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1.
Eur Heart J ; 40(15): 1173-1174, 2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-30982068
2.
Front Immunol ; 9: 2766, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30564229

RESUMO

Two unrelated patients with GATA2-haploinsufficiency developed a hemophagocytic lymphohistiocytosis (HLH)-like disease during a varicella zoster virus (VZV) infection. High copy numbers of VZV were detected in the blood, and the patients were successfully treated with acyclovir and intravenous immunoglobulins. After treatment with corticosteroids for the HLH, both patients made a full recovery. Although the mechanisms leading to this disease constellation have yet to be characterized, we hypothesize that impairment of the immunoregulatory role of NK cells in GATA2-haploinsufficiency may have accentuated the patients' susceptibility to HLH. Expansion of a double negative T-lymphocytic population identified with CyTOF could be a further factor contributing to HLH in these patients. This is the first report of VZV-triggered HLH-like disease in a primary immunodeficiency and the third report of HLH in GATA2-haploinsufficiency. Since HLH was part of the presentation in one of our patients, GATA2-haploinsufficiency represents a potential differential diagnosis in patients presenting with the clinical features of HLH-especially in cases of persisting cytopenia after recovery from HLH.


Assuntos
Deficiência de GATA2/imunologia , Fator de Transcrição GATA2/imunologia , Herpesvirus Humano 3/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Linfócitos T/imunologia , Infecção pelo Vírus da Varicela-Zoster/imunologia , Criança , Feminino , Deficiência de GATA2/virologia , Humanos , Linfo-Histiocitose Hemofagocítica/virologia , Masculino , Projetos Piloto , Linfócitos T/virologia , Infecção pelo Vírus da Varicela-Zoster/virologia
3.
Nat Commun ; 9(1): 1239, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29588478

RESUMO

Ikaros family zinc finger 1 (IKZF1) is a haematopoietic transcription factor required for mammalian B-cell development. IKZF1 deficiency also reduces plasmacytoid dendritic cell (pDC) numbers in mice, but its effects on human DC development are unknown. Here we show that heterozygous mutation of IKZF1 in human decreases pDC numbers and expands conventional DC1 (cDC1). Lenalidomide, a drug that induces proteosomal degradation of IKZF1, also decreases pDC numbers in vivo, and reduces the ratio of pDC/cDC1 differentiated from progenitor cells in vitro in a dose-dependent manner. In addition, non-classical monocytes are reduced by IKZF1 deficiency in vivo. DC and monocytes from patients with IKZF1 deficiency or lenalidomide-treated cultures secrete less IFN-α, TNF and IL-12. These results indicate that human DC development and function are regulated by IKZF1, providing further insights into the consequences of IKZF1 mutation on immune function and the mechanism of immunomodulation by lenalidomide.

4.
Front Immunol ; 9: 543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599784

RESUMO

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

5.
BMC Infect Dis ; 18(1): 33, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29325543

RESUMO

BACKGROUND: We report a rare case of Mammalian orthoreovirus (MRV) infection in a child with a primary immunodeficiency (PID). Infections with Mammalian orthoreovirus are very rare and probably of zoonotic origin. Only a few cases have been described so far, including one with similar pathogenesis as in our case. CASE PRESENTATION: The patient, age 11, presented with flu-like symptoms and persistent severe diarrhea. Enterovirus has been detected over several months, however, exact typing of a positive cell culture remained inconclusive. Unbiased metagenomic sequencing then detected MRV in stool samples from several time points. The sequencing approach further revealed co-infection with a recombinant Coxsackievirus and Adenovirus. MRV-specific antibodies detected by immunofluorescence proved that the patient seroconverted. CONCLUSION: This case highlights the potential of unbiased metagenomic sequencing in supplementing routine diagnostic methods, especially in situations of chronic infection with multiple viruses as seen here in an immunocompromised host. The origin, transmission routes and implications of MRV infection in humans merit further investigation.


Assuntos
Infecções por Adenoviridae/virologia , Infecções por Coxsackievirus/virologia , Síndromes de Imunodeficiência/complicações , Metagenômica/métodos , Infecções por Reoviridae/virologia , Infecções por Adenoviridae/etiologia , Criança , Coinfecção , Infecções por Coxsackievirus/etiologia , Diarreia/virologia , Enterovirus/genética , Enterovirus/patogenicidade , Infecções por Enterovirus/virologia , Feminino , Humanos , Síndromes de Imunodeficiência/virologia , Orthoreovirus de Mamíferos/genética , Orthoreovirus de Mamíferos/patogenicidade , Infecções por Reoviridae/etiologia
6.
Ann Rheum Dis ; 77(4): 612-619, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29358286

RESUMO

OBJECTIVES: To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype. METHODS: We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM). RESULTS: We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1ß were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth. CONCLUSIONS: Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.

7.
Pediatr Allergy Immunol ; 28(2): 124-134, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27612320

RESUMO

Phagocytic neutrophil granulocytes are among the first immune cells active at sites of infection, forming an important first-line defense against invading microorganisms. Congenital immune defects concerning these phagocytes may be due to reduced neutrophil numbers or function. Management of affected patients depends on the type and severity of disease. Here, we provide an overview of causes and treatment of diseases associated with congenital neutropenia, as well as defects of the phagocytic respiratory burst.


Assuntos
Doença Granulomatosa Crônica/imunologia , Síndromes de Imunodeficiência/imunologia , Neutropenia/congênito , Neutrófilos/imunologia , Fagocitose , Verrugas/imunologia , Animais , Antibioticoprofilaxia , Diferenciação Celular , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunidade Inata , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Mielopoese/genética , Neutropenia/genética , Neutropenia/imunologia , Neutropenia/terapia , Fagocitose/genética , Explosão Respiratória/genética , Verrugas/genética , Verrugas/terapia
8.
Blood Adv ; 1(15): 1101-1106, 2017 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29296752

RESUMO

FAS-dependent apoptosis in Vδ1 T cells makes the latter possible culprits for the lymphadenopathy observed in patients with FAS mutations.Rapamycin and methylprednisolone resistance should prompt clinicians to look for Vδ1 T cell proliferation in ALPS-FAS patients.

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