RESUMEN
Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Enfermedad Celíaca/inmunología , Glútenes/inmunología , Interleucina-15/inmunología , Tretinoina/farmacología , Administración Oral , Adolescente , Adulto , Animales , Enfermedad Celíaca/inducido químicamente , Enfermedad Celíaca/etiología , Células Cultivadas , Niño , Preescolar , Técnicas de Cocultivo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/enzimología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Dieta , Factores de Transcripción Forkhead/metabolismo , Gliadina/administración & dosificación , Gliadina/inmunología , Glútenes/administración & dosificación , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/inmunología , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Inflamación/inmunología , Interleucina-12/biosíntesis , Interleucina-12/inmunología , Interleucina-12/metabolismo , Interleucina-15/genética , Interleucina-23/inmunología , Interleucina-23/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Receptores de Interleucina-12/deficiencia , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Tretinoina/inmunología , Adulto JovenRESUMEN
Zinc is an abundant trace element in the human body that is essential for growth and development and immune function. It is important for the formation of biomembranes and zinc finger motifs found in DNA transcription factors and has catalytic function in metalloenzymes. The intestine is the site of zinc absorption and the major route of zinc excretion. Dietary inadequacy or conditions that decrease zinc absorption or increase its losses from the gastrointestinal tract, urine, or skin may quickly cause zinc deficiency due to the limited availability of rapidly exchangeable zinc pools in the body. Diarrhea is both a sign and a cause of zinc deficiency. The mechanism by which zinc deficiency causes diarrhea is not known. At this time, there is no readily available sensitive test for the detection of zinc deficiency, and therefore clinical suspicion remains the main mode of detection. In some individuals with diarrheal disease, zinc supplementation lessens diarrhea. Those receiving prolonged supplemental zinc therapy need to be monitored for copper deficiency.