anion exchanger 2 (ae2) in the liver and lymphocytes of patients with pbc. This alteration seems to play a pathogenic role in the disease, since targeted disruption of ae2a,b in mice indeed results in hepatobiliary and immunological changes resembling pbc. Ae2 is a widely expressed protein that mediates the electroneutral sodium-independent chloride\/bicarbonate exchange across the plasma membrane and may therefore participate in the regulation of intracellular ph (phi). Cd3-stimulated proliferation of t-lymphocytes involves phi alkalinization via sodium\/proton exchange. Chloride\/bicarbonate exchangers and sodium\/bicarbonate cotransporters may function as acid loaders for extruding bicarbonate to restore phi homeostasis. Of note, mice knockout for ae2 were found to eventually develop prominent expansion of cd8+ cytotoxic t-lymphocytes (ctls) among other features. Here, we analyzed isolated ctls for their ae2 activity (as operating at the reverse mode) through flow-cytometry monitoring phi changes after chloride removal. While ctls from ae2a,b\u00c2\u00bf\/\u00c2\u00bf mice were deprived of the anion-exchange activity recorded in wildtype ctls, the other ae2a,b\u00c2\u00bf\/\u00c2\u00bf lymphocyte subpopulations continued displaying exchange activity, though diminished compared with wildtype counterparts. Moreover, ae2a,b\u00c2\u00bf\/\u00c2\u00bf mouse ctls lacked sodium\/bicarbonate cotransport activity (indeed detected in total lymphocytes) as a possible acid-loader surrogate. Cd3 stimulation increased the anion-exchange activity as well as cell proliferation and il-2 receptor alpha (il-2ralpha, cd25) expression in wildtype ctls, but these latter effects were more pronounced in ae2-deficient ctls. Since the liver of ae2a,b\u00c2\u00bf\/\u00c2\u00bf mice may show serious damage of  biliary epithelial cells by ctls similarly to what is encountered in pbc livers, we decided to explore the mechanisms leading to this particular loss of self-tolerance in ae2a,b-deficient mice and found that it is a progressive phenomenon. At early ages, t and b cells appear to be both activated and deleted in the liver. In the elderly, however, activated ctls manage to down-regulate pd-1 expression. Pd-1\/pd-l1 interaction could therefore be prevented, accounting for the diminished apoptosis and accumulation of ctls. Since elderly ctls retain their cytotoxicity ability, expanded and activated ctls may further contribute to bile duct destruction.<\/p>\n<p>&nbsp;<\/p>\n<h3>Datos acad\u00e9micos de la tesis doctoral \u00ab<strong>Mecanismos moleculares implicados en las alteraciones inmunol\u00f3gicas de los ratones deficientes ae2a,b<\/strong>\u00ab<\/h3>\n<ul>\n<li><strong>T\u00edtulo de la tesis:<\/strong>\u00a0 Mecanismos moleculares implicados en las alteraciones inmunol\u00f3gicas de los ratones deficientes ae2a,b <\/li>\n<li><strong>Autor:<\/strong>\u00a0 Axel Rolando Concepci\u00f3n Gonz\u00e1lez <\/li>\n<li><strong>Universidad:<\/strong>\u00a0 Navarra<\/li>\n<li><strong>Fecha de lectura de la tesis:<\/strong>\u00a0 27\/09\/2012<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<h3>Direcci\u00f3n y tribunal<\/h3>\n<ul>\n<li><strong>Director de la tesis<\/strong>\n<ul>\n<li>Juan  Francisco Medina Cabrera<\/li>\n<\/ul>\n<\/li>\n<li><strong>Tribunal<\/strong>\n<ul>\n<li>Presidente del tribunal: Jes\u00fas m. Prieto valtue\u00f1a <\/li>\n<li>Luis m Botana l\u00f3pez (vocal)<\/li>\n<li>albert Par\u00e9s darnaculleta (vocal)<\/li>\n<li>Manuel Ort\u00edz de land\u00e1zuri busca (vocal)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tesis doctoral de Axel Rolando Concepci\u00f3n Gonz\u00e1lez Molecular mechanisms involved in the immunological abnormalities in ae2a,b-deficient mice axel r. Concepcion [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""}},"footnotes":""},"categories":[115,1737,17749],"tags":[20460,224975,15059,50683,2447,4670],"class_list":["post-113237","post","type-post","status-publish","format-standard","hentry","category-bioquimica-molecular","category-inmunologia","category-navarra","tag-albert-pares-darnaculleta","tag-axel-rolando-concepcion-gonzalez","tag-jesus-m-prieto-valtuena","tag-juan-francisco-medina-cabrera","tag-luis-m-botana-lopez","tag-manuel-ortiz-de-landazuri-busca"],"_links":{"self":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/posts\/113237","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/comments?post=113237"}],"version-history":[{"count":0,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/posts\/113237\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/media?parent=113237"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/categories?post=113237"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/tags?post=113237"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}