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1.
Clin Genet ; 96(4): 330-340, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31254389

RESUMO

In the digital age, a genetics cohort has become much more than a simple means of determining the cause of a disease. Two-sided markets, of which 23andMe, Ancestry DNA and MyHeritage are the best known, have showed this perfectly over the last few years: a cohort has become a means of producing massive amounts of data for medical, scientific and commercial exploitation, and for genetic use in particular. French law does not currently allow these foreign private companies to develop on French national territory and also forbids the creation of similar entities in France. However, at least in theory, this same law does not preclude the creation of new types of cohorts in France inspired by the success of two-sided markets but retaining features specific to the French healthcare management system. We propose an optimal solution for France, for genomic studies associated with multi-subject questionnaires, still purely theoretical for the moment: the development, with no need for any change in the law, of France's own version of "Genetics v.2.0": "e-CohortE."

2.
Sci Eng Ethics ; 25(5): 1597-1602, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30864046

RESUMO

Networks for the exchange and/or sharing of genetic data are developing in many countries. We focus here on the situations in the US and France. We highlight some recent and remarkable differences between these two countries concerning the mode of access to, and the storage and use of genetic data, particularly as concerns two-sided markets and dynamic consent or dynamic electronic informed consent (e-IC). This brief overview suggests that, even though the organization and function of these two-sided markets remain open to criticism, dynamic e-IC should be more widely used, especially in France, if only to determine its real effectiveness.

3.
Med Sci (Paris) ; 34(8-9): 735-739, 2018 Aug-Sep.
Artigo em Francês | MEDLINE | ID: mdl-30230447

RESUMO

Over the last three decades, various biotech companies, mostly in North America, have become experts in the production, processing and analysis of large volumes of genetic data. They have surpassed the performance of traditional academic platforms, by appropriating a new economic model: the two-sided market. Thus, by applying web 2.0 ideas, these biotech companies have made it possible for millions of users to produce and "share" data including genetic data, with each other and with third parties through a digital network rich in information and "free" services. However, in reality, data have become a means of payment for access to these networks and the use of these services. In the era of the digital economy, data sharing has become synonymous with commercial exchange and genetic data synonymous with capital.

4.
Elife ; 72018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29537367

RESUMO

Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.

6.
Sci Eng Ethics ; 24(1): 307-322, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28281147

RESUMO

The practice and development of modern medicine requires large amounts of data, particularly in the domain of cancer. The future of personalized medicine lies neither with "genomic medicine" nor with "precision medicine", but with "data medicine" (DM) (big data, data mining). The establishment of this DM has required far-reaching changes, to establish four essential elements connecting patients and doctors: biobanks, databases, bioinformatic platforms and genomic platforms. The "transformation" of scientific research areas, such as genetics, bioinformatics and biostatistics, into clinical specialties has generated a new vision of care. Molecular tumor boards (MTB) are one response to these changes and are now providing better access to next-generation sequencing (NGS) and new cancer treatments to patients with inoperable or metastatic cancers, and those for whom the usual treatment has failed. However, MTB face a crucial ethical challenge: maintaining and improving the trust of patients, clinicians, researchers and industry in academic medical centers supported by private or public funding rather than providing genetic data directly to private companies. We believe that, in this era of DM, appropriate modern digital communication networks will be required to maintain this trust and to improve the organization and effectiveness of the system. There is, therefore, a need to reconsider the form and content of informed consent (IC) documents at all academic medical centers and to introduce dynamic and electronic informed consent (e-IC).

7.
Med Sci (Paris) ; 34(12): 1100-1104, 2018 Dec.
Artigo em Francês | MEDLINE | ID: mdl-30623772

RESUMO

In France, genetic data are not covered by property laws. They are considered to be equivalent to a part of the human body, to be protected rather than as something of economic value. However, in this highly competitive world, France must find solutions to increase the scientific and economic values of its genetic data. One possibility would be to define genetic data as raw information with no value for use. The choice of such a value of use (clinical, scientific, economic, etc.), following various key analysis and treatment processes will thus transform genetic data into useful information. In this case, and under certain conditions, intellectual property law could consider this information to be an original creation with an economic value, whilst maintaining current levels of protection for genetic data. France thus faces a choice between changing its laws concerning the protection of genetic data, bringing them into line with the North American approach, according to which data are a form of capital that everyone has the right to increase or sell, and making the distinction between genetic data and information clearer.


Assuntos
Acesso à Informação , Bases de Dados Genéticas , Propriedade Intelectual , Propriedade , Acesso à Informação/ética , Confidencialidade/ética , Bases de Dados Genéticas/ética , Bases de Dados Genéticas/normas , Bases de Dados Genéticas/tendências , França , Testes Genéticos/ética , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/ética , Estudo de Associação Genômica Ampla/tendências , Humanos , Propriedade/ética , Propriedade/tendências
8.
Med Sci (Paris) ; 33(2): 188-192, 2017 Feb.
Artigo em Francês | MEDLINE | ID: mdl-28240211

RESUMO

"Personalized medicine" or "data medicine" should make it possible to use mass data to tailor patient treatment. These data are collected from analyses of biological samples, combined with clinical data. At a time when all sorts of information are instantly available via the Internet, the protection of genetic data, in particular, raises new issues with regard to the nature, means, status and usage of these data. Solutions to these problems are required, together with a clear, unambiguous legal, moral and ethical stance, to facilitate the spatial and temporal development of personalized medicine. At the forefront of these issues is the model of informed consent, which consent that has not been modified, despite many advances in technology. Medicine is now much more dynamic, and the possibilities for the real-time exchange and sharing of information, genetic data, or even biological samples, between patients, clinicians, researchers and industrial partners, must now be considered. We describe herein the particular advantages of a so-called "dynamic" and "enriched" consent, given via electronic means, in the context of the development of personalized medicine.


Assuntos
Consentimento Livre e Esclarecido , Medicina de Precisão , Confidencialidade , Consenso , Tomada de Decisões/ética , Revelação/legislação & jurisprudência , França , Testes Genéticos/legislação & jurisprudência , Testes Genéticos/normas , Humanos , Consentimento Livre e Esclarecido/legislação & jurisprudência , Consentimento Livre e Esclarecido/normas , Medicina de Precisão/ética
9.
Cell ; 166(4): 920-934, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27499022

RESUMO

Understanding how membrane nanoscale organization controls transmembrane receptors signaling activity remains a challenge. We studied interferon-γ receptor (IFN-γR) signaling in fibroblasts from homozygous patients with a T168N mutation in IFNGR2. By adding a neo-N-glycan on IFN-γR2 subunit, this mutation blocks IFN-γ activity by unknown mechanisms. We show that the lateral diffusion of IFN-γR2 is confined by sphingolipid/cholesterol nanodomains. In contrast, the IFN-γR2 T168N mutant diffusion is confined by distinct actin nanodomains where conformational changes required for Janus-activated tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) activation by IFN-γ could not occur. Removing IFN-γR2 T168N-bound galectins restored lateral diffusion in lipid nanodomains and JAK/STAT signaling in patient cells, whereas adding galectins impaired these processes in control cells. These experiments prove the critical role of dynamic receptor interactions with actin and lipid nanodomains and reveal a new function for receptor glycosylation and galectins. Our study establishes the physiological relevance of membrane nanodomains in the control of transmembrane receptor signaling in vivo. VIDEO ABSTRACT.


Assuntos
Fibroblastos/metabolismo , Mutação de Sentido Incorreto , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Transdução de Sinais , Actinas/química , Actinas/metabolismo , Animais , Células COS , Membrana Celular/química , Membrana Celular/metabolismo , Cercopithecus aethiops , Difusão , Endocitose , Ativação Enzimática , Glicosilação , Humanos , Interferon gama/metabolismo , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Receptores de Interferon/química
10.
BMC Med Ethics ; 17: 19, 2016 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-27059184

RESUMO

BACKGROUND: Since 2006, the genetic testing company 23andMe has collected biological samples, self-reported information, and consent documents for biobanking and research from more than 1,000,000 individuals (90% participating in research), through a direct-to-consumer (DTC) online genetic-testing service providing a genetic ancestry report and a genetic health report. However, on November 22, 2013, the Food and Drug Administration (FDA) halted the sale of genetic health testing, on the grounds that 23andMe was not acting in accordance with federal law, by selling tests of undemonstrated reliability as predictive tests for medical risk factors. Consumers could still obtain the genetic ancestry report, but they no longer had access to the genetic health report in the United States (US). However, this did not prevent the company from continuing its health research, with previously obtained and future samples, provided that consent had been obtained from the consumers concerned, or with health reports for individuals from other countries. Furthermore, 23andMe was granted FDA authorization on February 19, 2015, first to provide reports about Bloom syndrome carrier status, and, more recently, to provide consumers with "carrier status" information for 35 genes known (with high levels of confidence) to cause disease. DISCUSSION: In this Debate, we highlight the likelihood that the primary objective of the company was probably two-fold: promoting itself within the market for predictive testing for human genetic diseases and ancestry at a low cost to consumers, and establishing a high-value database/biobank for research (one of the largest biobanks of human deoxyribonucleic acid (DNA) and personal information). By dint of this marketing approach, a two-sided market has been established between the consumer and the research laboratories, involving the establishment of a database/DNA biobank for scientific and financial gain. We describe here the profound ethical issues raised by this setup.


Assuntos
Bancos de Espécimes Biológicos/ética , Pesquisa Biomédica/ética , Conflito de Interesses , Testes Genéticos/ética , Consentimento Livre e Esclarecido , Marketing , Setor Privado , Bancos de Espécimes Biológicos/economia , Bancos de Espécimes Biológicos/legislação & jurisprudência , Síndrome de Bloom/genética , DNA , Predisposição Genética para Doença , Testes Genéticos/economia , Testes Genéticos/legislação & jurisprudência , Humanos , Reprodutibilidade dos Testes , Fatores de Risco , Estados Unidos , United States Food and Drug Administration
11.
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
12.
Blood ; 122(14): 2390-401, 2013 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23963039

RESUMO

We report a molecular study of the two known patients with autosomal recessive, partial interferon-γ receptor (IFN-γR)2 deficiency (homozygous for mutations R114C and G227R), and three novel, unrelated children, homozygous for S124F (P1) and G141R (P2 and P3). IFN-γR2 levels on the surface of the three latter patients' cells are slightly lower than those on control cells. The patients' cells also display impaired, but not abolished, response to IFN-γ. Moreover, the R114C, S124F, G141R and G227R IFNGR2 hypomorphic alleles all encode misfolded proteins with abnormal N-glycosylation. The mutants are largely retained in the endoplasmic reticulum, although a small proportion reach and function at the cell surface. Strikingly, the IFN-γ response of the patients' cells is enhanced by chemical modifiers of N-glycosylation, as previously shown for patients with gain-of-glysosylation T168N and misfolding 382-387dup null mutations. All four in-frame IFNGR2 hypomorphic mutant alleles encoding surface-expressed receptors are thus deleterious by a mechanism involving abnormal N-glycosylation and misfolding of the IFN-γR2 protein. The diagnosis of partial IFN-γR2 deficiency is clinically useful, as affected patients should be treated with IFN-γ, [corrected] unlike patients with complete IFN-γR2 deficiency. Moreover, inhibitors of glycosylation might be beneficial in patients with complete or partial IFN-γR2 deficiency due to misfolding or gain-of-glycosylation receptors.


Assuntos
Deficiências na Proteostase/genética , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Alcaloides/farmacologia , Sequência de Bases , Western Blotting , Criança , Inibidores Enzimáticos/farmacologia , Feminino , Citometria de Fluxo , Predisposição Genética para Doença/genética , Glicosilação/efeitos dos fármacos , Humanos , Masculino , Microscopia Confocal , Dados de Sequência Molecular , Mutação , Infecções por Mycobacterium/genética , Linhagem , Transfecção
13.
Proc Natl Acad Sci U S A ; 110(14): 5558-63, 2013 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-23509278

RESUMO

High-throughput genomic data reveal thousands of gene variants per patient, and it is often difficult to determine which of these variants underlies disease in a given individual. However, at the population level, there may be some degree of phenotypic homogeneity, with alterations of specific physiological pathways underlying the pathogenesis of a particular disease. We describe here the human gene connectome (HGC) as a unique approach for human mendelian genetic research, facilitating the interpretation of abundant genetic data from patients with the same disease, and guiding subsequent experimental investigations. We first defined the set of the shortest plausible biological distances, routes, and degrees of separation between all pairs of human genes by applying a shortest distance algorithm to the full human gene network. We then designed a hypothesis-driven application of the HGC, in which we generated a Toll-like receptor 3-specific connectome useful for the genetic dissection of inborn errors of Toll-like receptor 3 immunity. In addition, we developed a functional genomic alignment approach from the HGC. In functional genomic alignment, the genes are clustered according to biological distance (rather than the traditional molecular evolutionary genetic distance), as estimated from the HGC. Finally, we compared the HGC with three state-of-the-art methods: String, FunCoup, and HumanNet. We demonstrated that the existing methods are more suitable for polygenic studies, whereas HGC approaches are more suitable for monogenic studies. The HGC and functional genomic alignment data and computer programs are freely available to noncommercial users from http://lab.rockefeller.edu/casanova/HGC and should facilitate the genome-wide selection of disease-causing candidate alleles for experimental validation.


Assuntos
Alelos , Genes/genética , Genômica/métodos , Fenótipo , Transdução de Sinais/genética , Software , Análise por Conglomerados , Genes/fisiologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Modelos Genéticos , Receptor 3 Toll-Like/genética
14.
Hum Mol Genet ; 22(4): 769-81, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23161749

RESUMO

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic etiologies of which impair the production of, or the response to interferon-gamma (IFN-γ). We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-γ, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-γR2 or STAT1 deficiency. Whole-exome sequencing (WES) and Sanger sequencing revealed only one candidate variation for both MSMD-causing and IFN-γ-related genes. P1 carried a heterozygous frame-shift IFNGR2 mutation inherited from her father. We show that the mutant allele is intrinsically loss-of-function and not dominant-negative, suggesting haploinsufficiency at the IFNGR2 locus. We also show that Epstein-Barr virus transformed B lymphocyte cells from 10 heterozygous relatives of patients with AR complete IFN-γR2 deficiency respond poorly to IFN-γ, in some cases as poorly as the cells of P1. Naive CD4(+) T cells and memory IL-4-producing T cells from these individuals also responded poorly to IFN-γ, whereas monocytes and monocyte-derived macrophages (MDMs) did not. This is consistent with the lower levels of expression of IFN-γR2 in lymphoid than in myeloid cells. Overall, MSMD in this patient is probably due to autosomal dominant (AD) IFN-γR2 deficiency, resulting from haploinsufficiency, at least in lymphoid cells. The clinical penetrance of AD IFN-γR2 deficiency is incomplete, possibly due, at least partly, to the variability of cellular responses to IFN-γ in these individuals.


Assuntos
Haploinsuficiência , Infecções por Micobactéria não Tuberculosa/genética , Receptores de Interferon/genética , Adolescente , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sequência de Bases , Estudos de Casos e Controles , Células Cultivadas , Feminino , Expressão Gênica , Genes Dominantes , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Humanos , Interferon gama/fisiologia , Infecções por Mycobacterium/genética , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fosforilação , Processamento de Proteína Pós-Traducional , Receptores de Interferon/deficiência , Análise de Sequência de DNA , Deleção de Sequência
15.
Science ; 337(6102): 1684-8, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-22859821

RESUMO

ISG15 is an interferon (IFN)-α/ß-inducible, ubiquitin-like intracellular protein. Its conjugation to various proteins (ISGylation) contributes to antiviral immunity in mice. Here, we describe human patients with inherited ISG15 deficiency and mycobacterial, but not viral, diseases. The lack of intracellular ISG15 production and protein ISGylation was not associated with cellular susceptibility to any viruses that we tested, consistent with the lack of viral diseases in these patients. By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes-granulocyte, in particular-reduced the production of IFN-γ by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease. This experiment of nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-γ-inducing secreted molecule for optimal antimycobacterial immunity.


Assuntos
Citocinas/imunologia , Interferon gama/imunologia , Infecções por Mycobacterium/imunologia , Ubiquitinas/imunologia , Viroses/imunologia , Animais , Anticorpos Antivirais/sangue , Citocinas/genética , Feminino , Granulócitos/imunologia , Humanos , Imunidade , Interleucina-12/imunologia , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Infecções por Mycobacterium/sangue , Infecções por Mycobacterium/genética , Linhagem , Linfócitos T/imunologia , Ubiquitinas/genética , Viroses/sangue
16.
J Exp Med ; 208(10): 2083-98, 2011 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-21911422

RESUMO

Autosomal dominant TLR3 deficiency has been identified as a genetic etiology of childhood herpes simplex virus 1 (HSV-1) encephalitis (HSE). This defect is partial, as it results in impaired, but not abolished induction of IFN-ß and -λ in fibroblasts in response to TLR3 stimulation. The apparently normal resistance of these patients to other infections, viral illnesses in particular, may thus result from residual TLR3 responses. We report here an autosomal recessive form of complete TLR3 deficiency in a young man who developed HSE in childhood but remained normally resistant to other infections. This patient is compound heterozygous for two loss-of-function TLR3 alleles, resulting in an absence of response to TLR3 activation by polyinosinic-polycytidylic acid (poly(I:C)) and related agonists in his fibroblasts. Moreover, upon infection of the patient's fibroblasts with HSV-1, the impairment of IFN-ß and -λ production resulted in high levels of viral replication and cell death. In contrast, the patient's peripheral blood mononuclear cells responded normally to poly(I:C) and to all viruses tested, including HSV-1. Consistently, various TLR3-deficient leukocytes from the patient, including CD14(+) and/or CD16(+) monocytes, plasmacytoid dendritic cells, and in vitro derived monocyte-derived macrophages, responded normally to both poly(I:C) and HSV-1, with the induction of antiviral IFN production. These findings identify a new genetic etiology for childhood HSE, indicating that TLR3-mediated immunity is essential for protective immunity to HSV-1 in the central nervous system (CNS) during primary infection in childhood, in at least some patients. They also indicate that human TLR3 is largely redundant for responses to double-stranded RNA and HSV-1 in various leukocytes, probably accounting for the redundancy of TLR3 for host defense against viruses, including HSV-1, outside the CNS.


Assuntos
Encefalite por Herpes Simples/imunologia , Imunidade/imunologia , Simplexvirus/imunologia , Receptor 3 Toll-Like/deficiência , Células Cultivadas , Análise Mutacional de DNA , Encefalite por Herpes Simples/genética , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Masculino , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Linhagem , Poli I-C/imunologia , Poli I-C/farmacologia , Simplexvirus/genética , Receptor 3 Toll-Like/genética , Adulto Jovem
17.
J Clin Invest ; 121(10): 3889-901, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21911939

RESUMO

Mycobacterium tuberculosis causes widespread, persistent infection, often residing in macrophages that neither sterilize the bacilli nor allow them to cause disease. How macrophages restrict growth of pathogens is one of many aspects of human phagocyte biology whose study relies largely on macrophages differentiated from monocytes in vitro. However, such cells fail to recapitulate the phenotype of tissue macrophages in key respects, including that they support early, extensive replication of M. tuberculosis and die in several days. Here we found that human macrophages could survive infection, kill Mycobacterium bovis BCG, and severely limit the replication of M. tuberculosis for several weeks if differentiated in 40% human plasma under 5%-10% (physiologic) oxygen in the presence of GM-CSF and/or TNF-α followed by IFN-γ. Control was lost with fetal bovine serum, 20% oxygen, M-CSF, higher concentrations of cytokines, or premature exposure to IFN-γ. We believe that the new culture method will enable inquiries into the antimicrobial mechanisms of human macrophages.


Assuntos
Macrófagos/imunologia , Macrófagos/patologia , Mycobacterium tuberculosis/imunologia , Animais , Carga Bacteriana , Bovinos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Técnicas In Vitro , Interferon gama/farmacologia , Interleucina-4/farmacologia , Ativação de Macrófagos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/microbiologia , Monócitos/imunologia , Monócitos/microbiologia , Monócitos/patologia , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/imunologia , Tuberculose/microbiologia , Tuberculose/patologia , Fator de Necrose Tumoral alfa/farmacologia , Vitamina D/farmacologia
18.
Nat Immunol ; 12(3): 213-21, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21278736

RESUMO

Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.


Assuntos
Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Macrófagos/imunologia , Glicoproteínas de Membrana/genética , NADPH Oxidases/genética , Tuberculose/genética , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Mutação , NADPH Oxidase 2 , NADPH Oxidases/imunologia
19.
J Med Genet ; 47(9): 631-4, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20587411

RESUMO

Disseminated squamous cell carcinoma (SCC) of the skin is exceedingly rare in children. SCC occurs after immunodeficiency from immunosuppression in organ transplant recipients or patients with HIV infection or leukaemia, but has not been reported in primary immunodeficiencies other than epidermodysplasia verruciformis. Interferon gamma receptor 2 (IFN gamma R2) deficiency is an exceedingly rare primary immunodeficiency, conferring almost selective predisposition to mycobacterial diseases. A disseminated, cutaneous SCC is described that occurred in a patient homozygous for a novel frameshift deletion at positions 949 and 950 (949delTG) in the IFNGR2 gene. The patient first presented at 1 year of age with disseminated Mycobacterium avium infection, with later infections of atypical mycobacteria (Mycobacterium fortuitum and Mycobacterium porcium). At 17 years of age, the patient developed multifocal SCC lesions on the face and both hands. Histopathological examination revealed well differentiated SCC. Despite local tumour excision, multiple lesions occurred and a large SCC on the right arm required amputation. The patient died at 20 years of age of disseminated SCC. Inherited disorders of IFN gamma mediated immunity may predispose patients to SCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Receptores de Interferon/deficiência , Neoplasias Cutâneas/metabolismo , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Carcinoma de Células Escamosas/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Receptores de Interferon/química , Receptores de Interferon/genética , Neoplasias Cutâneas/patologia , Coloração e Rotulagem
20.
Hum Mol Genet ; 19(3): 434-44, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19880857

RESUMO

IFN-gammaR1 deficiency is a genetic etiology of Mendelian susceptibility to mycobacterial diseases, and includes two forms of complete recessive deficiency, with or without cell surface expression, and two forms of partial deficiency, dominant or recessive. We report here a novel form of partial and recessive Interferon gamma receptor 1 (IFN-gammaR1) deficiency, which is almost as severe as complete deficiency. The patient is homozygous for a mutation of the initiation codon (M1K). No detectable expression and function of IFN-gammaR1 were found in the patient's fibroblasts. However, IFN-gammaR1 expression was found to be impaired, but not abolished, on the EBV-transformed B cells, which could respond weakly to IFN-gamma. The mechanism underlying this weak expression involves leaky translation initiation at both non-AUG codons and the third AUG codon at position 19. It results in the residual expression of IFN-gammaR1 protein of normal molecular weight and function. The residual IFN-gamma signaling documented in this novel form of partial IFN-gammaR1 deficiency was not ubiquitous and was milder than that seen in other forms of partial IFN-gammaR1 deficiency, accounting for the more severe clinical phenotype of the patient, which was almost as severe as that of patients with complete deficiency.


Assuntos
Códon de Iniciação , Mutação em Linhagem Germinativa , Infecções por Mycobacterium/genética , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Linfócitos B/metabolismo , Linhagem Celular , Células Cultivadas , Criança , Feminino , Fibroblastos/metabolismo , Predisposição Genética para Doença , Humanos , Interferon gama/metabolismo , Mutação de Sentido Incorreto , Infecções por Mycobacterium/metabolismo , Infecções por Mycobacterium/microbiologia , Especificidade da Espécie
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