Egregio Dottor Moschini, sono sempre stato bene, fino a due anni fa, una lieve ipertensione arteriosa, saltuariamente, ogni 30 giorni circa mi viene una febbre che dura poco tempo, passa, ritorna dopo diversi giorni.
Ho eseguito gli esami che le metto in PDF.
La visita di consulenza infettivologica mi ha consigliato di effettuare una tipizzazione linfocitaria che ha dimostrato: “da cui poi nella tipizzazione linfocitaria è risultata la presenza di “popolazione linfocitaria B con fenotipo CD19+ CD20+ CD5+ FMC7- CD9- CD38- CD23+ CD200+ Monoclonalità K Fenotipo suggestivo di B-LLC/K.”.
Vorrei un suo consiglio sulla causa di questa febbre e del risultato della tipizzazione.
VES 29, alta, GammaGT 107 molto alte, il virus di Epstein Barr come è evidente, è presente nel fegato, insieme possibilmente al Cytomegalovirus, esame non eseguito, Epstein Barr VCA IgG 82,00 anche se Epstein Barr EBNA 12,30, il virus è presente ed è il responsabile della febbre che lei presenta saltuariamente da due anni, ma ha anche determinato "popolazione linfocitaria B con fenotipo CD19+ CD20+ CD5+ FMC7- CD9- CD38- CD23+ CD200+ Monoclonalità K Fenotipo suggestivo di B-LLC/K."
Il virus deve sempre essere sempre individuato, soprattutto quando sono presenti sintomi di processi infiammatori.
Ho la possibilità di accertare la sua presenza, stabilire la diagnosi esatta, procedere alla strategia terapeutica.
Nel caso in cui due anni fa le avessero individuato esattamente la presenza del virus di Epstein Barr, responsabile della febbre, stabilita la terapia, il virus sarebbe stato eliminato con la certezza della sua effettiva uscita dall'organismo, dalle cellule e lei non avrebbe presentato i sintomi sospetti della leucemia cronica, come rilevato dalla tipizzazione linfocitaria. Ho a disposizione molti farmaci che hanno influenza sul virus di Epstein Barr e la certezza della sua effettiva uscita dall'organismo e dalle cellule. Attualmente è possibile procedere alla eliminazione del virus di Epstein barr, evitare il procedere dei sintomi e della eventuale patologia.
La risposta dell'ematologo,
Esempio della presenza del Virus di Epstein Barr, anche se IgM negative, il virus rimane attivo e persistente, continua a provocare processi infiammatori che possono condurre alla B-LLC/K leucemia cronica.
Bibliografia dimostra la associazione fra Epstein Barr e Leucemia
EBioMedicine. 2015 Apr 29;2(6):572-82. doi: 10.1016/j.ebiom.2015.04.018. eCollection 2015.
Epstein-Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival.
Ferrajoli A1,
Ivan C2,
Ciccone M3,
Shimizu M4,
Kita Y4,
Ohtsuka M4,
D'Abundo L5,
Qiang J6,
Lerner S1,
Nouraee N4,
Rabe KG7,
Rassenti LZ8,
Van Roosbroeck K4,
Manning JT9,
Yuan Y10,
Zhang X2,
Shanafelt TD11,
Wierda WG1,
Sabbioni S12,
Tarrand JJ13,
Estrov Z1,
Radovich M14,
Liang H15,
Negrini M12,
Kipps TJ8,
Kay NE11,
Keating M1,
Calin GA16.
Abstract
Although numerous studies highlighted the role of Epstein-Barr Virus (EBV) in B-cell transformation, the involvement of EBV proteins or genome in the development of the most frequent adult leukemia, chronic lymphocytic leukemia (CLL), has not yet been defined. We hypothesized that EBV microRNAs contribute to progression of CLL and demonstrated the presence of EBV miRNAs in B-cells, in paraffin-embedded bone marrow biopsies and in the plasma of patients with CLL by using three different methods (small RNA-sequencing, quantitative reverse transcription PCR [q-RT-PCR] and miRNAs in situ hybridization [miRNA-ISH]). We found that EBV miRNA BHRF1-1 expression levels were significantly higher in the plasma of patients with CLL compared with healthy individuals (p < 0 · 0001). Notably, BHRF1-1 as well as BART4 expression were detected in the plasma of either seronegative or seropositive (anti-EBNA-1 IgG and EBV DNA tested) patients; similarly, miRNA-ISH stained positive in bone marrow specimens while LMP1 and EBER immunohistochemistry failed to detect viral proteins and RNA. We also found that BHRF1-1 plasma expression levels were positively associated with elevated beta-2-microglobulin levels and advanced Rai stages and observed a correlation between higher BHRF1-1 expression levels and shorter survival in two independent patients' cohorts. Furthermore, in the majority of CLL cases where BHRF1-1 was exogenously induced in primary malignant B cells the levels of TP53 were reduced. Our findings suggest that EBV may have a role in the process of disease progression in CLL and that miRNA RT-PCR and miRNAs ISH could represent additional methods to detect EBV miRNAs in patients with CLL.
KEYWORDS:
BHRF1-1; Chronic lymphocytic leukemia; Epstein–Barr Virus; Overall survival; miRNAs
The mir-BHRF1-1 microRNA precursor found in Human herpesvirus 4 (Epstein-Barr virus) and Cercopithicine herpesvirus 15. In Epstein-Barr virus, mir-BHRF1-1 is found in the 5' UTR of the BHRF1 (Bam HI fragment H rightward open reading frame 1) gene, which is known to encode a distant Bcl-2 homolog. The mature sequence is excised from the 5' arm of the hairpin.[1] Two other miRNA precursors were found in this reading frame, namely Mir-BHRF1-2 and Mir-BHRF1-3.[1]
BHRF-1-1 miRNA is thought to operate as part of a 'miRNA cluster' with two other microRNAs also found in the Epstein-Barr virus genome.[2]BHRF-1-1 has been shown to be expressed in latency-III infected lymphoblasts.[3]
Blood. 1995 Sep 1;86(5):1893-902.
BHRF1, the Epstein-Barr virus (EBV) homologue of the BCL-2 protooncogene, is transcribed in EBV-associated B-cell lymphomas and in reactive lymphocytes.
Abstract
BHRF1, one of many Epstein-Barr virus (EBV)-encoded proteins, shows strong functional homology to the human bcl-2 proto-oncogene product, a protein involved in the pathogenesis of a subset of B-cell lymphomas, ie, follicle center cell lymphomas (FCCL). We have investigated the presence of possible latent and lytic transcripts of BHRF1 using a reverse transcriptase-polymerase chain reaction (RT-PCR)-based assay in a group of EBV-associated B-cell lymphomas in patients with (N = 5) or without overt immunodeficiency (N = 4), in T-cell lymphomas (N = 9), and in cases of Hodgkin's disease (N = 6). BHRF1 transcription was found consistently in EBV-associated (ie, diffuse EBER 1/2-positive) B-cell lymphomas in patients with or without immune deficiency, whereas in EBV-associated T-cell lymphomas or in EBV-associated Hodgkin's disease, BHRF1 transcription was only detected in two T-cell lymphomas and one case of Hodgkin's disease, which also harbored EBER 1/2-positive reactive cells. Moreover, weak BHRF1 signals were found in two T-cell lymphomas where EBER 1/2 expression was detected mainly in sporadic reactive lymphocytes and in one reactive tonsil with sporadic EBER 1/2-positive lymphocytes. BHRF1 transcripts were found to be generated by the C or W promoter (associated with viral latency) and/or by the H promoter (associated with the virus lytic cycle). In all cases with H promoter-derived BHRF1 transcripts, transcripts encoding ZEBRA were also detected, suggesting a reactivation of the virus lytic cycle. Analysis of other EBV genes revealed transcription of BARFO in all tested EBV-harboring tissues. Transcription of EBNA1 and LMP1 was usually detected, whereas EBNA2 transcription was found exclusively in B-cell lymphomas in immunocompromised patients. These data demonstrate that BHRF1 transcripts are exclusively found in EBV-associated B-cell lymphomas. When BHRF1 transcripts are detected in T-cell lymphomas or in Hodgkin's disease, it is probably due to the presence of reactive EBER 1/2-positive lymphocytes. The consistent transcription of BHRF1 in EBV-associated B-celllymphomas suggests a possible pathogenic role for this gene product in EBV-positive B-cell lymphomas analogous to bcl-2.
EBV encoded miR-BHRF1-1 potentiates viral lytic replication by downregulating host p53 in nasopharyngeal carcinoma.
Li Z1,
Chen X,
Li L,
Liu S,
Yang L,
Ma X,
Tang M,
Bode AM,
Dong Z,
Sun L,
Cao Y.
Abstract
miRNAs (microRNAs) are a class of non-coding small RNAs. The Epstein-Barr-virus (EBV) encoded miR-BHRF1-1 is barely expressed in most nasopharyngeal carcinoma (NPC) cells with EBV latent infection. Here, we used a strategy of overexpression and inhibition of miR-BHRF1-1 and showed that miR-BHRF1-1 is involved in TPA-induced accumulation of EBV lytic proteins and viral copies in late lytic cycle. The data further suggested that the miR-BHRF1-1-potentiated induction of EBV lytic replication was accompanied by inhibiting p53 expression. Our results demonstrated that the EBV original pathogen miR-BHRF1-1 is involved in the control of EBV late lytic replication by directly targeting the host p53 gene.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Human leukocyte antigens and genetic susceptibility to lymphoma.
Abstract
Familial aggregation, coupled with ethnic variation in incidence, suggests that inherited susceptibility plays a role in the development of lymphoma, and the search for genetic risk factors has highlighted the contribution of the human leukocyte antigen (HLA) complex. In a landmark study published almost 50 years ago, Hodgkin lymphoma (HL) was the first disease to be associated with HLA variation. It is now clear that Epstein-Barrvirus (EBV)-positive and -negative HL are strongly associated with specific HLA polymorphisms but these differ by EBV status of the tumours. HLA class I alleles are consistently associated with EBV-positive HL while a polymorphism in HLA class II is the strongest predictor of risk of EBV-negative HL. Recent investigations, particularly genome-wide association studies (GWAS), have also revealed associations between HLA and common types of non-Hodgkin lymphoma (NHL). Follicular lymphoma is strongly associated with two distinct haplotypes in HLA class II whereas diffuse large B-cell lymphoma is most strongly associated with HLA-B*08. Although chronic lymphocytic leukaemia is associated with variation in HLA class II, the strongest signals in GWAS are from non-HLA polymorphisms, suggesting that inherited susceptibility is explained by co-inheritance of multiple low risk variants. Associations between B-cell derived lymphoma and HLA variation suggest that antigen presentation, or lack of, plays an important role in disease pathogenesis but the precise mechanisms have yet to be elucidated.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
KEYWORDS:
B-cell lymphoma; Epstein-Barr virus; Hodgkin lymphoma; human leukocyte antigen
EBV encoded miR-BHRF1-1 potentiates viral lytic replication by downregulating host p53 in nasopharyngeal carcinoma.
Li Z1,
Chen X,
Li L,
Liu S,
Yang L,
Ma X,
Tang M,
Bode AM,
Dong Z,
Sun L,
Cao Y.
Oncotarget. 2016 Jan 12;7(2):2135-42. doi: 10.18632/oncotarget.6281.
Prognostic impact of Epstein-Barr virus (EBV)-DNA copy number at diagnosis in chronic lymphocytic leukemia.
Liang JH1,
Gao R2,
Xia Y1,
Gale RP3,
Chen RZ1,
Yang YQ1,
Wang L1,
Qu XY1,
Qiu HR1,
Cao L1,
Hong M1,
Wang R1,
Wang Y1,
Fan L1,
Chen YY1,
Hu ZB4,
Li JY1,5,
Xu W1.
Abstract
Epstein-Barr virus (EBV)-DNA is detected in the blood of some persons with chronic lymphocytic leukemia (CLL) at diagnosis. Whether this is important in the development or progression of CLL is controversial. We interrogated associations between blood EBV-DNA copy number and biological and clinical variables in 243 new-diagnosed consecutive subjects with CLL. Quantification of EBV-DNA copies was done by real-time quantitative PCR (RQ-PCR). All subjects had serological evidence of prior EBV-infection. However, only 24 subjects (10%) had a EBV-DNA-positive test at diagnosis. EBV-DNA-positive subjects at diagnosis had lower hemoglobin concentrations and platelet levels, higher thymidine kinase-1 and serum ferritin levels, un-mutated IGHV genes and a greater risk of Richter transformation compared with EBV-DNA-negative subjects. Percent CD20-, CD148- and ZAP70-positive cells and mean fluorescence intensity (MFI) of each cluster designation were also increased in EBV-DNA-positive subjects at diagnosis. EBV-DNA test positivity was associated with a briefer time-to-treatment interval (HR 1.85; [95% confidence interval, 1.13, 3.03]; P=0.014) and worse survival (HR 2.77; [1.18, 6.49]; P=0.019). Reduction in EBV copies was significantly associated with therapy-response. A positive blood EBV-DNA test at diagnosis and sequential testing of EBV copies during therapy were significantly associated with biological and clinical variables, time-to-treatment, therapy-response and survival. If validated these data may be added to CLL prognostic scoring systems.
KEYWORDS:
Epstein-Barr virus; chronic lymphocytic leukemia; prognosis
PLoS One. 2015 Oct 13;10(10):e0140178. doi: 10.1371/journal.pone.0140178. eCollection 2015.
High Viral Loads of Epstein-Barr Virus DNA in Peripheral Blood of Patients with Chronic Lymphocytic Leukemia Associated with Unfavorable Prognosis.
Grywalska E1,
Roliński J1,
Pasiarski M2,
Korona-Glowniak I3,
Maj M4,
Surdacka A1,
Grafka A1,
Stelmach-Gołdyś A2,
Zgurski M4,
Góźdź S5,
Malm A3,
Grabarczyk P6,
Starosławska E7.
Abstract
Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus that infects more than 90% of the world population. The potential involvement of EBV in the clinical course of chronic lymphocytic leukemia (CLL) remains unexplained. The aim of this study was to determine whether EBV-DNA load in the peripheral blood mononuclear cells (PBMCs) of CLL patients may influence heterogeneity in the course of the disease. The study included peripheral blood samples from 115 previously untreated patients with CLL (54 women and 61 men) and 40 healthy controls (16 women and 24 men). We analyzed the association between the EBV-DNA load in PBMCs and the stage of the disease, adverse prognostic factors, and clinical outcome. Detectable numbers of EBV-DNA copies in PBMCs were found in 62 out of 115 CLL patients (53.91%). The EBV-DNA copy number/μg DNA was significantly higher in patients who required early implementation of treatment, presented with lymphocyte count doubling time <12 months, displayed CD38-positive or ZAP-70-positive phenotype, and with the del(11q22.3) cytogenetic abnormality. Furthermore, the EBV-DNA copy number/μg DNA showed significant positive correlation with the concentrations of lactate dehydrogenase (LDH) and beta-2-microglobulin. We have shown that in CLL patients, higher EBV-DNA copy number predicted shorter survival and shorter time to disease progression, and it was associated with other established unfavorable prognostic factors. This suggests that EBV may negatively affect the outcome of CLL.
Aberrant Epstein-Barr virus antibody patterns and chronic lymphocytic leukemia in a Spanish multicentric case-control study.
Casabonne D1,
Benavente Y1,
Robles C2,
Costas L1,
Alonso E3,
Gonzalez-Barca E4,
Tardón A5,
Dierssen-Sotos T6,
Vázquez EG7,
Aymerich M8,
Campo E8,
Castaño-Vinyals G9,
Aragones N10,
Pollan M10,
Kogevinas M11,
Juwana H12,
Middeldorp J12,
de Sanjose S1.
Abstract
BACKGROUND:
Epstein-Barr virus (EBV)-related malignancies harbour distinct serological responses to EBV antigens. We hypothesized that EBV serological patterns can be useful to identify different stages of chronic lymphocytic leukemia.
METHODS:
Information on 150 cases with chronic lymphocytic leukemia and 157 frequency-matched (by age, sex and region) population-based controls from a Spanish multicentre case-control study was obtained. EBV immunoglobulin G serostatus was evaluated through a peptide-based ELISA and further by immunoblot analysis to EBV early antigens (EA), nuclear antigen (EBNA1), VCA-p18, VCA-p40 and Zebra. Two independent individuals categorized the serological patterns of the western blot analysis. Patients with very high response and diversity in EBV-specific polypeptides, in particular with clear responses to EA-associated proteins, were categorized as having an abnormal reactive pattern (ab_EBV). Adjusted odds ratios (OR) and 95% confidence interval (CI) were estimated using logistic regression models.
RESULTS:
Almost all subjects were EBV-IgG positive (>95% of cases and controls) whereas ab_EBV patterns were detected in 23% of cases (N = 34) and 11% of controls (N = 17; OR: 2.44, 95% CI, 1.29 to 4.62; P = 0.006), particularly in intermediate/high risk patients. Although based on small numbers, the association was modified by smoking with a gradual reduction of ab_EBV-related OR for all Rai stages from never smokers to current smokers.
CONCLUSIONS:
Highly distinct EBV antibody diversity patterns revealed by immunoblot analysis were detected in cases compared to controls, detectable at very early stages of the disease and particularly among non smokers. This study provides further evidence of an abnormal immunological response against EBV in patients with chronic lymphocytic leukemia.
KEYWORDS:
Case-control; Chronic lymphocytic leukemia; Epstein-Barr virus; Serology; Smoking
Exp Hematol Oncol. 2016 Mar 1;5:7. doi: 10.1186/s40164-016-0036-3. eCollection 2015.
New CD20 alternative splice variants: molecular identification and differential expression within hematological B cell malignancies.
Gamonet C1, Bole-Richard E1, Delherme A1, Aubin F2, Toussirot E3, Garnache-Ottou F4, Godet Y4, Ysebaert L5, Tournilhac O6, Caroline D7, Larosa F8, Deconinck E9, Saas P4, Borg C4, Deschamps M1, Ferrand C10.
Abstract
BACKGROUND:
CD20 is a B cell lineage-specific marker expressed by normal and leukemic B cells and targeted by several antibody immunotherapies. We have previously shown that the protein from a CD20 mRNA splice variant (D393-CD20) is expressed at various levels in leukemic B cells or lymphoma B cells but not in resting, sorted B cells from the peripheral blood of healthy donors.
RESULTS:
Western blot (WB) analysis of B malignancy primary samples showed additional CD20 signals. Deep molecular PCR analysis revealed four new sequences corresponding to in-frame CD20 splice variants (D657-CD20, D618-CD20, D480-CD20, and D177-CD20) matching the length of WB signals. We demonstrated that the cell spliceosome machinery can process ex vivo D480-, D657-, and D618-CD20 transcript variants by involving canonical sites associated with cryptic splice sites. Results of specific and quantitative RT-PCR assays showed that these CD20 splice variants are differentially expressed in B malignancies. Moreover, Epstein-Barr virus (EBV) transformation modified the CD20 splicing profile and mainly increased the D393-CD20 variant transcripts. Finally, investigation of three cohorts of chronic lymphocytic leukemia (CLL) patients showed that the total CD20 splice variant expression was higher in a stage B and C sample collection compared to routinely collected CLL samples or relapsed refractory stage A, B, or C CLL.
CONCLUSION:
The involvement of these newly discovered alternative CD20 transcript variants in EBV transformation makes them interesting molecular indicators, as does their association with oncogenesis rather than non-oncogenic B cell diseases, differential expression in B cellmalignancies, and correlation with CLL stage and some predictive CLL markers. This potential should be investigated in further studies.
KEYWORDS:
Alternative splicing; B malignancies; CD20; CLL; EBV transformation
