RESUMEN
Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.
Asunto(s)
Enfermedades Inflamatorias del Intestino/inmunología , Telómero/inmunología , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/genética , Interleucina-18/genética , Interleucina-18/inmunología , Mucosa Intestinal/inmunología , Ratones , Telomerasa/genética , Telomerasa/inmunología , Telómero/genética , Proteínas Señalizadoras YAP/genética , Proteínas Señalizadoras YAP/inmunologíaRESUMEN
Delusional parasitosis is a psychiatric illness in which patients believe that they are infested by parasites without any evidence to support this belief. Cases typically involve cutaneous manifestations. We present 2 cases of gastrointestinal delusional parasitosis, with one unfortunate fatal outcome. Our main goal is to highlight the importance of early recognition of this disease to facilitate appropriate management. Delusional infestation is considered a somatic delusional disorder, and first-line treatment involves the use of atypical antipsychotics, as recommended by the Diagnostic and Statistical Manual, 5th edition.