Latent membrane protein 1, tumor necrosis factor receptor-associated factor (TRAF) 1, TRAF-2, TRAF-3, and nuclear factor kappa B expression in posttransplantation lymphoproliferative disorders.
BACKGROUND
Most posttransplantation lymphoproliferative disorders (PTLDs) are associated with Epstein-Barr virus (EBV) infection. The EBV latent membrane protein 1 (LMP-1) is important in the transformation of B lymphocytes through its interaction with intracellular tumor necrosis factor receptor-associated factors (TRAFs) that, in turn, can activate transcription factors such as nuclear factor kappa B (NFkappaB) and Jun-N-kinase. Of the 6 members of the TRAF family, TRAF-1, TRAF-2, and TRAF-3 are most commonly associated with LMP-1. Recently, it has been suggested that LMP-1-induced TRAF activation is important in the pathogenesis of PTLDs.


OBJECTIVE
To characterize the expression patterns of these proteins in PTLDs, we studied a series of well-characterized cases for expression of LMP-1, TRAF-1, TRAF-2, TRAF-3, and NFkappaB by immunohistochemical analysis.


METHODS
A total of 27 specimens from 25 patients were analyzed for LMP-1, TRAF-1, TRAF-2, TRAF-3, and NFkappaB (active form) by immunohistochemical analysis. Expression of EBV-encoded RNA (EBER) was evaluated by in situ hybridization. Correlation between the expression of the different markers was performed using the Mantel-Haenszel chi(2) test. Cox proportional hazards analysis and Kaplan-Meier analysis with log-rank testing were used to analyze antigen expression and clinical outcome.


RESULTS
Ninety-six percent of PTLDs expressed NFkappaB, 74% to 84% expressed TRAFs, 78% expressed EBER, and 77% expressed LMP-1. TRAF-1, TRAF-2, and TRAF-3 expression did not correlate with either EBER or LMP-1 expression. TRAF-2, but not TRAF-1 or TRAF-3, expression correlated with NFkappaB expression (P =.02).


CONCLUSIONS
These results suggest that TRAF molecules and active NFkappaB are expressed in PTLDs regardless of EBV positivity. Given the association of TRAF-2 and active NFkappaB expression, TRAF-2 may play an important role in regulating this transcription factor in PTLD.
Ramalingam
Preetha
P
Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Chu
Wei-Sing
WS
Tubbs
Raymond
R
Rybicki
Lisa
L
Pettay
James
J
Hsi
Eric D
ED
D016026:Bone Marrow Transplantation / Q000009:adverse effects; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000378:metabolism* / Q000821:virology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D016377:Organ Transplantation / Q000009:adverse effects; D011506:Proteins / Q000276:immunology / Q000378:metabolism*; D012367:RNA, Viral / Q000032:analysis; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D011506:Proteins; D012367:RNA, Viral; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D014763:Viral Matrix Proteins