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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2477-2483
Analysis of Major Histocompatibility Complex Class I, TAP
Expression, and LMP2 Epitope Sequence in Epstein-Barr
Virus-Positive Hodgkin's Disease
By
Paul G. Murray,
Christothea M. Constandinou,
John Crocker,
Lawrence S. Young, and
Richard F. Ambinder
From the CRC Institute for Cancer Studies, University of Birmingham,
Edgbaston, Birmingham; the School of Health Sciences, University of
Wolverhampton, Wolverhampton; the Department of Histopathology,
Birmingham Heartland Hospital, Birmingham, UK; and Johns Hopkins
Oncology Center, Baltimore, MD.
 |
ABSTRACT |
The Epstein-Barr virus (EBV)-encoded latent membrane proteins, LMP1
and LMP2, are consistently expressed by the malignant Hodgkin/Reed-Sternberg (HRS) cells of EBV-associated Hodgkin's disease
(HD). Cytotoxic T lymphocyte (CTL) responses to both of these proteins
have been shown in the blood of EBV-seropositive individuals, yet in HD
the apparent failure of the CTL response to eliminate HRS cells
expressing LMP1 and LMP2 in vivo has given rise to the suggestion that
HD may be characterized by the presence of defects in antigen
processing/presentation or in CTL function. This study has used
immunohistochemistry to show high-level expression of major
histocompatibility complex (MHC) class I molecules by the HRS cells of
EBV-associated HD and either low level or absence of expression of MHC
class I molecules on HRS cells of EBV-negative tumors. In addition, HRS
cells expressed high levels of transporter-associated proteins (TAP-1,
-2), irrespective of the presence of latent EBV infection. These
results suggest that global downregulation of MHC class I molecules
does not account for the apparent ability of EBV-infected HRS cells to
evade CTL responses, but may be important in the understanding of
EBV-negative disease.We have also sequenced an epitope in LMP2A
(CLGGLLTMV) that is restricted through HLA A2.1, a relatively
common allele in Caucasian populations, and showed that
this epitope is wild type in a small group of EBV-associated HLA
A2.1-positive HD tumors. This result may be relevant to proposed immunotherapeutic approaches for EBV-positive HD patients that target
CTL epitopes.
| |
INTRODUCTION |
THE EPSTEIN-BARR VIRUS (EBV) is a human
herpesvirus that infects approximately 95% of the world's adult
population.1 EBV is generally carried as a clinically
silent infection but is strongly implicated in the pathogenesis of a
number of human malignancies including African Burkitt's
lymphoma,2,3 nasopharyngeal carcinoma,4,5 and
more recently, Hodgkin's disease (HD). EBV DNA has been detected in
the tumor samples of HD patients by Southern blotting and polymerase chain reaction (PCR) analysis6-9 and a variety of studies
have localized viral DNA10 and virus gene
products11-13 to the malignant Hodgkin/Reed-Sternberg (HRS)
cells of HD. Furthermore, using EBV terminal repeat probes, the EBV
genomes within individual cases have been shown to be monoclonal in
origin, suggesting that monoclonal proliferation occurred after EBV
infection.7,8,10,14 The frequent occurrence of abnormally
elevated titers of antibodies against EBV antigens before the onset of
overt disease and the detection of impaired cellular responses to EBV
in HD patients have led to the hypothesis that a defective control of
EBV-infected cells might be important in the pathogenesis of a
proportion of HD tumors.15-19 EBV-infected HRS cells are
characterized by a pattern of viral protein expression that is
restricted to EBNA1, LMP1, and LMP2.12,20-23 Although the
dominant CTL responses seem to be directed to epitopes in proteins of
the EBNA3 family, LMP1 and LMP2 have been shown to be targets for
autologous cytotoxic T lymphocytes (CTLs) in vitro.24-27 The apparent failure of the immune system to eliminate HRS cells expressing potential targets for CTLs has provided further support for
immunologic dysfunction in EBV-associated HD.
One possible mechanism of CTL escape in EBV-associated HD may be
downregulation of major histocompatibility complex (MHC) class I
molecules on HRS cells. CTLs recognize endogenously processed virus
proteins only when presented at the cell surface as peptides bound to
MHC class I molecules. A reduction or the absence of MHC class I
expression can therefore render virus-infected cells resistant to CTL
destruction. Such a mechanism has been shown previously for some
virus-associated tumors, including EBV-associated Burkitt's lymphoma
(BL) and a proportion of human papilloma virus (HPV)-infected cervical
carcinomas.28-31 In the case of HPV-positive cervical
carcinomas, MHC class I downregulation was associated with the loss of
function of one of the transporter-associated proteins
(TAP-1).32,33
It has been shown that amino acid substitutions at key positions within
peptides presented by MHC class I molecules may reduce or completely
abrogate CTL responses. For example, two HLA A11-restricted CTL
epitopes (residues 399-408 and 416-424) from the EBNA3B protein are
regularly mutated in EBV strains from Southeast Asia,34,35 and memory CTL responses specific for the variant epitopes have not
been detectable in HLA A11-positive Chinese donors infected with the
mutated viruses. It is possible that similar mechanisms might also
account for the failure of CTLs to eliminate EBV-infected HRS cells.
Therefore, the aim of this current study was to investigate the
expression of MHC class I and TAP molecules in both EBV-positive and
EBV-negative HD. The identification of an epitope in LMP2 (CLGGLLTMV) that is restricted through HLA A2.1, a relatively common allele in Caucasian populations, provides an ideal
target to study the possibility that epitope variations in EBV genes expressed in tumor tissues might be responsible for CTL
escape.36
| |
MATERIALS AND METHODS |
Preparation of specimens.
Paraffin-wax sections and paraffin-wax-embedded tissue blocks from 39 cases of HD were available from the pathology files of the Johns
Hopkins Hospital, Baltimore, MD; and the Queen Elizabeth Hospital,
Birmingham, UK. From tissue blocks 4-µm paraffin sections were
prepared and all sections were deparaffinized and washed in
Tris-buffered saline (TBS), pH 7.6. Cryostat sections were also
prepared from selected samples. Hematoxylin and eosin-stained sections
of HD tumors were reviewed and subtyped according to the Rye
classification system.
Detection of latent EBV infection.
In situ hybridization for the detection of the Epstein-Barr virus early
RNAs (EBERs) was performed according to standard methods.37 Positive controls for EBER in situ hybridization included paraffin-wax sections of lymphoblastoid cell lines (LCL) grown as solid tumors in
severe combined immunodeficiency (SCID) mice (LCL-SCID tumors) and a
known EBER-positive HD case. U6 and sense control probes were included
in all runs.
Immunohistology.
Immunohistochemistry for LMP1 and LMP2 was also performed on selected
cases to confirm the presence of latent EBV infection in HRS cells.
Immunostaining for MHC class I and TAP-1 was performed on acetone-fixed
frozen and paraffin-wax sections of HD tissues and on a variety of cell
lines (Table 1), including the HD lines HDLM2, L428, HS445, and Km-H2. HD cell lines and selected HD biopsies were also stained for TAP-2. Immunohistochemistry for TAP-1 and TAP-2
was additionally performed on acetone-fixed cytospin preparations of
the BL lines, Mutu I (group I BL) and Mutu III (group III BL).
The demonstration of some antigens in paraffin material required
microwave pretreatment in 0.1 mol/L citrate buffer, pH 6.0. The optimum
microwave pretreatment times were determined for each antigen and are
listed in Table 2. After pretreatment,
endogenous peroxidase activity was blocked in 0.3% hydrogen peroxide
in methanol and sections transferred to TBS.
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Table 2.
Primary Antibodies Used in the Immunohistochemical
Analyses, Together With Optimum Dilutions and Microwave
Pretreatment Times
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Sections were then incubated in primary antibodies at optimum dilutions
previously determined for each antibody (Table 2). All primary
antibodies were diluted in 10% normal sheep serum. Mouse monoclonal
antibodies were detected either using the peroxidase-based Dako Duet
system (Dako Ltd cat no: K492; Dako Ltd, Glostrup,
Denmark) or the standard alkaline phosphatase and alkaline
phosphatase (APAAP) method. The rat monoclonal antibody to
LMP2 was detected using rabbit anti-rat immunoglobulins (Dako Ltd cat
no: Z455) at a dilution of 1:400, followed by the Dako Catalyzed Signal Amplification system (Dako Ltd cat no:K0620).
Positive controls for LMP1 and LMP2 immunostaining consisted of
paraffin-wax sections of LCL-SCID tumors. Positive controls for MHC
class I, TAP-1, and TAP-2 included paraffin-wax and frozen sections of
human tonsil. Negative controls for immunohistochemistry consisted of
consecutive test sections in which the primary antibody was replaced
with nonimmune serum of the same IgG subclass. Full details of
antibodies used are given in Table 2.
Epitope sequencing.
A series of frozen HD biopsies were initially studied to determine
their EBV and MHC status. The presence of latent EBV infection was
determined as described above. HLA A2.1-positive tumor samples were
identified in APAAP immunohistochemical assays using the MA2.1 antibody
(Table 2). A variety of HLA A2.1-positive cell lines (both homozygous
and heterozygous) and HLA A2.1-negative cell lines (Table 1) were used
as controls in these immunohistochemical assays. Both acetone-fixed
cytospin preparations and frozen sections of SCID tumors generated from
these lines were tested.
HLA A2.1 and EBV-positive HD samples identified in this way were
subjected to DNA extraction and PCR sequencing to determine the
sequence of the LMP2A epitope, CLGGLLTMV, previously identified to be
restricted through HLA A2.1. Sequences were compared with wild-type
(B95.8) DNA. To obtain sufficient DNA from HD biopsies for sequencing
it was necessary to extract DNA from agarose gels for reamplification.
Primers, D5639LY and D5640LY (Fig 1A), were used in both PCR amplification and sequencing steps. Sequencing was
performed twice in both directions on all samples.
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| Fig 1.
(A) LMP2A sequence showing position of epitope and
primers used in the PCR and sequencing analyses. (B) Autoradiograph of
sequencing gel showing wild-type LMP2 sequence.
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| |
RESULTS |
Detection of latent EBV gene expression.
EBER expression was shown in HRS cells of 18 of 39 examined HD cases.
The expression of LMP1 in all EBER-positive HD cases was confirmed by
immunohistochemistry. LMP2 protein was also detectable in the cytoplasm
of HRS cells in 16 of 16 EBV-positive HD cases (Fig 2).
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| Fig 2.
Immunohistochemical demonstration of LMP2 expression by
HRS cells in a case of EBV-positive HD.
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MHC class I staining.
In all tissue sections, the presence of MHC class I-positive cells
served as an internal control. Expression of MHC class I was mainly
confined to the cell membrane of positively stained cells. Of 17 cases
of EBER-positive HD analyzed, 13 showed the presence of MHC class I
expression on HRS cells. However, MHC class I expression was detectable
on HRS cells in only 4 of 21 cases of EBV-negative HD. In most
EBV-positive HD samples, HRS cells could be easily identified because
the intensity of class I staining was often stronger than on
surrounding reactive cells (Fig 3A). This
was in contrast to the majority of EBV-negative HD tumors, where HRS
cells were either not stained or only weakly stained for class I (Fig
3B). Class I expression was not related to subtype, and similar results
were obtained on paraffin and frozen sections of HD tumors. In all
cases, reactivity of surrounding reactive cells could be distinguished
from staining on HRS cells. The HD cell lines, HDLM2, Km-H2, and HS445,
all showed strong expression of MHC class I, whereas the HD cell line,
L428, was consistently negative in all assays (not shown).
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| Fig 3.
Immunohistochemistry for MHC class I expression. Long
black arrows show class I expression on HRS cells (A) or its absence
(B). The intensity of class I staining on surrounding small reactive
cells (short red arrows) is less than that of the HRS cells in (A) and
greater than that of the HRS cells in (B).
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Immunohistochemistry for TAP-1 and TAP-2.
On control tonsil tissue, germinal center cells were generally not
stained for TAP-1 and TAP-2, with the exception of occasional positive
cells. The interfollicular cells were most strongly stained for both
markers and the squamous epithelium, when present, was also positively
stained (data not shown). Similar results were obtained on both frozen
and paraffin-wax sections. Cell preparations (both acetone-fixed
cytospins and pelleted paraffin-wax sections) of Mutu I and Mutu III
cell lines expressed both TAP-1 and TAP-2, although staining for both
markers was noticeably weaker in Mutu I cells when compared with the
Mutu III line. All the HD cell lines tested (HDLM2, L428, HS445, and
Km-H2) were strongly stained for both TAP-1 and TAP-2. Frozen and
paraffin wax-embedded HD tumors were also analyzed for TAP-1 and TAP-2
expression. With the exception of two HD cases, HRS cells showed strong
staining for TAP-1 (Fig 4), irrespective of
the presence of latent EBV infection in these cells. Selected HD cases
were also stained for TAP-2. In all cases, HRS cells showed strong
staining for TAP-2 (not shown).The results of EBER in situ
hybridization, MHC I, and TAP-1 immunohistochemical assays are
summarized in Table 3.
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Table 3.
Expression of MHC Class I and TAP-1 by HRS Cells in HD
Specimens: Correlation With the Presence of EBV Within HRS Cells as
Determined by EBER In Situ Hybridization (EBERs) and Subtype
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Epitope sequencing.
A series of LCLs prepared from HLA A2.1-positive and -negative donors
(Table 1) initially served as controls for the MA2.1 antibody. All cell
lines from A2.1-positive donors reacted strongly with this antibody in
APAAP assays, and all A2.1-negative cell lines, as expected, were
nonreactive (data not shown).
Of the 20 HD biopsies available as frozen material, 9 contained
EBER-positive HRS cells, and a further 6 of these were HLA A2.1
positive by immunohistochemistry. These 6 biopsies were subjected to
PCR analysis to determine the sequence of the A2.1-restricted LMP2A-derived CTL epitope, CLGGLLMTV (Fig 1B). All 6 HD tumors showed
wild-type epitope sequence.
| |
DISCUSSION |
There are strong indications that the outgrowth of EBV-infected tumors
in vivo is dependent on the pattern of viral antigens expressed by the
tumor and also the level of immunocompetence of the host. For example,
the role of immunosurveillance in limiting the proliferation of
EBV-infected cells in vivo is clearly illustrated by the development of
EBV-positive lymphoproliferative disease in immunocompromised
individuals.38-41 These lymphoproliferations may be
regarded as the in vivo counterpart of LCLs. Indeed, these lesions
often regress when immunosuppressive therapy is withdrawn or
reduced.42,43 Many of these lesions express the full
spectrum of EBV latent genes, with high cell surface expression of
ICAM1 and LFA3 providing a wide range of potential targets for the
immune system.44 It generally has been assumed that the
sensitivity of these lesions to EBV-specific CTLs may be similar to
LCLs. Evidence supporting this assumption has recently been provided by
adoptive transfer experiments in which donor lymphocytes were used as a
source of virus-specific CTLs to treat EBV lymphoproliferative disease
in bone marrow transplant recipients.45,46
In contrast to posttransplant lymphoproliferative disease and related
conditions, HD arises in relatively immunocompetent hosts. The
consistent expression of LMP1 and LMP2 in EBV-positive HD3,12,20,21 and the demonstration of effective CTL
responses to epitopes derived from these proteins in
vitro36,47,48 implies that defects in the antigen
processing/recognition machinery may be a feature of these tumors. The
mechanisms accounting for the failure of CTLs to eliminate EBV-infected
HRS cells have not been established yet, although MHC class I
downregulation by HRS cells, as originally demonstrated by Poppema and
Visser,49 has been suggested as a possible mechanism.
This study has shown high-level expression of MHC class I molecules on
the surface of HRS cells in EBV-associated HD cases, and much lower
levels of expression or the absence of expression on HRS cells in
EBV-negative samples, and is in accordance with the results of a
previous study.50 These results suggest that MHC class I
downregulation is unlikely to account for the failure of CTLs to
eliminate the tumor cells, at least in EBV-positive cases. The
mechanism responsible for downregulation or absence of MHC molecules in
EBV-negative HD has yet to be determined. Unlike cervical carcinomas,
where downregulation of MHC class I was associated with low-level
expression of TAP molecules,32 downregulation of TAP
molecules was not shown in this present study. The high-level
expression of MHC class I molecules on EBV-positive HRS cells
potentially could be mediated by LMP1 expression. LMP1 has been shown
to upregulate class I expression when transfected into EBV-negative
B-cell lines51 and epithelial cells (Dawson C. and L.S.Y.,
unpublished observations). LMP1 also has been shown to
increase the stimulatory capacity of EBV-negative BL lines in
allogeneic mixed lymphocyte cultures,51 to upregulate the expression of adhesion molecules,52 and to enhance the
presentation of endogenous and exogenous antigens.53,54
Another possible mechanism of CTL escape is suggested by the finding
that memory CTL responses specific for variant epitopes in two HLA
A11-restricted CTL epitopes (residues 399-408 and 416-424) from the
EBNA3B protein were not detectable in HLA A11-positive Chinese donors
infected with strain variants.34,35 This present study has
established that a recently identified epitope in LMP2 that is
restricted through HLA A2.155 is wild type in a small
series of HLA A2-positive HD tumors, suggesting that mutation in virus
epitope sequences may not be a common feature of EBV-positive HD, at
least in this group of patients. Similar data showing that this same
epitope is not commonly mutated has been presented by Bryden et
al.56 The lack of mutation may have important implications
for potential CTL therapy for HD patients, particularly because the CTL
response to this epitope previously has been shown to be reactive
against a range of virus isolates, including type-1 and type-2
Caucasian, Southeast Asian, New Guinean, and African
isolates. Some of these isolates contained amino acid substitutions
within the epitope, but were nevertheless recognized by CTLs raised
against the B95.8 virus.36 The finding of similar,
functionally conserved epitopes restricted through relatively common
HLA alleles may be important for the future development of CTL therapy
for EBV-associated HD.
Recent studies have shown that the HD cell line, HDLM2, is able to
process and present epitopes from LMP1 and LMP2 in the context of
multiple class I alleles including HLA A2 and is sensitive to lysis by
EBV-specific CTLs.48 Furthermore, using autologous fibroblasts infected with a vaccinia recombinant encoding LMP2 as a
target, the same authors were able to identify and expand LMP2-specific
CTLs from the peripheral blood of an HD patient. However, recent data
have pointed to the possibility of local suppression of EBV-specific
immunity in the vicinity of the tumor that may confound certain
immunotherapeutic strategies in HD. This was first suggested by a
comparative study of EBV-specific responses in patients with
EBV-positive and EBV-negative HD which failed to show virus-specific
cytotoxicity in the tumor-infiltrating lymphocytes of six EBV-positive
cases.57 However, CTL precursors were detected in the blood
of one of the EBV-positive patients. A possible explanation of this
finding was reported by Herbst et al,58 who showed that
significantly higher proportions of EBV-positive HD cases contained
interleukin-10 (IL-10)-expressing tumor cells when compared with
EBV-negative tumors, suggesting that IL-10 production by HRS cells may
be responsible for local downregulation of the CTL response in
EBV-positive cases.58
The results of this present study provide some encouragement for the
pursuit of CTL therapy for EBV-associated HD. However, further work is
required to establish if the microenvironment of EBV-positive HRS cells
is responsible for the inhibition of virus-specific CTLs and whether
this effect is likely to confound immunotherapeutic strategies targeted
at EBV-positive HD patients.
| |
NOTE ADDED IN PROOF |
Similar data regarding MHC class I and TAP expression in Hodgkin's
disease have recently been presented.67
| |
FOOTNOTES |
Submitted April 24, 1998;
accepted June 2, 1998.
R.F.A. is a Leukemia Society Scholar.
Supported by the Cancer Research Campaign and the National Institutes
of Health Grants No. PO1 CA15396 and PO1 CA69266.
Address reprint requests to Richard F. Ambinder, MD, PhD, Johns Hopkins
Oncology Center, 418 N Bond St, Baltimore, MD 21231.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract
