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The authors reviewed the clinical, phenotypic, genotypic, and Epstein-Barr virus (EBV)-findings of 18 patients with nasal T-cell lymphoma(NTL). The clinical features were characterized as prolonged fever, widespread dissemination into distant sites, and poor prognosis with median survival of only 6 months. EBV-encoded small nuclear early region(EBER) transcripts were identified in 16 of 18 patients. Monoclonal EBV genome, EBV-encoded nuclear antigen(EBNA)-1, and latent membrane protein(LMP)-1 were also detected in all EBER-positive cases tested. All EBV-positive NTL showed coexpression of natural killer(NK) cell phenotype CD56 and CD2. Of 9 EBV-positive NTL, seven cases expressed T-cell receptor (TCR)-delta chain with rearranged beta-, gamma- and/or delta- genes. These data suggest that some cases of EBV-positive NTL may be derived from the lineage of NK-like T-cells or gamma delta T-cells, and that EBV may play a role in the lymphomagenesis.

Family members of patients with adult T-cell leukemia (ATL) in non-ATL-endemic Hokkaido, the northernmost part of Japan, were assessed for the prevalence of HTLV-I infection. Immunofluorescence assay showed that 53 out of 133 (39.8%) healthy family members of 23 ATL patients were positive for antibodies to HTLV-I. When general inhabitants in Hokkaido were examined, 3 out of 18 (16.7%) family members of 5 seropositive healthy persons had HTLV-I antibodies. The overall seropositivity in Hokkaido was 0.7%. Of 26 family members of 6 patients with non-T-cell leukemia seroconverted by blood transfusion, none (0%) was seropositive.

Peripheral blood lymphocytes from 4 asymptomatic HIV-1 carriers with normally retained EBV-specific cytotoxic T-cell activity were exposed to EBV and incubated with 0.2 ng/ml 4-deoxyphorbol ester, an immunosuppressive substance derived from an African plant Euphorbia tirucalli. The regression of EBV-induced B-cell transformation by EBV-specific cytotoxic T-cells was significantly impaired in the presence of a small amount of 4-deoxyphorbol ester, but not so in 5 HIV-1-seronegative healthy counterparts. When the EBV-specific cytotoxic T-cells from the asymptomatic carriers were exposed to 0.2ng/ml 4-deoxyphorbol ester and incubated with 51Cr-labeled autologous EBV-transformed B lymphocytes, the released radioactivity was significantly smaller than that of the healthy counterparts. The results suggest that the cellular immunity of the asymptomatic HIV-1 carriers is cryptically impaired, and the cryptic immunological dysfunction is actualized by exposure to a small amount of the immunosuppressive substance, a dose which does not affect the immunity of uninfected healthy individuals.

In contrast to adult T-cell leukemia (ATL)-endemic southwestern Japan, the northernmost island Hokkaido has a small number of ATL patients annually. In this study, we surveyed 32,587 healthy inhabitants throughout Hokkaido for antibodies to human T-cell leukemia virus type 1 (HTLV-I). Only 244 individuals (0.8%) were seropositive as HTLV-I carriers; 0.6% (123 of 19,512) in males and 0.9% (121 of 13,075) in females. In some areas, however, the inhabitants had relatively high seropositivity (2%). The highest rate was 5.2% with a cluster of ATL patients in a certain town of the Hidaka area near the Pacific Ocean, in southeast Hokkaido.

Two human Burkitt's lymphoma cell lines (HBL-4 and HBL-5) were established individually from two patients with small noncleaved cell lymphoma (Burkitt's type). The HBL-4 cell line is Epstein-Barr virus (EBV)-negative, and the HBL-5 cell line is EBV-positive. Cytogenetically, both cell lines had the same chromosomal translocation, t(8;14)(q24;q32) as those observed in the primary malignant cells from individual patients. Morphologic, immunophenotypic, cytogenetic, and molecular studies confirmed that both cell lines were derived from the primary lymphoma cells in vivo. HBL-4 cells lacked CD23(H107), CD11a(LFA-1), and latent membrane protein (LMP) but expressed CD54(ICAM-1) at low levels, whereas HBL-5 cells showed the high level of expression of CD54 and faint expression of LMP but lacked CD11a. In addition, the EBV-positive lymphoblastoid cell line (LCL) expressed CD11a, CD23, CD54, and LMP at high levels. Therefore, an HBL-5 phenotype with expression of CD54 and LMP tends toward an LCL phenotype, and the augmentation of CD54 on the HBL-5 cells in comparison with primary lymphoma cells is likely to be upregulated by LMP, probably resulting from the EBV infection. There was little difference in the BrdUrd uptake in vivo and in vitro, doubling time, tumorigenicity, and dynamics of tumor growth in athymic nude mice between both cell lines. These findings indicate that the potentiality of cell growth and tumorigenicity of these two cell lines are unlikely to be related with EBV.

Five cases of lethal midline granuloma were identified histologically and phenotypically as peripheral T-cell lymphomas. Epstein-Barr virus (EBV) DNA was detected in the nasal tumour biopsy specimens by Southern blotting and in-vitro hybridisation with simultaneous detection of EBV-determined nuclear antigen (EBNA) and T-cell surface markers by two-colour immunofluorescence. Further immunofluorescence and northern blotting revealed that EBNA2 gene and also latent membrane protein gene were expressed in the nasal tumour cells. The patients had high titres of antibodies to EBV. These findings suggest that lethal midline granuloma is causally associated with EBV.

In order to investigate the spread of adult T-cell leukemia (ATL) virus in the inhabitants of ATL-non-endemic Hokkaido, we surveyed the antibodies to ATL-associated antigen (ATLA) in 29516 healthy individuals by indirect immunofluorescence test using MT-1 for target cell. Of the healthy inhabitants, only 219 individuals (0.74%) were anti-ATLA positive as carriers. Prevalence of anti-ATLA was 0.63% (111 of 17590) in males and 0.91% (108 of 11926) in females. This difference by sex is significant. In several regions, the inhabitants were found to show relatively high incidence (greater than 2%) of the antibodies, and these regions have a tendency to cluster around the western side of Hidaka mountains or Akan area. The highest rate (5.2%) of anti-ATLA positive carriers was shown in a certain town of Hidaka area.

Sera and peripheral blood lymphocytes in 40 clinical cases of adult T-cell leukemia (ATL) and 66 cases of mature T-cell malignancies in Hokkaido district, the most northern part of Japan, were examined for the infection with ATL virus (ATLV). All of the 40 ATL patients (100%) had antibodies to ATLV-associated antigen (ATLA) and 13 (19.7%) of the 66 patients with mature T-cell malignancies other than ATL were also positive for anti-ATLA. When the peripheral ATL lymphocytes were assessed after short time cultivation, both ATLA antigen and C type virus particles were detectable. In contrast to the high prevalence of ATLV antibodies in these patients, the positivity in 30,000 control individuals in this district was 0.73%. It was calculated that 8 patients of a 40,000 seropositive population are diagnosed annually as ATL in this particular northern part of Japan.

Family members of non-endemic Hokkaido patients with adult T-cell leukemia (ATL) were assessed for the prevalence of ATL virus (ATLV) infection. Immunofluorescence test showed that 53 (39.8%) of 133 healthy family members of 23 ATL patients were positive for antibodies of ATLV-associated antigen (ATLA). When seropositive T-cell malignancies other than ATL and healthy controls in Hokkaido were examined, 10 of 33 family members (30.3%) of 9 patients and 3 of 18 family members (16.7%) of 5 donors had ATLA antibodies, respectively. In sharp contrast, the overall seropositivity in this northern part of Japan was 0.73%. None were seropositive (0%), when 26 family members of 6 patients with acute myeloid leukemia sero-converted by blood transfusion during the course of the disease.

A chronic active Epstein-Barr virus (EBV) infection with no significant underlying diseases was evidenced in 7 Japanese children and adolescents. In these patients, massive EBV-positive polyclonal lymphoproliferation occurred with extremely high EBV antibody titers.

Lymphomas occurred in 3 of 16 Japanese patients with ataxia telangiectasia (AT) and Wiskott-Aldrich syndrome (WAS). The patients had a persistently reactivated Epstein-Barr virus (EBV) infection with a remarkable decrease in virus-specific cellular immunity. In these patients, the B lymphocytes were more sensitive to EBV-induced events and to cellular proto-oncogene activation than seen in the healthy counterparts. This immunologic and genetic background was considered to explain the massive lymphoproliferation in these primary immunodeficiency disorders.

Two continuously growing in vito cell lines, PB-1049 and LN-1049, were established from a patient with Ph1-positive chronic myelogenous leukemia in extramedullary blastic crisis. PB-1049 was established from Epstein-Barr virus (EBV)-infected peripheral lymphocytes of the patient and had a 46,XY,t(9;22) karyotype. This cell line was shown to be tumorigenic in nude mice, and cultured cells recovered from the tumor nodule showed a 46,XY,6p+,t(9;22) stem line karyotype. LN-1049 was derived from a lymph node culture of the same patient, and was found to be non-tumorigenic in nude mice and karyotypically normal. Immunological examinations on EBV-induced antigens, surface and cytoplasmic immunoglobulin, and monoclonal antibodies, and some enzymatic and electron microscopic studies revealed that both cell lines had attained differentiation into late-B cell stage.