The latency pattern of Epstein–Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas

Abstract

SummaryThe nasal type, extranodal natural killer or T(NK/T)-cell lymphoma is usually associated with latent Epstein-Barr virus (EBV) infection. In order to elucidate the EBV gene expression patterns in vivo, we examined eight patients with cutaneous EBV-related NK/T-cell lymphomas, including six patients with a NK-cell phenotype and two patients with a T-cell phenotype. The implication of EBV in the skin lesions was determined by the presence of EBV-DNA, EBV-encoded nuclear RNA (EBER) and a clonality of EBV-DNA fragments containing the terminal repeats. Transcripts of EBV-encoded genes were screened by reverse transcription-polymerase chain reaction (RT-PCR), and confirmed by Southern blot hybridization. The expression of EBV-related antigens was examined by immunostaining using paraffinembedded tissue sections and cell pellets of EBV-positive cell lines. Our study demonstrated that all samples from the patients contained EBV nuclear antigen (EBNA)-1 mRNA which was transcribed using the Q promoter, whereas both the Q promoter and another upstream promoter (Cp/Wp) were used in EBV-positive cell lines, B95.8, Raji and Jiyoye. Latent membrane protein-1 (LMP-1) mRNA was detected in seven of eight patients and all cell lines, whereas EBNA-2 transcripts were found only in the cell lines. Immunostaining showed no LMP-1, EBNA-2 or ZEBRA antigens in the paraffin-embedded tissue sections, although they were positive in the cell line cells. Latent BHRF1 transcripts encoding bcl-2 homologue and BCRF1 transcripts encoding viral interleukin (vIL)-10 were detected in one and two of eight patients, respectively. A patient with NK-cell lymphoma expressing both transcripts died of rapid progression of the illness. Our results indicate that the restricted expression of the latency-associated EBV genes and the production of vIL-10 and bcl-2 homologue may favour tumour growth, evading the host immune surveillance.

Retracted: Transactivation of the CCL5/RANTES gene by Epstein‐Barr virus latent membrane protein 1

“…Thereafter, cDNA was amplified for 25-40 cycles. The oligonucleotide primers used were as follows: for CCL5, sense, 5Ј-CCGTGCCCACATCAAGGAGTA-TTT-3Ј and antisense, 5Ј-CCAGCCTGGGGAAGGTTTTTGTAA-3Ј; 34 for LMP-1, sense, 5Ј-GTGACTGGACTGGAGGAGCC-3Ј and antisense, 5Ј-GAGGGAGTCATCGTGGTGGTG-3Ј; 35 and for ␤-actin, sense, 5Ј-GTGGGGCGCCCCAGGCACCA-3Ј and antisense, 5Ј-CTCCTTAATGTCACGCACGATTTC-3Ј. Product sizes were 311 bp for CCL5, 480 bp for LMP-1 and 548 bp for ␤-actin.…”

Epstein-Barr virus–associated lymphoproliferative disorders

“…The EBV association has evolved since the viral genomes were detected in Asian patients by Southern blot and in situ hybridization techniques [96][97][98]. A latency II program has been reported, which includes the expression of the latent EBV proteins LMP1, EBNA1, and EBER [99]. As in all EBV-associated T-cell lymphoproliferative disorders, the exact mechanism by which EBV gains access and infects T cells has yet to be determined.…”

Chronic immune activation and inflammation as the cause of malignancy

“…BL and natural killer/Tcell lymphomas growth is supported by EBV-encoded poly(A)(-) RNA through induction of IL-10 (Kitagawa et al, 2000). In nasal type extranodal cutaneous natural killer or T(NK/T)-cell lymphoma recent evidence indicates that expression of the latency associated EBV genes BHRF1, encoding the bcl-2 homologue, and BCRF1, encoding viral IL-10 favour tumour growth (Xu et al, 2001). EBV-encoded latent membrane protein 1 (LMP1) activation of the p38 mitogen-activated protein kinase pathway has been demonstrated to co-regulate IL-6 and IL-8 (a pro-angiogenic, HI associated chemokine) production (Eliopoulos et al, 1999, Mauray et al, 2000.…”