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2.
Medicine (Baltimore) ; 98(20): e15726, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096528

RESUMO

RATIONALE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent autoimmune encephalitis in children, and its presentation is various. The disease can be triggered by various infections. PATIENT CONCERNS: Case 1 was a 7-year-old female with the presentation of seizure, repeated fever, language disorder, and decreased muscle strength of the right limbs; Case 2 was a 7-year-old male with the manifestation of repeated emesis, headache, involuntary movement, altered personality, seizures, and cognitive impairment; Case 3 was a 2-year-old female with repeated fever, emesis, seizures, coma, and decreased muscle strength of limbs. Anti-NMDAR antibody was identified in cerebrospinal fluid (CSF) in the 3 cases, confirming the diagnosis of anti-NMDAR encephalitis. Pathogenic examinations revealed positive serum Epstein-Barr virus (EBV)-nuclear antigen and EBV-capsid antigen (CA)-IgG antibodies in the 3 cases, as well as positive EBV-early antigen (EA)-IgG antibody in CSF. Case 1 also had positive EBV-CA-IgA antibody; Case 3 also had positive EBV-CA-IgA and EBV-CA-IgG antibodies. DIAGNOSES: Anti-NMDAR antibody and EBV-EA-IgG antibody in CSF were tested positive in the 3 cases. Thus, they were diagnosed as anti-NMDAR encephalitis associated with reactivated EBV infection. INTERVENTIONS: All of the 3 cases received immunoglobulin, corticosteroid, and ganciclovir treatment. Cases 2 and 3 also received antiepileptic drugs due to repeated seizures. In addition, Case 3 also received assistant respiration, plasma exchange, and rituximab. OUTCOMES: The 3 cases were substantially recovered after treatment. Repeat CSF analysis showed decreased titer of the anti-NMDAR antibody. LESSONS: Reactivated EBV infection may trigger anti-NMDAR encephalitis in children, which has not been reported previously. Related possible virology tests should be completed while diagnosing the disease.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/tratamento farmacológico , Encefalite Antirreceptor de N-Metil-D-Aspartato/virologia , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Convulsões/tratamento farmacológico , Corticosteroides/uso terapêutico , Encefalite Antirreceptor de N-Metil-D-Aspartato/líquido cefalorraquidiano , Anticonvulsivantes/uso terapêutico , Autoanticorpos/líquido cefalorraquidiano , Proteínas do Capsídeo/imunologia , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/líquido cefalorraquidiano , Infecções por Vírus Epstein-Barr/complicações , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Ganciclovir/uso terapêutico , Humanos , Imunoglobulinas/uso terapêutico , Masculino , Convulsões/líquido cefalorraquidiano , Convulsões/etiologia , Resultado do Tratamento
3.
Clin Lab ; 65(4)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30969068

RESUMO

BACKGROUND: The aim of this study was to prove the difference between 37°C water incubation method and the BEP III automated immunoassay analyzer incubation method in anti-EBNA1-IgA antibody detection and to find the best way to improve the consistency of the two incubation methods. METHODS: The 37°C water incubation method and BEP III analyzer incubation method were used with the same panel of samples (n = 39) in anti-EBNA1-IgA antibody detection. Except for incubation, the rest of the steps were performed by the BEP III analyzer in both groups. All the data were analyzed by SPSS 17.0 software. Line charts and bar charts were used to compare the difference between the two incubation methods in anti-EBNA1-IgA antibody detection. We planned to find the best incubation scheme for BEP III analyzer, consistent with the water incubation method, using three groups of prolonged incubation time experiments. RESULTS: A sample panel of 39 outpatients were analyzed by two incubation methods. The results showed by line charts that the water incubation method had higher S/CO values than the BEP III analyzer incubation method. Meanwhile the water incubation group had more positive results (61.5%) and less borderline positive results (35.9%) than that of the BEP III analyzer incubation group which were 43.5% and 51.2%, respectively, in the stacked bar charts. We found that by prolonging the incubation time in the BEP III analyzer for 6 minutes in the first and second incubation steps the S/CO values we increased and achieved statistically coincident results with water incubation group. CONCLUSIONS: There were biases between the 37°C water incubation method and the BEP III analyzer incubation method in anti-EBNA1-IgA antibody detection. The water incubation method had higher S/CO values than the BEP III analyzer incubation method in paired groups and led partly to a difference in test results. By prolonging the BEP III analyzer incubation time properly, it can reduce the difference to some extent resulting in statistically similar results with the water incubation method.


Assuntos
Anticorpos Antivirais/isolamento & purificação , Infecções por Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Imunoensaio/métodos , Imunoglobulina A/isolamento & purificação , Antígenos Virais/imunologia , Automação , Proteínas do Capsídeo/imunologia , Ensaio de Imunoadsorção Enzimática , Herpesvirus Humano 4/imunologia , Humanos , Pacientes Ambulatoriais , Controle de Qualidade , Reprodutibilidade dos Testes , Manejo de Espécimes
4.
Reumatismo ; 71(1): 1-12, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30932437

RESUMO

Rheumatoid factor and antibodies against cyclic citrullinated peptides represent a diagnostic hallmark in rheumatoid arthritis (RA). However, over the last decades many other autoantibodies have been identified. Several proteins can trigger an aberrant autoimmune response in their native form while others acquire this feature after post-translational modifications such as citrullination, carbamylation or acetylation. It is of interest that also the enzymes catalyzing such post-translational modifications (e.g. the protein arginine deiminases) can transform themselves into autoantibodies in RA. The purpose of this review article is to provide an overview of relevant literature published over the last years regarding novel autoantibodies and their possible diagnostic and prognostic significance in RA.


Assuntos
Autoanticorpos/metabolismo , Citrulinação , Peptídeos Cíclicos/imunologia , Vimentina/imunologia , Anticorpos Antinucleares/imunologia , Anticorpos Antinucleares/metabolismo , Especificidade de Anticorpos , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Humanos , Hidrolases/imunologia , Hidrolases/metabolismo , Queratinas/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Carbamilação de Proteínas , Fator Reumatoide , Vimentina/metabolismo , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
5.
J Infect Dis ; 219(6): 955-963, 2019 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-30312417

RESUMO

BACKGROUND: The Epstein-Barr virus (EBV) viral glycoprotein gp350 has been proposed as a candidate antigen for an EBV vaccine. However, the proposed formulations of these vaccines have not taken into account the presence of 2 unique EBV strains (EBV-1 and EBV-2) present in areas of high incidence of the EBV-associated cancer, Burkitt lymphoma. METHODS: In this study, we analyze the kinetics of EBV-1 and EBV-2 infection in an asymptomatic infant cohort from Kisumu, Kenya. We also analyzed the kinetics of the antibody response against 5 EBV antigens, gp350 (IgG and IgA), VCA (IgG), EBNA-1 (IgG), EAd (IgG), and Zta (IgG). RESULTS: We observed a high frequency of coinfection with both EBV types over time, with the only observable defect in the antibody response in infants coinfected being a significantly lower level of anti-gp350 IgA at peak response. Gp350 IgA levels were also significantly lower in coinfected infants 2.5 months postinfection and at the time of coinfection. CONCLUSIONS: These results suggest that anti-gp350 IgA antibodies may be important for sterilizing immunity against secondary infection. These findings have implications for the development of an efficacious EBV vaccine to prevent both EBV-1 and EBV-2 infection in a population at high risk for Burkitt lymphoma.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Imunoglobulina A/imunologia , Glicoproteínas de Membrana/imunologia , Adulto , Idoso , Criança , Pré-Escolar , Coinfecção/imunologia , Infecções por Vírus Epstein-Barr/classificação , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Humanos , Lactente , Quênia , Masculino , Pessoa de Meia-Idade , Carga Viral
6.
Leukemia ; 33(1): 88-98, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29925906

RESUMO

Chronic lymphocytic leukemia (CLL) is the most frequent B cell malignancy in Caucasian adults. The therapeutic armamentarium against this incurable disease has recently seen a tremendous expansion with the introduction of specific pathway inhibitors and innovative immunotherapy. However, none of these approaches is curative and devoid of side effects. We have used B-cell-specific antibodies conjugated with antigens (AgAbs) of the Epstein-Barr virus (EBV) to efficiently expand memory CD4+ cytotoxic T lymphocytes (CTLs) that recognized viral epitopes in 12 treatment-naive patients with CLL. The AgAbs carried fragments from the EBNA3C EBV protein that is recognized by the large majority of the population. All CLL cells pulsed with EBNA3C-AgAbs elicited EBV-specific T cell responses, although the intensity varied across the patient collective. Interestingly, a large proportion of the EBV-specific CD4+ T cells expressed granzyme B (GrB), perforin, and CD107a, and killed CLL cells loaded with EBV antigens with high efficiency in the large majority of patients. The encouraging results from this preclinical ex vivo study suggest that AgAbs have the potential to redirect immune responses toward CLL cells in a high percentage of patients in vivo and warrant the inception of clinical trials.


Assuntos
Anticorpos/química , Anticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Linfócitos T Citotóxicos/imunologia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas
7.
PLoS One ; 13(12): e0208957, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30533036

RESUMO

OBJECTIVE: The objective of the present study was to investigate Epstein-Barr virus (EBV) infection as an environmental factor for the development of rheumatoid arthritis (RA). METHODS: Synovial tissues were collected during surgery from 128 RA and 98 osteoarthritis (OA) patients. DNA was extracted from synovial tissues. The EBV gene was assessed by nested PCR for the amplification of EBV nuclear antigen-1 (EBNA-1). The nucleotide sequence of the PCR product was elucidated. HLA-DRB1 genotyping was also performed. RESULTS: EBV DNA was more frequently detected in the synovial tissues of RA patients (32.8%) than OA patients (15.3%) (p<0.01). The frequency of EBNA-1 variants did not significantly differ between RA and OA (RA: 17%, OA: 13%). The population with the HLA-DRB1 shared epitope (SE) was significantly higher in RA patients (70.3%) than in OA patients (44.9%) (p<0.001). In RA patients, the presence of EBV DNA was similar among SE-positive and -negative patients (SE-positive: 34.4%, -negative: 28.9%). The population with the EBNA-1 variant did not significantly differ between SE-positive and -negative patients (SE-positive: 12.9%, -negative: 27.3%). DISCUSSION: The present results indicate that EBV infection contributes to the onset of RA and chronic inflammation in synovial tissues. The frequency of EBNA-1 gene variants was low and not significantly different between RA and OA, suggesting that EBNA-1 gene variants are not a risk factor for RA. HLA-DRB1 with SE is a genetic risk factor for the development of RA. However, neither the presence of EBV nor EBNA-1 gene variants differed between SE-positive and -negative RA patients. Therefore, these two risk factors, SE and EBV, may be independent. CONCLUSION: EBV infection may be an environmental risk factor for the development of RA, while nucleotide variants of EBNA-1 do not appear to contribute to its development.


Assuntos
Artrite Reumatoide/virologia , Infecções por Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/genética , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Epitopos/genética , Epitopos/imunologia , Infecções por Vírus Epstein-Barr/fisiopatologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/isolamento & purificação , Feminino , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 4/patogenicidade , Humanos , Masculino , Osteoartrite/genética , Osteoartrite/fisiopatologia , Osteoartrite/virologia , Fatores de Risco , Líquido Sinovial/virologia
8.
Ann Dermatol Venereol ; 145 Suppl 7: VIIS24-VIIS31, 2018 Dec.
Artigo em Francês | MEDLINE | ID: mdl-30583754

RESUMO

What's new in internal medicine will be dedicated to three topics: i) inflammatory myopathies constituting a heterogenous group of diseases whose clinical manifestations, immunological abnormalities, treatment response and outcomes vary widely; ii) alterations of gut microbiota contributing to the occurrence or development of a range of conditions, including autoimmune diseases for which further work is necessary to understand the correlation of dysbiosis with these diseases; iii) the reciprocal relationship between obesity, metabolic syndrome, atherosclerosis and autoimmune diseases. New data concerning systemic sclerosis, cutaneous vasculitis, adult Still's disease, autoantibodies anti DFS70, Epstein Barr virus and autoimmune diseases were also highlighted.


Assuntos
Doenças Autoimunes/etiologia , Microbioma Gastrointestinal , Miosite/diagnóstico , Aterosclerose/complicações , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Humanos , Medicina Interna/tendências , Síndrome Metabólica/complicações , Miosite/classificação , Miosite/terapia , Obesidade/complicações , Terminologia como Assunto , Vasculite/classificação , Vasculite/diagnóstico , Proteínas Virais/genética , Proteínas Virais/imunologia , Deficiência de Vitamina D/complicações
9.
Sci Rep ; 8(1): 17079, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30459443

RESUMO

Targeted antiviral immune responses to the widespread human pathogens cytomegalovirus (CMV) and Epstein-Barr virus (EBV) play a pivotal role in determining immune fitness. We show here for the first time that tumor-infiltrating B cell (TIB)- derived immunoglobulin G (IgG) from patients with pancreatic cancer or glioblastoma have unique anti-CMV/EBV immune recognition patterns compared to serum IgG. There is also great heterogeneity between patients, as well as between serum and TIB-IgG, while some viral targets elicited strongly both T-cell and IgG reactivity in tumor infiltrating T- and B-cells. These observations suggest that the anti-CMV/EBV humoral immune response in situ is highly unique and can be instrumental in developing next-generation immuno-biomarkers in addition to supplementing cellular therapy strategies for personalized cancer therapy targeting CMV or EBV in the tumor microenvironment.


Assuntos
Linfócitos B/imunologia , Citomegalovirus/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Glioblastoma/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/imunologia , Proteínas Virais/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/virologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/virologia , Feminino , Glioblastoma/virologia , Humanos , Imunoglobulina G/imunologia , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Neoplasias Pancreáticas/virologia , Fragmentos de Peptídeos/imunologia , Microambiente Tumoral
10.
JCI Insight ; 3(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30429369

RESUMO

BACKGROUND: Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy. METHODS: An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses. RESULTS: Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher's exact test). CONCLUSION: EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000422527. FUNDING: MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd., and donations from private individuals who wish to remain anonymous.


Assuntos
Herpesvirus Humano 4/imunologia , Esclerose Múltipla/terapia , Linfócitos T/imunologia , Linfócitos T/transplante , Adulto , Idoso , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Humanos , Imunoterapia Adotiva , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/virologia , Resultado do Tratamento , Proteínas da Matriz Viral/imunologia
11.
Indian J Med Microbiol ; 36(1): 143-144, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29735847

RESUMO

Epstein-Barr virus (EBV) is the cause of systemic infection known as infectious mononucleosis with classic presentation of fever, oropharyngitis and lymphadenitis. EBV rarely causes acute hepatitis. In this report, we present a 19-year-old patient presented with nausea, fatigue and jaundice. Her physical examination and laboratory tests revealed the diagnosis as acute hepatitis due to EBV with cross-reacting antibodies to cytomegalovirus.


Assuntos
Anticorpos Antivirais/imunologia , Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/diagnóstico , Hepatite Viral Humana/virologia , Herpesvirus Humano 4/isolamento & purificação , Adulto , Reações Cruzadas/imunologia , DNA Viral/sangue , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Humanos , Fígado/virologia , Reação em Cadeia da Polimerase , Adulto Jovem
12.
Clin Lab ; 64(4): 425-431, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29739075

RESUMO

BACKGROUND: Epstein-Barr virus is a worldwide disease that can cause a wide range of human diseases, the person will become a lifelong carrier of the virus once infected. To investigate the mechanism of Epstein-Barr virus nuclear antigen 2 (EBNA2) on B-lymphocytic activity, sera from 35 patients with infectious mononucleosis and from 34 cases without Epstein-Barr virus infection are collected for experimental analysis. METHODS: Quantitative real-time PCR, western blot, and MTT assays were used to evaluate the relative expression level of EBNA2 and to examine its impact on cell vitality. RESULTS: Research found that the average EBNA2 mRNA and protein levels in 35 patients with infectious mononucleosis were higher than that 34 cases without Epstein-Barr virus infection. The MTT assay indicates that EBNA2 can promote the growth and proliferation of B lymphocytes. CONCLUSIONS: Combining the above implies that EBNA2 plays an important role in diseases that are induced by the Epstein-Barr virus. Other experiments reveal that ATO promotes the degradation of EBNA2 protein and induces the apoptosis of B lymphocytes which are EBNA2-positive.


Assuntos
Linfócitos B/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Mononucleose Infecciosa/imunologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Trióxido de Arsênio/farmacologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/virologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Células Cultivadas , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/fisiologia , Humanos , Mononucleose Infecciosa/metabolismo , Mononucleose Infecciosa/virologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
13.
EBioMedicine ; 30: 184-191, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29606628

RESUMO

Our previous study found that smoking was associated with an elevated level of the antibody against VCA in the Epstein-Barr virus (EBV) lytic phase, which was an important predictive marker of the risk of nasopharyngeal carcinoma (NPC). It remained unknown whether environmental factors were associated with the levels of other EBV antibodies, such as Zta-IgA, EA-IgA, EBNA1-IgA, and LMP1-IgA, in the lytic and latent infection periods. We aimed to investigate the possible environmental inducers that could affect EBV antibody levels in two independent healthy male populations from endemic NPC areas in South China (N=1498) and non-endemic NPC areas in North China (N=1961). We performed ELISA and immunoenzymatic assays to test the levels of antibodies specific to the EBV antigens. The seropositive rates of antibodies against the antigens expressed in both the EBV latent and lytic infection periods, namely, LMP1-IgA, EBNA1-IgA, and Zta-IgA, in endemic areas (28.65%, 5.43% and 14.49%, respectively) were significantly higher than those in non-endemic areas (14.43%, 1.07% and 6.32%, respectively). Smoking was associated with higher seropositivity for EBNA1-IgA (OR=1.47, 95% CI=1.12-1.93) and Zta-IgA (OR=1.28, 95% CI=0.99-1.66), with dose-response effects, while not associated with the levels of LMP1-IgA. In conclusion, smoking was an important environmental factor, which associated with increased levels of EBNA1-IgA, and Zta-IgA.


Assuntos
Anticorpos Antivirais/imunologia , Carcinoma/imunologia , Carcinoma/virologia , Meio Ambiente , Herpesvirus Humano 4/imunologia , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/virologia , Adulto , Antígenos Virais/imunologia , China/epidemiologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Humanos , Imunoglobulina A/imunologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Fatores de Risco , Fumar/efeitos adversos
14.
Nat Genet ; 50(5): 699-707, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29662164

RESUMO

Explaining the genetics of many diseases is challenging because most associations localize to incompletely characterized regulatory regions. Using new computational methods, we show that transcription factors (TFs) occupy multiple loci associated with individual complex genetic disorders. Application to 213 phenotypes and 1,544 TF binding datasets identified 2,264 relationships between hundreds of TFs and 94 phenotypes, including androgen receptor in prostate cancer and GATA3 in breast cancer. Strikingly, nearly half of systemic lupus erythematosus risk loci are occupied by the Epstein-Barr virus EBNA2 protein and many coclustering human TFs, showing gene-environment interaction. Similar EBNA2-anchored associations exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease. Instances of allele-dependent DNA binding and downstream effects on gene expression at plausibly causal variants support genetic mechanisms dependent on EBNA2. Our results nominate mechanisms that operate across risk loci within disease phenotypes, suggesting new models for disease origins.


Assuntos
Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Fatores de Transcrição/genética , Proteínas Virais/genética , Proteínas Virais/imunologia , Autoimunidade/genética , Linhagem Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Herpesvirus Humano 4/genética , Humanos , Lúpus Eritematoso Sistêmico/genética , Dose Máxima Tolerável , Neoplasias/genética , Fenótipo , Ligação Proteica , Sequências Reguladoras de Ácido Nucleico
15.
Front Immunol ; 9: 187, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29497417

RESUMO

This study was aimed to evaluate the role of B-cell epitopes of Epstein-Barr virus (EBV) Early antigen protein D (EA), envelope glycoprotein GP340/membrane antigen (MA), latent membrane protein (LMP)-1, and LMP-2A in systemic lupus erythematosus (SLE). B-cell epitopes were predicted by analyzing secondary structure, transmembrane domains, surface properties, and homological comparison. 60 female mice were randomized equally into 12 groups: 1-10 groups were immunized by epitope peptides (EPs) 1-10, respectively, while 11 and 12 groups were PBS and Keyhole limpet hemocyanin (KLH) control groups. Immunoglobulin G (IgG) and autoantibody to nuclear antigen (ANA) concentrations in mice serum were determined at week 8. Indirect levels of EP1-10 were further detected by enzyme-linked immuno sorbent assay (ELISA) in 119 SLE patients and 64 age- and gender-matched health controls (HCs). 10 probable EBV EA, MA, LMP-1, and LMP-2A B-cell epitopes related to SLE self-antigens were predicted and corresponding EP1-10 were synthesized. IgG concentrations at week 8 were increased in EP1-10 and KLH groups compared with PBS group in mice; while ANA levels were elevated in only EP1-4, EP6-7, and EP10 groups compared to KLH group by ELISA, and ANA-positive rates were increased in only EP1, EP2, EP4, EP6, and EP10 groups by indirect immunofluorescence assay. EP1-4, EP6, and EP10 indirect levels were increased in SLE patients than HCs, while EP1, EP3, EP6, and EP9 were correlated with SLE disease activity index score. In conclusion, EBV EA, MA, LMP-1, and LMP-2A B-cell EPs increased SLE-related autoantibodies in mice, and their indirect levels might be served as potential biomarkers for SLE diagnosis and disease severity.


Assuntos
Anticorpos Antinucleares/sangue , Epitopos de Linfócito B/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Lúpus Eritematoso Sistêmico/sangue , Adulto , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Peptídeos/imunologia , Proteínas da Matriz Viral/imunologia
16.
East Mediterr Health J ; 23(12): 821-829, 2018 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-29528092

RESUMO

In Bahrain, adequate epidemiological information is lacking concerning the rate of EBV infection, which could be helpful in order to develop measures to protect against EBV infections. The aim of this study, was to investigate the trend of EBV infection in Bahrain over a 15-year period, 2001-2015. The EBV serological results of 10 560 patients with possible EBV infection were evaluated. Samples taken at the Salmaniya Medical Complex during 2001-2015 were included. The presence or absence of EBV viral capsid antigen (VCA) IgG, VCA IgM and EBV nuclear antigen (EBNA) IgG antibodies was recorded. Of the 10 560 samples, 10 333 were usable; of these, 86.1% were seropositive with an increasing trend of EBV infection over the study period. Primary EBV infection was found in 7.4% of the seropositive samples; of these, 47.3% were between 5 and 19 years. EBV reactivation was found in 11% of the seropositive samples; of these, 50% were > 25 years of age. The youngest seropositive patient was 11 months old. EBV is a common viral infection in Bahrain. Most primary infections occur between 1 and 5 years while most reactivation infections occur after the age of 25 years. Serial surveillance of EBV infection is needed in Bahrain. Measures to protect against EBV infections should be implemented.


Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/imunologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Barein , Proteínas do Capsídeo/imunologia , Criança , Pré-Escolar , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estudos Soroepidemiológicos , Adulto Jovem
17.
Neurol Sci ; 39(2): 297-304, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29127522

RESUMO

Despite extensive studies focusing on the changes in expression of microRNAs (miRNAs) in multiple sclerosis (MS) compared to healthy controls, few studies have evaluated the association of genetic variants of miRNAs with MS clinical course. We investigated whether a functional polymorphism in the MS associated miR-146a gene predicted clinical course (hazard of conversion to MS and of relapse, and annualized change in disability), using a longitudinal cohort study of persons with a first demyelinating event followed up to their 5-year review. We found the genotype (GC+CC) of rs2910164 predicted relapse compared with the GG genotype (HR=2.09 (95% CI 1.42, 3.06), p=0.0001), as well as a near-significant (p=0.07) association with MS conversion risk. Moreover, we found a significant additive interaction between rs2910164 and baseline anti-EBNA-1 IgG titers predicting risk of conversion to MS (relative excess risk due to interaction [RERI] 2.39, p=0.00002) and of relapse (RERI 1.20, p=0.006). Supporting these results, similar results were seen for the other EBV-correlated variables: anti-EBNA-2 IgG titers and past history of infectious mononucleosis. There was no association of rs2910164 genotype for disability progression. Our findings provide evidence for miR-146a and EBV infection in modulating MS clinical course.


Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idade de Início , Anticorpos/sangue , Avaliação da Deficiência , Progressão da Doença , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Recidiva , Índice de Gravidade de Doença
18.
PLoS Pathog ; 13(12): e1006772, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29261800

RESUMO

Epstein-Barr virus (EBV) and related lymphocryptoviruses (LCV) from non-human primates infect B cells, transform their growth to facilitate life-long viral persistence in the host, and contribute to B cell oncogenesis. Co-evolution of LCV with their primate hosts has led to species-specificity so that LCVs preferentially immortalize B cells from their natural host in vitro. We investigated whether the master regulator of transcription, EBV nuclear antigen 2 (EBNA2), is involved in LCV species-specificity. Using recombinant EBVs, we show that EBNA2 orthologues of LCV isolated from chimpanzees, baboons, cynomolgus or rhesus macaques cannot replace EBV EBNA2 for the immortalization of human B cells. Thus, LCV species-specificity is functionally linked to viral proteins expressed during latent, growth-transforming infection. In addition, we identified three independent domains within EBNA2 that act through species-specific mechanisms. Importantly, the EBNA2 orthologues and species-specific EBNA2 domains separate unique roles for EBNA2 in the initiation of B cell immortalization from those responsible for maintaining the immortalized state. Investigating LCV species-specificity provides a novel approach to identify critical steps underlying EBV-induced B cell growth transformation, persistent infection, and oncogenesis.


Assuntos
Linfócitos B/virologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Proteínas Virais/imunologia , Animais , Transformação Celular Viral/genética , Transformação Celular Viral/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Especificidade de Hospedeiro/genética , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Lymphocryptovirus/genética , Lymphocryptovirus/imunologia , Lymphocryptovirus/patogenicidade , Macaca fascicularis , Macaca mulatta , Pan troglodytes , Papio , Vírus Reordenados/genética , Vírus Reordenados/imunologia , Vírus Reordenados/patogenicidade , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Ativação Transcricional , Proteínas Virais/genética
19.
JCI Insight ; 2(19)2017 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-28978808

RESUMO

Subsets of mature B cell neoplasms are linked to infection with intracellular pathogens such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), or Helicobacter pylori. However, the association between infection and the immunoglobulin-secreting (Ig-secreting) B proliferative disorders remains largely unresolved. We investigated whether the monoclonal IgG (mc IgG) produced by patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) targets infectious pathogens. Antigen specificity of purified mc IgG from a large patient cohort (n = 244) was determined using a multiplex infectious-antigen array (MIAA), which screens for reactivity to purified antigens or lysates from 9 pathogens. Purified mc IgG from 23.4% of patients (57 of 244) specifically recognized 1 pathogen in the MIAA. EBV was the most frequent target (15.6%), with 36 of 38 mc IgGs recognizing EBV nuclear antigen-1 (EBNA-1). MM patients with EBNA-1-specific mc IgG (14.0%) showed substantially greater bone marrow plasma cell infiltration and higher ß2-microglobulin and inflammation/infection-linked cytokine levels compared with other smoldering myeloma/MM patients. Five other pathogens were the targets of mc IgG: herpes virus simplex-1 (2.9%), varicella zoster virus (1.6%), cytomegalovirus (0.8%), hepatitis C virus (1.2%), and H. pylori (1.2%). We conclude that a dysregulated immune response to infection may underlie disease onset and/or progression of MGUS and MM for subsets of patients.


Assuntos
Anticorpos Antivirais/sangue , Imunoglobulina G/sangue , Gamopatia Monoclonal de Significância Indeterminada/imunologia , Mieloma Múltiplo/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Epitopos/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Infecções por Helicobacter/complicações , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Herpes Simples/complicações , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/microbiologia , Mieloma Múltiplo/microbiologia , Viroses/complicações , Viroses/imunologia , Adulto Jovem
20.
Pan Afr Med J ; 27: 29, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28761605

RESUMO

Henoch-Schönlein purpura (HSP) is the most common form of childhood vasculitis. Various viral and bacterial infections, drugs, vaccines, food allergy and even insect bites have been considered as triggering factors in pathogenesis of HSP. Epstein-Barr virus (EBV) infection, which is associated with HSP, have been rarely reported. Herein we present HSP patient possibly caused by EBV infection. A 8-year old boy was admitted to our department with fever, rashes on legs and arms and intermittent mild abdominal pain. Multiple purpuric rashes were on his extremities, abdomen and buttock. Laboratory investigations revealed that monospot test was positive, EBV serology tests; Anti-EA-D Ig G: 3+, Anti-VCA gp125 Ig G: 3+, Anti-VCA p19 Ig M: 2+, Anti EBNA-1 Ig M: negative, Anti EBNA-1 Ig M: negative, Anti EBNA-1 Ig G: negative. The patient was interpreted as the primary active acute EBV infection. A skin biopsy showed leucocytoclastic vasculitis. The other viral and bacterial investigations were negative. The patient was diagnosed as HSP vasculitis according to EULAR criteria and treated with intravenous hydration and ibuprofen. He was discharged after 15 days with normal laboratory findings and physical examination. We think that EBV infection may be stimulant factor for autoimmune reactions and may cause HSP vasculitis. Hence, it may be useful to investigate the EBV infection in etiology of HSP cases.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Púrpura de Schoenlein-Henoch/diagnóstico , Vasculite Leucocitoclástica Cutânea/diagnóstico , Dor Abdominal/etiologia , Biópsia , Criança , Infecções por Vírus Epstein-Barr/diagnóstico , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Humanos , Masculino , Púrpura de Schoenlein-Henoch/virologia
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