Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.211
Filtrar
1.
Vet J ; 248: 71-73, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31113566

RESUMO

The highly selective breeding of Arabian horses results in inbreeding depression and genetic disorders, thereby causing significant economic loss. The Polish population of Arabians has a great impact on many breeding programmes. The aim of the current study was to monitor genetic variants involved in the most common genetic disorders of this breed. A total of 808 elite Arabian horses were screened for cerebellar abiotrophy (CA), severe combined immunodeficiency (SCID) and lavender foal syndrome (LFS) genetic disorders by Sanger sequencing and allelic discrimination methods. The investigated population was clear of LFS. The unfavourable SCID allele was detected in three heterozygous horses (q = 0.00185). Regarding CA, the minor allele frequency was q = 0.04029. This is the first report of SCID carriers in Poland. This investigation demonstrates the value of genetic testing to support breeding decisions and to facilitate genetic disease monitoring.


Assuntos
Doenças Cerebelares/veterinária , Testes Genéticos/veterinária , Doenças dos Cavalos/genética , Amaurose Congênita de Leber/veterinária , Imunodeficiência Combinada Severa/veterinária , Animais , Doenças Cerebelares/genética , Feminino , Predisposição Genética para Doença , Doenças dos Cavalos/imunologia , Cavalos , Amaurose Congênita de Leber/genética , Masculino , Linhagem , Polônia , Imunodeficiência Combinada Severa/genética , Síndrome
2.
Nat Rev Drug Discov ; 18(6): 447-462, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30858502

RESUMO

Pioneering gene therapy trials have shown that the genetic engineering of haematopoietic stem and progenitor cells can be an alternative to allogeneic transplantation in the treatment of primary immunodeficiencies. Early trials also highlighted the risk of insertional mutagenesis and oncogene transactivation associated with the first generation of gammaretroviral vectors. These events prompted the development of safer, self-inactivating lentiviral or gammaretroviral vectors. These lentiviral vectors have been successfully used to treat over 200 patients with 10 different haematological disorders (including primary immunodeficiencies, haemoglobinopathies and metabolic disorders) and for the generation of chimeric antigen receptor-T cells for cancer therapy. However, several challenges, such as effective reconstitution during inflammation, remain if gene therapy is to be extended to more complex diseases in which haematopoietic stem and progenitor cells can be altered by the disease environment. We discuss the progress made and future challenges for gene therapy and contrast gene therapy with gene-editing strategies.


Assuntos
Anemia Falciforme/terapia , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Imunodeficiência Combinada Severa/terapia , Talassemia beta/terapia , Anemia Falciforme/genética , Animais , Engenharia Genética , Humanos , Imunodeficiência Combinada Severa/genética , Talassemia beta/genética
3.
Immunogenetics ; 71(4): 299-305, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30610243

RESUMO

Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by autosomal recessive mutations in Cat Eye Syndrome Chromosome Region 1 (CECR1) gene. In this report, we aimed to describe the clinical manifestations, immunological features, genotype, and treatments of one Chinese patient with novel CECR1 gene mutations. This patient initially presented with recurrent fever and rashes from the age of 3 months, but no pathogen was found. She then developed dry gangrene of the fingers at 5 months of age. Laboratory examinations revealed elevated levels of C-reactive protein and thrombocytes. The expression of interleukin-6 (IL-6) and IL-8 were both elevated. Sequencing results revealed that she had compound heterozygous mutations in CECR1 gene (c.1211T>C, p.Phe404Ser and c.1114 G>A, p.Val372Met). Subsequently, treatment with anti-IL-6 (tocilizumab) was started. However, she developed blurred vision in the right eye with occlusion of the central retinal artery, accompanied by unsteady gait. Magnetic resonance imaging (MRI) showed infarction of the right thalamus. Finally, she underwent hematopoietic stem cell transplantation (HSCT) and is currently in remission. Our findings suggest that HSCT could cure this disease.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Doenças Hereditárias Autoinflamatórias/terapia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Imunodeficiência Combinada Severa/terapia , Adenosina Desaminase/genética , Agamaglobulinemia/diagnóstico por imagem , Agamaglobulinemia/genética , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , China , Feminino , Doenças Hereditárias Autoinflamatórias/diagnóstico por imagem , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Lactente , Imagem por Ressonância Magnética , Indução de Remissão , Análise de Sequência de DNA , Imunodeficiência Combinada Severa/diagnóstico por imagem , Imunodeficiência Combinada Severa/genética
4.
Nat Immunol ; 20(2): 152-162, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643259

RESUMO

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway.


Assuntos
Interferon Tipo I/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Animais , Cercopithecus aethiops , Pré-Escolar , DNA Viral/imunologia , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Fibroblastos , Técnicas de Inativação de Genes , Células HEK293 , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Humanos , Imunidade Inata , Células Jurkat , Macrófagos , Masculino , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Células NIH 3T3 , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Cultura Primária de Células , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/imunologia , Células Vero
5.
Proc Natl Acad Sci U S A ; 116(3): 970-975, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30591564

RESUMO

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.


Assuntos
Diferenciação Celular , Imunidade nas Mucosas/genética , Doenças Inflamatórias Intestinais , Mucosa Intestinal , Proteína Serina-Treonina Quinases de Interação com Receptores , Imunodeficiência Combinada Severa , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Células HCT116 , Células HEK293 , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Mutação , NF-kappa B/genética , NF-kappa B/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
6.
Indian Pediatr ; 55(8): 693-697, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30218520

RESUMO

We present the case of a 3-month-old girl who was admitted with complaints of loose stools and respiratory distress. She also had a history of rash and alopecia. Laboratory investigations revealed lymphopenia with reduced immunoglobulin G and immunoglobulin A. Lymphocyte subset analysis by flow cytometry revealed T-B+NK+ severe combined immunodeficiency (SCID). She died due to severe pneumonia, shock and pulmonary hemorrhage. Autopsy findings revealed disseminated cytomegalovirus infection in the lung, liver, adrenals and heart. Thymus was found to be dysplastic and showed characteristic histopathologic features of SCID.


Assuntos
Diarreia/etiologia , Insuficiência Respiratória/etiologia , Imunodeficiência Combinada Severa/diagnóstico , Evolução Fatal , Feminino , Humanos , Lactente , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/genética
7.
Science ; 361(6404): 810-813, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30026316

RESUMO

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.


Assuntos
Artrite/genética , Doenças Inflamatórias Intestinais/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Imunodeficiência Combinada Severa/genética , Alelos , Artrite/imunologia , Citocinas/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Linfopenia/genética , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Linhagem , Imunodeficiência Combinada Severa/imunologia
8.
Medicine (Baltimore) ; 97(23): e10939, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29879038

RESUMO

INTRODUCTION: Hereditary multiple intestinal atresia associated with severe combined immunodeficiency (MIA-SCID) is a very rare disease caused by deleterious mutations in the tetratricopeptide repeat domain-containing protein 7A gene TTC7A. It is characterized by intestinal obstruction, sepsis, and a poor prognosis. Insights into phenotype-genotype correlations could help to guide genetic counseling and increase our knowledge of the natural history of this disease. CASE PRESENTATION: We report the case of a newborn in which his fetal magnetic resonance imaging showed jejunal atresia and microcolon and an abdominal x-ray at birth confirmed intestinal obstruction. The clinical course was complicated by multiple episodes of sepsis, and laboratory investigations showed SCID. The genetic analysis identified a homozygous c.53344_53347 mutation in the TTC7A gene compatible with MIA-SCID syndrome. The patient required 3 operations because of new intestinal atresias in the first months of life. She underwent bone marrow transplantation at 8 months of age but died of liver failure secondary to graft-versus-host disease. CONCLUSION: Immunologic assessment and genetic screening for TTC7A mutations are important in patients with MIA. Greater knowledge of the functions of the TTC7A protein will have important therapeutic implications for patients with MIA-SCID syndrome.


Assuntos
Atresia Intestinal/genética , Proteínas/genética , Sepse/congênito , Imunodeficiência Combinada Severa/genética , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Atresia Intestinal/microbiologia , Mutação
9.
Zhonghua Er Ke Za Zhi ; 56(3): 186-191, 2018 Mar 02.
Artigo em Chinês | MEDLINE | ID: mdl-29518828

RESUMO

Objective: To investigate the clinical characteristics of 8 immunodeficiency cases caused by human recombination activating gene 1 (RAG1) mutations, and to explore the relationship among genotypes, clinical manifestations and immunophenotypes. Methods: Clinical data were collected and analyzed from patients with RAG1 mutations who visited the Department of Clinical Immunology, Children's Hospital of Fudan University between October 2013 and June 2017. The data included clinical manifestations, immunophenotypes and genotypes. Results: A total of 8 patients were diagnosed with RAG1 deficiency (6 boys and 2 girls). The minimum age of onset was 2 months, and the maximum age was 4 months. The minimum age of diagnosis was 2 months, and the maximum age was 13 years. Four patients had a family history of infant death due to severe infections. Two cases were born to the same consanguineous parents. All cases had recurrent infections, including involvement of respiratory tract (8 cases), digestive tract (6 cases), urinary tract (1 case), and central nervous system (1 case). The pathogens of infection included bacteria, viruses and fungi. Rotavirus was found in 3 cases, cytomegalovirus (CMV) in 5 cases, bacillus Calmette-Guérin adverse reaction in 2 cases (1 of whom had a positive acid-fast smear from lymph node puncture fluid), fungal infection in 3 cases. One case had multiple nodular space-occupying lesions in lungs and abdominal cavity complicated with multiple bone destruction. The peripheral blood lymphocyte counts of all patients ranged between 0.1 ×10(9)/L and 3.3×10(9)/L (median, 0.65×10(9)/L). Eosinophilia was found in 3 cases (range, (0.48-1.69) ×10(9)/L). The patients were classified according to immunophenotype as severe combined immunodeficiency phenotype (4 cases), leaky severe combined immunodeficiency (2 cases), Omenn syndrome (1 case) and combined immunodeficiency (1 case) . Decreased serum IgG levels were found in 3 cases, increased serum IgM levels in 3 cases, increased serum IgE levels in 5 cases. RAG1 homozygous mutations were detected in 5 cases and RAG1 compound heterozygous mutations in 3 cases. Two novel mutations and six previously reported mutations were identified. Three cases were successfully treated with hematopoietic stem cell transplantation. Four cases died due to infections, and the 13 year-old patient was still under follow-up in the outpatient clinic. Conclusions: Different RAG1 gene mutations can lead to diverse clinical presentations and immune phenotypes. Clinicians should pay attention to the family history of infant death with severe infection. In that situation, immunological evaluation and gene detection should be performed as early as possible.


Assuntos
Proteínas de Homeodomínio/genética , Fenótipo , Imunodeficiência Combinada Severa/genética , Adolescente , Criança , Pré-Escolar , Consanguinidade , Citomegalovirus , Feminino , Genes RAG-1/genética , Genótipo , Transplante de Células-Tronco Hematopoéticas , Homozigoto , Humanos , Imunofenotipagem , Lactente , Linfócitos , Masculino , Mutação
10.
Biochem Biophys Res Commun ; 497(2): 719-725, 2018 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-29462620

RESUMO

AK2 is an adenylate phosphotransferase that localizes at the intermembrane spaces of the mitochondria, and its mutations cause a severe combined immunodeficiency with neutrophil maturation arrest named reticular dysgenesis (RD). Although the dysfunction of hematopoietic stem cells (HSCs) has been implicated, earlier developmental events that affect the fate of HSCs and/or hematopoietic progenitors have not been reported. Here, we used RD-patient-derived induced pluripotent stem cells (iPSCs) as a model of AK2-deficient human cells. Hematopoietic differentiation from RD-iPSCs was profoundly impaired. RD-iPSC-derived hemoangiogenic progenitor cells (HAPCs) showed decreased ATP distribution in the nucleus and altered global transcriptional profiles. Thus, AK2 has a stage-specific role in maintaining the ATP supply to the nucleus during hematopoietic differentiation, which affects the transcriptional profiles necessary for controlling the fate of multipotential HAPCs. Our data suggest that maintaining the appropriate energy level of each organelle by the intracellular redistribution of ATP is important for controlling the fate of progenitor cells.


Assuntos
Trifosfato de Adenosina/metabolismo , Adenilato Quinase/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Leucopenia/patologia , Imunodeficiência Combinada Severa/patologia , Adenilato Quinase/genética , Células Cultivadas , Metabolismo Energético , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucopenia/genética , Leucopenia/metabolismo , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/metabolismo , Regulação para Cima
11.
Mucosal Immunol ; 11(1): 50-60, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28513593

RESUMO

Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1tm1Ven/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC precursor and the pre-NK cell progenitor. We further demonstrate that the pan-JAK inhibitor tofacitinib and the specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis. Both tofacitinib and PF-06651600 are currently in clinical trials for several other immune-mediated conditions. Our data suggest that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Células da Medula Óssea/fisiologia , Janus Quinase 3/genética , Células Matadoras Naturais/fisiologia , Mutação/genética , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Imunodeficiência Combinada Severa/genética , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Humanos , Imunidade Inata , Interferon gama/metabolismo , Janus Quinase 3/antagonistas & inibidores , Camundongos , Camundongos Mutantes , Fenótipo , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia
12.
Rheumatol Int ; 38(1): 129-136, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28516235

RESUMO

Deficiency of adenosine deaminase type 2 (DADA2) is a rare form of autoinflammatory disorder with limited reported cases. In this paper, we have presented the clinico-immunological, radiological and genetic characteristics of five surviving and three deceased childhood-onset DADA2 patients. We aimed to compare surviving and deceased patients in terms of clinical features and treatment modalities. Moreover, we have evaluated the causes of death in our DADA2 subjects together with the previously reported cases. Demographic features, clinical characteristics, imaging findings, mutations and pharmacological treatments of DADA2 subjects were noted from patient records of pediatric and adult rheumatology clinics in a retrospective and longitudinal nature. Eight patients from seven families were enrolled. While five of them were surviving, three of them had died due to various reasons. Median age of the patients at disease onset and diagnosis was 7 years (range 0.5-13 years) and 14 years (range 5-27 years), respectively. The main clinical manifestations were cutaneous findings (7/8), recurrent low-grade fever (6/8), neurological involvement (6/8) and gastrointestinal involvement (5/8). All patients had increased acute phase reactants at presentation and also during the disease flares. Until the diagnosis of DADA2 was confirmed, five patients have been followed-up with the diagnosis of PAN: two patients both with PAN and FMF, and one patient with CAPS and vasculitis. Demographic, clinical, neurological features and genetic mutations did not differ in surviving and deceased DADA2 patients. Deceased and surviving subjects differed in terms of treatment modalities after the diagnosis of DADA2. Anti-TNF alpha treatment has been initiated in five surviving patients as soon as the diagnosis of DADA2 was established. However, three patients who have died were not able to use sufficient doses of anti-TNF alpha treatment; in one case due to reluctance of patient and in two cases due to establishment of the definite diagnosis by genetic analysis at the same time with the last fatal DADA2 episode. Despite limited number of patients, this case series for the first time compares the phenotypic, genotypic and medication differences between surviving and deceased DADA2 patients. Anti-TNF alpha treatment seems to be efficient and lifesaving in DADA2 patients.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/diagnóstico , Produtos Biológicos/uso terapêutico , Imunodeficiência Combinada Severa/diagnóstico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adenosina Desaminase/genética , Adolescente , Adulto , Agamaglobulinemia/diagnóstico por imagem , Agamaglobulinemia/tratamento farmacológico , Agamaglobulinemia/genética , Idade de Início , Criança , Pré-Escolar , Genótipo , Humanos , Lactente , Angiografia por Ressonância Magnética , Imunodeficiência Combinada Severa/diagnóstico por imagem , Imunodeficiência Combinada Severa/tratamento farmacológico , Imunodeficiência Combinada Severa/genética , Adulto Jovem
14.
FASEB J ; 32(4): 1733-1740, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-31282760

RESUMO

Gene therapy is emerging as a viable option for clinical therapy of monogenic disorders and other genetically defined diseases, with approved gene therapies available in Europe and newly approved gene therapies in the United States. In the past 10 years, gene therapy has moved from a distant possibility, even in the minds of much of the scientific community, to being widely realized as a valuable therapeutic tool with wide-ranging potential. The U.S. Food and Drug Administration has recently approved Luxturna (Spark Therapeutics Inc, Philadelphia, PA, USA), a recombinant adeno-associated virus (rAAV) 2 gene therapy for one type of Leber congenital amaurosis 2 ( 1 , 2 ). The European Medicines Agency (EMA) has approved 3 recombinant viral vector products: Glybera (UniQure, Amsterdam, The Netherlands), an rAAV vector for lipoprotein lipase deficiency; Strimvelis (Glaxo Smith-Kline, Brentford, United Kingdom), an ex vivo gammaretrovirus-based therapy for patients with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID); and Kymriah (Novartis, Basel, Switzerland), an ex vivo lentivirus-based therapy to engineer autologous chimeric antigen-receptor T (CAR-T) cells targeting CD19-positive cells in acute lymphoblastic leukemia. These examples will be followed by the clinical approval of other gene therapy products as this field matures. In this review we provide an overview of the state of gene therapy by discussing where the field stands with respect to the different gene therapy vector platforms and the types of therapies that are available.-Gruntman, A. M., Flotte, T. R. The rapidly evolving state of gene therapy.


Assuntos
Dependovirus/genética , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos/administração & dosagem , Doenças Raras/terapia , Proteínas Recombinantes/genética , Imunodeficiência Combinada Severa/terapia , Humanos , Doenças Raras/genética , Proteínas Recombinantes/administração & dosagem , Imunodeficiência Combinada Severa/genética
15.
Front Immunol ; 9: 2959, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30666249
16.
Rev Paul Pediatr ; 35(1): 25-32, 2017 Jan-Mar.
Artigo em Português, Inglês | MEDLINE | ID: mdl-28977313

RESUMO

OBJECTIVE: To validate the quantification of T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) by real-time polymerase chain reaction (qRT-PCR) for newborn screening of primary immunodeficiencies with defects in T and/or B cells in Brazil. METHODS: Blood samples from newborns and controls were collected on filter paper. DNA was extracted and TRECs, and KRECs were quantified by a duplex real-time PCR. The cutoff values were determined by receiver operating characteristic curve analysis using SPSS software (IBM®, Armonk, NY, USA). RESULTS: Around 6,881 samples from newborns were collected and TRECs and KRECs were quantified. The TRECs values ranged between 1 and 1,006 TRECs/µL, with mean and median of 160 and 139 TRECs/µL, respectively. Three samples from patients with severe combined immunodeficiency (SCID) showed TRECs below 4/µL and a patient with DiGeorge syndrome showed undetectable TRECs. KRECs values ranged from 10 to 1,097 KRECs/µL, with mean and median of 130 and 108 KRECs/µL. Four patients with agammaglobulinemia had results below 4 KRECs/µL. The cutoff values were 15 TRECs/µL and 14 KRECs/µL and were established according to the receiver operating characteristic curve analysis, with 100% sensitivity for SCID and agammaglobulinemia detection, respectively. CONCLUSIONS: Quantification of TRECs and KRECs was able to diagnose children with T- and/or B-cell lymphopenia in our study, which validated the technique in Brazil and enabled us to implement the newborn screening program for SCID and agammaglobulinemia.


Assuntos
Triagem Neonatal/métodos , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/diagnóstico , Brasil , Estudos Transversais , DNA/análise , Humanos , Lactente , Recém-Nascido , Projetos Piloto , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos B/genética , Imunodeficiência Combinada Severa/genética
18.
Mol Diagn Ther ; 21(6): 677-684, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28900865

RESUMO

BACKGROUND: Primary immunodeficiency disorders (PIDs) are a heterogeneous group of diseases of the immune system leading to life-threatening infections, and, unless urgently treated with immune reconstitution, patients do not usually survive. With the continuing progress in molecular diagnosis, many mutations have been described in more than 300 genes. Genetic counseling has recently been considered an essential part of the management of PIDs. This study presents the experience of genetic counseling services in the largest PID center in Egypt, and reports on our management plan and the impact of prenatal diagnosis (PND) on families. METHODS: Based on the biochemical and molecular diagnosis of index cases, PND was offered for 10 families in 12 subsequent pregnancies. Five different genes were sequenced by Sanger sequencing in fetal samples. RESULTS: Seven fetuses were either normal or were carriers, while five fetuses were affected and human leukocyte antigen typing was performed, seeking a suitably related donor for stem cell transplantation. CONCLUSION: In spite of the genetic heterogeneity behind PIDs, genetic counseling should play a critical role in the management and future decisions of affected families.


Assuntos
Aconselhamento Genético , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Proteínas de Ligação a DNA/genética , Egito , Feminino , Testes Genéticos , Heterozigoto , Humanos , Síndromes de Imunodeficiência/psicologia , Mutação , Proteínas Nucleares/genética , Linhagem , Gravidez , Diagnóstico Pré-Natal/métodos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética
19.
Hematol Oncol Clin North Am ; 31(5): 809-822, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28895849

RESUMO

Successful gene therapy for genetic disorders requires marrow niches to be opened to varying degrees to engraft gene-corrected hematopoietic stem cells (HSC). For example, in severe combined immunodeficiency, relatively limited chimerism is necessary for both T- and B-cell immune reconstitution, whereas for inborn errors of metabolism maximal donor chimerism is the goal. Currently, alkylating chemotherapy is used for this purpose. Significant pharmacokinetic variability exists in drug clearance in children less than 12 years old. Thus, pharmacokinetic monitoring is needed to achieve the targeted exposure goal for busulfan.


Assuntos
Medula Óssea/metabolismo , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Nicho de Células-Tronco , Animais , Antineoplásicos/farmacologia , Expressão Gênica , Técnicas de Transferência de Genes , Terapia Genética/métodos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hemoglobinopatias/genética , Hemoglobinopatias/terapia , Humanos , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/terapia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Transdução Genética , Transgenes , Condicionamento Pré-Transplante , Transplante Autólogo
20.
J Clin Immunol ; 37(8): 751-758, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28932937

RESUMO

Since the discovery of FOXN1 deficiency, the human counterpart of the nude mouse, a growing body of evidence investigating the role of FOXN1 in thymus and skin, has been published. FOXN1 has emerged as fundamental for thymus development, function, and homeostasis, representing the master regulator of thymic epithelial and T cell development. In the skin, it also plays a pivotal role in keratinocytes and hair follicle cell differentiation, although the underlying molecular mechanisms still remain to be fully elucidated. The nude severe combined immunodeficiency phenotype is indeed characterized by the clinical hallmarks of athymia with severe T cell immunodeficiency, congenital alopecia, and nail dystrophy. In this review, we summarize recent discoveries in the field and give interesting perspective about new and promising therapeutic approaches for disorders of immune system with athymia.


Assuntos
Fatores de Transcrição Forkhead/deficiência , Folículo Piloso/fisiologia , Unhas/patologia , Imunodeficiência Combinada Severa/genética , Pele/metabolismo , Linfócitos T/fisiologia , Timo/fisiologia , Alopecia , Animais , Diferenciação Celular , Repressão Epigenética , Fatores de Transcrição Forkhead/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Camundongos , Camundongos Nus , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA