Novel Mutation in the Moesin (MSN) Gene Leads to Immunodeficiency with Epstein-Barr Virus (EBV) Infection and Dermatomyositis-Like Symptoms.

PURPOSE: Moesin (MSN) deficiency is a recently reported combined immunodeficiency, and few cases have been reported to date. We describe a Chinese patient with a novel mutation causing MSN deficiency and a novel phenotype. METHODS: Clinical and immunological data were collected. Whole-exome sequencing was performed to identify gene mutations. MSN protein expression and T cell proliferation and activation were determined by flow cytometry. Cell migration was confirmed with a Transwell assay. Autoantibody levels were analyzed using antigen microarrays. RESULTS: The patient was a 10-year-old boy who presented with recurrent fever, oral ulcers and dermatomyositis-like symptoms, such as periorbital edema, facial swelling, elevated creatine kinase levels, and abnormal electromyography and muscle biopsy results. Epstein-Barr virus (EBV) DNA was detected in the serum, cells and tissues of this patient. He further developed nasal-type NK/T-cell lymphoma. A novel hemizygous mutation (c.68 A > G, p.N23S) in the MSN gene was found. The immunological phenotype of this patient included persistent decreases in T and B lymphocyte counts but normal immunoglobulin IgG levels. The patient had attenuated MSN protein expression and impaired T-cell proliferation and migration. The proportions of Tfh cells and CD21low B cells in the patient were higher than those in the controls. Moreover, 82 IgG and 102 IgM autoantibodies were more abundant in the patient than in the healthy controls. CONCLUSIONS: The novel mutation N23S is pathogenic and leads to a severe clinical phenotype. EBV infection, tumor, and dermatomyositis-like autoimmune symptoms may be associated with MSN deficiency, further expanding the understanding of the disease.

Prevention of post-transplant lymphoproliferative disorder in pediatric kidney transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a devastating complication of immunosuppressive treatment in both solid organ transplantations (SOT) and hematopoietic stem cell transplantations (HSCT). Epstein-Barr virus (EBV) infection precedes PTLD in 90% of patients. Rituximab, a monoclonal anti-CD20 antibody, depletes B-lymphocytes, which are the ultimate reservoir for EBV. Although rituximab therapy is commonly used as a preventive measure for PTLD in high-risk HSCT, it is not established in SOT. METHODS: Pediatric kidney transplant recipients (PKTR) underwent routine EBV-PCR surveillance. Patients with increasing viral loads, despite immunosuppressive dose reduction, were managed with preventive rituximab therapy. RESULTS: Between 2012 and 2023, we identified eight episodes of asymptomatic EBV-PCR-positive blood tests in seven out of 65 PKTR (11%) under our care. EBV DNAemia emerged 120-720 days post-transplantation. Five of seven patients with EBV DNAemia (71%) were EBV-seronegative prior to transplantation. All five patients did not respond to MMF dose reduction and were therefore treated with preventive rituximab therapy. Following this treatment, EBV PCR clearance was observed in all patients with only minimal complications. CONCLUSIONS: PKTR who are EBV-naïve prior to transplantation are expected to have a higher prevalence of EBV DNAemia. We found that PKTR who were EBV seronegative prior to transplantation were less likely to achieve EBV clearance in response to immunosuppression dose reduction. We suggest that rituximab therapy in PKTR may be safe and effective in EBV clearance and PTLD prevention.

Chronic active Epstein-Barr virus infection involving gastrointestinal tract with hemophagocytic lymphohistiocytosis.

Chronic active EBV infection (CAEBV) is a lymphoproliferative disorder of T- or NK-cell type in Asian countries. CAEBV involving the gastrointestinal tract (GI CAEBV) is a rare condition with poor prognosis that may rapidly progress with hemophagocytic lymphohistiocytosis (HLH) and life-threatening complications such as GI bleeding and/or perforation. The approach to CAEBV with GI tract involvement (GI CAEBV) is still an unmet clinical need. In this case series study, we summarized the clinical features, treatment, and prognosis of seven cases of GI CAEBV with HLH, particularly focusing on its prognosis and the possible salvage therapy combining surgery, novel therapeutic agents, and/or autologous(auto-) hematopoietic stem cell transplantation (HSCT) based on successful cases from our center. GI CAEBV is often misdiagnosed as inflammatory bowel diseases and certain infections. The key to its early recognition is the integrative consideration of its systemic manifestation, serum virology, endoscopic, and imaging findings along with pathology. Surgical intervention should not be hesitated when life-threatening GI complications occur. Resection of the involved bowel segment is an effective way of controlling bleeding and reducing tumor burden. In addition to upfront allogeneic HSCT, new therapeutic modalities including PD-1 antibody and auto-HSCT may be effective in certain patients.

Epstein-Barr Virus and Multiple Sclerosis: A Convoluted Interaction and the Opportunity to Unravel Predictive Biomarkers.

Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS and likely predates the first clinical symptoms. The molecular mechanisms of this association are complex and may involve different immunological routes, perhaps all running in parallel (i.e., molecular mimicry, the bystander damage theory, abnormal cytokine networks, and coinfection of EBV with retroviruses, among others). However, despite the large amount of evidence available on these topics, the ultimate role of EBV in the pathogenesis of MS is not fully understood. For instance, it is unclear why after EBV infection some individuals develop MS while others evolve to lymphoproliferative disorders or systemic autoimmune diseases. In this regard, recent studies suggest that the virus may exert epigenetic control over MS susceptibility genes by means of specific virulence factors. Such genetic manipulation has been described in virally-infected memory B cells from patients with MS and are thought to be the main source of autoreactive immune responses. Yet, the role of EBV infection in the natural history of MS and in the initiation of neurodegeneration is even less clear. In this narrative review, we will discuss the available evidence on these topics and the possibility of harnessing such immunological alterations to uncover predictive biomarkers for the onset of MS and perhaps facilitate prognostication of the clinical course.

[A viral splenic rupture]. / L'image du mois. Une rupture splénique d'origine virale.

A 28-year-old patient is admitted in the emergency department for management of localized pain in the left hypochondrium and left flank that appeared 48 hours before his visit to the emergency room. At the same time, the patient describes the presence of fever, odynophagia and myalgia present for 8 days. The clinical examination highlights the presence of multiple upper cervical and submandibular bilateral and soft adenopathies of about 1.5 cm. There is also an abdominal defense at the level of the left hypochondrium and the left flank. The exploration will attest the presence of a primary EBV infection associated with a splenic rupture complicated by hemoperitoneum without hemodynamic repercussions. This clinical case illustrates the presence of a rare and potentially fatal complication following a very common disease, infectious mononucleosis.

Un patient de 28 ans se présente au service des urgences pour prise en charge d'une douleur localisée au niveau de l'hypochondre gauche et du flanc gauche, apparue 48h avant son passage aux urgences. Parallèlement, le patient décrit la présence de fièvre, d'une odynophagie et de myalgies présentes depuis 8 jours. L'examen clinique met en évidence la présence de multiples adénopathies cervicales supérieures et sous-mandibulaires bilatérales et molles d'environ 1.5 cm. On note également une défense abdominale au niveau de l'hypochondre gauche et du flanc gauche. Le bilan attestera la présence d'une primo-infection à EBV associée à une rupture splénique compliquée d'un hémopéritoine sans répercussion hémodynamique. Ce cas clinique illustre la présence d'une complication rare et potentiellement mortelle au décours d'une infection très fréquente qu'est la mononucléose infectieuse.

EBV-ENCEPHALITIS IN CHILDREN: DIAGNOSTIC CRITERIA.

OBJECTIVE: The aim: To investigate the clinical characteristics of EBV infection in the pediatric nervous system using laboratory methods and brain MRI data. PATIENTS AND METHODS: Materials and methods: We observed 41 children with EBV encephalitis ranging from 8 months to 17 years old. The diagnosis of EBV-encephalitis was established on the basis of clinical and medical history, laboratory and instrumental (brain MRI) data. The main thing in the diagnosis was clinical symptoms, combining general infection, cerebral syndromes and focal neurological symptoms. The etiology of Epstein-Barr virus was determined using ELISA and PCR. RESULTS: Results: EBV-encephalitis can be as a manifestation of reactivation of persistent EBV infection (85%), much less often - acute primary EBV infection (15%). By nature, the duration of EBV encephalitis has distinguished two forms of its course: acute (63%) and chronioc (37%). The criteria of differential diagnosis of acute and chronic forms of EBV-encephalitis are proposed, which include the most common anamnesis data, clinical manifestations and changes in brain MRI. CONCLUSION: Conclusions: The proposed criteria specifically for acute and chronic forms of EBV-encephalitis can contribute to the timely and more accurate diagnosis of this disease in children.

The superiority of Epstein-Barr virus DNA in plasma over in peripheral blood mononuclear cells for monitoring EBV-positive NK-cell lymphoproliferative diseases.

Epstein-Barr virus (EBV), characterized as an omnipresent virus, has been found able to infect NK cells and leads to NK-cell type EBV-positive lymphoproliferative diseases (EBV-NK-LPDs). We retrospective analyzed 202 EBV-NK-LPDs (including 64 CAEBV-NK, 27 aggressive natural killer-cell leukemia (ANKL), and 111 extranodal NK/T-cell lymphoma (ENKTL)) patients' relationships between EBV DNA copies laboratory test results and clinical features. In CAEBV-NK cohort, EBV DNA loads in either plasma or PBMCs had significant differences between the active state and the inactive state. Receiver operating characteristic curves were used to measure the diagnosis accuracy of EBV DNA copies. After comparing the area under the curve, EBV DNA loads in plasma had significantly higher accuracy in distinguishing disease activation than in PBMCs. Therefore, we propose redefining CAEBV-NK diagnosis criteria as increased EBV DNA copies in plasma (over 7.1 × 102 copies/ml) instead of in peripheral blood. In ANKL and ENKTL cohorts, patients who received effective therapy had significantly lower EBV DNA copies in plasma & PBMCs than in those with ineffective therapy. The significant and consistent decline indicated EBV DNA loads in plasma being a more sensitive biomarker in monitoring EBV-NK-LPDs therapy responses. Hemophagocytic lymphohistiocytosis (HLH) can occur secondary to EBV-NK-LPDs, mostly associated with a poor prognosis, so we try to estimate the combination of HLH by monitoring EBV DNA copies. When comparing the Receiver operating characteristic curves of EBV DNA copies, EBV DNA loads in plasma had higher diagnosis accuracy. When the copies level over 4.16 × 103 copies/ml, it might indicate combining with HLH.

A Case of severe mosquito bite allergy complicated by fatal hemophagocytic lymphohistiocytosis.

Severe mosquito bite allergy (SMBA) is characterized by necrotic skin lesions and systemic symptoms. Chronic active Epstein-Barr virus (EBV) infection, when superimposed with SMBA, is a key driver for catastrophic clinical consequences, such as uncontrolled lymphoproliferation. This interplay is of clinical significance due to its association with hemophagocytic lymphohistiocytosis (HLH) and/or EBV-driven malignancies. Here, we report a case of SMBA that developed in a 14-year-old Hispanic boy that led to fatal secondary HLH.

Monitoring EBV infection, MSI, PDL-1 expression, Her-2/neu amplification as a biomarker for PD-1 inhibition in gastric cancer.

BACKGROUND: The anti-PD-1 monoclonal antibody pembrolizumab has been shown to be associated with a good response in patients with metastatic gastric cancer. Excellent therapeutic results of pembrolizumab have been shown in patients with tumours showing a high microsatellite instability (MSI) and Epstein-Barr virus (EBV) positivity. GOAL: This is a retrospective study of 40 bioptic specimens from the patients, who underwent gastrectomy for gastric carcinoma. The goal of the study was to identify biomarkers (EBV, MLH-1, PDL-1 expression) that are potentially relevant for selecting the patients, who may benefit from PD-1 inhibition therapy. METHODS: Immunohistochemical (IHC) expression of PDL-1 and MSI, cytogenetic FISH amplification of the HER-2/neu gene and polymerase chain reaction of EBV RNA, including charge quantification, were performed in selected patients with metastatic or advanced gastric cancer. RESULTS: EBV-encoded RNA was detected in nine patients. None of them exhibited Her-2 overexpression or CMV infection. PD-L1 was detected in twelve patients. Ten patients were MLH1 positive. All nine cases of EBV infection showed a high expression of PD-L1 and MLH-1 (Tab. 1, Ref. 14).

Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.

BACKGROUND: Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis. CASE PRESENTATION: A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years. CONCLUSION: Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.

Magnesium transporter 1 (MAGT1) deficiency causes selective defects in N-linked glycosylation and expression of immune-response genes.

Magnesium transporter 1 (MAGT1) critically mediates magnesium homeostasis in eukaryotes and is highly-conserved across different evolutionary branches. In humans, loss-of-function mutations in the MAGT1 gene cause X-linked magnesium deficiency with Epstein-Barr virus (EBV) infection and neoplasia (XMEN), a disease that has a broad range of clinical and immunological consequences. We have previously shown that EBV susceptibility in XMEN is associated with defective expression of the antiviral natural-killer group 2 member D (NKG2D) protein and abnormal Mg2+ transport. New evidence suggests that MAGT1 is the human homolog of the yeast OST3/OST6 proteins that form an integral part of the N-linked glycosylation complex, although the exact contributions of these perturbations in the glycosylation pathway to disease pathogenesis are still unknown. Using MS-based glycoproteomics, along with CRISPR/Cas9-KO cell lines, natural killer cell-killing assays, and RNA-Seq experiments, we now demonstrate that humans lacking functional MAGT1 have a selective deficiency in both immune and nonimmune glycoproteins, and we identified several critical glycosylation defects in important immune-response proteins and in the expression of genes involved in immunity, particularly CD28. We show that MAGT1 function is partly interchangeable with that of the paralog protein tumor-suppressor candidate 3 (TUSC3) but that each protein has a different tissue distribution in humans. We observed that MAGT1-dependent glycosylation is sensitive to Mg2+ levels and that reduced Mg2+ impairs immune-cell function via the loss of specific glycoproteins. Our findings reveal that defects in protein glycosylation and gene expression underlie immune defects in an inherited disease due to MAGT1 deficiency.

Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis.

The spectrum of Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations is broad and ranges from reactive self-limited disorders to neoplastic processes with a fulminant clinical course. EBV plays an important role promoting lymphomagenesis, although the precise mechanisms remain elusive. EBV-positive lymphoproliferative disorders (LPD) are more common in East Asia (China, Japan, Korea and Taiwan), and Latin America suggesting a strong genetic predisposition. The revised 2016 World Health Organization (WHO) lymphoma classification recognizes the following malignant NK- and T-cell lymphomas; extranodal NK/T-cell lymphoma, nasal type (ENKTCL), aggressive NK-cell leukemia (ANKL), and the provisional entity within the group of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) "primary EBV-positive nodal T or NK cell lymphoma". Disorders presenting mainly in children and young adults include chronic active EBV infection (CAEBV) - systemic and cutaneous forms - which are not considered malignant disorders but were included in the WHO classification for the first time because of the differential diagnosis with other T- or NK-cell lymphomas. CAEBV, cutaneous form, includes hydroa vacciniforme-like LPD (HV-LPD) and severe mosquito bite allergy (SMBA). Finally, systemic EBV-positive T-cell lymphoma of childhood was recognized as lymphoma because of its fulminant clinical course. Given the shared pathogenesis of these disorders, overlapping features are common demanding a close clinical, morphological and molecular correlation for an accurate diagnosis. This review summarizes the clinical, histopathological and molecular features of EBV-associated T and NK-cell LPD, highlighting the main features that might aid in the differential diagnosis.

Viral DNA Loads in Various Blood Components of Patients With Epstein-Barr Virus-Positive T-Cell/Natural Killer Cell Lymphoproliferative Diseases.

To evaluate diagnostic values for Epstein-Barr virus (EBV) DNA loads in different blood components of patients with EBV-positive T-cell/natural killer cell lymphoproliferative diseases, EBV DNA loads were compared among disease categories in each blood component from 59 patients. Plasma viral loads were significantly higher in "active" disease in chronic active EBV infection. EBV DNA was not detected in the plasma from 7 patients in whom EBV DNA was detected in peripheral blood mononuclear cells and whole blood. Diagnostic cutoff values for whole blood EBV DNA loads of patients with chronic active EBV infection compared with those of infectious mononucleosis was 104.2 (15 800) IU/mL.

Inherited Interleukin 2-Inducible T-Cell (ITK) Kinase Deficiency in Siblings With Epidermodysplasia Verruciformis and Hodgkin Lymphoma.

Biallelic mutations in the ITK gene cause a T-cell primary immunodeficiency with Epstein-Barr virus (EBV)-lymphoproliferative disorders. We describe a novel association of a homozygous ITK mutation with ß-human papillomavirus (HPV)-positive epidermodysplasia verruciformis. Thus, loss of function in ITK can result in broad dysregulation of T-cell responses to oncogenic viruses, including ß-HPV and EBV.

Screening for Epstein-Barr virus (EBV) infection status in university freshmen: acceptability of a gingival swab method.

Prophylactic vaccines against Epstein-Barr virus (EBV) are under development. EBV-naïve college freshmen are ideal candidates for an efficacy trial, because their incidence of infectious mononucleosis (mono) during freshman year is as high as 20%. To assess perceptions about mono and a mono vaccine, and to learn if EBV immune status could be determined using a gingival swab rather than phlebotomy, we performed a cross-sectional study of 235 healthy students at the beginning of their freshman year. Subjects completed questionnaires and donated oral washes, gingival swabs and venous blood. Overall, 90% of students found the swab easy to use and 80% preferred the swab over venepuncture. Of the 193 students with sufficient samples, 108 (56%) had EBV antibodies in blood vs. 87 (45.1%) in the gingival swab. The sensitivity and specificity of the swab compared with blood for detecting EBV antibodies was 75.9% and 94.1%, respectively, with an accuracy of 89.3%. EBV DNA was detected in the oral wash and swab of 39.2% and 30.4% of blood-antibody-positive individuals, respectively. In conclusion, 44% of our freshmen were EBV-naïve and thus vaccine candidates, the gingival swab was an acceptable alternative to phlebotomy for detecting EBV antibody but needs improved sensitivity, and the perceived value of EBV vaccine was high (72% believed they would benefit).

Concomitant Infection With Epstein-Barr Virus and Cytomegalovirus Infection Leading to Portal Vein Thrombosis.

BACKGROUND: Portal vein thrombosis (PVT) is well recognized as a complication of hepatic cirrhosis and is likely to be suspected in patients with hypercoagulable syndromes, however, it is rarely recognized as a possibility in otherwise healthy patients with Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infection. We report a case of a healthy 27-year-old man with fever and weight loss who was found to have PVT in the setting of acute EBV and CMV infection. CASE REPORT: A 27-year-old man with no known medical history presented to the emergency department (ED) for fever for 18 days. Patient reported daily high fevers associated with chills, night sweats, generalized myalgia, nausea with appetite loss, and unquantified weight loss. Vital signs showed temperature of 100.5°F. Patient reported discomfort upon palpation of abdomen on physical examination. There was no lymphadenopathy, cardiac murmur, rash, or jaundice. Laboratory tests revealed titers diagnostic of acute EBV and CMV infection with elevated liver function tests and leukocytosis with lymphocyte predominance (white blood cell count 15,400/µL; 43% atypical lymphocytes). Computed tomography of the abdomen/pelvis with i.v. contrast showed a filling defect in the anterior portal vein. The patient was admitted with the ED diagnosis of PVT secondary to viral infection and was initiated on anticoagulation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although rarely considered, CMV has been associated with PVT in up to 6% of cases, and EBV infection has been implicated as well. Emergency physicians should be aware of this potentially serious complication of these common viral infections and consider imaging modalities to rule out thrombosis, if appropriate.

Proposed Molecular and miRNA Classification of Gastric Cancer.

Gastric cancer (GC) is a common malignant neoplasm worldwide and one of the main cause of cancer-related deaths. Despite some advances in therapies, long-term survival of patients with advanced disease remains poor. Different types of classification have been used to stratify patients with GC for shaping prognosis and treatment planning. Based on new knowledge of molecular pathways associated with different aspect of GC, new pathogenetic classifications for GC have been and continue to be proposed. These novel classifications create a new paradigm in the definition of cancer biology and allow the identification of relevant GC genomic subsets by using different techniques such as genomic screenings, functional studies and molecular or epigenetic characterization. An improved prognostic classification for GC is essential for the development of a proper therapy for a proper patient population. The aim of this review is to discuss the state-of-the-art on combining histological and molecular classifications of GC to give an overview of the emerging therapeutic possibilities connected to the latest discoveries regarding GC.

Environmental factors in the development of multiple sclerosis.

Epidemiology of Multiple Sclerosis (MS) has been intensively studied and we know now that its occurrence result from the combined action of genetic and environmental factors. There are significant geographic and temporal variations in MS incidence and the risk associated with the development of MS may be affected by many potential factors (including infections, climate, diet, etc.). But none of these factors has been identified as "causal". The accumulation of these different agents as well as their interactions probably contribute to the development of the disease.

Clinicopathological analysis of 12 patients with Epstein-Barr virus-positive primary intestinal T/natural killer-cell lymphoma (EBV+ ITNKL).

AIMS: Epstein-Barr virus-positive (EBV+ ) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patient's background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV+ ITNKL. METHODS AND RESULTS: We enrolled 12 patients with EBV+ ITNKL without nasal involvement into the study. All patients were characterized by involvement of the small intestine with concurrent lesions of the large intestine in two patients. Seven patients (58%) had Lugano stages IIE/IV disease and eight (67%) were categorized as high-intermediate/high-risk according to the Prognostic Index for PTCL (PIT). Three patients (25%) with an age of onset of less than 50 years had chronic active EBV infection (CAEBV). Five CD56-positive patients (42%) had a poorer prognosis than those without CD56 expression (P = 0.008). NK cell-type lymphoma defined by the absence of any TCR expression or clonal TCR-γ rearrangement was found in six patients (50%). Interestingly, EBV+ intra-epithelial lymphocytosis was observed in one case with a background of CAEBV. CONCLUSIONS: This study is the first to shed light on the significant heterogeneity of EBV+ ITNKL and its relationship with CAEBV, especially in patients younger than 50 years of age. These observations will provide a guide for diagnostic and therapeutic approaches in routine practice.

Wogonin as a targeted therapeutic agent for EBV (+) lymphoma cells involved in LMP1/NF-κB/miR-155/PU.1 pathway.

BACKGROUND: Wogonin is an encouraging choice for clinical use owing to its potent anti-tumor and anti-inflammatory effects with the high safety profile. However, wogonin for targeted therapy of lymphoma was not well addressed. In this study, we focused on its anticancer effect alongside with the underlying mechanisms for targeted therapy in EBV-positive lymphoma. This will facilitate its introduction to clinical use, which is planned in the near future. METHODS: Cell proliferation was studied by CCK8. Flow cytometry was used to analyze the apoptosis and the cycle arrest of cells. Further, we also used immunofluorescent staining to detect the morphologic changes of the apoptotic cells. The expression of LMP1/miR-155/p65/pp65/PU.1 was evaluated by quantitative real-time PCR (qRT-PCR) and western blot, while that of NF-κB was analyzed by EMSA. At last, immunohistochemical staining was applied to assess the expression of target proteins and relevant molecules. RESULTS: In vitro, wogonin induced the apoptosis of Raji cells by downregulating the expression of NF-κB through LMP1/miR-155/NF-κB/PU.1 pathway, which was in a dose and time-dependent manner. In vivo, wogonin could suppress tumor growth, associated with the downregulation of ki67, p65 and upregulation of PU.1. CONCLUSIONS: Wogonin could suppress tumor growth and induce cell apoptosis by inhibiting the expression of NF-κB. Taken these findings, we concluded that wogonin could be a potential targeted therapeutic agent for EBV-positive lymphoma with the expression of LMP1 through the pathway of LMP1/NF-κB/miR-155/PU.1.