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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 617-623
Tumor Necrosis Factor Receptor-Associated Factor 1 Is Overexpressed
in Reed-Sternberg Cells of Hodgkin's Disease and
Epstein-Barr Virus-Transformed Lymphoid Cells
By
Horst Dürkop,
Hans-Dieter Foss,
Gudrun Demel,
Heike Klotzbach,
Corinna Hahn, and
Harald Stein
From the Institut für Pathologie, UK Benjamin Franklin, Freie
Universität Berlin, Berlin, Germany.
 |
ABSTRACT |
The tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1)
is a member of the recently defined TRAF family. It takes part in the
signal transduction of the TNF receptor 2 (TNFR2), the lymphotoxin-
receptor (LT-R), CD40, CD30, and LMP1; is induced by LMP1 in vitro;
and protects lymphoid cells from apoptosis. To identify the cells in
which TRAF1 is active in vivo, we studied TRAF1 transcripts in normal
lymphoid tissue, in Epstein-Barr virus (EBV)-induced
lymphoproliferations, and in malignant lymphomas with special reference
to those that overexpress the cytokine receptor CD30 and CD40 of the
TNF receptor family at the single-cell level using a radioactive in
situ hybridization. In normal lymphoid tissue, TRAF1 message proved to
be absent from all resting B and T cells as well as from macrophages
and accessory cells (follicular dendritic cells and interdigitating
cells) and present in few perifollicular and intrafollicular lymphoid
blasts. In contrast, there was a high and consistent TRAF1
overexpression in EBV-induced lymphoproliferations and Hodgkin's
disease. Nearly all non-Hodgkin's lymphoma show low or no TRAF1
expression. Only some cases of diffuse large B-cell lymphoma showed a
moderate to high TRAF1 signal. Several of the latter cases were
EBV+. These data confirm that TRAF1 is an inducible
molecule and indicates its deregulation in the mentioned disorders with
the potential of a blockage of the apoptotic pathway.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
THE TUMOR NECROSIS factor (TNF)
receptor-associated factor (TRAF) family is a recently established
group of molecules that are involved in the intracellular signal
transduction of several members of the tumor necrosis factor receptor
(TNFR) family, eg, the TNF receptor 2 (TNFR2), the lymphotoxin-
receptor (LT-R), the Epstein-Barr virus (EBV)-encoded latent
membrane protein 1 (LMP1), CD40, and CD30.1-8 The TRAF
family is defined by a C-terminal homology region, the TRAF
domain,1-3 which is further divided into two subdomains.
The N-terminal TRAF domain sequences are less conserved than the
C-terminal part and appear to contribute to the oligomerization of TRAF
proteins.1 The highly conserved C-terminal portion of the
TRAF domain is capable of binding to the intracellular portion of
TNFR2, CD40, CD30, LT-R, and LMP1.1 These members of the
TNFR family, like TNFR1 and Fas (APO-1/CD95), are known to transduce
signals regulating cell death and proliferation9 but lack
the intracellular death domain present in TNFR1 and Fas. Recently, it
has been shown that TNFR2, CD40, CD30, LT-R, and LMP1 exert their
function by interacting with TRAF1 (EBI6), TRAF2 (TRAP), TRAF3
(CD40bp/CRAF1/LAP1), TRAF5,7,8 or TRAF6,10 whereas the Fas and TNFR1 receptors bind to another group of molecules, including FADD (MORT1),11,12 RIP,13 and
TRADD,14 by their death domain.
Several members of the TNFR family mediate pleiotropic signals in
distinct lymphoid cells and there are examples that members of this
receptor group transduce contrary effects.9,15,16 These
different effects may be related in part to the differential expression
of receptor-associated molecules resulting in different signaling
pathways in these cells. To understand the mechanisms in the signal
transduction of lymphoid cells, one prerequisite is the knowledge of
the expression pattern of its components under normal, inflammatory,
and dysregulated neoplastic conditions. Although considerable data have
been accumulated about the function and molecular structure of the
members of the TRAF family, little is known about their expression in
vivo. Most data are derived from Northern blotting of RNA prepared from
murine tissues, demonstrating that TRAF2, TRAF3, TRAF5, and TRAF6 are
ubiquitously expressed, with the highest levels of TRAF2 and TRAF5
messages being observed in the spleen8 and in the lung and
spleen, respectively.10 In contrast, the expression of
TRAF1 and TRAF4 (CART1) appears to be more restricted, with selective
expression of TRAF4 in breast carcinoma17 and TRAF1 in
tonsils, spleen, and lung.4 TRAF1 expression was shown to
be induced in B-lymphoblast cell line BL41/B95-8 by the EBV-encoded
LMP1.4 These data suggest that, among the members of the
TNFR family, TRAF1 is the main candidate for being predominantly and
differentially expressed in the lymphoid system. Our interest in the
TRAF1 molecule was further raised by the observation that TRAF1 can
exert an apoptosis protective effect on CD8+ T
cells,18 pointing to the possibility that this molecule
might be involved in the regulation of apoptosis in certain reactive lymphoid cells and their neoplastic counterparts. To identify the
lymphoid populations in which TRAF1 is active, we investigated reactive
lymphoid tissues, EBV-induced lymphoproliferations, and a variety of
malignant lymphomas for the expression of TRAF1 transcripts.
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MATERIALS AND METHODS |
Material.
Paraffin-embedded specimens were drawn from the files of the Institute
of Pathology, Universitätsklinikum Benjamin Franklin, Freie
Universität Berlin (Berlin, Germany). The present series consisted of 23 cases of classical Hodgkin's disease (HD; 12 cases of
mixed cellularity and 11 cases of nodular sclerosis), 5 cases of
lymphocyte-predominant HD (LPHD), 13 cases of anaplastic large-cell lymphoma (ALCL; 6 cases of B-ALCL, 5 cases of T-ALCL, and 2 cases of
0-ALCL), 5 cases of B-cell chronic lymphocytic leukemia/lymphoma (B-CLL), 15 cases of diffuse large B-cell lymphoma (DLBCL), 5 cases of
plasmoblastic lymphoma (PLBLL), 2 cases of Burkitt's lymphoma, 6 cases
of atypical EBV-associated lymphoproliferative disorders (ALP), 7 tonsils with the diagnosis of infectious mononucleosis, and further 5 tonsils with the diagnosis of follicular hyperplasia.
The lymphomas were classified according to the REAL
classification.19
TRAF1 and EBV-encoded small RNA (EBER) probes.
RNA was prepared from the large anaplastic lymphoma cell line Karpas
299.20 The cDNA was generated with the Moloney murine reverse transcriptase. The complete open reading frame of TRAF1 cDNA
from nucleotide position 76 to 1326 of the published
sequence4 was amplified with the following primers:
5 -ATGGCTGCAGCTAGCGT-3 and
5-TTAGAGCCCTGTCAGGTCC-3 by polymerase chain reaction
(PCR; 40 cycles with 55°C annealing temperature, 72°C
elongation step, and 94°C denaturation). The EBER probe was a
generous gift from Dr Niedobitek (Birmingham,
UK).21
In situ hybridization.
After cloning of the PCR product into the pAMP1 vector (GIBCO-BRL,
Eggenstein, Germany) and linearization, antisense and sense probes were
generated by SP6 and T7 polymerases (GIBCO-BRL, Eggenstein, Germany),
respectively. In situ hybridization was performed as described
previously.22 Two sections of each case were incubated with
the TRAF1 antisense probe and a further section of each case was
hybridized with the TRAF1 sense probe as negative control. Autoradiography was performed after coating the slides with
radiographic emulsion (Amersham, Braunschweig, Germany) exposed at
4°C for 3 to 6 weeks, developed in Kodak D19 developer (Kodak,
Hemel Hempstead, UK), and counterstained with hematoxylin and eosin.
The detection of EBER was performed according to Herbst et
al.23
Evaluation.
The number of positive and negative cells was counted. The intensity of
the TRAF1 signal was estimated by counting the grains over 20 cells of
each case after an exposure time of 6 weeks. An average of grains was
calculated for each case. The hybridizations with the TRAF1 sense probe
showed only weak background staining of about 5 to 8 grains per cell.
Cells that showed 10 or less than 10 grains after hybridization with
the TRAF1 antisense probe were considered to be
TRAF1 . Low intensity was defined as less than 30 grains but more than 10 grains, medium intensity was defined as more
than 30 grains but less than 150 grains, and strong intensity was
defined as more than 150 grains above one cell.
Immunohistochemistry.
Paraffin sections of 5 to 6 µm were mounted, dried, and boiled for 2 minutes in 10 mmol/L citrate buffer, pH 6.0. Subsequently, immunohistochemistry and immunocytochemistry were performed using the
alkaline phosphatase anti-alkaline phosphatase (APAAP)
technique.24 EBV infection was analyzed by immunostaining
for LMP1 with the mixture of monoclonal antibodies (MoAbs; CS1-4; DAKO,
Hamburg, Germany) in every case. In LMP1+ cases, the EBV
latency infection type was further characterized by immunostainings for
EBNA2 (MoAb PE2; DAKO) and ZEBRA (MoAb BZ1; DAKO).
The data were statistically analyzed using the  2 test.
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RESULTS |
TRAF1 expression in reactive lymphoid tissue.
In all 5 hyperplastic tonsils investigated, a weak to intermediate
TRAF1 message was detected in a few extrafollicular and intrafollicular
blasts (Fig 1). Resting lymphoid cells,
including mantle cells and small paracortical lymphoid cells as well as nearly all cells of the follicular center, were
TRAF1. Macrophages and accessory cells, such as
follicular dendritic cells and interdigitating cells, also did not show
any TRAF1 message.
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| Fig 1.
Hyperplastic tonsil hybridized with a TRAF1 antisense
probe (exposure, 6 weeks; original magnification × 250; original
magnification of the insert × 900). Note the few faintly
TRAF1+ lymphoid blasts (arrows and insert).
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TRAF1 expression in EBV-associated disorders (infectious
mononucleosis and atypical lymphoproliferation [ALP]).
In 6 of 7 tonsils affected by infectious mononucleosis, moderate to
strong TRAF1 hybridization signals were detectable in about half of the
interfollicular lymphoid blasts (Table 1). Simultaneous hybridization with an EBER and TRAF1 antisense probe showed in 5 of 6 cases that more than 50% of EBV+ lymphoid
blasts coexpressed a medium to great amount of TRAF1 mRNA
(Fig 2A and B). In ALP, the TRAF1
expression was moderate or high (Table 2).
In 2 cases, nearly all lymphoid blasts harbored an intermediate or high
amount of TRAF1 mRNA. In the remaining 4 cases, 30% to 40% of the
lymphoid blasts showed medium to high amounts of TRAF1 transcripts.
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| Fig 2.
(A and B) Double-labeling of tonsillar tissue from
patients with infectious mononucleosis with the TRAF1 (black) and EBER
(red) antisense probes (exposure of autoradiography, 6 weeks; original
magnifications × 350 [A] and × 150 [B]). The TRAF1 probe was
labeled by 35S-UTP, whereas the EBER probe was labeled by
UTP-digoxigenin and detected by antidigoxin alkaline phosphatase
conjugates.
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TRAF1 expression in lymphomas.
The Hodgkin and Reed-Sternberg (HRS) cells of 23 cases of classic HD
studied contained in 16 cases a high amount and in 5 cases an
intermediate amount of TRAF1 transcripts
(Fig 3A and B; Table 3). Seven of the 23 cases showed a few TRAF1+ bystander cells, with low amount
of TRAF1 mRNA in 6 and large amounts in 1 case. In LPHD, the level of
TRAF1 message seemed to be lower than in classical HD.
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| Fig 3.
(A and B) TRAF1 in situ hybridization of two cases of
classical HD. (A) represents a case of the nodular sclerosis subtype
(exposure, 6 weeks; original magnification × 175), whereas a case of
the mixed cellularity subtype is shown in (B) (exposure, 6 weeks;
original magnification × 350). Note the distinct label of the tumor
cells in both cases.
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ALCLs were found to express lower amounts of TRAF1 when compared with
HD (P < .001). Among ALCL, the TRAF1 expression was lowest in
T-ALCL. In general, a minority of tumor cells showed a low to moderate
TRAF1 expression in cases of DLBCL. Only in 2 cases was more than 50%
of tumor cells moderately to strongly TRAF1+, whereas 1 case of DLBCL was completely TRAF1. In PLBLL, TRAF1
expression was detectable in only 1 of 5 cases. The low-grade B-cell
lymphoma of B-CLL type was TRAF1, except for some
paraimmunoblasts.
A correlation between TRAF1 expression and EBV infection was also found
in lymphomas. A high TRAF1 expression was found more frequently in the
lymphomas with EBV+ tumor cells than in those ones with
EBV tumor cells (P < .001). This
association was confirmed by double-labeling for TRAF1 and EBER
transcripts in several cases of EBV+ classical HD,
showing that most of the HRS cells were
TRAF1+/EBV+.
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DISCUSSION |
This study presents the first data about TRAF1 expression in human
reactive and neoplastic lymphoid tissues at the single-cell level. We
focussed our work on TRAF1 because Northern blot data4 had
shown that, in comparison with other members of the TRAF family, TRAF1
appears to be most restricted in its expression to the lymphoid tissue.
To identify the lymphoid cells that express TRAF1, we applied a highly
sensitive in situ hybridization technique using radioactive probes
specific for TRAF1. These studies showed that TRAF1 message is absent
from resting lymphoid cells, including mantle cells and small
paracortical T cells. Among the proliferating cells of the normal
lymphoid tissue, only a few extrafollicular and intrafollicular
lymphoid blasts contained significant amounts of TRAF1 message. This
distribution resembles that of CD30+ blasts,25
suggesting that these blasts coexpress TRAF1 and CD30. A moderate to
strong expression of TRAF1 was found in the EBV-infected blasts present
in infectious mononucleosis and EBV-induced atypical
lymphoproliferations. In both lesions, many of the infected cells also
express the EBV-encoded LMP1. These findings are of interest in respect
to observations showing that LMP1 induces TRAF1 expression in
EBV-transformed B-lymphoblastic cell lines and that LMP1 binds most of
the TRAF1 protein in these cells.4,26 Our findings
demonstrate that this mechanism might also work in vivo.
The TRAF1 expression pattern found in normal and reactively diseased
lymphoid tissue fits in with the TRAF1 expression encountered in
malignant lymphomas. Among these, the most constant and highest TRAF1
expression was found in HRS cells of HD. The TRAF1 transcript signals
were strongest in the EBV+ cases. Moderate to low amounts
of TRAF1 message were seen in EBV-infected DLBCL, whereas the
non-Hodgkin's lymphoma (NHL) of B-CLL type that closely corresponds to
normal resting B cells was TRAF1 except for a few
paraimmunoblasts. TRAF1 expression in other NHLs was low and/or
heterogeneous, with the number of cases being too small to be
representative.
Recently, Liebowitz27 demonstrated that TRAF1 colocalizes
with LMP1 by double-immunofluorescence microscopy and that both proteins could be coimmunoprecipitated in all LMP1+ cases
of acquired immunodeficiency syndrome (AIDS)-associated NHL and
posttransplantational lymphoproliferative disease. He found functional
consequences of the TRAF1-LMP1 cooperation in all of these
LMP1+ cases by the demonstration of activated NF- B
in electrophoretic mobility shift assays. Our data extend the
expression pattern of TRAF1 reported, particularly in the cases of
EBV-associated HD and infectious mononucleosis, and suggest that
similar mechanisms might lead to NF-B induction in the HRS cells of
EBV-associated HD.28
There is compelling evidence that B cells that are unable to express
Igs are eliminated by apoptosis.29 HRS cells of most cases
of HD have recently been shown to contain clonally rearranged Ig
genes30,31 but consistently lack Ig
expression.32 Hence, it follows that HRS cells represent B
cells that should die of apoptosis. The fact that this usually does not
happen points towards a blockage of the apoptotic pathway in HRS cells.
Recent studies provided evidence that NF-B is involved in the
protection of HRS cells from apoptosis.28 Devergne et
al26 showed that NF-B activation is likely mediated by
TRAF1/TRAF2 heteroaggregates. In view of the findings by Speiser et
al18 that TRAF1 overexpression in transgenic mice inhibits
antigen-induced apoptosis in CD8+ T lymphocytes, it is
tempting to speculate that TRAF1 is involved in the blockage of
apoptosis in HRS cells.
TRAF1 takes part in the signal transduction of TNFR2, LT-R, CD40,
CD30, and LMP1.1,4,33 In HD and EBV-induced
lymphoproliferations, CD40 and CD30 are most consistently
expressed.34-36 Therefore, CD40 and CD30 are the most
likely cooperation partners of TRAF1 in these disorders apart from LMP1
in the EBV+ cases. Further studies are needed to clarify
how these receptors interact with TRAF1 to transduce their signals.
Messineo et al37 published that TRAF1 expression is highly
heterogenous in the HRS cells of 6 cases of HD. They used a single-cell PCR technique on suspended lymphoid tissues. These results are partially in contradiction with our data demonstrating that TRAF1 is
highly overexpressed in the majority of HRS cells. This discrepancy may
be due to the difficulty in identifying HRS cells in cellular suspensions.38
Taken together, the data presented here confirm that TRAF1 is an
inducible molecule and show that TRAF1 in normal lymphoid tissue is
expressed rarely and weakly, but in EBV-induced lymphoproliferations and HD is consistently and strongly expressed. The
differential expression of TRAF1 demonstrated here might partially
explain that one and the same member of the TNFR family can induce cell death after its stimulation in one cell type and proliferation in
another type.9,15,16 Further investigations are necessary to clarify the role of TRAF1 in EBV-associated lymphoproliferations and
in HD.
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ACKNOWLEDGMENT |
The authors are indebted to E. Berg for the excellent technical
assistance.
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FOOTNOTES |
Submitted June 4, 1998;
accepted September 14, 1998.
Supported by Deutsche Forschungsgemeinschaft (SFB 366) and the Deutsche
Krebshilfe (Grants No. W76/93/Dü1 and Ste318/5-2).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Horst Dürkop, MD, Institut für
Pathologie, UK Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin,
Germany.
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Single-cell analysis of Hodgkin and Reed-Sternberg cells: Molecular heterogeneity of gene expression and p53 mutations.
Blood
81:3097, 1993[Abstract/Free Full Text]
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Abstract
Introduction