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2.
Sci Rep ; 8(1): 1016, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343815

RESUMO

Kawasaki Disease (KD) is an acute inflammatory disease that takes the form of systemic vasculitis. Endothelial microparticles (EMPs) have been recognized as an important transcellular delivery system. We hypothesized whether EMPs are involved in vasculitis in acute KD. Fifty patients with acute KD were enrolled, divided into two subgroups: those with coronary artery lesions (CAL) (n = 5) and those without CAL (NCAL) (n = 45). EMPs were measured using flow cytometry, and microRNA (miR) expression profiling was performed by microRNA array. The percentage of EMPs in acute KD was significantly higher than in controls (P < 0.0001). EMPs in patients with CAL rapidly increased after the initial treatment, and was significantly higher than those in NCAL (P < 0.001). In patients with CAL, we identified 2 specific miRs encapsulated in EMPs, hsa-miR-145-5p and hsa-miR-320a, which are predicted to affect monocyte function using in silico analysis, and were demonstrated to upregulate inflammatory cytokine mRNAs in THP-1 monocytes. In situ hybridization confirmed that hsa-miR-145-5p was preferentially expressed in CAL. EMPs may serve as a sensitive marker for the severity of vasculitis in acute KD. Moreover, these 2 specific miRs encapsulated in EMPs might be involved in inflammatory cytokine regulation and the pathogenesis of vasculitis in acute KD.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Doença da Artéria Coronariana/genética , Células Endoteliais/metabolismo , MicroRNAs/genética , Síndrome de Linfonodos Mucocutâneos/genética , Adolescente , Micropartículas Derivadas de Células/química , Micropartículas Derivadas de Células/patologia , Criança , Pré-Escolar , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Vasos Coronários , Citocinas/genética , Citocinas/metabolismo , Progressão da Doença , Células Endoteliais/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , MicroRNAs/metabolismo , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/metabolismo , Síndrome de Linfonodos Mucocutâneos/patologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células THP-1
4.
J Allergy Clin Immunol ; 140(1): 223-231, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27939403

RESUMO

BACKGROUND: Ikaros, which is encoded by IKZF1, is a transcriptional factor that play a critical role in hematopoiesis. Somatic IKZF1 alterations are known to be involved in the pathogenesis of leukemia in human subjects. Recently, immunodeficiency caused by germline IKZF1 mutation has been described. OBJECTIVE: We sought to describe the clinical and immunologic phenotypes of Japanese patients with heterozygous IKZF1 mutations. METHODS: We performed whole-exome sequencing in patients from a dysgammaglobulinemia or autoimmune disease cohort and used a candidate gene approach in 4 patients. Functional and laboratory studies, including detailed lymphopoiesis/hematopoiesis analysis in the bone marrow, were performed. RESULTS: Nine patients from 6 unrelated families were identified to have heterozygous germline mutations in IKZF1. Age of onset was 0 to 20 years (mean, 7.4 years). Eight of 9 patients presented with dysgammaglobulinemia accompanied by B-cell deficiency. Four of 9 patients had autoimmune disease, including immune thrombocytopenic purpura, IgA vasculitis, and systemic lupus erythematosus. Nonautoimmune pancytopenia was observed in 1 patient. All of the mutant Ikaros protein demonstrated impaired DNA binding to the target sequence and abnormal diffuse nuclear localization. Flow cytometric analysis of bone marrow revealed reduced levels of common lymphoid progenitors and normal development of pro-B to pre-B cells. CONCLUSIONS: Germline heterozygous IKZF1 mutations cause dysgammaglobulinemia; hematologic abnormalities, including B-cell defect; and autoimmune diseases.


Assuntos
Doenças Autoimunes/genética , Doenças Hematológicas/genética , Fator de Transcrição Ikaros/genética , Adolescente , Adulto , Doenças Autoimunes/imunologia , Autoimunidade , Linfócitos B/imunologia , Criança , Feminino , Mutação em Linhagem Germinativa , Doenças Hematológicas/imunologia , Hematopoese/genética , Humanos , Fator de Transcrição Ikaros/imunologia , Contagem de Linfócitos , Masculino , Linfócitos T/imunologia , Adulto Jovem
5.
J Clin Immunol ; 35(3): 280-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25739914

RESUMO

BACKGROUND: Recombination-activating gene (RAG) 1 and 2 deficiency is seen in patients with severe combined immunodeficiency (SCID) and Omenn syndrome. However, the spectrum of the disease has recently expanded to include a milder phenotype. OBJECTIVE: We analyzed a 4-year-old boy who was initially given the diagnosis of selective immunoglobulin A deficiency (SIgAD) based on immunoglobulin serum levels without any opportunistic infections, rashes, hepatosplenomegaly, autoimmunity or granulomas. The patient was found to be infected with varicella zoster; however, the clinical course was not serious. He produced antiviral antibodies. METHODS: We performed lymphocyte phenotyping, quantification of T cell receptor excision circles (TRECs) and kappa deleting recombination excision circles (KRECs), an analysis of target sequences of RAG1 and 2, a whole-genome SNP array, an in vitro V(D)J recombination assay, a spectratype analysis of the CDR3 region and a flow cytometric analysis of the bone marrow. RESULTS: Lymphocyte phenotyping demonstrated that the ratio of CD4+ to CD8+ T cells was inverted and the majority of CD4+T cells expressed CD45RO antigens in addition to the almost complete lack of B cells. Furthermore, both TRECs and KRECs were absent. Targeted DNA sequencing and SNP array revealed that the patient carried a deletion of RAG1 and RAG2 genes on the paternally-derived chromosome 11, and two maternally-derived novel RAG1 missense mutations (E455K, R764H). In vitro analysis of recombination activity showed that both RAG1 mutant proteins had low, but residual function. CONCLUSIONS: The current case further expands the phenotypic spectrum of mild presentations of RAG deficiency, and suggests that TRECs and KRECs are useful markers for detecting hidden severe, as well as mild, cases.


Assuntos
Proteínas de Homeodomínio/genética , Deficiência de IgA/sangue , Deficiência de IgA/genética , Pré-Escolar , Proteínas de Homeodomínio/metabolismo , Humanos , Deficiência de IgA/imunologia , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos T/metabolismo , Recombinação V(D)J
6.
Iran J Allergy Asthma Immunol ; 14(5): 462-71, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26742434

RESUMO

Epstein-Barr virus (EBV) was discovered 50 years ago from an african Burkitt lymphoma cell line. EBV-associated lymphoproliferative disorders (LPDs) are life- threatening diseases, especially in children. In this article, we review EBV-associated LPDs, especially in the area of primary immunodeficiency disease (PID). We searched PubMed for publications with key words including EBV infection, lymphoma, LPDs and PID, and selected the manuscripts written in English that we judged to be relevant to the topic of this review.On the basis of the data in the literature, we grouped the EBV-associated LPDs into four categories: nonmalignant disease, malignant disease, acquired immunodeficiency disease and PID. Each category has its own risk factor for LPD development. EBV-associated LPD is a complex disease, creating new challenges for diagnosis and treatment.


Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Transtornos Linfoproliferativos , Linfoma de Burkitt , Infecções por HIV , Doença de Hodgkin , Humanos , Síndromes de Imunodeficiência , Mononucleose Infecciosa , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Imunodeficiência Combinada Severa , Síndrome de Wiskott-Aldrich
7.
J Clin Immunol ; 34 Suppl 1: S35-45, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24793544

RESUMO

IgM exists as both a monomer on the surface of B cells and a pentamer secreted by plasma cells. Both pre-immune "natural" and antigen-induced "immune" IgM antibodies are important for protective immunity and for immune regulation of autoimmune processes by recognizing pathogens and self-antigens. Effector proteins interacting with the Fc portion of IgM, such as complement and complement receptors, have thus far been proposed but fail to fully account for the IgM-mediated protection and regulation. A major reason for this deficit in our understanding of IgM function seems to be lack of data on a long elusive Fc receptor for IgM (FcµR). We have recently identified a bona fide FcµR in both humans and mice. In this article we briefly review what we have learned so far about FcµR.


Assuntos
Linfócitos B/imunologia , Imunoglobulina M/imunologia , Receptores Fc/imunologia , Animais , Autoantígenos/imunologia , Humanos , Imunomodulação , Camundongos , Receptores Fc/isolamento & purificação
8.
Herpesviridae ; 3(1): 1, 2012 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-22325832

RESUMO

BACKGROUND: X-linked lymphoproliferative syndrome (XLP) is a rare inherited immunodeficiency by an extreme vulnerability to Epstein-Barr virus (EBV) infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP are now divided into type 1 (XLP-1) and type 2 (XLP-2), which are caused by mutations of SH2D1A/SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis protein (XIAP) genes, respectively. The diagnosis of XLP in individuals with EBV-associated HLH (EBV-HLH) is generally difficult because they show basically similar symptoms to sporadic EBV-HLH. Although EBV-infected cells in sporadic EBV-HLH are known to be mainly in CD8+ T cells, the cell-type of EBV-infected cells in EBV-HLH seen in XLP patients remains undetermined. METHODS: EBV-infected cells in two patients (XLP-1 and XLP-2) presenting EBV-HLH were evaluated by in EBER-1 in situ hybridization or quantitative PCR methods. RESULTS: Both XLP patients showed that the dominant population of EBV-infected cells was CD19+ B cells, whereas EBV-infected CD8+ T cells were very few. CONCLUSIONS: In XLP-related EBV-HLH, EBV-infected cells appear to be predominantly B cells. B cell directed therapy such as rituximab may be a valuable option in the treatment of EBV-HLH in XLP patients.

9.
J Clin Immunol ; 32(3): 411-20, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22228567

RESUMO

Deficiency of X-linked inhibitor of apoptosis (XIAP) caused by XIAP/BIRC4 gene mutations is an inherited immune defect recognized as X-linked lymphoproliferative syndrome type 2. This disease is mainly observed in patients with hemophagocytic lymphohistiocytosis (HLH) often associated with Epstein-Barr virus infection. We described nine Japanese patients from six unrelated families with XIAP deficiency and studied XIAP protein expression, XIAP gene analysis, invariant natural killer T (iNKT) cell counts, and the cytotoxic activity of CD8(+) alloantigen-specific cytotoxic T lymphocytes. Of the nine patients, eight patients presented with symptoms in infancy or early childhood. Five patients presented with recurrent HLH, one of whom had severe HLH and died after cord blood transplantation. One patient presented with colitis, as did another patient's maternal uncle, who died of colitis at 4 years of age prior to diagnosis with XIAP deficiency. Interestingly, a 17-year-old patient was asymptomatic, while his younger brother suffered from recurrent HLH and EBV infection. Seven out of eight patients showed decreased XIAP protein expression. iNKT cells from patients with XIAP deficiency were significantly decreased as compared with age-matched healthy controls. These results in our Japanese cohort are compatible with previous studies, confirming the clinical characteristics of XIAP deficiency.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/deficiência , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Japão , Leucócitos Mononucleares/imunologia , Contagem de Linfócitos , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Masculino , Mutação , Células T Matadoras Naturais/imunologia , Linfócitos T Citotóxicos/imunologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/imunologia
10.
J Infect Dis ; 201(12): 1923-32, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20443735

RESUMO

Epstein-Barr virus (EBV) is the pathogen that most commonly triggers infection-associated hemophagocytic lymphohistiocytosis (HLH) and ectopically infects CD8(+) T cells in EBV-associated HLH (EBV-HLH). We recently described an EBV-HLH patient who had a clonally expanded population of EBV-infected CD8(+) T cells with CD5 down-regulation. To determine whether this finding could serve as a useful marker for EBV-HLH, we investigated 5 additional patients. We found a significant increase in the subpopulation of CD8(+) T cells with CD5 down-regulation and bright human leukocyte antigen (HLA)-DR expression in all patients with EBV-HLH but not in patients with infectious mononucleosis or in control subjects. Such T cells were frequently found to be larger cells that stained positive for a specific T cell receptor VB. We also demonstrated that those cells were the major cellular target of EBV, and their numbers progressively declined in parallel with the serum ferritin levels. All together, our findings reveal the immunophenotypic characteristics of EBV-infected CD8(+) T cells and may provide a valuable tool for the diagnosis of EBV-HLH.


Assuntos
Antígenos CD5/biossíntese , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/patogenicidade , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/virologia , Criança , Pré-Escolar , Regulação para Baixo , Infecções por Vírus Epstein-Barr/complicações , Feminino , Antígenos HLA-DR/biossíntese , Herpesvirus Humano 4/imunologia , Humanos , Lactente , Masculino , Receptores de Antígenos de Linfócitos T/biossíntese , Adulto Jovem
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