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1.
J Interferon Cytokine Res ; 39(10): 642-649, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31260374

RESUMO

Hepatitis C virus (HCV) genotype 3 is very prevalent in Europe and Asia and is associated with worst outcomes than other genotypes. Genetic factors have been associated with HCV infection; however, no extensive genome-wide study has been performed among HCV genotype 3 patients. In this study, using a large cohort of 1,759 patients infected with HCV genotype 3, we explore the role of genetic variants on the response to interferon (IFN) and direct-acting antiviral (DAA) regimens and viremia in a combined candidate gene and genome-wide analysis. We show that genetic variants within the IFN lambda 4 (IFNL4) locus are the major factors associated with the studied traits, accordingly with observations in other HCV genotypes and with comparable effect sizes. In particular, the functional dinucleotide polymorphism rs368234815 was associated with IFN-based sustained virologic response (SVR) [odds ratio (OR) = 1.5, P = 2.3 × 10-7], viremia (beta = -0.23, P = 8.8 × 10-10), and also DAA-based SVR (OR = 1.7; P = 4.2 × 10-4). Our results provide evidence for a role of genetic variants on HCV viremia and SVR, notably DAA-based, in patients infected with HCV genotype 3.

2.
Nat Genet ; 51(7): 1131-1136, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31209392

RESUMO

Epstein-Barr virus (EBV) infection is ubiquitous worldwide and is associated with multiple cancers, including nasopharyngeal carcinoma (NPC). The importance of EBV viral genomic variation in NPC development and its striking epidemic in southern China has been poorly explored. Through large-scale genome sequencing of 270 EBV isolates and two-stage association study of EBV isolates from China, we identify two non-synonymous EBV variants within BALF2 that are strongly associated with the risk of NPC (odds ratio (OR) = 8.69, P = 9.69 × 10-25 for SNP 162476_C; OR = 6.14, P = 2.40 × 10-32 for SNP 163364_T). The cumulative effects of these variants contribute to 83% of the overall risk of NPC in southern China. Phylogenetic analysis of the risk variants reveals a unique origin in Asia, followed by clonal expansion in NPC-endemic regions. Our results provide novel insights into the NPC endemic in southern China and also enable the identification of high-risk individuals for NPC prevention.

3.
Sci Rep ; 8(1): 7224, 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29740042

RESUMO

Hepatitis C virus (HCV)-specific T cell responses are critical for immune control of infection. Viral adaptation to these responses, via mutations within regions of the virus targeted by CD8+ T cells, is associated with viral persistence. However, identifying viral adaptation to HCV-specific CD4+ T cell responses has been difficult although key to understanding anti-HCV immunity. In this context, HCV sequence and host genotype from a single source HCV genotype 1B cohort (n = 63) were analyzed to identify viral changes associated with specific human leucocyte antigen (HLA) class II alleles, as these variable host molecules determine the set of viral peptides presented to CD4+ T cells. Eight sites across the HCV genome were associated with HLA class II alleles implicated in infection outcome in this cohort (p ≤ 0.01; Fisher's exact test). We extended this analysis to chronic HCV infection (n = 351) for the common genotypes 1A and 3A. Variation at 38 sites across the HCV genome were associated with specific HLA class II alleles with no overlap between genotypes, suggestive of genotype-specific T cell targets, which has important implications for vaccine design. Here we show evidence of HCV adaptation to HLA class II-restricted CD4+ T cell pressure across the HCV genome in chronic HCV infection without a priori knowledge of CD4+ T cell epitopes.

4.
Hepatology ; 2018 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-29534310

RESUMO

New directly acting antivirals (DAAs) provide very high cure rates in most patients infected by hepatitis C virus (HCV). However, some patient groups have been relatively harder to treat including those with cirrhosis or infected with HCV genotype 3. In the recent BOSON trial, genotype 3, cirrhotic patients receiving a 16 week course of sofosbuvir and ribavirin had a sustained virologic response rate (SVR) of around 50%. In cirrhotic patients, IFNL4 CC genotype was significantly associated with SVR. This genotype was also associated with a lower interferon-stimulated gene (ISG) signature in peripheral blood and in liver at baseline. Unexpectedly, patients with the CC genotype showed a dynamic increase in ISG expression between weeks 4 and 16 of DAA therapy, while the reverse was true for non-CC patients. These data provide an important dynamic link between host genotype and phenotype in HCV therapy also potentially relevant to naturally acquired infection. This article is protected by copyright. All rights reserved.

5.
Nat Genet ; 49(5): 666-673, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28394351

RESUMO

Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. Here we use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3. We show that both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism. Additionally, we show that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific amino acid residue in the HCV NS5A protein. These findings highlight the interplay between the innate immune system and the viral genome in HCV control.


Assuntos
Imunidade Adaptativa/genética , Genoma Humano/genética , Genoma Viral/genética , Hepacivirus/genética , Hepatite C Crônica/genética , Imunidade Inata/genética , Alelos , Variação Genética , Genótipo , Antígenos HLA/genética , Hepacivirus/fisiologia , Hepatite C Crônica/virologia , Interações Hospedeiro-Patógeno/genética , Humanos , Interleucinas/genética , Modelos Logísticos , Análise de Componente Principal , Carga Viral/genética , Proteínas não Estruturais Virais/genética
6.
Cell ; 168(5): 789-800.e10, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28235196

RESUMO

The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Lipopolissacarídeos/metabolismo , Glicoproteínas de Membrana/deficiência , Receptores de Interleucina-1/deficiência , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Ácidos Teicoicos/metabolismo , Imunidade Adaptativa , Criança , Feminino , Fibroblastos/metabolismo , Humanos , Imunidade Inata , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Monócitos/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Linhagem , Fagócitos/metabolismo , Mutação Puntual , Isoformas de Proteínas/análise , Isoformas de Proteínas/genética , Receptores de Interleucina-1/análise , Receptores de Interleucina-1/genética , Infecções Estafilocócicas/tratamento farmacológico , Ácidos Teicoicos/imunologia , Receptor 2 Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo
8.
J Allergy Clin Immunol ; 138(4): 957-969, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27720020

RESUMO

The advent of next-generation sequencing (NGS) in 2010 has transformed medicine, particularly the growing field of inborn errors of immunity. NGS has facilitated the discovery of novel disease-causing genes and the genetic diagnosis of patients with monogenic inborn errors of immunity. Whole-exome sequencing (WES) is presently the most cost-effective approach for research and diagnostics, although whole-genome sequencing offers several advantages. The scientific or diagnostic challenge consists in selecting 1 or 2 candidate variants among thousands of NGS calls. Variant- and gene-level computational methods, as well as immunologic hypotheses, can help narrow down this genome-wide search. The key to success is a well-informed genetic hypothesis on 3 key aspects: mode of inheritance, clinical penetrance, and genetic heterogeneity of the condition. This determines the search strategy and selection criteria for candidate alleles. Subsequent functional validation of the disease-causing effect of the candidate variant is critical. Even the most up-to-date dry lab cannot clinch this validation without a seasoned wet lab. The multifariousness of variations entails an experimental rigor even greater than traditional Sanger sequencing-based approaches in order not to assign a condition to an irrelevant variant. Finding the needle in the haystack takes patience, prudence, and discernment.


Assuntos
Exoma/genética , Doenças Genéticas Inatas , Genoma Humano/genética , Síndromes de Imunodeficiência/genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
9.
Proc Natl Acad Sci U S A ; 113(24): 6713-8, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27247391

RESUMO

Principal component analysis (PCA), homozygosity rate estimations, and linkage studies in humans are classically conducted through genome-wide single-nucleotide variant arrays (GWSA). We compared whole-exome sequencing (WES) and GWSA for this purpose. We analyzed 110 subjects originating from different regions of the world, including North Africa and the Middle East, which are poorly covered by public databases and have high consanguinity rates. We tested and applied a number of quality control (QC) filters. Compared with GWSA, we found that WES provided an accurate prediction of population substructure using variants with a minor allele frequency > 2% (correlation = 0.89 with the PCA coordinates obtained by GWSA). WES also yielded highly reliable estimates of homozygosity rates using runs of homozygosity with a 1,000-kb window (correlation = 0.94 with the estimates provided by GWSA). Finally, homozygosity mapping analyses in 15 families including a single offspring with high homozygosity rates showed that WES provided 51% less genome-wide linkage information than GWSA overall but 97% more information for the coding regions. At the genome-wide scale, 76.3% of linked regions were found by both GWSA and WES, 17.7% were found by GWSA only, and 6.0% were found by WES only. For coding regions, the corresponding percentages were 83.5%, 7.4%, and 9.1%, respectively. With appropriate QC filters, WES can be used for PCA and adjustment for population substructure, estimating homozygosity rates in individuals, and powerful linkage analyses, particularly in coding regions.


Assuntos
Consanguinidade , Ligação Genética , Estudo de Associação Genômica Ampla , Homozigoto , Feminino , Humanos , Masculino , Oriente Médio , América do Norte
12.
PLoS One ; 10(12): e0145105, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26670100

RESUMO

BACKGROUND: Human genetic factors influence the outcome of pegylated interferon and ribavirin hepatitis C therapy. We explored the role of IL28B, APOH and ITPA SNPs on the outcomes of triple therapy including telaprevir or boceprevir in patients with compensated cirrhosis chronically infected with HCV-1. PATIENTS AND METHODS: A total of 256 HCV-1 Caucasian treatment-experienced patients with compensated cirrhosis from the ANRS CO20-CUPIC cohort were genotyped for a total of 10 candidate SNPs in IL28B (rs12979860 and rs368234815), APOH (rs8178822, rs12944940, rs10048158, rs52797880, rs1801689 and rs1801690) and ITPA (rs1127354 and rs7270101). We tested the association of IL28B and APOH SNPs with sustained virological response and of ITPA SNPs with anemia related phenotypes by means of logistic regression assuming an additive genetic model. RESULTS: None of the six APOH SNPs were associated with sustained virological response. The favorable alleles of the IL28B SNPs rs12979860 and rs368234815 were associated with sustained virological response (rs12979860: OR = 2.35[1.50-3.70], P = 2x10(-4)). Refined analysis showed that the effect of IL28B SNPs on sustained virological response was restricted to prior PegIFN/RBV relapse (OR = 3.80[1.82-8.92], P = 8x10(-4)). We also confirmed the association between ITPA low activity alleles and protection against early hemoglobin decline in triple therapy (P = 2x10(-5)). CONCLUSION: Our results suggest that the screening of rs12979860 may remain interesting for decision making in prior relapse HCV-1 Caucasian patients with compensated cirrhosis eligible for a telaprevir- or boceprevir-based therapy.


Assuntos
Hepatite C Crônica/genética , Interleucinas/genética , Cirrose Hepática/complicações , Oligopeptídeos/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Prolina/análogos & derivados , Pirofosfatases/genética , beta 2-Glicoproteína I/genética , Anemia/complicações , Quimioterapia Combinada , Hemoglobinas/metabolismo , Hepacivirus/fisiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Cirrose Hepática/virologia , Oligopeptídeos/efeitos adversos , Prolina/efeitos adversos , Prolina/uso terapêutico , Resultado do Tratamento
13.
N Engl J Med ; 372(25): 2409-22, 2015 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-26083206

RESUMO

Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).


Assuntos
Doenças Genéticas Inatas/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Síndromes de Imunodeficiência/genética , Mutação , Linfócitos T/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Pré-Escolar , Evolução Fatal , Feminino , Genes Recessivos , Doenças Genéticas Inatas/terapia , Fatores de Troca do Nucleotídeo Guanina/deficiência , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndromes de Imunodeficiência/terapia , Lactente , Células Matadoras Naturais/imunologia , Masculino , Linhagem , Linfócitos T/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo
14.
Science ; 348(6233): 448-53, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25814066

RESUMO

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.


Assuntos
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
15.
J Allergy Clin Immunol ; 135(6): 1558-68.e2, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25702837

RESUMO

BACKGROUND: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained. OBJECTIVE: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only. METHODS: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients. RESULTS: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the 3 patients with Candida albicans-induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans-induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis). CONCLUSION: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Candidíase Invasiva/genética , Sistema Nervoso Central/patologia , Colite/genética , Trato Gastrointestinal/patologia , Meningoencefalite/genética , Adolescente , Adulto , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/imunologia , Candida/imunologia , Candidíase Invasiva/imunologia , Candidíase Invasiva/microbiologia , Candidíase Invasiva/patologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/microbiologia , Criança , Colite/imunologia , Colite/microbiologia , Colite/patologia , Consanguinidade , Feminino , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Homozigoto , Humanos , Masculino , Meningoencefalite/imunologia , Meningoencefalite/microbiologia , Meningoencefalite/patologia , Linhagem , Análise de Sequência de DNA
16.
J Infect Dis ; 211(8): 1241-50, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25057046

RESUMO

BACKGROUND: Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa. METHODS: We investigated an 8-year-old girl from a nonconsanguineous Angolan kindred, who was born in France and developed disseminated E. dermatitidis disease and a 26 year-old woman from an Iranian consaguineous kindred, who was living in Iran and developed disseminated E. spinifera disease. Both patients were otherwise healthy. RESULTS: We sequenced CARD9 and found both patients to be homozygous for loss-of-function mutations (R18W and E323del). The first patient had segmental uniparental disomy of chromosome 9, carrying 2 copies of the maternal CARD9 mutated allele. CONCLUSIONS: These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/genética , Feoifomicose/genética , Adulto , Alelos , Criança , Cromossomos Humanos Par 9/genética , Exophiala , Feminino , Homozigoto , Humanos , Mutação/genética , Feoifomicose/microbiologia
17.
J Clin Immunol ; 34(8): 904-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25135595

RESUMO

Interferon-γ receptor 2 (IFN-γR2) deficiency is a rare primary immunodeficiency characterized by predisposition to infections with weakly virulent mycobacteria, such as environmental mycobacteria and BCG vaccines. We describe here two children with IFN-γR2 deficiency, from unrelated, consanguineous kindreds of Arab and Israeli descent. The first patient was a boy who died at the age of 4.5 years, from recurrent, disseminated disease caused by Mycobacterium simiae. His IFN-γR2 defect was autosomal recessive and complete. The second patient was a girl with multiple disseminated mycobacterial infections, including infection with M. simiae. She died at the age of 5 years, a short time after the transplantation of umbilical cord blood cells from an unrelated donor. Her IFN-γR2 defect was autosomal recessive and partial. Autosomal recessive IFN-γR2 deficiency is life-threatening, even in its partial form, and genetic diagnosis and familial counseling are therefore particularly important for this condition. These two cases are the first of IFN-γR2 deficiency associated with M. simiae infection to be described.


Assuntos
Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/genética , Infecções por Mycobacterium/complicações , Infecções por Mycobacterium/patologia , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Pré-Escolar , Evolução Fatal , Feminino , Predisposição Genética para Doença , Humanos , Síndromes de Imunodeficiência/imunologia , Masculino , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/mortalidade
18.
PLoS One ; 9(7): e102501, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25025336

RESUMO

Over 95% of the adult population worldwide is infected with Epstein-Barr virus (EBV). EBV infection is associated with the development of several cancers, including Hodgkin lymphoma (HL). Elevated levels of anti-EBV antibodies have been associated with increased risk of HL. There is growing evidence that genetic factors control the levels of antibodies against EBV antigens. Here, we conducted linkage and association studies to search for genetic factors influencing either anti-viral capsid antigen (VCA) or anti-Epstein Barr nuclear antigen-1 (EBNA-1) IgG levels in a unique cohort of 424 individuals of European origin from 119 French families recruited through a Hodgkin lymphoma (HL) patient. No major locus controlling anti-VCA antibody levels was identified. However, we found that the HLA region influenced anti-EBNA-1 IgG titers. Refined association studies in this region identified a cluster of HLA class II variants associated with anti-EBNA-1 IgG titers (e.g. p = 5×10(-5) for rs9268403). The major allele of rs9268403 conferring a predisposition to high anti-EBNA-1 antibody levels was also associated with an increased risk of HL (p = 0.02). In summary, this study shows that HLA class II variants influenced anti-EBNA-1 IgG titers in a European population. It further shows the role of the same variants in the risk of HL.


Assuntos
Imunidade Adaptativa/genética , Anticorpos Antivirais/sangue , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/biossíntese , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
19.
Immunity ; 39(4): 676-86, 2013 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-24120361

RESUMO

Patients with inborn errors of interleukin-17F (IL-17F) or IL-17RA display chronic mucocutaneous candidiasis (CMC). We report a biallelic missense mutation (T536I) in the adaptor molecule ACT1 in two siblings with CMC. The mutation, located in the SEFIR domain, abolished the homotypic interaction of ACT1 with IL-17 receptors, with no effect on homodimerization. The patients' fibroblasts failed to respond to IL-17A and IL-17F, and their T cells to IL-17E. By contrast, healthy individuals homozygous for the common variant D10N, located in the ACT1 tumor necrosis factor receptor-associated factor-interacting domain and previously associated with psoriasis, had impaired, but not abolished, responses to IL-17 cytokines. SEFIR-independent interactions of ACT1 with other proteins, such as CD40, heat shock protein 70 (HSP70) and HSP90, were not affected by the T536I mutation. Overall, human IL-17A and IL-17F depend on ACT1 to mediate protective mucocutaneous immunity. Moreover, other ACT1-dependent IL-17 cytokines seem to be largely redundant in host defense.


Assuntos
Candidíase Mucocutânea Crônica/genética , Interleucina-17/genética , Mutação de Sentido Incorreto , Receptores de Interleucina-17/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Adulto , Sequência de Aminoácidos , Antígenos CD40/genética , Antígenos CD40/imunologia , Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/patologia , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Homozigoto , Humanos , Imunidade Inata , Imunidade nas Mucosas , Interleucina-17/imunologia , Masculino , Dados de Sequência Molecular , Linhagem , Multimerização Proteica , Estrutura Terciária de Proteína , Receptores de Interleucina-17/imunologia , Irmãos , Linfócitos T/imunologia , Linfócitos T/patologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/imunologia
20.
J Exp Med ; 210(9): 1743-59, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23897980

RESUMO

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.


Assuntos
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
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