RESUMEN
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.
Asunto(s)
Diferenciación Celular , Inmunidad Mucosa/genética , Enfermedades Inflamatorias del Intestino , Mucosa Intestinal , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Inmunodeficiencia Combinada Grave , Linfocitos B/inmunología , Linfocitos B/patología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Células HCT116 , Células HEK293 , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Masculino , Mutación , FN-kappa B/genética , FN-kappa B/inmunología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/deficiencia , Proteína Serina-Treonina Quinasas de Interacción con Receptores/inmunología , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/patología , Linfocitos T/inmunología , Linfocitos T/patologíaAsunto(s)
Síndrome Linfoproliferativo Autoinmune/genética , Síndrome Linfoproliferativo Autoinmune/inmunología , Caspasa 8/genética , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Células Epiteliales/inmunología , Intestinos/inmunología , Linfocitos/inmunología , Edad de Inicio , Animales , Apoptosis , Síndrome Linfoproliferativo Autoinmune/terapia , Biopsia , Colitis Ulcerosa/patología , Colitis Ulcerosa/terapia , Endoscopía Gastrointestinal , Células Epiteliales/patología , Predisposición Genética a la Enfermedad , Herencia , Humanos , Inflamasomas/inmunología , Mediadores de Inflamación/inmunología , Intestinos/patología , Linfocitos/patología , Ratones Noqueados , Mutación , FenotipoRESUMEN
Transforming growth factor (TGF)-ß1 (encoded by TGFB1) is the prototypic member of the TGF-ß family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-ß in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-ß1-LAP complex, which is suggestive of perturbed bioavailability of TGF-ß1. Our study shows that TGF-ß1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.