RESUMEN
Leptin has been shown to modulate intestinal inflammation in mice. However, clinical evidence regarding its immune-stimulatory potential in human Crohn's disease remains sparse. We here describe a patient with the unique combination of acquired generalized lipodystrophy and Crohn's disease (AGLCD) featuring a lack of adipose tissue, leptin deficiency and intestinal inflammation. Using mass and flow cytometry, immunohistochemistry and functional metabolic analyses, the AGLCD patient was compared to healthy individuals and Crohn's disease patients regarding immune cell composition, function and metabolism and the effects of recombinant N-methionylleptin (rLeptin) were evaluated. We provide evidence that rLeptin exerts diverse pro-inflammatory effects on immune cell differentiation and function, including the metabolic reprogramming of immune cells and the induction of TNFα, ultimately aggravating Crohn's disease in the AGLCD patient, which can be reversed by anti-TNFα therapy. Our results indicate that leptin is required for human immune homeostasis and contributes to autoimmunity in a TNFα-dependent manner.
Asunto(s)
Inflamación/tratamiento farmacológico , Leptina/uso terapéutico , Lipodistrofia Generalizada Congénita/complicaciones , Línea Celular , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/patología , Humanos , Células Asesinas Naturales , Masculino , Fenotipo , Linfocitos T/citología , Factor de Necrosis Tumoral alfa/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Massively parallel DNA sequencing of clinical samples holds great promise for the gene-based diagnosis of human inherited diseases because it allows rapid detection of putatively causative mutations at genome-wide level. Without additional evidence complementing their initial bioinformatics evaluation, however, the clinical relevance of such candidate genetic variants often remains unclear. In consequence, dedicated 'matching' services have been established in recent years that aim at the discovery of other, comparable case reports to facilitate individual diagnoses. However, legal concerns have been raised about the global sharing of genetic data, particularly in Europe where the recently enacted General Data Protection Regulation EU-2016/679 classifies genetic data as highly sensitive. Hence, unrestricted sharing of genetic data from clinical cases on platforms outside the national jurisdiction increasingly may be perceived as problematic. To allow collaborative data producers, particularly large consortia of diagnostic laboratories, to acknowledge these concerns while still practicing efficient case matching internally, novel tools are required. To this end, we developed VarWatch, an easy-to-deploy and highly scalable case matching software that provides users with comprehensive programmatic tools and a user-friendly interface to fulfil said purpose.
Asunto(s)
Biología Computacional/instrumentación , Enfermedades Genéticas Congénitas/diagnóstico , Pruebas Genéticas/instrumentación , Genómica/instrumentación , Programas Informáticos , Conjuntos de Datos como Asunto , Enfermedades Genéticas Congénitas/genética , Variación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia de ADNRESUMEN
Recent advances in the development of sequencing technologies provide researchers with unprecedented possibilities for genetic analyses. In this review, we will discuss the history of genetic studies and the progress driven by next-generation sequencing (NGS), using complex inflammatory bowel diseases as an example. We focus on the opportunities, but also challenges that researchers are facing when working with NGS data to unravel the genetic causes underlying diseases.
