Identification of rare Epstein-Barr virus infected memory B cells and plasma cells in non-monomorphic post-transplant lymphoproliferative disorders and the signature of viral signaling.
OBJECTIVE
In early and polymorphic post-transplant lymphoproliferative disorders (PTLD) Epstein-Barr virus (EBV), through its latency proteins, drives the proliferation of B lymphocytes, a process which in immunocompetent individuals leads to the establishment of latently infected memory B cells.


METHODS
We analyzed 11 cases, which included early and polymorphic PTLD, and 12 controls for latency of EBV infection and their antigenic profile.


RESULTS
We identified a minority of terminally differentiated EBER+ IRTA1+ memory B cells and EBER+ CD138+ PRDM1+ plasma cells in these samples. These elements were identified both in PTLD and in tumor-free tonsils from post-transplant patients but not in EBV- control tonsils. The expression of EBV latency proteins is heterogeneous, and is associated with activation of the NF-kB pathway. EBV signaling (through EBNA2, LMP1 and LMP2A) and NF-kB activation correlated with upregulation of target proteins: cMYC, JunB, CCL22, TRAF1 and IRF4. EBV-infected lymphocytes in early and polymorphic PTLDs represent a mixture of latencies II, III and, in at least 1/3 of infected cells, of latency 0.


CONCLUSIONS
EBV infection correlates with NF-kB activation, with EBV-dependent cell signaling, and lastly, with the presence of EBV-infected plasma cells and memory cells.
Shaknovich
Rita
R
Department of Pathology, Columbia University Medical Center, Columbia University, New York, NY 10032, USA. rshaknov@montefiore.org
Basso
Katia
K
Bhagat
Govind
G
Mansukhani
Mahesh
M
Hatzivassiliou
Georgia
G
Murty
Vundavalli V
VV
Buettner
Maike
M
Niedobitek
Gerald
G
Alobeid
Bachir
B
Cattoretti
Giorgio
G
D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000473:pathology* / Q000821:virology*; D002648:Child; D002675:Child, Preschool; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000821:virology; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000473:pathology* / Q000821:virology*; D008297:Male; D010950:Plasma Cells / Q000473:pathology* / Q000821:virology*; D015398:Signal Transduction / Q000235:genetics; D019737:Transplants / Q000821:virology*