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LABORATORY INVESTIGATION
Vol. 82, No. 4, p. 403, 2002
Copyright © 2002 by The United States and Canadian Academy of Pathology, Inc.
Printed in U.S.A.
An Immunohistochemical Study of the Distribution of
the Measles Virus Receptors, CD46 and SLAM, in
Normal Human Tissues and Subacute
Sclerosing Panencephalitis
Stephen McQuaid and Sara Louise Cosby
Neuropathology Laboratory (SM), Royal Victoria Hospital, and School of Biology and Biochemistry (SLC), Queen’s
University Belfast, Belfast, Northern Ireland
SUMMARY: We have compared the expression of the known measles virus (MV) receptors, membrane cofactor protein (CD46)
and the signaling lymphocyte-activation molecule (SLAM), using immunohistochemistry, in a range of normal peripheral tissues
(known to be infected by MV) as well as in normal and subacute sclerosing panencephalitis (SSPE) brain. To increase our
understanding of how these receptors could be utilized by wild-type or vaccine strains in vivo, the results have been considered
with regard to the known route of infection and systemic spread of MV. Strong staining for CD46 was observed in endothelial cells
lining blood vessels and in epithelial cells and tissue macrophages in a wide range of peripheral tissues, as well as in Langerhans’
and squamous cells in the skin. In lymphoid tissues and blood, subsets of cells were positive for SLAM, in comparison to CD46,
which stained all nucleated cell types. Strong CD46 staining was observed on cerebral endothelium throughout the brain and also
on ependymal cells lining the ventricles and choroid plexus. Comparatively weaker CD46 staining was observed on subsets of
neurons and oligodendrocytes. In SSPE brain sections, the areas distant from lesion sites and negative for MV by
immunocytochemistry showed the same distribution for CD46 as in normal brain. However, cells in lesions, positive for MV, were
negative for CD46. Normal brain showed no staining for SLAM, and in SSPE brain only subsets of leukocytes in inflammatory
infiltrates were positive. None of the cell types most commonly infected by MV show detectable expression of SLAM, whereas
CD46 is much more widely expressed and could fulfill a receptor function for some wild-type strains. In the case of wild-type
stains, which are unable to use CD46, a further as yet unknown receptor(s) would be necessary to fully explain the pathology of
MV infection. (Lab Invest 2002, 82:403–409).
easles virus (MV) causes approximately one
million deaths per year despite the availability
Membrane cofactor protein (CD46), a regulator of
complement-mediated lysis, has been shown to act as
a receptor for vaccine strains of MV but not all
wild-type strains of the virus (Dorig et al, 1994; Gerlier
et al, 1995). CD46 is expressed on all nucleated cells
in tissue culture, and in normal tissues CD46 has been
found to be widely distributed on lymphocytes, epi-
thelium, and endothelium (Berryman et al, 1993;
Franck et al, 1993; Johnstone et al, 1993b; Seya et al,
M
of an effective live-attenuated vaccine. Acute infection
is associated with initial infection of the respiratory
epithelium, with virus spread to lymph nodes followed
by viremia and infection of epithelial and endothelial
cells (EC) in many peripheral organs, including skin.
The latter is responsible for a delayed-type hypersen-
sitivity reaction, giving rise to the typical rash. Com-
plications of MV infection include giant cell pneumonia
and otitis media. Infections of the central nervous
system (CNS), which are less common, include mea-
sles inclusion body encephalitis and subacute scle-
rosing panencephalitis (SSPE) (Griffin and Bellini,
1988). These are the susceptible cell types for MV in
lymphoid tissues and other organs, including skin,
kidney, gastrointestinal tract, and liver during child-
hood measles infection (Moench et al, 1988). We and
others have previously established that MV receptor
competent CD46 proteins are expressed in brain
tissue from patients with persistent CNS MV infections
1
996). Neurons and oligodendrocytes are the most
common cell types infected in the CNS. However,
infection of astrocytes, macrophages, endothelium,
and infiltrating lymphocytes has been detected (Allen
et al, 1996; Cosby et al, 1989; Kirk et al, 1991).
(Buchholz et al, 1996; Ogata et al, 1997), and we have
shown that the receptor is absent in MV-positive
lesions, suggesting down-regulation of the molecule
(Ogata et al, 1997).
More recently the signaling lymphocyte-activation
molecule (SLAM) or CDw150, a membrane glycopro-
tein expressed on primary B cells, activated T cells
and memory T cells, T-cell clones, and immature
thymocytes (Sidorenko et al, 1992), has been shown
to act as a receptor for both the vaccine strain and
Received October 15, 2001.
Address reprint requests to: Dr. Stephen McQuaid, Department of Neuro-
pathology, Institute of Pathology, Royal Victoria Hospital, Grosvenor Road,
Belfast, Northern Ireland, BT12 6BL. E-mail: s.mcquaid@qub.ac.uk
Laboratory Investigation • April 2002 • Volume 82 • Number 4 403

McQuaid and Cosby
clinical isolates of MV (Erlenhoefer et al, 2001; Tatsuo
et al, 2000). Expression of SLAM has previously been
examined in lymphomas (Sidorenko et al, 1992), but
expression in peripheral tissues and brain, from nor-
mal individuals, has not been investigated. Further-
more, SLAM has not been examined in brain tissue
from SSPE patients.
In this study we have compared the expression of
both CD46 and SLAM, using immunohistochemistry,
in a range of normal peripheral tissues (known to be
infected by MV) as well as in normal and SSPE brain.
To increase our understanding of how these two
receptors could be utilized by wild-type or vaccine
strains in vivo, the results have been considered with
regard to the known route of infection and systemic
spread of MV.
Expression of CD46 and SLAM in Normal and SSPE
Brain Tissue
The distribution of CD46 by cell type and neuroana-
tomical area in normal brain is shown in Table 1.
Strong staining was observed on cerebral EC in all
blood vessels throughout the brain (Fig. 2a) and also
on ependymal cells lining the ventricles and choroid
plexus (Fig. 2b). Comparatively weaker CD46 staining
was observed on a subset of neurons (Fig. 2c) and
cells identified morphologically as oligodendrocytes in
all brain regions examined (Fig. 2a). Small numbers of
astrocytes (identified by glial fibrillary acidic protein
staining, data not shown) also showed weak staining
in the frontal cortex and hippocampus. All cells in the
normal brain parenchyma, cerebral EC, and ependy-
mal cells showed no staining for SLAM (Fig. 2, d and
e).
In SSPE brain sections, the results for CD46 were as
previously described (Ogata et al, 1997). Areas distant
from lesion sites and negative for MV by immunocy-
tochemistry showed the same distribution for CD46 as
in normal brain (Fig. 2f). However, cells in lesions
positive for MV, were negative for CD46, whereas
dual-labeling immunocytochemistry revealed MV-
negative CD46-positive cells (Fig. 2g).
When cryostat sections of SSPE brain labeled with
antibody to SLAM were examined by light and confo-
cal microscopy, all neural cell types (neurons, astro-
cytes, oligodendrocytes, microglia) and cerebral EC in
areas distant from lesions were not stained (Fig. 2h). In
MV-positive lesions, with abundant virus present in
neurons and oligodendrocytes, SLAM was also not
observed in any cells. However, in areas showing
perivascular inflammation, SLAM-positive leukocytes
were present in the infiltrates and in the surrounding
brain parenchyma (Fig. 2i).
Results
Preliminary investigations revealed that the mAb to
SLAM was not immunoreactive on formalin-fixed,
paraffin-embedded tissue sections despite the use of
microwave antigen retrieval. Therefore, cryostat sec-
tions were used to assess the distribution of SLAM in
tissues. The use of an mAb for detection of SLAM (no
polyclonal antibody is available) also did not allow dual
labeling with cell-specific mAbs to definitively identify
cells types not distinguishable morphologically. Poly-
clonal antibody to CD46 showed strong immunoreac-
tivity on paraffin sections after microwave antigen
retrieval.
Expression of CD46 and SLAM in Peripheral Tissues
Strong immunohistochemical staining for CD46 was
observed in EC lining blood vessels and epithelial cells
in a wide range of peripheral tissues including lung
alveoli, kidney tubules, skin, lymphoid tissues, and
intestine (Fig. 1, a and b). CD46 immunoreactivity was
also observed in tissue macrophages, as identified by
CD68 positivity on serial sections (Fig. 1a, arrow), and
in Langerhans’ cells in the dermis layer of the skin, as
identified by CD1a positivity on serial sections (Fig. 1,
c and d). Very strong CD46 immunoreactivity was also
present on the squamous cells in the epidermis of the
skin (Fig. 1c). All these cell types showed no expres-
sion of SLAM (Fig. 1, e and f). In the germinal center of
lymphoid tissues, subsets of cells were positive for
SLAM (Fig. 1g), in comparison to CD46, which showed
staining of all cell types. In control sections where the
primary antibodies were omitted, no staining was
observed in any of the tissues.
Discussion
All isoforms of CD46 have been shown to function as
receptors for MV vaccine strains in tissue culture
systems (Bartz et al, 1998; Dorig et al, 1994; Franck et
al, 1993), whereas the receptor usage by wild-type
strains remains unclear. Bartz et al (1998) have shown
that CD46 is only utilized by some wild-type strains
and with low binding affinity, whereas Manchester et
al (2000) reported that all clinical isolates tested could
infect cells in a CD46-dependent manner. In contrast,
SLAM has been identified as a receptor for both MV
vaccine and wild-type strains (Tatsuo et al, 2000), and
it has recently been demonstrated that B-cell lines,
which express SLAM and lack a complete CD46, can
be used to isolate MV from patients (Ono et al, 2001).
To gain an understanding as to how these receptors
may be utilized in vivo, it is necessary to determine
their expression in normal human tissues and during
MV infection.
CD46 labeled all lymphocyte common antigen-
positive lymphocytes in peripheral blood preparations
(
Fig. 1, h and i), whereas only subsets of cells were
stained with antibody to SLAM (Fig. 1j). Cell counts on
eight high-power fields showed that only 28% of
leukocyte common antigen (LCA)-positive or CD46-
positive cells were also SLAM positive.
Many human and monkey cell lines can be infected
by MV, whereas MV replication is much more re-
stricted in vivo. Evidence from primate models and
human postmortem samples, taken during the early
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CD46 and SLAM Distribution in Human Tissues
Figure 1.
Membrane cofactor protein (CD46) and signaling lymphocyte-activation molecule (SLAM) immunoreactivity in peripheral tissues. Strong immunoreactivity for CD46
on (a) epithelium and macrophages (arrow) in lung, (b) glomerular epithelium of the kidney, and (c) squamous epithelial cells in the dermis and epidermis of the
skin. CD46-positive dendritic cells are also present (arrow) as identified by CD1a positivity on a serial section (d). No expression of SLAM is observed in sections
of (e) lung and (f) skin. g, Strong immunoreactivity for SLAM is observed in populations of cells in spleen. h to j, Cytospin preparations of isolated peripheral blood
leukocytes immunostained for (h) LCA, (i) CD46, and (j) SLAM. Note that similar numbers of cells are labeled with antibodies to LCA and CD46, but relatively fewer
cells are labeled with mAb to SLAM. All images are digital and were processed in Adobe PhotoShop at 300 dpi.
stages of MV infection, shows that the virus enters
through the respiratory tract, and initial replication is in
tracheal and bronchial epithelial cells (reviewed in
Griffin and Bellini, 1996). Although CD46 RNA tran-
scripts are produced in all human tissues by tissue-
specific RNA splicing (Johnstone et al, 1993b), it has
shown that there is marked variation in expression of
CD46 protein between tissues. Strong expression was
found on epithelial cells lining exocrine ducts and
glands, such as salivary gland and pancreas, and on
kidney tubules and glomerular epithelium (Johnstone
et al, 1993a). This is in agreement with the results
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McQuaid and Cosby
Table 1. Distribution of CD46 in Normal Brain as Determined by Immunohistochemistry
Neurons (a/b)
ODs (a/b)
Astrocytes (a/b)
Endothelium (a/b)
Cerebellum
ϩ/ϩϩ
ϩ/ϩ
ϩ/ϩ
ϩϩ/ϩϩ
ϩϩ/ϩϩ
ϩ/ϩ
Ϫ/Ϫ
ϩ/ϩ
ϩ/ϩ
ϩ/ϩ
ϩ/ϩ
ϩ/ϩ
ϩ/ϩ
Ϫ/Ϫ
ϩ/ϩ
ϩ/ϩ
Ϫ/Ϫ
ϩ/ϩ
ϩ/ϩ
Ϫ/Ϫ
ϩϩϩϩ/ϩϩ
Frontal cortex
Hippocampus
Basal ganglia
Corpus callosum
Optic nerves
Cervical cord
ϩϩϩϩ/ϩϩϩϩ
ϩϩϩϩ/ϩϩϩϩ
ϩϩϩϩ/ϩϩϩϩ
ϩϩϩϩ/ϩϩϩϩ
ϩϩϩϩ/ϩϩϩϩ
ϩϩϩϩ/ϩϩϩϩ
ϩ/ϩϩ
ODs, oligodendrocytes.
a ϭ number of positive cells: Ϫ ϭ absent; ϩ ϭ few; ϩϩ ϭ moderate number; ϩϩϩ ϭ many; ϩϩϩϩ ϭ abundant.
b ϭ intensity of immunoreactivity; Ϫ ϭ absent; ϩ ϭ weak; ϩϩ ϭ moderate; ϩϩϩ ϭ intense; ϩϩϩϩ ϭ very intense.
presented in this article, because we found strong
expression of CD46 on epithelial cells in a wide range
of peripheral tissues, including lung alveoli, kidney
tubules, skin, lymphoid tissue, and intestine.
Virus RNA has been demonstrated in esterase-
positive cells in the blood of infected children and in
postmortem spleen tissue, indicating that monocyte/
macrophages rather than lymphocytes are primarily
infected (Brown et al, 1989). In agreement with previ-
ous studies (Johnstone et al, 1993a), we have shown
that all nucleated cells in blood as well as all cells in
the germinal centers of the spleen and lymph nodes
show expression of CD46. In contrast, SLAM staining
was only observed on a subset of cells in both blood
and the germinal centers of lymphoid tissues. Along
In contrast, the lack of detection of SLAM on
epithelial cells is difficult to reconcile with the use of
this molecule as a receptor for initial infection of the
respiratory tract epithelium. It is possible that inflam-
matory infiltrates containing SLAM-positive T and B
cells, present in the respiratory tract as a result of
other unrelated infection or allergens, could allow
initial infection. However, for the observed widespread
presence of MV antigen in epithelial cells to occur,
either another receptor would be necessary or epithe-
lial cells would have to acquire virus by fusing with
SLAM-positive inflammatory cells. Fusion of epithelial
cells in many tissues is observed during measles
infection and is also a characteristic of the MV com-
plication, giant cell pneumonia. Replication of virus in
many other tissues, after viremia, occurs in endothe-
lium, giving rise to vasculitis (reviewed in Griffin and
Bellini, 1996). Again these cells were heavily stained
for CD46 and showed no expression of SLAM. In
lymphoid tissue fusion of epithelium also causes the
production of Warthin-Finkeldey giant cells (Warthin,
ϩ
with B and T cells, CD34 bone marrow–derived DC
are also present in lymphoid and other tissues, includ-
ing skin (Banchereau and Steinman, 1998), and have
been shown to be infected by MV in vitro (Fugier-Vivier
et al, 1997; Grosjean et al, 1997; Schnorr et al, 1997;
Steineur et al, 1998). In this study, staining of the
resident population of skin DC, Langerhans cells,
proved positive for CD46 but negative for SLAM,
indicating that the latter is unlikely to act as a receptor
for infection of bone-derived DC.
The route of MV infection of the CNS is unknown but
may occur either by direct infection of EC or by
passage of infected leukocytes across the blood-brain
barrier as demonstrated in canine distemper infection
in dogs (Appel, 1969). We have previously reported
infection of cerebral EC in cases of SSPE (Kirk et al,
1991), and in this study we show that as for peripheral
EC, these cells express a high level of CD46 but not
SLAM. All cell types in normal brain sections were
negative for SLAM, and only a subset of cells in the
inflammatory infiltrate were SLAM positive in SSPE
brain tissue. We have previously shown that leuko-
cytes in perivascular cuffs in SSPE contain MV RNA
and antigen (Allen et al, 1996; Cosby et al, 1989). It is
possible that virus could be carried into the CNS in
infected leukocytes or infection of these cells could
occur after initial infection of EC, as previously sug-
gested (Kirk et al, 1991).
1931). However, there is no evidence to support fusion
between either epithelial or endothelial cells and
leukocytes.
After initial infection, MV spreads to local lymphatic
tissues, with some evidence from monkey studies that
suggests that this may occur via pulmonary macro-
phages (Kamahora and Nii, 1961; Sergiev et al, 1960).
We have shown that tissue macrophages, including
those in the lung, are positive for CD46 but fail to stain for
SLAM. It has been previously reported (Cocks et al,
ϩ
1
995; Sidorenko et al, 1992) that CD14 monocytes are
negative for SLAM, whereas a recent study (Ohgimoto et
al, 2001) has found that dendritic cells (DC), derived from
these, express SLAM. We have shown that SLAM does
not seem to be induced to any significant level after
differentiation of monocytes to macrophages, which
indicates that different lineages of cells, derived from
monocytes, vary in expression of SLAM.
Studies in primate models have shown that after
spread to the lymphatic system, MV replication occurs
in thymus, spleen, and lymph nodes as well as appen-
dix and tonsils (reviewed in Griffin and Bellini, 1996).
In SSPE, neurons and oligodendrocytes are the
most commonly infected cells with occasional astro-
cyte infection (Allen et al, 1996). None of these cells
showed staining for SLAM, and only a small propor-
tion of neurons and oligodendrocytes showed rela-
tively weak staining for CD46. This indicates that a
further receptor(s) would be required by all strains of
MV to directly infect neural cells at a level observed in
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CD46 and SLAM Distribution in Human Tissues
Figure 2.
CD46 and SLAM immunoreactivity in brain tissue. Strong immunoreactivity for CD46 in normal brain on (a) endothelium in the cortex, (b) endothelium and
oligodendrocytes in the hippocampus, and (c) ependymal cells lining the ventricle (arrow). However, in normal brain SLAM is not expressed on (d) ependymal cells
or (e) cells in the brain parenchyma. In measles virus (MV)-positive subacute sclerosing panencephalitis (SSPE) brain sections, CD46 expression is observed on (f)
endothelium and the cell body and processes of neurons (arrow). g, Double labeling of CD46 (diaminobenzidine-brown) and MV-positive cells (arrowed, red),
demonstrates no dual labeling of individual cells. h to j, Frozen section of SSPE brain tissue (h) immunostained for MV. Note MV-positive neurons and presence of
virus in cell processes. i, Strong expression of SLAM on cells within a perivascular cuff. j, A small number of SLAM-positive cells are present in a cuff and also
infiltrating into the surrounding brain parenchyma (arrows). All images are digital and were processed in Adobe PhotoShop at 300 dpi.
SSPE tissue. Alternatively, wild-type strains, which
could use CD46 as a receptor, could infect a percent-
age of cells directly, including a limited number of
neurons, and spread throughout the CNS transsynap-
tically (Allen et al, 1996; Lawrence et al, 2000). We
have previously shown that MV-infected cells in SSPE
are negative for CD46 and visa versa (Ogata et al,
1997), suggesting that virus may down-regulate this
molecule and could therefore use it as a receptor in
the CNS. However, although both of these functions
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McQuaid and Cosby
require interaction of the virus hemagglutinin protein
with CD46, they can be independent (Bartz et al, 1998;
Galbraith et al, 1998).
CD46 or mAbs to SLAM or MV nucleocapsid overnight
at 4° C. For paraffin sections a microwave antigen re-
trieval step was used for CD46, MV, LCA, and CD1a as
described previously (McQuaid et al, 1995). For both
cryostat and paraffin sections, immunoperoxidase-
bound antibodies were detected as described previously
using diaminobenzidine as peroxidase substrate (Allen et
al, 1996). Sections were counterstained with hematoxy-
lin, and assessment and photomicroscopy were per-
formed on a Leitz Aristoplan microscope.
Alternatively, bound antibodies were detected by im-
munofluorescence using Alexa 488 rabbit anti-mouse
(monoclonal) or Alexa 488 goat anti-rabbit (polyclonal)
secondary antibodies. Nuclei were then counterstained
in propidium iodide (2 ␮g/ml; Sigma Chemical, Poole,
Dorset, United Kingdom) for 30 seconds and washed in
PBS, and the sections were mounted using Citiflour
A further possibility is spread of virus from infected
ECs to neurons via cell-to-cell processes. This is
further supported by a previous in vitro study in which
we demonstrated that spread of virus from neuroepi-
thelial to neuronal cells could occur along cell pro-
cesses (McQuaid et al, 1998). It is also possible that
MV could enter the brain via the choroid plexus, as
occurs with mumps virus (Takano et al, 1999). Once
again our results indicate that either CD46 or a recep-
tor(s) other than SLAM would have to be utilized.
In conclusion, the evidence from our own and other
laboratories indicates that measles primarily infects
epithelial cells, ECs, and monocytes/macrophages in
the periphery, while neurons and oligodendrocytes are
preferentially infected in the CNS. We have found that
none of these cells show detectable expression of
SLAM, although it is possible that very low levels
could be present and allow some degree of infection.
CD46 is much more widely expressed and could fulfill
a receptor function for vaccine strains in vivo and in
vitro as well as possibly some wild-type strains. How-
ever, in the case of wild-type strains that are unable to
use CD46 (Bartz et al, 1998; Ono et al, 2001), a further
as yet unknown receptor(s) would be necessary to
fully explain the pathology of MV infection.
(Amersham Corporation, Paisley, United Kingdom). A
Leica TCS/NT confocal scanning laser microscope
equipped with a krypton/argon laser was used to exam-
ine the samples for fluorescence. Alexa 488-labeled
samples were visualized by excitation at 488 nm with a
506–538 band-pass emission filter.
In dual-labeling experiments on paraffin sections
from SSPE brain tissue, CD46 was applied first and
reaction sites were visualized with peroxidase-
diaminobenzidine. Subsequently antibodies to MV,
glial fibrillary acidic protein (1:100; Dako) for astrocyte
or CD68 (1:50, Dako) for macrophage identification,
were applied and detected using streptavidin-alkaline
phosphatase and Vector Red substrate.
Materials and Methods
Tissues
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