Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma.

Epstein-Barr virus (EBV) is classified as a member in the order herpesvirales, family herpesviridae, subfamily gammaherpesvirinae and the genus lymphocytovirus. The virus is an exclusively human pathogen and thus also termed as human herpesvirus 4 (HHV4). It was the first oncogenic virus recognized and has been incriminated in the causation of tumors of both lymphatic and epithelial nature. It was reported in some previous studies that 95% of the population worldwide are serologically positive to the virus. Clinically, EBV primary infection is almost silent, persisting as a life-long asymptomatic latent infection in B cells although it may be responsible for a transient clinical syndrome called infectious mononucleosis. Following reactivation of the virus from latency due to immunocompromised status, EBV was found to be associated with several tumors. EBV linked to oncogenesis as detected in lymphoid tumors such as Burkitt's lymphoma (BL), Hodgkin's disease (HD), post-transplant lymphoproliferative disorders (PTLD) and T-cell lymphomas (e.g. Peripheral T-cell lymphomas; PTCL and Anaplastic large cell lymphomas; ALCL). It is also linked to epithelial tumors such as nasopharyngeal carcinoma (NPC), gastric carcinomas and oral hairy leukoplakia (OHL). In vitro, EBV many studies have demonstrated its ability to transform B cells into lymphoblastoid cell lines (LCLs). Despite these malignancies showing different clinical and epidemiological patterns when studied, genetic studies have suggested that these EBV- associated transformations were characterized generally by low level of virus gene expression with only the latent virus proteins (LVPs) upregulated in both tumors and LCLs. In this review, we summarize some clinical and epidemiological features of EBV- associated tumors. We also discuss how EBV latent genes may lead to oncogenesis in the different clinical malignancies.

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Epstein- Barr Virus: Clinical and Epidemiological Revisits and Genetic Basis of Oncogenesis

Background: Nasopharyngeal carcinoma (NPC) is frequently associated with Epstein-Barr virus (EBV). The incidence of NPC in Western countries is lower than in the Far East, and EBV latency in NPC is less prevalent. Israel, as a part of the Mediterranean area, is one of the countries with an intermediate risk for NPC. Methods: Immunohistochemistry (IHC) for latent membrane protein 1 (LMP-1) and in situ hybridisation (ISH) for EBV encoded RNA (EBER) were used to evaluate the prevalence and possible prognostic value of EBV latency among Israeli patients with NPC. Forty five patients with different NPC histologies were studied. Results: LMP-1 IHC was positive in six samples only, all with undifferentiated histology. EBER ISH was positive in 40 of the 45 samples. According to histological type, three of five patients with squamous cell carcinoma were EBV positive and 37 of 40 non-keratinising and undifferentiated carcinoma cases were positive. Although EBV was more prevalent in patients with non-squamous carcinoma, the difference was not significant, probably because of the small number of patients with keratinising carcinoma. With regard to the clinical categories and survival, no significant difference could be detected between patients who were positive or negative for EBER ISH. No association was found between EBV latency and patient sex, age, origin, stage, or survival. Conclusions: NPC in Israel is highly associated with EBV latency as detected by EBER ISH. LMP-1 IHC is considerably less sensitive in detecting EBV latency in NPC among the same patient group.

https://jcp.bmj.com/content/jclinpath/57/3/290.full.pdf

Prevalence and relevance of EBV latency in nasopharyngeal carcinoma in Israel.

Early diagnosis of allograft rejection helps to improve the immune-related management of transplant recipients. The clinically-used core needle biopsy method is invasive and subject to sampling error. In vivo fluorescence imaging for monitoring immune-related processes has the advantages of non-invasiveness, fast feedback and high sensitivity. Herein, we report a responsive second near-infrared (NIR-II) fluorescent nanosensor (ErGZ) to detect early allograft rejection. ErGZ allows ratiometric in vivo fluorescence sensing of granzyme B, which is overexpressed in recipients' T cells during the onset of rejection. The sensor demonstrates efficacious detection of allograft rejection with high sensitivity and specificity, which accomplishes non-invasive diagnosis of rejection in skin and deep buried islets transplant mice models 2 d and 5 d earlier than biopsy, by in vivo fluorescence imaging and urinary detection, respectively, providing a valuable approach for therapeutical management.

Noninvasive Early Diagnosing of Allograft Rejection by a Granzyme B Protease Responsive NIR-II Bioimaging Nanosensor.

BACKGROUND The management of small bowel transplantation is unique because signs of rejection can be obtained visually by endoscopy. The aim of this study was to evaluate the accuracy of endoscopic appearance in assessing histologic evidence of acute cellular rejection (ACR). METHODS Endoscopies were performed in 66 asymptomatic "surveillance" small bowel transplant recipients and 71 symptomatic recipients from a single center. For surveillance patients, 125 ileoscopies were performed to collect 590 biopsies, and for the symptomatic group, 229 ileoscopies and jejunoscopies were conducted to obtain 434 biopsies. RESULTS The sensitivity and specificity of endoscopic visualization in detecting ACR was 50% and 91.5% for the surveillance group and 43% and 67% for the symptomatic patients. In surveillance, visual impression alone would have missed three cases of moderate and no cases of severe ACR, whereas in the symptomatic group, visual inspection alone would have missed 20 cases of moderate ACR, and findings from visual inspection of the chimney were normal in 55% of cases with proximal ACR. However, chimney biopsy was generally representative of biopsy findings in the proximal graft but would have missed moderate to severe rejection in three patients (1%). In a subset of 23 endoscopies, zoom endoscopy did not improve visual discrimination. The only complication was a biopsy-related non-life-threatening bleed. CONCLUSIONS In symptomatic patients, visual inspection detected all cases of severe rejection but would have missed patients with early readily treatable rejection and thus making biopsy mandatory in clinical practice. Our results support the current practice of ileoscopic biopsy alone for graft surveillance in asymptomatic patients.

Endoscopic evaluation of small intestine transplant grafts.

In human heart and kidney transplantations, granzyme B (GrB) and perforin have both been shown to be predictive markers for acute cellular rejection (ACR). We investigated the tissue expression and possible relationship of GrB and perforin to the clinical outcome, histopathology, and function of intestinal transplants. In 13 consecutive patients undergoing small intestine transplantation, histologic/immunohistochemical rejection monitoring was performed together with GrB and perforin immunostaining (score “0”, 0%–10% positive lymphocytes; “1”, 10%–25%; “2”, 25%–50%; “3”, >50%). Eleven patients are currently alive and well. All 11 had at least one episode of ACR: one patient had 6 episodes of severe ACR requiring retransplantation; the remaining 10 experienced only mild or moderate rejection. Both GrB and perforin were always co-expressed. A highly significant correlation was observed between GrB/perforin scores and histological severity of ACR (Pearson's coefficient, R < 0.0009). Interestingly, score 3 GrB/perforin immunostaining was recorded only in the context of severe ACR; all the histologically negative or “indeterminate” biopsies (n = 6) taken from a single affected patient showed GrB/perforin scores of 1 or 2. By contrast, none of the other tested histologically negative/“indeterminate” biopsies (n = 350), including those performed during graft stabilization, had raised GrB or perforin scores. We conclude that in intestinal transplantation recipients, a direct correlation seems to exist between histologically confirmed ACR and raised GrB/perforin immunohistochemical scores. Our findings suggest the need to investigate the possibility of predicting ACR by routine serum polymerase chain reaction (PCR) monitoring, which would reduce discomfort to patients.

Granzyme B and perforin as predictive markers for acute rejection in human intestinal transplantation.

Nasopharingeal carcinoma (NPC) is frequently associated with Epstein-Barr virus (EBV), but little is known about its pathogenesis in Western countries, where its incidence is low and EBV is not endemic. We studied 26 Italian cases of NPC: 24 of the non-keratinizing subtype, and 2 keratinizing. We used immunohistochemistry to evaluate p53, bcl-2 and Ki-67 protein expression, and in situ hybridization (ISH) to assess bcl-2 mRNA and the EBV transcript, EBER1, with bcl-2 protein and mRNA expression being compared in serial sections. As regards bcl-2, the protein or mRNA was expressed in 15/26 (58%) and 17 (65%) cases respectively, with co-expression being found only in 9 (35%) cases; 23 (88%) cases were positive for one or the other. EBER1 was detected in 17/26 (65%) cases, of which 80% and 71% coexpressed bcl-2 protein or mRNA, respectively. Only 9/26 (35%) cases had a high Ki67 proliferative index; 3/26 (12%) overexpressed p53. This study of NPC in Italy confirms the importance of EBV and bcl-2 in Western cases. The discrepancy between bcl-2 mRNA and protein expression invites investigation into a possible internal bcl-2 regulation system.

Expression of Epstein-Barr virus-encoded RNA and biological markers in Italian nasopharingeal carcinomas.

Estrogen (ER) and progesterone (PgR) receptors are commonly represented on normal and neoplastic thyroid tissues, while a few data are available about their expression in Hurthle cells tumors. Seventeen patients who underwent thyroidectomy for a neoplasia that showed oxyphilic elements were studied by an immunohistochemical method and the presence of PgR in the 30% of them, was demonstrated, while no ER expression could be found. We tried, therefore, to establish a correlation between these proteins and age, sex or indexes of the supposed estro-progestinic concentration of our patients. None of these factors resulted significantly related to the receptors expression. Since PgR are expressed in the oxyphilic cells neoplasms, further studies on both ER, and PgR are needed in order to point out their possible biological importance.

An immunohistochemical study of progesterone receptor in thyroidal Hürthle cells tumors.

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Granzyme B and perforin as predictive markers for acute rejection in human intestinal transplantation.

Expression of Epstein-Barr virus-encoded RNA and biological markers in Italian nasopharingeal carcinomas.

An immunohistochemical study of progesterone receptor in thyroidal Hürthle cells tumors.