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Epstein-Barr virus encoded latent membrane protein 1 (LMP1) and TNF receptor associated factors (TRAF): colocalisation of LMP1 and TRAF1 in primary EBV infection and in EBV associated Hodgkin lymphoma

¹ Institute for Pathology, Friedrich-Alexander-University, Krankenhausstr. 8–10, 91054 Erlangen, Germany
² Institute for Molecular Immunology, GSF, Marchioninistr. 25, 81377 München, Germany
³ Institute for Clinical Molecular Biology and Tumour Genetics, GSF, Marchioninistr. 25, 81377 München, Germany

Correspondence to:
Dr G Niedobitek, Pathologisches Institut, Friedrich-Alexander Universität, Krankenhausstr. 8–10, 91054 Erlangen, Germany;
gerald.niedobitek{at}patho.imed.uni-erlangen.de

Aims: Epstein-Barr virus (EBV) immortalises B cells in vitro and is associated with several malignancies. Most phenotypic effects of EBV are mediated by latent membrane protein 1 (LMP1), which interacts with tumour necrosis factor receptor associated factors (TRAFs) to activate NF-B. This study examines TRAF1 and LMP1 expression in EBV associated lymphoproliferations.

Methods: TRAF1 expression was investigated in 26 Hodgkin lymphomas (HL; 18 EBV⁺, eight EBV^-), seven EBV⁺ Burkitt lymphomas (BL), two infectious mononucleosis (IM) tonsils, and lymphoreticular tissue from eight chronic virus carriers. Seven anaplastic large cell lymphomas and 10 follicular B cell lymphomas were also studied. Colocalisation of TRAF1 and LMP1 was studied by immunofluorescent double labelling and confocal laser microscopy.

Results: TRAF1 colocalises with LMP1 in EBV infected cells in IM. EBV positive lymphocytes from chronic virus carriers were negative for TRAF1 and LMP1. In HL biopsies, TRAF1 was strongly expressed independently of EBV status, whereas all BL cases were TRAF1^-. In EBV⁺ HL cases, TRAF1 colocalised with LMP1. Eight of 10 follicular lymphomas expressed TRAF1 in centroblast-like cells. Four of seven anaplastic large cell lymphomas weakly expressed TRAF1.

Conclusions: These results suggest that in non-neoplastic lymphocytes, TRAF1 expression is dependent on the presence of LMP1, and that in IM B cells in vivo, LMP1 associated signalling pathways are active. In HL, TRAF1 is expressed independently of EBV status, probably because of constitutive NF-B activation. The function of TRAF1 in HL remains to be determined.

Keywords: Epstein-Barr virus; tumour necrosis factor receptor associated factor 1; latent membrane protein 1; infectious mononucleosis; Hodgkin lymphoma; Burkitt lymphoma

Abbreviations: ALC, anaplastic large cell; BL, Burkitt lymphoma; CTAR, C-terminal activating region; EBER, Epstein-Barr virus encoded non-polyadenylated small nuclear RNA; EBNA, Epstein-Barr virus encoded nuclear antigen; EBV, Epstein-Barr virus; GST, glutathione-S-transferase; HL, Hodgkin lymphoma; HRS, Hodgkin and Reed-Sternberg; IDC, interdigitating reticulum cells; IM, infectious mononucleosis; LCL, lymphoblastoid cell line; LFA, leucocyte function antigen; LMP, latent membrane protein; NF-B, nuclear factor B; RPA, RNase protection assay; TNF, tumour necrosis factor; TRADD, tumour necrosis factor receptor associated death domain; TRAF, tumour necrosis factor receptor associated factor; TRIP, tumour necrosis factor receptor associated factor interacting protein