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/ß-Producing Cells) Accumulate in Cutaneous Lupus Erythematosus Lesions
From the Laboratory for Immunohistochemistry and Immunopathology, Institute and Department of Pathology, University of Oslo, Rikshospitalet, Oslo, Norway
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Abstract |
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/ß when triggered by
viruses. However, when incubated with interleukin-3 and CD40
ligand, the same precursors differentiate into mature DCs that
stimulate naïve CD4+ T cells to produce Th2
cytokines. We recently reported that P-DCs accumulate in nasal mucosa
of experimentally induced allergic rhinitis, supporting a role
for this DC subset in Th2-dominated inflammation. Here we examined
whether P-DCs accumulate in cutaneous lesions of lupus erythematosus
(LE), a disorder associated with increased IFN-/ß
production. Our results showed that P-DCs were present in 14 out of 15
tissue specimens of cutaneous LE lesions, but not in normal
skin. Importantly, the density of P-DCs in affected skin
correlated well (rs = 0.79,P < 0.0005) with the high number of cells
expressing the IFN-/ß-inducible protein MxA, suggesting
that P-DCs produce IFN-/ß locally. Accumulation of P-DCs coincided
also with the expression of L-selectin ligand peripheral
lymph node addressin on dermal vascular endothelium, adding
further support to the notion that these adhesion molecules are
important in P-DC extravasation to peripheral tissue sites.
Together, our findings suggested that P-DCs are an important
source of IFN-/ß in cutaneous LE lesions and may therefore be of
pathogenic importance.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain (CD123) combined with other cell
markers such as CD45RA, CD68, and HLA-DR.1-5
For many
years, pathologists have observed these plasma cell-like cells
(previously known as plasmacytoid T cells or plasmacytoid monocytes)
within secondary lymphoid tissues, but without having any knowledge of
their function. Only recently, experimental studies have suggested that
these cells play an important role in the initiation of immune
responses.1,3,4
In the presence of interleukin-3 and
CD40L, P-DCs developed into mature DCs and induced naïve T
cells to produce Th2 cytokines, suggesting a role in T-cell-mediated
allergic responses.6
However, it subsequently became clear
that circulating P-DC precursors are identical to natural interferon
(IFN)-/ß-producing cells, which produce large amounts of these
type I IFNs when triggered by certain viruses and bacterial
stimuli.2,7-10
Paradoxically, whereas
interleukin-3-stimulated P-DCs induced naïve
CD4+ T cells to produce Th2 cytokines,
virus-triggered P-DCs activated naïve
CD4+ T cells to produce IFN-
and
interleukin-10.6,11
Thus, P-DCs apparently could have
multiple functions in innate as well as adaptive immunity, and might
integrate these two arms of the immune
system.
Knowledge about P-DCs has primarily been acquired from in
vitro experiments; therefore, testing of current ideas about the
function of these cells will depend on studies in their natural
environment—that is, in situ. Interestingly, we have
recently shown that P-DCs accumulate in nasal mucosa during
experimentally induced allergic rhinitis. This finding demonstrates
that P-DCs are able to migrate to mucosal effector sites, and suggests
that these cells may be directly involved in a Th2-dominated
inflammatory reaction.5
The aim of the present study was
to examine whether P-DCs also can be involved in inflammatory disorders
associated with elevated IFN-/ß production.
Lupus erythematosus (LE) is an autoimmune disease ranging from a benign
chronic cutaneous form [discoid LE (DLE)] to a severe multisystemic
disease [systemic LE (SLE)].12
Although the etiology of
DLE and SLE remains elusive, increased production of IFN-/ß has
been suggested as a pathogenic factor. In SLE patients, especially
those with active disease, elevated blood levels of IFN- have been
found,13-15
and increased expression of the
IFN-/ß-inducible protein MxA has been detected in cutaneous
lesions of SLE and DLE.16
In view of the data derived from
recent in vitro experiments, we hypothesized that P-DCs
might be an important source of IFN-/ß in LE. To investigate this
possibility we examined whether P-DCs accumulate in skin lesions of DLE
and SLE associated with local expression of MxA.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The study was performed on routine formalin-fixed,
paraffin-embedded biopsy specimens (n = 15)
obtained from the archives of the Department of Pathology,
Rikshospitalet. Based on available clinical information, 10
patients were diagnosed as having DLE whereas 5 had symptoms
characteristic of SLE. All included biopsy specimens were
histologically examined by an experienced pathologist and found to
display features characteristic for LE except in one case of SLE (no.13
in Table 1
) that showed a mixed
histopathological picture compatible with both LE and lichen planus. A
scoring system was established to grade the extent of mononuclear cell
infiltration. The following scores were assigned: 0, almost no
mononuclear cells present; 1, very few, loosely scattered single cells
(no aggregates) in papillary dermis and/or around some adnexal
structures/vessels; 2, few and only small aggregates of mononuclear
cells in papillary dermis and/or around less than half of adnexal
structures/vessels; 3, prominent but discontinuous aggregates of
mononuclear cells in papillary dermis and/or around at least half of
adnexal structures/vessels; and 4, massive and confluent accumulation
of mononuclear cells in papillary dermis and around all adnexal
structures/dermal vessels.
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Serial paraffin sections were cut at 6 µm, dewaxed, immersed in a 10 mmol/L citrate buffer (pH 6.0) and microwaved for 4 x 5 minutes at 160 W. The buffer was allowed to cool at room temperature, thereafter the sections were washed in phosphate-buffered saline for 2 x 3 minutes and immediately immunostained (see below). Microwaving for antigen retrieval was not needed for MECA-79 immunostaining (see below).
Skin Organ Culture
After removing the subcutaneous tissue from a normal control skin
specimen obtained at plastic surgery (no.17 in Table 1
), it was divided
in two, each piece having a diameter of 1 cm. One piece was injected
with 1 x 106
IU recombinant human (rh)
IFN--2b (Introna, Schering-Plough, Madison, NJ) and incubated
overnight in a 12-well plate (Corning Costar, Corning, NY) containing
RPMI 1640 supplemented with 10% fetal calf serum, 50 µg/ml
gentamicin, 1 mmol/L L-glutamine, and 3 x
105
IU/ml rhIFN--2b at 37°C in humidified
CO2/95% air. The other piece was incubated in
the same buffer without IFN-. After incubation, both tissue samples
were handled exactly as described above.
Multicolor Immunofluorescence Staining
The tissue density and phenotype of P-DCs was determined by a multicolor immunostaining technique as described elsewhere.5 Briefly, a mouse monoclonal antibody (mAb) of the IgG2a subclass specific for human CD123 (IgG2a, clone 7G3, 1 µg/ml; Pharmingen, San Diego, CA) was combined with mouse mAbs to either: CD45RA (IgG1, clone L48, 1.25 µg/ml; Becton Dickinson Immunocytometry Systems, San Jose, CA), HLA-DR (IgG1, clone TAL.1B5, 10 µg/ml), or CD68 (IgG3, clone PG-M1, 7 µg/ml; both from DAKO, Glostrup, Denmark) overnight at room temperature. A mixture of Cy3-labeled (red) goat anti-mouse IgG2a (1.5 µg/ml) and fluorescein isothiocyanate (FITC)-labeled (green) goat anti-mouse IgG1 (5 µg/ml) or FITC-labeled goat anti-mouse IgG3 (20 µg/ml; all from Southern Biotechnology, Birmingham, AL) was next applied for 3 hours at room temperature. In some experiments, rabbit antiserum to human cytokeratin (1/100; authors’ laboratory) and 7-amino-4-methylcoumarin-3-acetic acid (AMCA)-labeled (blue) goat anti-rabbit IgG (15 µg/ml; Vector Laboratories, Burlingame, CA) were added to the primary and secondary antibody mixtures, respectively. Immunostaining of T cells and mast cells was performed on selected sections. Rabbit anti-human CD3 (1 µg/ml, DAKO) combined with mouse mAb to CD45RA (IgG1) were applied overnight at room temperature, followed by Cy3-labeled anti-rabbit IgG (0.3 µg/ml; Sigma, Saint Louis, MO) and FITC-labeled goat anti-mouse IgG1. To identify skin mast cells, both a mouse mAb to mast cell tryptase (IgG1, clone AA1, 2 µg/ml) and a rabbit anti-human c-kit (CD117) (1 µg/ml, both from DAKO) were combined with anti-CD123 (IgG2a), followed by a mixture of either FITC-labeled goat anti-mouse IgG1 or Alexa Fluor 488-labeled (green) goat anti-rabbit IgG (1 µg/ml, Molecular Probes, Eugene, OR) and Cy-3-labeled goat anti-mouse IgG2a. To ensure efficiency of the antigen retrieval procedure, routine formalin-fixed tonsil sections were always included as a positive control.
In situ IFN-/ß production was evaluated by
immunostaining for MxA, an IFN-/ß-inducible intracellular protein
well established as a surrogate marker for local IFN-/ß
production.16-18
Tissue sections were incubated overnight
at room temperature with mouse mAb to human MxA (IgG2a, clone M143, 1.5
µg/ml; courtesy of Dr. O. Haller, Freiburg, Germany), followed by
Cy3-labeled goat anti-mouse IgG (0.8 µg/ml; Jackson ImmunoResearch
Laboratories, West Grove, PA) for 3 hours at room temperature. The
sections were finally mounted with a medium containing
4,6-diamidino-2-phenylindole (DAPI) (Vectashield; Vector Laboratories)
for nuclear (blue) fluorescent staining. As a positive control for MxA
expression, sections from IFN--stimulated skin specimens were
immunostained in parallel.
Vascular L-selectin ligand peripheral lymph node addressin (PNAd) expression was determined by applying a combination of mAb MECA-79 (rat IgM, 2 µg/ml; courtesy of Dr. E. C. Butcher, Stanford, CA) and FITC-labeled pan-endothelial marker Ulex europaeus lectin-1 (10 µg/ml; Vector Laboratories) overnight at room temperature, followed by Cy3-labeled goat anti-rat IgM (1.5 µg/ml; Jackson ImmunoResearch) for 3 hours at room temperature.
In all staining experiments, negative controls were obtained both by omission of primary mAbs and by incubation with irrelevant isotype- and concentrated-matched primary mAbs.
Evaluation of Immunohistochemical Results
P-DCs and MxA+ cells were counted in adjacent tissue sections in a fluorescence microscope (model E800; Nikon Corp., Tokyo, Japan). P-DCs were identified as CD123highCD45RA+ cells, and enumerated at x400 magnification per tissue unit as defined by an ocular grid representing a section area of 0.058 mm2. Because of the high density of MxA+ cells in many tissue sections, images were recorded with a Hamamatsu C-5810 3-charge-coupled device cooled video camera (Hamamatsu Photonics KK, Hammatsu-City, Shizuoka-ken, Japan) allowing enumeration on a monitor screen including a section area of 0.040 mm2 as described elsewhere.19 A short exposure time (0.16 seconds) was used for red emission, to enable counting of only brightly stained cells with a discernible nucleus visualized with DAPI.
Both series of cell counts were performed in a systematic manner throughout each parallel section. For CD123highCD45RA+ cells and MxA+ cells every second and every fourth tissue unit was counted, respectively. At least 17 tissue units were included for the CD123highCD45RA+ cells and 11 tissue units for MxA+ cells; this approach provided a cell number sufficiently large to obtain a stabilized mean for both phenotypes.
For endothelial MECA-79 reactivity, both the extent and staining
intensity of immunoreactive vessels were evaluated, as previously
described.5
The vessels were divided into two groups
according to their smallest outer diameter (<10 µm or 
10 µm)
outlined by U. europaeus lectin-1 staining. All detectable
vessels throughout the biopsy were counted and graded with regard to
the staining intensity for MECA-79 on an arbitrary scale from nil (-)
to strong (++). More than 45 vessels with a diameter of <10 µm and
33 with a diameter of 10 µm were counted in every specimen.
Statistics
Spearman’s rank correlation coefficient was used to evaluate the relationship between the number of P-DCs, MxA+ cells, and the score of the mononuclear cell infiltration.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We identified P-DCs in tonsillar tissue (mostly located in T-cell
areas) and LE skin as CD123high cells
co-expressing CD45RA, CD68, and HLA-DR (Figure 1; a, c, d, e, and f
, and data not
shown), a phenotype unique for this DC subset.1-5
P-DCs
were present in 14 out of 15 skin samples from DLE and SLE patients,
whereas normal control tissue was virtually negative (Figure 2
and Table 1
). Large individual
variations were observed, some DLE samples displaying particularly high
numbers of P-DCs. Interestingly, the number of P-DCs correlated well
with the score of the mononuclear cell infiltration
(rs = 0.65, P <
0.009, n = 15). This relationship explained the fact
that most SLE samples contained relatively few P-DCs (Table 1)
. The
localization of P-DCs was similar in both types of lesions with
predominant accumulation along the dermal-epidermal junction (Figure 1a)
, around hair follicles (Figure 1c)
, and perivascularly (Figure 1d)
.
In addition, positive cells occurred scattered in the dermis.
Interestingly, when we immunostained for
CD123highCD45RA+ P-DCs,
many LE specimens (and especially those with high number of P-DCs)
contained many cells positive only for CD45RA (Figure 1; a, c, and d
).
The majority of these cells were deemed to be naïve
(CD3+CD45RA+) T cells
(Figure 1h
and data not shown).
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, which is in agreement with
previous studies in humans.22-24 Accumulation of P-DCs Is Related to Expression of MxA
To investigate whether P-DCs produced IFN-/ß locally, we
examined the cellular expression of the IFN-/ß-inducible protein
marker MxA. All DLE and SLE tissue samples contained
MxA+ cells, often in very high numbers, whereas
such cells were only infrequently present in the controls (Figure 1b
and Table 1
). The MxA+ cells were located
throughout the epidermis (mainly keratinocytes) and the dermis as well
as skin appendages (Figure 1b)
. Importantly, the number of
MxA+ cells was well correlated with the density
of P-DCs in adjacent tissue sections of LE lesions
(rs = 0.79, P <
0.0005, n = 15) (Figure 2)
. This finding strongly
suggested that P-DCs produced IFN-/ß in these lesions.
IFN--stimulated skin served as a positive control for MxA expression
and contained positive keratinocytes and endothelial cells, whereas
unstimulated skin was negative (data not shown).
Endothelial PNAd Is Strongly Expressed in Cutaneous DLE and SLE Lesions
The mechanisms directing emigration of DC precursors to different
tissue sites are poorly understood. Accumulation of P-DCs in and around
high endothelial venules (HEVs) in secondary lymphoid organs, and
especially in inflamed lymph nodes, suggests that these cells
extravasate through the specialized HEV endothelium.1,2
In
support of this possibility, circulating P-DC precursors express high
levels of L-selectin,2,3
an adhesion molecule
that together with PNAd form a homing receptor-endothelial ligand pair
involved in lymphocyte trafficking via HEVs. Interestingly, we have
recently reported that accumulation of P-DCs concurred with PNAd
expression on the vascular endothelium in experimentally induced
allergic rhinitis.5
Therefore, we investigated vascular
PNAd expression by means of MECA-79 immunoreactivity in the LE lesions.
All 10 DLE and 4 out of 5 SLE tissue samples contained vessels reactive
with MECA-79, whereas normal skin was invariably negative. The majority
(>70%) of the MECA-79 reactive vessels had a diameter 10 µm, and
in some skin lesions >30% of such vessels were strongly positive
(Figure 1i)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain (CD123) and
co-expression of CD45RA, CD68, and HLA-DR. The latter markers
discriminate P-DCs from other CD123high cells
such as endothelial cells (which are negative for CD45RA) and basophils
(which are negative for CD45RA and HLA-DR). Mouse mast cells also
express CD123,21
but human dermal and lung mast cells have
previously been shown to lack this receptor.22-24
In the
present study we confirmed the latter observation because dermal mast
cells, identified by mast cell tryptase and c-kit, were
always negative for CD123. The density of P-DCs in LE lesions
correlated well with the presence of a high number of cells expressing
the IFN-/ß-inducible protein MxA; this strongly suggested that
P-DCs produce IFN-/ß locally in both DLE and SLE. Our finding
contrasts with the situation in allergic nasal mucosa where
MxA-positive cells were virtually absent.5
Our in
situ observation thus accords with recent in vitro
data, suggesting that the function of P-DCs depends on their
microenvironment.11
The etiology of LE remains elusive but increased production of
IFN-/ß has been proposed as a pathogenic factor. In support of
this hypothesis, IFN- therapy of patients with nonautoimmune
diseases occasionally induces SLE-like
syndromes.26-28
Our finding is therefore of
considerable interest because the cellular source of IFN-/ß in DLE
and SLE has been unclear. Although P-DCs has been proposed to be one
source of IFN- in SLE, a recent report showed that the number of
such precursors was markedly decreased in peripheral blood of SLE
patients.29
Our results may explain this paradox, because
we show that these cells have the capacity to migrate into inflamed
skin in LE where they most likely produce and secrete IFN-/ß.
The high number of MxA+ cells in cutaneous LE
lesions, contrasting our principally negative result for this
IFN-/ß marker in allergic nasal mucosa,5
suggests
that inflamed skin afflicted with LE contains specific factors
triggering P-DCs to produce IFN-/ß. Viruses and bacteria are known
to induce P-DCs for such production in
vitro,2,7-10
and both types of pathogens have been
discussed as etiological factors in LE.30-34
Another
possibility of IFN-/ß induction is the increased apoptosis of
cells seen in cutaneous LE lesions.35-37
Båve and
colleagues38
recently showed that apoptotic cells from
several human cell lines combined with serum IgG from SLE patients
triggered P-DCs to produce IFN- in vitro. The underlying
mechanisms remains elusive but several lines of evidence suggest that
DNA molecules containing unmethylated CpG can activate human peripheral
blood DCs.39
In particular, CpG oligonucleotides, but not
lipopolysaccharide or poly IC, potently triggered survival, growth,
activation, and maturation of P-DCs and certain CpG sequence motifs
induced IFN-/ß production in these cells (G. Hartmann, personal
communication).40
Furthermore, it has been shown that
serum from SLE patients contains complexes of anti-DNA antibodies and
double-stranded DNA especially effective in stimulating IFN-
production in P-DCs.41
Whether this DNA is of human or
microbial origin is unknown.
Immature DCs, such as Langerhans’ cells, reside in nonlymphoid tissues where they take up antigen and migrate to draining lymph nodes in response to inflammatory signals. P-DCs, however, seem to migrate to lymphoid tissues in the absence of such signals and most likely enter directly from blood via HEVs.1-3 Therefore, it has been unclear how P-DCs encounter and take up antigen. It has previously been reported that cells with morphological and certain immunophenotypic characteristics of P-DCs are present in some skin disorders,42-44 suggesting that they may migrate to nonlymphoid tissues in response to certain inflammatory stimuli. This possibility was recently supported by our study on experimental allergic rhinitis where we demonstrated that accumulation of P-DCs in allergic nasal mucosa concurred with strong expression of the L-selectin ligand PNAd on the mucosal vascular endothelium.5 PNAd is constitutively expressed on HEVs and mediates homing of naïve lymphocytes to organized lymphoid tissue. Similar to naïve lymphocytes, circulating P-DCs also express high levels of L-selectin, which most likely explains their extravasation preference in HEV-containing lymphoid tissue. In this study we found that PNAd also is expressed by dermal endothelial cells in cutaneous LE lesions. Together, our findings suggest that P-DCs are recruited to inflamed peripheral tissues by the same adhesion molecules that normally mediate leukocyte extravasation in secondary lymphoid tissues. The finding that many naïve CD45RA+ T cells were present in LE lesions further supports this notion. We are currently testing this hypothesis by comparing adhesion molecule profiles in allergic rhinitis and cutaneous LE lesions with chronic inflammatory conditions where P-DCs are virtually absent such as nasal polyps, celiac disease, and inflammatory bowel disease (F. L. Jahnsen and colleagues, unpublished observations).
In summary, we found that P-DCs accumulate in cutaneous DLE and SLE
lesions. The density of these cells correlated well with the high
number MxA+ cells (a surrogate marker for
IFN-/ß), suggesting that P-DCs produce these type I IFNs locally
in these lesions. P-DCs could therefore be an important source of the
increased levels of IFN-/ß found in LE patients and therefore be
of pathogenic importance.
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Acknowledgements |
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Footnotes |
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Supported by the Norwegian Foundation for Health and Rehabilitation, the Norwegian Cancer Society, the Research Council of Norway, and the Research Fund for Asthma and Allergy.
Accepted for publication March 29, 2001.
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