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1.
J Clin Immunol ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31858364

RESUMO

PURPOSE: Early differentiation of adenosine deaminase deficient severe combined immunodeficiency (ADA-SCID) from other forms of SCID may initiate appropriate treatment interventions with the aim of metabolic detoxification and improved outcome. Our hypothesis was that previously described radiological features (inferior scapular angle squaring and spurring and costochondral cupping) can differentiate ADA-SCID from other forms of SCID. METHODS: Chest radiographs at clinical presentation between 2000 and 2017 of children with ADA-SCID were retrospectively included, provided that the radiological features were assessable. Random chest radiographs of children with other forms of SCID were included for comparison. Three paediatric radiologists (2 senior, 1 junior) assessed the radiographs for the specific radiological features and stated their diagnosis (ADA-SCID or non-ADA-SCID). An optimal threshold for test performance was defined using a ROC curve. RESULTS: Thirty-six patients with ADA-SCID and twenty-five patients with non-ADA-SCID were included (median age 3.8 months). The optimal threshold for test performance was at approximately < 7 months old: sensitivity 91.7%, specificity 80.7%, interreader agreement was k = 0.709, AUC 0.862. The positive likelihood ratio for scapular squaring, scapular spur, and costochondral cupping was 4.0, 54.6 and 7.8, respectively. The test was valid when performed by both senior and junior paediatric radiologists. CONCLUSION: Radiological features such as scapular spurring, scapular squaring and costochondral cupping can reliably differentiate between ADA-SCID and other forms of SCID. This is true for children aged approximately < 7 months, and this is reliable when assessed by both senior and junior paediatric radiologists.

2.
Front Pediatr ; 7: 435, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31709205

RESUMO

Haematopoietic stem cell transplantation currently remains the only curative treatment of primary forms of haemophagocytic lymphohistiocytosis (HLH). Rapid diagnosis, efficient primary treatment of hyperinflammation, and conditioning regimens tailored to this demanding condition have substantially improved prognosis in the past 40 years. However, refractory hyperinflammation, central nervous system (CNS) involvement, unavailability of matched donors, susceptibility to conditioning-related toxicities, and a high frequency of mixed chimaerism remain a challenge in a substantial proportion of patients. Gene therapeutic approaches for several genetic defects of primary HLH are being developed at pre-clinical and translational levels.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31775019

RESUMO

CAPSULE SUMMARY: We characterise the immunopathogenesis of autoinflammation, HLH, and early onset intestinal inflammation caused by homozygous mutation in DNASE2, and provide the first description of favourable therapeutic response to JAK1/JAK2 blockade in this disease.

4.
Hum Mol Genet ; 28(R1): R15-R23, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31297531

RESUMO

Gene therapy is now being trialled as a therapeutic option for an expanding number of conditions, based primarily on the successful treatment over the past two decades of patients with specific primary immunodeficiencies (PIDs) including severe combined immunodeficiency and Wiskott-Aldrich syndrome and metabolic conditions such as leukodystrophy. The field has evolved from the use of gammaretroviral vectors to more sophisticated lentiviral platforms that offer an improved biosafety profile alongside greater efficiency for hematopoietic stem cells gene transfer. Here we review more recent developments including licensing of gene therapies, use of gene corrected autologous T cells as an alternative strategy for some PIDs and the potential of targeted gene correction using various gene editing platforms. Given the promising results of recent clinical trials, it is likely that autologous gene therapies will become standard of care for a number of devastating diseases in the coming decade.

6.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

7.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

8.
Blood ; 132(19): 2088-2096, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30104219

RESUMO

Asymptomatic carriers (ACs) of pathogenic biallelic mutations in causative genes for primary hemophagocytic lymphohistiocytosis (HLH) are at high risk of developing life-threatening HLH, which requires allogeneic hematopoietic stem cell transplantation (HSCT) to be cured. There are no guidelines on the management of these asymptomatic patients. We analyzed the outcomes of pairs of index cases (ICs) and subsequently diagnosed asymptomatic family members carrying the same genetic defect. We collected data from 22 HSCT centers worldwide. Sixty-four children were evaluable. ICs presented with HLH at a median age of 16 months. Seven of 32 ICs died during first-line therapy, and 2 are alive after chemotherapy only. In all, 23/32 underwent HSCT, and 16 of them are alive. At a median follow-up of 36 months from diagnosis, 18/32 ICs are alive. Median age of ACs at diagnosis was 5 months. Ten of 32 ACs activated HLH while being observed, and all underwent HSCT: 6/10 are alive and in complete remission (CR). 22/32 ACs remained asymptomatic, and 6/22 have received no treatment and are in CR at a median follow-up of 39 months. Sixteen of 22 underwent preemptive HSCT: 15/16 are alive and in CR. Eight-year probability of overall survival (pOS) in ACs who did not have activated HLH was significantly higher than that in ICs (95% vs 45%; P = .02), and pOS in ACs receiving HSCT before disease activation was significantly higher than in ACs receiving HSCT after HLH activation (93% vs 64%; P = .03). Preemptive HSCT in ACs proved to be safe and should be considered.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica/terapia , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Mutação , Análise de Sobrevida , Resultado do Tratamento
9.
J Clin Invest ; 128(9): 3957-3975, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29969437

RESUMO

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.


Assuntos
Doença Granulomatosa Crônica/genética , Mutação com Perda de Função , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Técnicas de Inativação de Genes , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/metabolismo , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Linhagem , Fagócitos/imunologia , Fagócitos/metabolismo , Fagócitos/microbiologia , Fenótipo , Fosfoproteínas/metabolismo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução Genética , Adulto Jovem
11.
Front Immunol ; 9: 666, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29670631

RESUMO

X-linked lymphoproliferative disease (XLP) was first described in the 1970s as a fatal lymphoproliferative syndrome associated with infection with Epstein-Barr virus (EBV). Features include hemophagocytic lymphohistiocytosis (HLH), lymphomas, and dysgammaglobulinemias. Molecular cloning of the causative gene, SH2D1A, has provided insight into the nature of disease, as well as helped characterize multiple features of normal immune cell function. Although XLP type 1 (XLP1) provides an example of a primary immunodeficiency in which patients have problems clearing primarily one infectious agent, it is clear that XLP1 is also a disease of severe immune dysregulation, even independent of EBV infection. Here, we describe clinical features of XLP1, how molecular and biological studies of the gene product, SAP, and the associated signaling lymphocyte activation molecule family receptors have provided insight into disease pathogenesis including specific immune cell defects, and current therapeutic approaches including the potential use of gene therapy. Together, these studies have helped change the outcome of this once almost uniformly fatal disease.


Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4/fisiologia , Transtornos Linfoproliferativos/imunologia , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Animais , Infecções por Vírus Epstein-Barr/genética , Terapia Genética , Humanos , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/terapia , Mutação/genética , Transdução de Sinais
12.
J Allergy Clin Immunol ; 142(1): 235-245.e6, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29705247

RESUMO

BACKGROUND: X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell-dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match. OBJECTIVES: Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene-corrected T cells could reconstitute known effector cell defects. METHODS: CD3+ lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen-specific responses. To efficiently transduce CD3+ cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model. RESULTS: In Sap-deficient mice 20% to 40% engraftment of gene-modified T cells led to significant recovery of germinal center formation and NP-specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model. CONCLUSIONS: These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética/métodos , Transtornos Linfoproliferativos , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Linfócitos T Citotóxicos/transplante , Animais , Xenoenxertos , Humanos , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Camundongos
13.
J Allergy Clin Immunol ; 142(3): 904-913.e3, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29355678

RESUMO

BACKGROUND: Mutations in the perforin 1 (PRF1) gene account for up to 58% of familial hemophagocytic lymphohistiocytosis syndromes. The resulting defects in effector cell cytotoxicity lead to hypercytokinemia and hyperactivation with inflammation in various organs. OBJECTIVE: We sought to determine whether autologous gene-corrected T cells can restore cytotoxic function, reduce disease activity, and prevent hemophagocytic lymphohistiocytosis (HLH) symptoms in in vivo models. METHODS: We developed a gammaretroviral vector to transduce murine CD8 T cells in the Prf-/- mouse model. To verify functional correction of Prf-/- CD8 T cells in vivo, we used a lymphocytic choriomeningitis virus (LCMV) epitope-transfected murine lung carcinoma cell tumor model. Furthermore, we challenged gene-corrected and uncorrected mice with LCMV. One patient sample was transduced with a PRF1-encoding lentiviral vector to study restoration of cytotoxicity in human cells. RESULTS: We demonstrated efficient engraftment and functional reconstitution of cytotoxicity after intravenous administration of gene-corrected Prf-/- CD8 T cells into Prf-/- mice. In the tumor model infusion of Prf-/- gene-corrected CD8 T cells eliminated the tumor as efficiently as transplantation of wild-type CD8 T cells. Similarly, mice reconstituted with gene-corrected Prf-/- CD8 T cells displayed complete protection from the HLH phenotype after infection with LCMV. Patients' cells showed correction of cytotoxicity in human CD8 T cells after transduction. CONCLUSION: These data demonstrate the potential application of T-cell gene therapy in reconstituting cytotoxic function and protection against HLH in the setting of perforin deficiency.


Assuntos
Linfócitos T CD8-Positivos/transplante , Coriomeningite Linfocítica/terapia , Linfo-Histiocitose Hemofagocítica/terapia , Perforina/genética , Animais , Linhagem Celular Tumoral , Pré-Escolar , Terapia Genética , Humanos , Vírus da Coriomeningite Linfocítica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
14.
J Allergy Clin Immunol ; 141(1): 322-328.e10, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28392333

RESUMO

BACKGROUND: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). METHODS: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. RESULTS: Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. CONCLUSION: RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.


Assuntos
Quebras de DNA de Cadeia Dupla , Distúrbios no Reparo do DNA/genética , Distúrbios no Reparo do DNA/terapia , Reparo do DNA , Transplante de Células-Tronco Hematopoéticas , Adolescente , Alelos , Criança , Pré-Escolar , Distúrbios no Reparo do DNA/diagnóstico , Distúrbios no Reparo do DNA/mortalidade , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Mutação , Prognóstico , Resultado do Tratamento , Viroses , Adulto Jovem
16.
Front Immunol ; 8: 798, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769923

RESUMO

Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

17.
Gut ; 66(6): 1060-1073, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-26953272

RESUMO

OBJECTIVE: Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. DESIGN: We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). RESULTS: Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. CONCLUSIONS: NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/metabolismo , Autofagia/genética , Doença de Crohn/genética , Granuloma/genética , Macrófagos/efeitos dos fármacos , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Adolescente , Adulto , Antibacterianos/farmacologia , Autofagia/efeitos dos fármacos , Bactérias , Células Cultivadas , Criança , Pré-Escolar , Clorpromazina/farmacologia , Doença de Crohn/complicações , Doença de Crohn/patologia , Antagonistas de Dopamina/farmacologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gentamicinas/farmacologia , Granuloma/patologia , Humanos , Imidazóis/farmacologia , Leucócitos Mononucleares , Lisossomos , Macrófagos/fisiologia , Masculino , Mutação , Doença de Niemann-Pick Tipo C/complicações , Proteína Adaptadora de Sinalização NOD2/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/deficiência , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Adulto Jovem
19.
Br J Haematol ; 175(4): 559-576, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27748521

RESUMO

Epstein-Barr virus (EBV) infection is ubiquitous in humans, but the majority of infections have an asymptomatic or self-limiting clinical course. Rarely, individuals may develop a pathological EBV infection with a variety of life threatening complications (including haemophagocytosis and malignancy) and others develop asymptomatic chronic EBV viraemia. Although an impaired ability to control EBV infection has long been recognised as a hallmark of severe T-cell immunodeficiency, the advent of next generation sequencing has identified a series of Primary Immunodeficiencies in which EBV-related pathology is the dominant feature. Chronic active EBV infection is defined as chronic EBV viraemia associated with systemic lymphoproliferative disease, in the absence of immunodeficiency. Descriptions of larger cohorts of patients with chronic active EBV in recent years have significantly advanced our understanding of this clinical syndrome. In this review we summarise the current understanding of the pathophysiology and natural history of these diseases and clinical syndromes, and discuss approaches to the investigation and treatment of severe or atypical EBV infection.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/fisiologia , Interações Hospedeiro-Patógeno , Síndromes de Imunodeficiência/complicações , Autoimunidade , Transformação Celular Viral , Doença Crônica , Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/diagnóstico , Predisposição Genética para Doença , Variação Genética , Genoma Viral , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade , Hospedeiro Imunocomprometido , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/metabolismo , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Transtornos Linfoproliferativos/etiologia , Neoplasias/etiologia , Índice de Gravidade de Doença , Ativação Viral
20.
Nat Commun ; 7: 11686, 2016 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-27221592

RESUMO

NF-κB is a key transcription factor that dictates the outcome of diverse immune responses. How NF-κB is regulated by multiple activating receptors that are engaged during natural killer (NK)-target cell contact remains undefined. Here we show that sole engagement of NKG2D, 2B4 or DNAM-1 is insufficient for NF-κB activation. Rather, cooperation between these receptors is required at the level of Vav1 for synergistic NF-κB activation. Vav1-dependent synergistic signalling requires a separate PI3K-Akt signal, primarily mediated by NKG2D or DNAM-1, for optimal p65 phosphorylation and NF-κB activation. Vav1 controls downstream p65 phosphorylation and NF-κB activation. Synergistic signalling is defective in X-linked lymphoproliferative disease (XLP1) NK cells entailing 2B4 dysfunction and required for p65 phosphorylation by PI3K-Akt signal, suggesting stepwise signalling checkpoint for NF-κB activation. Thus, our study provides a framework explaining how signals from different activating receptors are coordinated to determine specificity and magnitude of NF-κB activation and NK cell responses.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Células Matadoras Naturais/metabolismo , NF-kappa B/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Humanos , Transtornos Linfoproliferativos/metabolismo , Proteínas Proto-Oncogênicas c-vav/metabolismo
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