Progressive multifocal leukoencephalopathy (PML) is a rare and lethal central nervous demyelinating disease caused by JC polyomavirus (JCV), particularly in patients with impaired immune system. The variation of JCV plays an important role in the pathogenesis of PML, including the recombination of non-coding regulatory region (NCCR), which is closely related to binding sites of transcription factors and affect the level of gene transcription. Nucleotide mutations in VP1 region determine the antigenicity and receptor specificity of JCV, play an important role in cell adsorption, immune-mediation and pathogenicity. In addition, immune cells are also involved in the pathogenesis of PML. T lymphocytes can recognize virus antigens, clear JCV, which are directly related to the prognosis of PML. B lymphocytes can serve as latent sites of JCV, and participate in viral transmission, replication, and coordination of the expression of transcription factors. This paper summarizes the roles of JCV variation and immune cells in pathogenesis of PML.
B-Lymphocytes ; immunology ; virology ; Capsid Proteins ; genetics ; immunology ; Humans ; JC Virus ; immunology ; Leukoencephalopathy, Progressive Multifocal ; pathology ; virology ; Mutation ; T-Lymphocytes ; immunology ; virology

The aim of this study was to analyze the clinical features and laboratory findings of adult Epstein-Barr virus associated T/NK cell lymphoproliferative disease (EBV+T/NK-LPD) and to investigate the early diagnosis and prognosis of EBV+T/NK-LPD. The clinical data of 19 adult patients with EBV+T/NK-LPD were retrospectively analyzed. The results indicated that there were 11 males and 8 females. The median age was 32 years (range: 20-70 years). The average duration from onset of symptoms to diagnosis was 3.5 months. The median survival time was 2.5 months. Unkown fever, hepatosplenomegaly, liver dysfunction and interstitial pneumonia were the main clinical features. High levels of β2-MG, LDH, TNF, IL-6 and significantly increased EBV-DNA level (median level > 10(6) copies/ml) were occurred in all the patients. Cytopenia was seen in 18 cases. Morphologically, atypical large granular lymphocytes and hemophagocytosis were common in bone marrow smears. Deletion of CD5 or CD7 were frequently observed in T/NK lymphocytes in bone marrow cells by flow cytometry. Bone marrow biopsy showed atypical lymphocyte interstitial infiltrated in 10 cases, while a few large cells infiltrated in 6 cases. Immunohistochemistry showed the expression of CD3(+)CD56(+) were seen in 2 cases, CD3(+)CD8(+) in 11 cases and CD3(+)CD4(+) in 3 cases. TIA-1 and EBER were positive in all biopsy specimens. Three cases underwent biopsy of lymph nodes showed reactive proliferations of lymphocytes. All the patients died of multiorgan failure. It is concluded that the fever, hepatosplenomegaly are the most common clinical features in adult EBV+T/NK-LPD, the bone marrow infiltration of EBV-infected T/NK lymphocytes and significantly increased EBV-DNA level can be observed in all cases, the clinical outcome of this disease is poor, these clinical and experimental features can be served as a reliable marker for the timely diagnosis of adult EBV+T/NK-LPD.
Adult ; Aged ; Epstein-Barr Virus Infections ; pathology ; Female ; Humans ; Immunophenotyping ; Killer Cells, Natural ; virology ; Lymphoproliferative Disorders ; pathology ; virology ; Male ; Middle Aged ; Retrospective Studies ; T-Lymphocytes ; virology ; Young Adult

We experienced a case of adult T cell leukemia/lymphoma (ATLL) in a 48-year-old Korean female, who has never been abroad since birth and no history of blood transfusion. The patient had hypercalcemia and multiple lymphadenopathy. Histopathologic study of left cervical lymph node (LN) and bone marrow (BM) revealed that infiltrates of malignant lymphoid cells were composed of small, medium and large cells with pleomorphic nuclei. Smears of peripheral blood (PB) showed lymphopenia (16%) with the appearance of a few atypical lymphoid cells (less than 2%), but not the typical clover leaf cells seen in ATLL. Immunophenotypic study of LN and BM revealed T cell phenotype. PB showed increased CD4+ T cell (T(H), CD3/CD4+, 57%) and decreased CD8+ T cell counts (T(S), CD3/CD8+, 6.7%). The sera of the patient and her family were reactive for HTLV-I antibody. The specific sequences of pol, env, and tax of HTLV-I DNA were detected in the lymphoma cells and peripheral blood mononuclear cells (PBMC) using polymerase chain reaction. Ultrastructural examination of PBMC confirmed numerous type c virus particles in extracellular space. This case was an acute type of ATLL without overt leukemic features in PB. Despite chemotherapy and intensive conservative treatment, she died 3 months after admission.
Biopsy ; Bone Marrow/pathology ; Case Report ; DNA, Viral/analysis ; Fatal Outcome ; Female ; Flow Cytometry ; Gene Products, env/genetics ; Gene Products, pol/genetics ; Gene Products, tax/genetics ; HTLV-BLV Infections/pathology ; HTLV-I ; Human ; Hypercalcemia/virology ; Hypercalcemia/pathology ; Immunophenotyping ; Korea ; Leukemia, T-Cell/virology ; Leukemia, T-Cell/pathology* ; Leukemia, T-Cell/immunology ; Lymph Nodes/pathology ; Lymphopenia/virology ; Lymphopenia/pathology* ; Lymphopenia/immunology ; Microscopy, Electron ; Middle Age ; Support, Non-U.S. Gov't ; T-Lymphocytes/virology ; T-Lymphocytes/ultrastructure ; T-Lymphocytes/pathology

No abstract available.
Epstein-Barr Virus Infections/*complications/diagnosis ; Herpesvirus 4, Human/pathogenicity ; Humans ; Lymphoma, Follicular/complications ; Lymphoproliferative Disorders/*complications/diagnosis/virology ; Male ; Middle Aged ; *T-Lymphocytes/pathology/virology

Antigen Presentation ; Apoptosis ; Hepatitis C ; Humans ; Lichen Planus, Oral ; etiology ; genetics ; pathology ; virology ; Polymorphism, Single Nucleotide ; T-Lymphocytes, Cytotoxic ; pathology ; T-Lymphocytes, Helper-Inducer ; pathology ; Tumor Necrosis Factor-alpha ; genetics ; metabolism

The development of highly immunodeficient mouse strains has allowed the reconstitution of functional human immune system components in mice. New-generation humanized mice generated in this manner have been extensively used for modeling viral infections that are exclusively human tropic. Epstein-Barr virus (EBV)-infected humanized mice reproduce cardinal features of EBV-associated B-cell lymphoproliferative disease and EBV-associated hemophagocytic lymphohistiocytosis (HLH). Erosive arthritis morphologically resembling rheumatoid arthritis (RA) has also been recapitulated in these mice. Low-dose EBV infection of humanized mice results in asymptomatic, persistent infection. Innate immune responses involving natural killer cells, EBV-specific adaptive T-cell responses restricted by human major histocompatibility and EBV-specific antibody responses are also elicited in humanized mice. EBV-associated T-/natural killer cell lymphoproliferative disease, by contrast, can be reproduced in a distinct mouse xenograft model. In this review, recent findings on the recapitulation of human EBV infection and pathogenesis in these mouse models, as well as their application to preclinical studies of experimental anti-EBV therapies, are described.
Animals ; Disease Models, Animal ; Epstein-Barr Virus Infections/complications/immunology/*virology ; Herpesvirus 4, Human/*physiology ; Heterografts ; Humans ; Killer Cells, Natural/pathology/virology ; Lymphoproliferative Disorders/etiology ; Mice ; Mice, SCID ; T-Lymphocytes/pathology/virology

OBJECTIVETo investigate role of CD4-CD8- T cells in murine hepatitis virus type 3 (MHV-3) induced chronic viral hepatitis in C3H/Hej mice and to identify their surface markers.

METHODSThirty C3H/Hej mice received 10 Pfu MHV-3 intraperitoneally, the CD4-CD8- T cells were isolated using magnetic bead sorting on 0, 4, 15, 30, 40 days post MHV-3 infection. The cytotoxic effects of CD4-CD8- T cells on normal and infected hepatocytes, CD8+ T cells and unrelated-virus (murine cytomegalovirus, MCMV) infected CD8+ T cells were examined by non-radioactive cytotoxicity assay. The surface markers of CD4-CD8- T cells were determined by flow cytometry.

RESULTSMHV-3 infected CD4-CD8- T cells showed significant cytotoxic effect on CD8+ T cells, but not on infected hepatocytes or MCMV infected CD8+ T cells. The analysis of cell surface markers demonstrated that the CD4-CD8- T cells are a completely new T cell subset.

CONCLUSIONSCD4-CD8- T cells have significant cytotoxic effect on virus specific CD8+ T cells in MHV-3 infected C3H/Hej mice, which suggests that CD4-CD8- T cells have immune modulatory functions in the development of chronic viral hepatitis. The phenotype of these CD4-CD8- T cells detected by flow cytometry is TCR alpha beta +CD3+CD4- CD8- CD25- CD28- CD30- CD44+.

Animals ; CD4-Positive T-Lymphocytes ; immunology ; CD8-Positive T-Lymphocytes ; immunology ; Coronavirus Infections ; immunology ; pathology ; virology ; Female ; Flow Cytometry ; Hepatitis, Viral, Animal ; immunology ; pathology ; virology ; Liver ; immunology ; pathology ; Mice ; Mice, Inbred C3H ; Murine hepatitis virus ; Spleen ; immunology ; pathology ; T-Lymphocyte Subsets ; immunology ; Time Factors

Infectious mononucleosis due to Epstein-Barr virus (EBV) infection sometimes causes acute hepatitis, which is usually self-limiting with mildly elevated transaminases, but rarely with jaundice. Primary EBV infection in children is usually asymptomatic, but in a small number of healthy individuals, typically young adults, EBV infection results in a clinical syndrome of infectious mononucleosis with hepatitis, with typical symptoms of fever, pharyngitis, lymphadenopathy, and hepatosplenomegaly. EBV is rather uncommonly confirmed as an etiologic agent of acute hepatitis in adults. Here, we report two cases: the first case with acute hepatitis secondary to infectious mononucleosis and a second case, with acute hepatitis secondary to infectious mononucleosis concomitantly infected with hepatitis A. Both cases involved young adults presenting with fever, pharyngitis, lymphadenopathy, hepatosplenomegaly, and atypical lymphocytosis confirmed by serologic tests, liver biopsy and electron microscopic study.
Acute Disease ; Adult ; CD8-Positive T-Lymphocytes/virology ; Female ; Hepatitis/*etiology/pathology ; Humans ; Infectious Mononucleosis/*complications ; Liver/pathology/ultrastructure ; Male ; Young Adult

OBJECTIVETo establish a method for efficient induction and expansion of Epstein Barr virus (EBV)-specific cytotoxic T lymphocytes (CTL) in vitro and evaluate the possibility of using this strategy for treatment of nasopharyngeal carcinoma (NPC).

METHODSEBV-transformed B lymphoblastoid cells (BLCLs) were used as the antigen stimuli and antigen-presenting cells. EBV-specific CTL was induced by co-culture of the autologous peripheral blood mononuclear cells (PBMCs) and the irradiated BLCLs, and expanded with a cocktail method consisting of OKT-3, irradiated homologous PBMC, and IL-2. The specific activity of the CTL against the NPC cells was measured with MTT assay.

RESULTSEBV-specific CTL was successfully induced and expanded by 600 folds. The killing efficiency of the CTL was 76% for autologous BLCLs, 13% for homologous BLCLs, 51% for autologous NPC cells, and 27% for homologous CNE cell line, and after expansion, the corresponding killing efficiencies were 63%, 25%, 49%, and 33%, respectively. The non-specific killing only slightly increased after the expansion.

CONCLUSIONEBV-specific CTL can be successfully induced and expanded in vitro for specific killing of autologous NPC cells, suggesting the potential of this strategy in the treatment of NPC.

Antigen-Presenting Cells ; cytology ; immunology ; Antigens, Viral ; immunology ; B-Lymphocytes ; cytology ; immunology ; virology ; Cells, Cultured ; Coculture Techniques ; Herpesvirus 4, Human ; immunology ; Humans ; Immunotherapy, Adoptive ; Nasopharyngeal Neoplasms ; immunology ; pathology ; therapy ; T-Lymphocytes, Cytotoxic ; cytology ; immunology ; virology ; Tumor Cells, Cultured

OBJECTIVETo investigate clinicopathological features of DiGeorge syndrome (DGS).

METHODThe clinical features, histological and immunohistochemical findings were analyzed in 5 cases of DGS by autopsy.

RESULTSFive cases of DGS in male infants aged 4 days, 1 month, 7 months, 10 months, and 13 months respectively. Gross and microscopic observations revealed that thymic cortex was depleted of lymphocytes or showed few, dispersed lymphocytes. The thymic medulla showed predominantly epithelial cells with calcified Hassall bodies as well as lymphocyte depletion. T lymphocytes were also scarce in the tonsils, lymph nodes, spleen, and mucosa-associated lymphatic tissue of ileum. In addition, 3 of the 5 patients also showed parathyroid aplasia or dysplasia, and congenital hypertrophy of the ventricular septum.

CONCLUSIONSThe pathological changes indicate that clinicians should be aware of defects of immune system if the infants suffer from severe infections. Pathologists should recognize the importance of abnormalities of lymphohematopoietic tissues in the diagnosis of primary immunodeficiency diseases such as DGS.

Autopsy ; DiGeorge Syndrome ; immunology ; pathology ; virology ; Hepatitis, Viral, Human ; pathology ; Humans ; Hypertrophy, Left Ventricular ; pathology ; Infant ; Infant, Newborn ; Lymphocyte Count ; Male ; Parathyroid Glands ; pathology ; Pneumonia, Viral ; pathology ; T-Lymphocytes ; immunology ; pathology ; Thymus Gland ; pathology