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J Exp Med ; 216(9): 2038-2056, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31217193


Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-ß and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN-mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.

Science ; 348(6233): 448-53, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25814066


Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.

Heterozigoto , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/imunologia , Fator Regulador 7 de Interferon/genética , Interferon Tipo I/biossíntese , Síndrome do Desconforto Respiratório do Adulto/imunologia , Criança , Células Dendríticas/imunologia , Feminino , Fibroblastos/imunologia , Genes Recessivos , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Influenza Humana/complicações , Influenza Humana/genética , Interferon Tipo I/genética , Leucócitos/imunologia , Pulmão/imunologia , Mutação , Síndrome do Desconforto Respiratório do Adulto/genética , Síndrome do Desconforto Respiratório do Adulto/virologia , Mucosa Respiratória/imunologia
Neurology ; 83(21): 1888-97, 2014 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-25339207


OBJECTIVE: To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency. METHODS: We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype. RESULTS: In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency <0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D+R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients. CONCLUSIONS: Childhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully.

Encefalite por Herpes Simples/diagnóstico , Encefalite por Herpes Simples/genética , Frequência do Gene/genética , Mutação/genética , Receptor 3 Toll-Like/deficiência , Receptor 3 Toll-Like/genética , Adolescente , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Linhagem , Recidiva , Fatores de Risco
J Exp Med ; 210(9): 1743-59, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23897980


Kaposi sarcoma (KS), a human herpes virus 8 (HHV-8; also called KSHV)-induced endothelial tumor, develops only in a small fraction of individuals infected with HHV-8. We hypothesized that inborn errors of immunity to HHV-8 might underlie the exceedingly rare development of classic KS in childhood. We report here autosomal recessive OX40 deficiency in an otherwise healthy adult with childhood-onset classic KS. OX40 is a co-stimulatory receptor expressed on activated T cells. Its ligand, OX40L, is expressed on various cell types, including endothelial cells. We found OX40L was abundantly expressed in KS lesions. The mutant OX40 protein was poorly expressed on the cell surface and failed to bind OX40L, resulting in complete functional OX40 deficiency. The patient had a low proportion of effector memory CD4(+) T cells in the peripheral blood, consistent with impaired CD4(+) T cell responses to recall antigens in vitro. The proportion of effector memory CD8(+) T cells was less diminished. The proportion of circulating memory B cells was low, but the antibody response in vivo was intact, including the response to a vaccine boost. Together, these findings suggest that human OX40 is necessary for robust CD4(+) T cell memory and confers apparently selective protective immunity against HHV-8 infection in endothelial cells.

Padrões de Herança/genética , Receptores OX40/deficiência , Receptores OX40/genética , Sarcoma de Kaposi/genética , Adulto , Idade de Início , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Formação de Anticorpos/imunologia , Sequência de Bases , Membrana Celular/metabolismo , Criança , Cisteína/genética , Feminino , Células HEK293 , Homozigoto , Humanos , Memória Imunológica/imunologia , Espaço Intracelular/metabolismo , Contagem de Linfócitos , Dados de Sequência Molecular , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Mutação/genética , Receptores OX40/química , Receptores OX40/metabolismo , Sarcoma de Kaposi/sangue , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/patologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
Ann Rehabil Med ; 37(2): 167-74, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23705110


OBJECTIVE: To obtain reliability and applicability of the Korean version Bayley Scale of Infant Development-II (BSID-II) in evaluating the developmental status of children with cerebral palsy (CP). METHODS: The inter-rater reliability of BSID-II scores from 68 children with CP (46 boys and 22 girls; mean age, 32.54±16.76 months; age range, 4 to 78 months) was evaluated by 10 pediatric occupational therapists. Patients were classified in several ways according to age group, typology, and the severity of motor impairment by the level of the Gross Motor Function Classification System (GMFCS). The measures were performed by video analysis, and the results of intraclass correlation (ICC) were obtained for each of the above classifications. To evaluate the clinical applicability of BSID-II for CP, its correlation with the Gross Motor Function Measure (GMFM), which has been known as the standard motor assessment for CP, was investigated. RESULTS: ICC was 0.99 for the Mental scale and 0.98 for the Motor scale in all subjects. The values of ICC ranged from 0.92 to 0.99 for each age group, 0.93 to 0.99 for each typology, and 0.99 to 1.00 for each GMFCS level. A strong positive correlation was found between the BSID-II Motor raw score and the GMFM total score (r=0.84, p<0.001), and a moderate correlation was observed between the BSID-II Mental raw score and the GMFM total score (r=0.65, p<0.001). CONCLUSION: The Korean version of BSID-II is a reliable tool to measure the functional status of children with CP. The raw scores of BSID-II showed a great correlation with GMFM, indicating validity of this measure for children with CP on clinical basis.

Science ; 332(6025): 65-8, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21350122


Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae caused by Candida albicans and, to a lesser extent, Staphylococcus aureus, in patients with no other infectious or autoimmune manifestations. We report two genetic etiologies of CMCD: autosomal recessive deficiency in the cytokine receptor, interleukin-17 receptor A (IL-17RA), and autosomal dominant deficiency of the cytokine interleukin-17F (IL-17F). IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. By contrast, IL-17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished, activity. These experiments of nature indicate that human IL-17A and IL-17F are essential for mucocutaneous immunity against C. albicans, but otherwise largely redundant.

Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Interleucina-17/imunologia , Candida albicans , Criança , Pré-Escolar , Feminino , Genes Dominantes , Genes Recessivos , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Receptores de Interleucina-17/genética , Transdução de Sinais/genética , Células Th17/imunologia