Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
J Clin Immunol ; 39(1): 81-89, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30607663

RESUMO

The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.


Assuntos
Reparo do DNA/genética , Granuloma/complicações , Granuloma/virologia , Síndromes de Imunodeficiência/complicações , Vírus da Rubéola/patogenicidade , Dermatopatias/etiologia , Dermatopatias/virologia , Adolescente , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/virologia , Criança , Pré-Escolar , Feminino , Granuloma/genética , Cabelo/anormalidades , Cabelo/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hirschsprung/genética , Doença de Hirschsprung/virologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/virologia , Masculino , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/virologia , Osteocondrodisplasias/congênito , Osteocondrodisplasias/genética , Osteocondrodisplasias/virologia , Rubéola (Sarampo Alemão)/genética , Rubéola (Sarampo Alemão)/virologia , Pele/virologia , Dermatopatias/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/virologia
2.
J Pediatr Hematol Oncol ; 37(2): e114-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25692616

RESUMO

Hematologic malignancies, in particular T-cell lymphomas/leukemias, are prevalent in patients with ataxia telangiectasia (AT), with most reported cases being clinically aggressive and high grade. Epstein-Barr virus (EBV) is often associated with lymphoid proliferations/neoplasms arising in immunodeficient patients. Reports of low-grade B-cell neoplasms in the ataxia telangiectasia population are extremely rare. Here, we describe a case of EBV-associated extranodal marginal zone lymphoma (mucosa-associated lymphoid tissue lymphoma) of the parotid gland in a 16-year-old boy with AT. In addition, we review the literature of hematologic malignancies in the AT population as well as the occurrence of EBV in mucosa-associated lymphoid tissue lymphoma.


Assuntos
Ataxia Telangiectasia/complicações , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/patogenicidade , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Glândula Parótida/patologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ataxia Telangiectasia/patologia , Ataxia Telangiectasia/virologia , Infecções por Vírus Epstein-Barr/virologia , Humanos , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/etiologia , Masculino , Glândula Parótida/virologia , Prognóstico
3.
J Pediatr Hematol Oncol ; 37(2): 154-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24663073

RESUMO

A 20-month-old girl diagnosed with T-cell acute lymphoblastic leukemia was treated according to the Nordic NOPHO ALL2000 protocol. The patient developed severe immunosuppression and experienced life-threatening adenovirus infection, which was treated with ribavirin and cidofovir. α-fetoprotein was 20- to 30-fold elevated, and genetic analysis confirmed the diagnosis of ataxia telangiectasia. Despite receiving only 7 weeks of anti-leukemic therapy, she has stayed in first remission now 8 years after the diagnosis. We speculate that this could be because of increased chemosensitivity of ATM-mutated leukemic cells, adenovirus causing a direct oncolytic effect, and/or high levels of endogenous cortisol during her severe infection.


Assuntos
Infecções por Adenovirus Humanos/complicações , Ataxia Telangiectasia/complicações , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Adenoviridae/efeitos dos fármacos , Infecções por Adenovirus Humanos/virologia , Antivirais/uso terapêutico , Ataxia Telangiectasia/virologia , Feminino , Humanos , Lactente , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Prognóstico , Indução de Remissão
4.
J Gen Virol ; 96(Pt 1): 144-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25252686

RESUMO

Infection of astrocytes by the neuropathogenic mutant of Moloney murine leukemia virus, ts1, exhibits increased levels of reactive oxygen species (ROS) and signs of oxidative stress compared with uninfected astrocytes. Previously, we have demonstrated that ts1 infection caused two separate events of ROS upregulation. The first upregulation occurs during early viral establishment in host cells and the second during the virus-mediated apoptotic process. In this study, we show that virus-mediated ROS upregulation activates the protein kinase, ataxia telangiectasia mutated, which in turn phosphorylates serine 15 on p53. This activation of p53 however, is unlikely associated with ts1-induced cell death. Rather p53 appears to be involved in suppressing intracellular ROS levels in astrocytes under oxidative stress. The activated p53 appears to delay retroviral gene expression by suppressing NADPH oxidase, a superoxide-producing enzyme. These results suggest that p53 plays a role as a retrovirus-mediated oxidative stress modulator.


Assuntos
Estresse Oxidativo/genética , Retroviridae/genética , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/genética , Astrócitos/virologia , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/virologia , Encéfalo/metabolismo , Encéfalo/virologia , Morte Celular/genética , Expressão Gênica/genética , Camundongos , Vírus da Leucemia Murina de Moloney/genética , NADPH Oxidases/genética , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/genética
5.
Am J Pathol ; 178(6): 2740-51, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21641396

RESUMO

Immune system-related pathology is common in ataxia-telangiectasia (A-T) patients and mice that lack the protein kinase, A-T mutated (ATM). However, it has not been studied how ATM influences immune responses to a viral infection. Using the lymphocytic choriomeningitis virus (LCMV) infection model, we show that ATM(-/-) mice, despite having fewer naïve CD8⁺ T cells, effectively clear the virus. However, aberrant CD8⁺ T-cell responses are observed, including defective expansion and contraction, effector-to-memory differentiation, and a switch in viral-epitope immunodominance. T-cell receptor-activated, but not naïve, ATM(-/-) splenic CD8⁺ T cells have increased ribosomal protein S6 and Akt phosphorylation and do not proliferate well in response to IL-15, a cytokine important for memory T-cell development. Accordingly, pharmacological Akt or mammalian target of rapamycin complex 1 (mTORC1) inhibition during T-cell receptor activation alone rescues the IL-15 proliferation defect. Finally, rapamycin treatment during LCMV infection in vivo increases the number of memory T cells in ATM(-/-) mice. Altogether, these results show that CD8⁺T cells lacking ATM have hyperactive Akt and mTORC1 signaling in response to T-cell receptor activation, which results in aberrant cytokine responses and memory T-cell development. We speculate that similar signaling defects contribute to the immune system pathology of A-T, and that inhibition of Akt and/or mTORC1 may be of therapeutic value.


Assuntos
Ataxia Telangiectasia/virologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Memória Imunológica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/imunologia , Proteínas Mutadas de Ataxia Telangiectasia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/patologia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Interleucina-15/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Coriomeningite Linfocítica/complicações , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/metabolismo
6.
J Virol ; 81(18): 9653-64, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17609267

RESUMO

The ataxia telangiectasia-mutated (ATM) protein, a member of the related phosphatidylinositol 3-like kinase family encoded by a gene responsible for the human genetic disorder ataxia telangiectasia, regulates cellular responses to DNA damage and viral infection. It has been previously reported that herpes simplex virus type 1 (HSV-1) infection induces activation of protein kinase activity of ATM and hyperphosphorylation of transcription factor, Sp1. We show that ATM is intimately involved in Sp1 hyperphosphorylation during HSV-1 infection rather than individual HSV-1-encoded protein kinases. In ATM-deficient cells or cells silenced for ATM expression by short hairpin RNA targeting, hyperphosphorylation of Sp1 was prevented even as HSV-1 infection progressed. Mutational analysis of putative ATM phosphorylation sites on Sp1 and immunoblot analysis with phosphopeptide-specific Sp1 antibodies clarified that at least Ser-56 and Ser-101 residues on Sp1 became phosphorylated upon HSV-1 infection. Serine-to-alanine mutations at both sites on Sp1 considerably abolished hyperphosphorylation of Sp1 upon infection. Although ATM phosphorylated Ser-101 but not Ser-56 on Sp1 in vitro, phosphorylation of Sp1 at both sites was not detected at all upon infection in ATM-deficient cells, suggesting that cellular kinase(s) activated by ATM could be involved in phosphorylation at Ser-56. Upon viral infection, Sp1-dependent transcription in ATM expression-silenced cells was almost the same as that in ATM-intact cells, suggesting that ATM-dependent phosphorylation of Sp1 might hardly affect its transcriptional activity during the HSV-1 infection. ATM-dependent Sp1 phosphorylation appears to be a global response to various DNA damage stress including viral DNA replication.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Herpes Simples/metabolismo , Herpesvirus Humano 1/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição Sp1/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Replicação Viral/fisiologia , Substituição de Aminoácidos , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/virologia , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Dano ao DNA/genética , Replicação do DNA/genética , DNA Viral/genética , DNA Viral/metabolismo , Proteínas de Ligação a DNA/genética , Inativação Gênica , Células HeLa , Herpes Simples/genética , Herpesvirus Humano 1/genética , Humanos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Fator de Transcrição Sp1/genética , Proteínas Supressoras de Tumor/genética , Proteínas Virais/metabolismo
7.
Pediatr Pulmonol ; 37(6): 559-60, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15114558

RESUMO

We describe a child with with Hodgkin disease and ataxia-telangiectasia who also developed an unusual pneumonitis caused by a cytomegalovirus which was fatal.


Assuntos
Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/virologia , Infecções por Citomegalovirus/complicações , Doença de Hodgkin/complicações , Doença de Hodgkin/virologia , Pneumonia/etiologia , Pneumonia/virologia , Criança , Evolução Fatal , Feminino , Humanos
8.
Crit Rev Oncol Hematol ; 44(3): 217-25, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12467962

RESUMO

Epstein-Barr virus (EBV) is involved in various clinical disorders and many of the disease entities are lymphoid and epithelial malignancies. The exact mechanisms that determine the exact form of EBV-related disorder are not clear at present. Many of the clinical manifestations of these diseases are based on the biological characteristics of the target cells for EBV infection and the expression and function of EBV gene, which also perturb host immune functions. In this monograph, I propose a hypothesis regarding the mechanism involved in shaping the manifestation of EBV infection that genomic instability of EBV-infected cells and how a defective immune surveillance system against such cells plays a critical role in determining the clinical manifestation of EBV infection. Using EBV-infected B-cells from patients and carriers with ataxia telangiectasia as an example of EBV infection, I present and discuss evidence in support of the proposed hypothesis.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/patogenicidade , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/virologia , Predisposição Genética para Doença , Humanos
9.
Hum Pathol ; 33(1): 133-6, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11823985

RESUMO

Chromosomal breakage syndromes, including ataxia-telangiectasia (AT), are autosomal recessive disorders in which DNA repair mechanisms are defective resulting in chromosomal instability. Affected individuals are at high risk for developing malignancy because of the widespread resulting cellular effects. One such effect, severe immunosuppression, can permit virally mediated neoplasms to manifest, similar to those seen in acquired immunodeficiency syndrome (AIDS), congenital immune deficiency syndromes, and posttransplant populations. Epstein-Barr virus (EBV) is a common viral agent known to be associated with lymphoid, epithelial, and smooth muscle malignancies in such patients. Although smooth muscle tumors have been reported in patients with AT, their association with EBV has not been evaluated. We present a case of EBV-associated laryngeal leiomyosarcoma and jejunal cellular leiomyoma in a child with AT. This case suggests that the development of neoplasia in patients with chromosomal breakage syndromes may be related to the immunosuppressive consequences of these diseases, and searching for infectious causes (such as EBV) is important.


Assuntos
Ataxia Telangiectasia/virologia , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/isolamento & purificação , Neoplasias do Jejuno/virologia , Neoplasias Laríngeas/virologia , Leiomiossarcoma/virologia , Ataxia Telangiectasia/patologia , Criança , Infecções por Vírus Epstein-Barr/patologia , Feminino , Herpesvirus Humano 4/patogenicidade , Humanos , Hospedeiro Imunocomprometido , Neoplasias do Jejuno/patologia , Neoplasias Laríngeas/patologia , Leiomiossarcoma/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA