Severe infectious disease in children may be a manifestation of primary immunodeficiency. These genetic disorders represent important experiments of nature with the capacity to elucidate nonredundant mechanisms of human immunity. We hypothesized that a primary defect of innate antiviral immunity was responsible for unusually severe viral illness in two siblings; the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection. Patient fibroblasts were indeed abnormally permissive for viral replication in vitro, associated with profound failure of type I IFN signaling and absence of STAT2 protein. Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells. Subsequently, other family members were identified with the same genetic lesion. Despite documented infection by known viral pathogens, some of which have been more severe than normal, surviving STAT2-deficient individuals have remained generally healthy, with no obvious defects in their adaptive immunity or developmental abnormalities. These findings imply that type I IFN signaling [through interferon-stimulated gene factor 3 (ISGF3)] is surprisingly not essential for host defense against the majority of common childhood viral infections.measles vaccine | viruses | rare diseases
Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis following inoculation of the live-attenuated measles, mumps and rubella (MMR) vaccine. By targeted resequencing we identified a homozygous mutation in the high-affinity * Correspondence to: christopher.duncan@ncl.ac.uk or sophie.hambleton@ncl.ac.uk.
Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied three children with an immunodysregulatory syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity and lymphoma of either B- (n=2) or T-cell (n=1) origin. All three showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole exome sequencing, we identified rare, homozygous, germline missense or nonsense variants in a known epigenetic regulator of gene expression, Ten-Eleven Translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was either absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole blood DNA hypermethylation. Circulating T-cells showed an abnormal immunophenotype including expanded double-negative but depleted follicular helper T-cell compartments, and impaired Fas-dependent apoptosis in 2/3 patients. Moreover, TET2 deficientB-cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced-pluripotent stem cells was skewed towards the myeloid lineage. These are the first reported cases of autosomal recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.
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