RESUMO
Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients' immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies.
Assuntos
Síndromes de Imunodeficiência , Fosfatidilinositol 3-Quinases , Animais , Camundongos , Humanos , Classe I de Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/genética , Mutação/genética , Linfócitos B , Síndrome , Diferenciação Celular/genética , Síndromes de Imunodeficiência/genética , Classe Ia de Fosfatidilinositol 3-Quinase/genéticaRESUMO
PURPOSE: To assess the efficacy, pharmacokinetics, and safety of a new, highly purified 10% IVIg (BT595, Yimmugo®) administered in children with PID. METHODS: This was an open-label, prospective, uncontrolled, multicenter Phase III pivotal trial. Among the 67 subjects in the trial were 18 pediatric patients aged 2 to 17 years with diagnosis of PID included in this analysis. They received doses between 0.2 and 0.8 g/kg body weight for approximately 12 months at intervals of either 3 or 4 weeks. Dosage and dosing interval were based on each patient's pre-trial infusion schedule. The rates of acute serious bacterial infections (SBI), secondary efficacy, safety, and pharmacokinetic outcomes were evaluated. RESULTS: No SBI occurred in the pediatric population. Two hundred sixty infusions were administered to the 18 pediatric patients. The mean (SD) IgG trough level was 8.55 (1.67) g/L at baseline and 8.84 (2.17) g/L at the follow-up visit after the last BT595 infusion. At the single infusions respectively, the average mean IgG trough levels ranged between 8.52 and 10.58 g/L. More than 85% of all infusions administered were not associated with any infusional AE (start during or within 72 h post-infusion). None of the severe or serious AEs were related to the investigational medicinal product (IMP). No premedication was used. Thirteen children reached a maximum infusion rate between > 2.0 and 8 mL/kg/h; no AE with an onset during the infusion occurred at these infusion rates. CONCLUSION: BT595 is effective, convenient, well tolerated, and safe for the treatment of children with PID. TRIAL REGISTRATION: EudraCT: 2015-003652-52; NCT02810444, registered June 23, 2016.
Assuntos
Infecções Bacterianas , Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Humanos , Criança , Estudos Prospectivos , Síndromes de Imunodeficiência/diagnóstico , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Doenças da Imunodeficiência Primária/tratamento farmacológicoRESUMO
Most of the currently known heterozygous pathogenic NFKB1 (Nuclear factor kappa B subunit 1) variants comprise deleterious defects such as severe truncations, internal deletions, and frameshift variants. Collectively, these represent the most frequent monogenic cause of common variable immunodeficiency (CVID) identified so far. NFKB1 encodes the transcription factor precursor p105 which undergoes limited proteasomal processing of its C-terminal half to generate the mature NF-κB subunit p50. Whereas p105/p50 haploinsufficiency due to devastating genetic damages and protein loss is a well-known disease mechanism, the pathogenic significance of numerous NFKB1 missense variants still remains uncertain and/or unexplored, due to the unavailability of accurate test procedures to confirm causality. In this study we functionally characterized 47 distinct missense variants residing within the N-terminal domains, thus affecting both proteins, the p105 precursor and the processed p50. Following transient overexpression of EGFP-fused mutant p105 and p50 in HEK293T cells, we used fluorescence microscopy, Western blotting, electrophoretic mobility shift assays (EMSA), and reporter assays to analyze their effects on subcellular localization, protein stability and precursor processing, DNA binding, and on the RelA-dependent target promoter activation, respectively. We found nine missense variants to cause harmful damage with intensified protein decay, while two variants left protein stability unaffected but caused a loss of the DNA-binding activity. Seven of the analyzed single amino acid changes caused ambiguous protein defects and four variants were associated with only minor adverse effects. For 25 variants, test results were indistinguishable from those of the wildtype controls, hence, their pathogenic impact remained elusive. In summary, we show that pathogenic missense variants affecting the Rel-homology domain may cause protein-decaying defects, thus resembling the disease-mechanisms of p105/p50 haploinsufficiency or may cause DNA-binding deficiency. However, rare variants (with a population frequency of less than 0.01%) with minor abnormalities or with neutral tests should still be considered as potentially pathogenic, until suitable tests have approved them being benign.
Assuntos
Mutação de Sentido Incorreto , NF-kappa B , DNA , Células HEK293 , Humanos , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-rel/metabolismoAssuntos
Células Matadoras Naturais/imunologia , Receptores de IgG/genética , Síndrome de DiGeorge/sangue , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/imunologia , Feminino , Variação Genética , Humanos , Recém-Nascido , Contagem de Leucócitos , Linfopenia/sangue , Linfopenia/genética , Linfopenia/imunologia , Receptores de Antígenos de Linfócitos T/sangueRESUMO
PURPOSE: Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. METHODS: Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. RESULTS: Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell-intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia. CONCLUSION: In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.
Assuntos
Linfócitos B/imunologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Células Matadoras Naturais/imunologia , Proteínas de Neoplasias/genética , Adolescente , Adulto , Criança , Pré-Escolar , Citocinas/imunologia , Expressão Gênica , Genótipo , Humanos , Lactente , Contagem de Leucócitos , Proteínas de Neoplasias/deficiência , Fenótipo , Adulto JovemRESUMO
In perinatally HIV-infected (PHIV) children, neurodevelopment occurs in the presence of HIV-infection, and even with combination antiretroviral therapy (cART) the brain can be a reservoir for latent HIV. Consequently, patients often demonstrate long-term cognitive deficits and developmental delay, which may be reflected in altered functional brain activity. Our objective was to examine brain function in PHIV on cART by quantifying the amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo). Further, we studied ALFF and ReHo changes with neuropsychological performance and measures of immune health including CD4 count and viral loads in the HIV-infected youths. We found higher ALFF and ReHo in cerebral white matter in the medial orbital lobe for PHIV (N = 11, age mean ± sd = 22.5 ± 2.9 years) compared to controls (N = 16, age = 22.5 ± 3.0 years), with age and gender as co-variates. Bilateral cerebral white matter showed increased spontaneous regional activity in PHIV compared to healthy controls. No brain regions showed lower ALFF or ReHo in PHIV compared to controls. Higher log10 viral load was associated with higher ALFF and ReHo in PHIV in bilateral cerebral white matter and right cerebral white matter respectively after masking the outcomes intrinsic to the brain regions that showed significantly higher ALFF and ReHo in the PHIV compared to the control. Reductions in social cognition and abstract thinking in PHIV were correlated with higher ALFF at the left cerebral white matter in the left medial orbital gyrus and higher ReHo at the right cerebral white matter in the PHIV patients. Although neuroinflammation and associated neuro repair were not directly measured, the findings support their potential role in PHIV impacting neurodevelopment and cognition.
Assuntos
Transtornos Cognitivos/patologia , Infecções por HIV/patologia , HIV-1/patogenicidade , Substância Branca/patologia , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/virologia , Mapeamento Encefálico , Criança , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/virologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/virologia , Feminino , Infecções por HIV/diagnóstico por imagem , Infecções por HIV/virologia , HIV-1/genética , Humanos , Transmissão Vertical de Doenças Infecciosas , Imageamento por Ressonância Magnética , Masculino , Neuroglia/patologia , Neuroglia/virologia , Carga Viral , Latência Viral , Substância Branca/diagnóstico por imagem , Substância Branca/virologia , Adulto JovemAssuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Hipersensibilidade Imediata/etiologia , Hipersensibilidade Imediata/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Sinusite/etiologia , Sinusite/metabolismo , Adulto , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Proteínas Adaptadoras de Sinalização CARD/genética , Doença Crônica , Suscetibilidade a Doenças , Feminino , Humanos , Hipersensibilidade Imediata/complicações , Hipersensibilidade Imediata/diagnóstico , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Sinusite/complicações , Sinusite/diagnóstico , Avaliação de SintomasRESUMO
Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a "cloning-free" saturation genome editing approach in a diploid cell line to simultaneously score 2,542 variants for decreased or increased function in the region of CARD11 associated with immunodeficiency. We also described an exon-skipping mechanism for CARD11 dominant-negative activity. The classification of reported clinical variants was sensitive (94.6%) and specific (88.9%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Variação Genética , Guanilato Ciclase/genética , Síndromes de Imunodeficiência/genética , Adenina/análogos & derivados , Adenina/farmacologia , Proteína 10 de Linfoma CCL de Células B/genética , Linfócitos B/citologia , Linhagem Celular , Diploide , Éxons , Genes Dominantes , Humanos , Células Jurkat , Linfoma/genética , Subunidade p50 de NF-kappa B/genética , Piperidinas/farmacologia , Polimorfismo de Nucleotídeo Único , Doenças da Imunodeficiência Primária/genética , Sensibilidade e EspecificidadeRESUMO
PURPOSE: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. METHODS: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. RESULTS: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the ß-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). CONCLUSION: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.
Assuntos
Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Alelos , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Doenças Genéticas Inatas/patologia , Humanos , Lactente , Fígado/patologia , Transplante de Fígado/efeitos adversos , Masculino , Músculo Esquelético/patologia , Mutação de Sentido Incorreto/genética , FenótipoRESUMO
Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-ß renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/ß stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.
Assuntos
Encefalite por Herpes Simples/genética , Herpesvirus Humano 1/genética , Neurônios/imunologia , RNA Nucleolar Pequeno/genética , Adulto , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Pré-Escolar , Encefalite por Herpes Simples/imunologia , Encefalite por Herpes Simples/patologia , Encefalite por Herpes Simples/virologia , Feminino , Predisposição Genética para Doença , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Humanos , Imunidade/genética , Lactente , Masculino , Metagenoma/genética , Metagenoma/imunologia , Pessoa de Meia-Idade , Neurônios/virologia , RNA Nucleolar Pequeno/imunologiaRESUMO
BACKGROUND: In 6.5 years of newborn screening for severe combined immunodeficiency in California, 3,252,156 infants had DNA from dried blood spots (DBSs) assayed for T-cell receptor excision circles. Infants with T-cell receptor excision circle values of less than a designated cutoff on a single DBS, 2 DBS samples with insufficient PCR amplification, or known genetic risk of immunodeficiency had peripheral blood complete blood counts and lymphocyte subsets assayed in a single flow cytometry laboratory. Cases in which immune defects were ruled out were available for analysis. OBJECTIVE: We sought to determine reference intervals for lymphocyte subsets in racially/ethnically diverse preterm and term newborns who proved to be unaffected by any T-lymphopenic immune disorder. METHODS: Effective gestational age (GA) was defined as GA at birth plus postnatal age at the time of sample collection. After determining exclusion criteria, we analyzed demographic and clinical information, complete and differential white blood cell counts, and lymphocyte subsets for 301 infants, with serial measurements for 33 infants. Lymphocyte subset measurements included total T cells, helper and cytotoxic T-cell subsets, naive and memory phenotype of each T-cell subset, B cells, and natural killer cells. RESULTS: Reference intervals were generated for absolute numbers and lymphocyte subsets from infants with effective GAs of 22 to 52 weeks. Sex and ethnicity were not significant determinants of lymphocyte subset counts in this population. Lymphocyte counts increased postnatally. CONCLUSION: This study provides a baseline for interpreting comprehensive lymphocyte data in preterm and term infants, aiding clinicians to determine which newborns require further evaluations for immunodeficiency.
Assuntos
Linfócitos B/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Recém-Nascido Prematuro/sangue , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Teste em Amostras de Sangue Seco , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro/imunologia , Contagem de Linfócitos , Masculino , Reação em Cadeia da Polimerase , Receptores de Antígenos de Linfócitos T/sangue , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologiaRESUMO
BACKGROUND: Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia. METHODS: We performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1. RESULTS: Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven. CONCLUSIONS: Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.).
Assuntos
Bussulfano/administração & dosagem , Terapia Genética , Vetores Genéticos , Subunidade gama Comum de Receptores de Interleucina/genética , Lentivirus , Condicionamento Pré-Transplante , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Antígenos de Diferenciação de Linfócitos T/sangue , Linfócitos B/fisiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoglobulina M/sangue , Lactente , Células Matadoras Naturais , Contagem de Linfócitos , Masculino , Linfócitos T , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologiaRESUMO
Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67 phox , activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Cell lines transfected with RAC2[E62K] displayed characteristics of active guanosine triphosphate (GTP)-bound RAC2 including enhanced superoxide production and increased membrane ruffling. Biochemical studies demonstrated that RAC2[E62K] retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2. Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients. This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates RAC2 from the related, ubiquitous RAC1.
Assuntos
Síndromes de Imunodeficiência/genética , Proteínas rac de Ligação ao GTP/genética , Adolescente , Adulto , Animais , Pré-Escolar , Citoesqueleto/patologia , Feminino , Mutação com Ganho de Função , Humanos , Lactente , Recém-Nascido , Linfopenia/genética , Camundongos , Camundongos Endogâmicos C57BL , Linhagem , Proteínas rac de Ligação ao GTP/imunologia , Proteína RAC2 de Ligação ao GTPRESUMO
We evaluated white matter microstructure integrity in perinatally HIV-infected (PHIV) youths receiving cART compared to age- and gender-matched healthy youths through DTI metrics using voxel-based morphometry (VBM). We investigated 14 perinatally HIV-infected patients (age 17.9 ± 2.5 years) on cART and 17 healthy youths (HC) (age 18.0 ± 3.0 years) using a 3T MRI scanner. Four DTI-derived metrics were fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Statistical analysis was done with voxel-based analysis of covariance (ANCOVA), with age and gender as covariates. Region-of-interest secondary analyses in statistically significant regions were also performed. Regional increases in FA in the PHIV youths were found in left middle frontal gyrus, right precuneus, right lingual gyrus, and left supramarginal gyrus. Increased MD was found in the right precentral gyrus while decreased MD was found in the white matter of the right superior parietal lobule and right inferior temporal gyrus/fusiform gyrus. Regions of increased/decreased RD overlapped with regions of increased/decreased MD. Both increased and decreased AD were found in three to four regions respectively. The regional FA, MD, RD, and AD values were consistent with the voxel-based analysis findings. The findings are mostly consistent with previous literature, but increased FA has not been previously reported for perinatally HIV-infected youths. Potentially early and prolonged therapy in our population may have contributed to this new finding. Both toxicity of antiretroviral therapy and indolent infection must be considered as causative factors in the DTI metric changes that we have observed.
Assuntos
Encéfalo/diagnóstico por imagem , Infecções por HIV/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adolescente , Antirretrovirais/uso terapêutico , Encéfalo/patologia , Encéfalo/virologia , Imagem de Tensor de Difusão/métodos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Processamento de Imagem Assistida por Computador , Transmissão Vertical de Doenças Infecciosas , Masculino , Substância Branca/patologia , Substância Branca/virologiaRESUMO
OBJECTIVES: Newborn screening for severe combined immunodeficiency (SCID) was instituted in California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified. METHODS: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes. RESULTS: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000-1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age. CONCLUSIONS: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening.
Assuntos
Teste em Amostras de Sangue Seco/métodos , Linfopenia/sangue , Linfopenia/diagnóstico , Triagem Neonatal/métodos , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/diagnóstico , Linfócitos T/metabolismo , California/epidemiologia , Feminino , Humanos , Recém-Nascido , Linfopenia/epidemiologia , Masculino , Imunodeficiência Combinada Severa/epidemiologiaRESUMO
Transcription factor NRF2, encoded by NFE2L2, is the master regulator of defense against stress in mammalian cells. Somatic mutations of NFE2L2 leading to NRF2 accumulation promote cell survival and drug resistance in cancer cells. Here we show that the same mutations as inborn de novo mutations cause an early onset multisystem disorder with failure to thrive, immunodeficiency and neurological symptoms. NRF2 accumulation leads to widespread misregulation of gene expression and an imbalance in cytosolic redox balance. The unique combination of white matter lesions, hypohomocysteinaemia and increased G-6-P-dehydrogenase activity will facilitate early diagnosis and therapeutic intervention of this novel disorder.The NRF2 transcription factor regulates the response to stress in mammalian cells. Here, the authors show that activating mutations in NRF2, commonly found in cancer cells, are found in four patients with a multisystem disorder characterized by immunodeficiency and neurological symptoms.