EBV Infection and Altered Control of Apoptotic Pathways in Posttransplant Lymphoproliferative Disorders (PTLD).

PTLD represent a spectrum of lymphoid diseases potentially complicating the clinical course of transplant recipients. Most PTLD are EBV associated with latency III of the virus. The interaction between EBV and the control of apoptosis is not precisely known. In fact, deregulation of Bcl-2 family proteins which has been implicated in the development of many malignancies can be divided into three groups: anti-apoptotic members (including Bcl-2, Bcl-XL and Mcl-1), pro-apoptotic proteins (including Bax and Bak) and the so-called BH3-only proteins. Among these BH3-only proteins, Bim plays a major role in the control of apoptosis in immune cells. To gain advantage in EBV linked tumorigenesis we undertook our investigations on PTLD. We carried out an immunohistochemical investigation concerning the expression of pro-apoptotic and anti-apoptotic molecules, possibly targeted by virus products. We have tested in a series of adult and pediatric PTLD: Bcl-2, Bax, Bak, Mcl-1, Bcl-xl, Bim, Bid, Bad, Puma and the apoptosis effector PARP.

62 PTLD were studied (44 EBV positive PTLD and 18 EBV negative PTLD). These cases were retrieved from four institutions: Bicetre/Paul Brousse University hospitals : 25 cases, Zurich University hospital : 29, Pavia University hospital : 8. This study focused exclusively on B-cell PTLD. Hematoxylin and eosin (H&E) stained paraffin sections were reviewed by four Hematopathologists, and classified according to WHO classification: 53 DLBCL, 7 Polymorphic-PTLD and 2 MNI-like lesions. Paraffin sections immunostainings were performed with streptavidin-biotin peroxidase complex method and antigen retrieval if needed. Expression of each marker was considered positive when more than 20% of neoplastic cells positive.

The expression of anti-apoptotic proteins (Bcl2, Mcl1, BclxL) did not display any correlation with the presence or not of EBV in PTLD (p>0.05) as well as the two pro-apoptotic proteins Bax and Bak. In constrast with the results without any significant differences between EBV positive and negative PTLD, for the BH3 only proteins Puma, Bad and Bid, the expression of Bim was significantly lower in EBV positive PTLD :4 out of 44 EBV positive PTLD (9%) were Bim positive while 13 cases out of 18 EBV negative PTLD (72%) expressed Bim (p<0.005). Moreover, the number of cases having more than 20% of PARP positive cells was significantly lower in EBV positive PTLD group (6/44 PARP+, 13%) than in EBV negative PTLD group 12/18 PARP+ (67%), (p<0,005).

The capacity of Bim to bind with all pro-survival Bcl-2 family proteins and its potential regulation via EBV latent proteins are known. In fact, our results strongly suggest, a major role of Bim in the disruption of apoptosis in EBV positive PTLD

No relevant conflicts of interest to declare.