Subject(s)
Autoimmune Lymphoproliferative Syndrome/genetics , Autoimmune Lymphoproliferative Syndrome/immunology , Caspase 8/genetics , Colitis, Ulcerative/genetics , Colitis, Ulcerative/immunology , Epithelial Cells/immunology , Intestines/immunology , Lymphocytes/immunology , Age of Onset , Animals , Apoptosis , Autoimmune Lymphoproliferative Syndrome/therapy , Biopsy , Colitis, Ulcerative/pathology , Colitis, Ulcerative/therapy , Endoscopy, Gastrointestinal , Epithelial Cells/pathology , Genetic Predisposition to Disease , Heredity , Humans , Inflammasomes/immunology , Inflammation Mediators/immunology , Intestines/pathology , Lymphocytes/pathology , Mice, Knockout , Mutation , PhenotypeABSTRACT
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.
Subject(s)
Cell Differentiation , Immunity, Mucosal/genetics , Inflammatory Bowel Diseases , Intestinal Mucosa , Receptor-Interacting Protein Serine-Threonine Kinases , Severe Combined Immunodeficiency , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Cell Differentiation/genetics , Cell Differentiation/immunology , Epithelial Cells/immunology , Epithelial Cells/pathology , Female , HCT116 Cells , HEK293 Cells , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/pathology , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Male , Mutation , NF-kappa B/genetics , NF-kappa B/immunology , Receptor-Interacting Protein Serine-Threonine Kinases/deficiency , Receptor-Interacting Protein Serine-Threonine Kinases/immunology , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/pathology , T-Lymphocytes/immunology , T-Lymphocytes/pathologyABSTRACT
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.
