Download Immunohistochemical sweat gland profiles

Original Contribution
Journal of Cosmetic Dermatology, 12, 179--186
Immunohistochemical sweat gland profiles
€l,1 Ge
rald E Pie
rard, MD, PhD,1,2 Philippe Delvenne, MD, PhD,1 Pascale Quatresooz, MD, PhD,1,3
Fanchon Noe
rard-Franchimont, MD, PhD1
Philippe Humbert, MD, PhD,2 & Claudine Pie
Department of Dermatopathology, Liege University Hospital, Liege, Belgium
Department of Dermatology, Saint-Jacques Hospital, University of Franche-Comte, Besancßon, France
3
Department of Histology, Liege University, Liege, Belgium
1
2
Summary
Background Human sweat glands are heterogeneous in their structures and functions.
Accordingly, eccrine, apocrine, and apoeccrine glands are distinguished.
Aims Some immunohistochemical markers are expected to distinguish the sweat
gland types in their secretory and excretory parts.
Methods This study used two sets of antibodies. The first panel was composed of
antibodies directed to well-defined sweat gland structures. The molecular targets
included the low-molecular-weight cytokeratins CAM 5.2, the S100-B protein, the
epithelial membrane antigen (EMA), the carcinoembryonic antigen (CEA), and the
lectin Ulex europaeus agglutinin-1 (UEA-1). A second exploratory panel of antibodies
targeted syndecan-1 (CD138), NKI-C3 (CD63), and CD68. They were used to disclose
some undescribed antigen expressions in human sweat glands.
Results The first set of antibodies confirmed previous findings. The immunoreactivities
of the three sweat gland types were similar in the excretory ducts. By contrast, they
were distinguished in the deeper coiled secretory portions of the glands.
Conclusion Clues supporting their distinction and probably their functional activity
were obtained by immunohistochemistry using the S100-B protein, CEA and CD63
antibodies. The immunoreactivity to the S100-B protein, CEA and CD63 possibly help
identifying apoeccrine sweat glands or a peculiar functional activity of eccrine sweat
glands.
Keywords: sweat gland, Ulex europaeus agglutinin-1, CD63, CD68, CD138
Background
In humans, two main types of sweat glands are distinguished according to their different secretory patterns of
production. Histomorphology is typically used for such
distinction.1 The eccrine sweat glands (ESG) also called
atrichial sweat glands,2 secrete high amounts of an
aqueous liquid following a merocrine mechanism. Thermoregulation is their main function during exposure to
warm environment and during body hyperthermia
related to fever and physical exercise. Other ESG stimuli
Correspondence: G E Pierard, Department of Dermatopathology, Liege
University Hospital, CHU Sart Tilman, BE-4000 Liege, Belgium. E-mail: [email protected]
Accepted for publication October 27, 2012
© 2013 Wiley Periodicals, Inc.
include psychologic stress and gustatory reflexes. The
ESG level of activity is variable in time and different from
one gland to another.3 They open directly onto the skin
surface through individual acrosyringia.4 The apocrine
sweat glands (ASG) also called epitrichial sweat glands2
secrete low amounts of a lipid-rich liquid, and they join
up into the hair canal instead of the skin surface.5 The
apocrine secretion is apparently derived from pinching
off of the apical cytoplasm of the secretory cells. A positivity for the gross cystic disease fluid protein-15 appears
typical for the ASG.6 A third group of sweat glands of
the apoeccrine type was reported predominating in axillary skin. This finding remains a controversial topic.7–10
They were described sharing characteristic features of
both ESG and ASG, and they possibly open onto the skin
surface. The distinction between these apoeccrine glands
179
Sweat gland immunohistochemistry
. F No€el et al.
and both the ESG and ASG was mainly assessed on gross
morphology.7 Skin of the forearms and the back exclusively contains ESG. By contrast, it was assumed that
axillary skin contains approximately equal numbers of
ESG, ASG, and apoeccrine glands.11
Although the morphological microanatomy remains
the basis of sweat gland classification, molecular phenotyping, and functional characteristics should be combined when possible to the criteria.11,12 They could help
the interpretation of the effects of dermocosmetic formulations on the sweat glands. In some conditions in
humans, it is uncertain whether some glands are ESG or
ASG depending on the selected criteria. Various immunohistochemical markers including cytokeratin (CK)
phenotyping, as well as the epithelial membrane antigen
(EMA), the carcinoembryonic antigen (CEA), and others
were introduced for this purpose.6,13–16 In addition, the
identification of glycoconjugates was used to charaterize
sweat glands in health and disease.17–22 These findings
are commonly extrapolated to identify the differentiation
of sweat gland neoplasms.23,24
The present study was focused on the distinction
between sweat gland types using conventional and
undescribed immunohistochemical reactivities. We used
a panel of antibodies directed to the low-molecularweight CAM 5.2 CK, the S100-B protein, EMA, CEA, the
lectin Ulex europaeus agglutinin-1 (UEA-1), syndecan-1
(CD138), NKI-C3 (CD63), and CD68.
The monoclonal CAM 5.2 CK antibody strongly reacts
with CK 8 and at a lower extent with CK 7. No reactivity
has been disclosed with CK 18. The polyclonal S100-B
protein antibody detects one of the 19 Ca (2+)-binding
proteins of the S100 family. The monoclonal anti-human
EMA antibody22,24,25 and the polyclonal anti-human CEA
antibody24,26 typically label sweat glands. UEA-1 is a
lectin specifically binding to a-L fucosyl moieties. The antiUEA-1 antibody reveals the lectin-binding sites
corresponding to oligosaccharides with terminal a-fucose,
some of which are present in sweat glands.20,24,27 The
monoclonal anti-human CD138 detects the transmembrane syndecan-1 proteoglycan.28–31 The monoclonal
antibody to CD63 detects various proteins whose molecular weights range 25–100 kD. They are probably part of
some lyzosomal antigens located in cytoplasmic vacuoles.32 No immunoreactivity of sweat glands has been
reported so far to CD63. CD68 is another antigen present
on lyzosomes, particularly in phagocytic cells.
Material and methods
This study was approved by the University Hospital Ethics Committee. It was conducted with the understanding
180
and consent of the volunteers. A total of 60 Caucasian
adults aged 20–48 years were enrolled. At the time of
biopsy, they were relaxed without any perceptible
sweating, and they rested in an indoor environment
controlled at 21 °C and 48–53% relative humidity. Deep
punch biopsies, 6 mm in diameter, were performed on
the mid inner forearm, the axillary vault, and the
mid-lateral part of the back.
Microscopic sections (6 lm thick) were cut from the
formalin-fixed paraffin-embedded punch biopsies. Sections were dewaxed in xylene and rehydrated through
grades of alcohol to PBS. They were subsequently processed for immunohistochemistry using a panel of antibodies (Table 1) and the avidin-biotin peroxidase
method. After a 1-h incubation time with any of the
primary antibodies, slides were washed in Tris-buffered
saline (TBS) and incubated for 30 min with the secondary antibody (biotinylated swine anti-rabbit, 1:300,
Dakopatts). Slides were rinsed in TBS and covered by
the EnVision (Dakopatts, Glostrup, Denmark) polymerbased revelation system. After TBS washing, Fast Red
(Dakopatts) was used as chromogen substrate. The last
steps consisted of counterstaining with Mayer’s hemalum before mounting. Negative immunohistochemical
controls were performed by omitting or substituting
the primary and the secondary antibodies of the
laboratory procedure.
Results
Data are summarized in Table 2.
Low-molecular-weight CAM 5.2 cytokeratins
The secretory coil and at a lesser extent the ductal cells
of the ESG were identified by the CAM 5.2 antibody
(Fig. 1a). All segments of the ASG including secretory
and ductal cells were decorated by this antibody.
Table 1 Panel of antibodies
Antigen/antibody
Dilution
Source
Carcinoembryonic antigen
CD68
Cytokeratins CAM 5.2
1:200
1:200
1:250
Epithelial membrane antigen
CD63
1:100
1:200
S100 protein
CD138
Ulex europaeus agglutinin-1
1:2000
1:100
1:2000
Dako, Glostrup, Denmark
Dako, Glostrup, Denmark
Becton Dickinson, San Jose,
CA, USA
Dako, Glostrup, Denmark
MP Biomedicals, Solon, OH,
USA
Dako, Glostrup, Denmark
Dako, Glostrup, Denmark
Vector laboratories,
Burlingame, CA, USA
© 2013 Wiley Periodicals, Inc.
Sweat gland immunohistochemistry
. F No€el et al.
Table 2 Immunolocalization of sweat gland components
Location
CEA
Acrosyringium
Luminal
+
Dermal duct
Luminal
+
Cytoplasm
+
Eccrine secretory coil
Clear cell
+
Dark cell
+
Apocrine secretory coil
Luminal
0
Cytoplasm
0
CD68
CAM 5.2
0
0
0
0
0
EMA
+
0
0
0
0
+
+
0
0
0
+
+
CD63
S100-B
0
0
CD138
UEA-1
+
0
0
0
+
0
0
0
+
0
0
0
+
+/
0
0
+
+
+: homogeneously positive, +/ : variable, : focally positive, 0: negative.
S100-B protein
The S100-B protein was found in the cytoplasm of
secretory cells in the ESG (Fig. 1b). A weaker immunostaining was present in a thin luminal lining of the
excretory duct. The ASG showed no immunoreactivity
to the S100-B protein.
In the secretory segments of ESG, clear cells exhibited
strong cytoplasmic UEA-1 staining (Fig. 2a). The luminal part of sweat ducts showed apical membranous
staining (Fig. 2b). The inner part of the acrosyringia
was strongly labeled (Fig. 2c). In addition, sweat was
strongly positive for UEA-1 (Fig. 2d). ASG globally
appeared intensely labeled. The acinar cells of ASG
revealed focal apical membrane UEA-1 immunostaining.
Epithelial membrane antigen
Epithelial membrane antigen (EMA) was present in
several segments of the ESG and ASG. EMA was
located in the luminal coating of the eccrine secretory
segment and in the dark cells as well (Fig. 1c). It was
present in the coiled intraepidermal portion of the
acrosyringium. Eccrine sweat was intensely positive for
the EMA (Fig. 1d). The ASG contained EMA in different segments including the glomerular structure and
the excretory duct.
Carcinoembryonic antigen
Carcinoembryonic antigen (CEA) was present at all levels of the ESG, particularly lining the lumen of secretory and ductal portions (Fig. 1e). The ductal labeling
appeared stronger than in the secretory epithelium.
The luminal part of the acrosyringium was intensely
positive (Fig. 1f). The ASG showed a heterogeneous
CEA labeling on the luminal coating of the duct
(Fig. 1g).
Ulex europaeus agglutinin-1
In the secretory coils of the various sweat glands, the
different cell types appeared to contain distinctive
a-fucose glycoconjugates in both their plasma
membranes and cytoplasm.
© 2013 Wiley Periodicals, Inc.
CD138
CD138 appeared abundant in the outer portion of the
acrosyringia in an intercellular pattern similar to the
epidermis (Fig. 3a). This antigen was present at a
weaker extent or absent in the luminar portion. A
variable number of cells of the secretory segment were
strongly positive (Fig. 3b, c) as well as sweat (Fig. 3d).
In the ASG, a thin CD138+ luminal lining was disclosed
in the excretory duct, while no immunoreactivity was
present in the secretory coil (Fig. 3e).
CD63
In ESG, CD63 immunostaining was present in the apical part of secretory cells (Fig. 4a). The luminal lining
was decorated in an irregular pattern in the acini and
ducts. A thin luminal lining and a faint cytoplasmic
positivity were disclosed in ASG (Fig. 4b,c,d).
CD68
No CD68 immunoreactivity was disclosed in the sweat
glands.
Discussion
The current concept about axillary sweat glands distinguishes ESG, producing abundant clear, nonodorous
181
Sweat gland immunohistochemistry
. F No€el et al.
(a)
(b)
(c)
(d)
(f)
(e)
(g)
Figure 1 Protein immunoreactivity in sweat glands. (a) CAM 5.2 cytokeratins, (b) S100-B protein, (c, d) EMA, (e, f, g) CEA.
sweat and ASG excreting small amounts of turbid,
odorous milky sweat. A third type of sweat glands
corresponding to the apoeccrine type was described
in the literature.7 So far, they are not clearly and specifically distinguished using immunohistochemistry,
and publications about this topic are scanty and
controversial.8,9
Each ESG consists of a coiled portion in continuation
with a straight intradermal duct ending as a spiral
intraepidermal acrosyringium. The secretory portion
represents about two-thirds of the coiled structure. It
182
consists of a single layer with clear and dark cells. The
majority of the cells are large and clear. They contain
glycogen and they produce the eccrine sweat. Changes
in their tiny granules occur after episodes of intense
sweating. Fine canaliculi collecting the secreted sweat
are present between adjacent clear cells. The smaller
granular dark cells are less numerous. They tend to be
pyramidal in shape with a relatively narrow contact
with the peripheral basement membrane. The intraepidermal acrosyringium is lined by cells resembling those
to the straight part of the intradermal duct.
© 2013 Wiley Periodicals, Inc.
Sweat gland immunohistochemistry
(a)
(b)
(c)
(d)
. F No€el et al.
Figure 2 Glycoconjugate immunoreactivity in sweat glands. (a, b, c, d) UEA-1.
(a)
(b)
(c)
(d)
(e)
Figure 3 Proteoglycan immunoreactivity in sweat glands. (a, b, c, d, e) CD138.
Each ASG consists of a coiled secretory portion
connected to a duct. The glandular portion is formed by
a single layer of cuboidal or columnar cells. The secretory cells contain granules and vacuoles, some of which
may be pigmented. The apocrine duct closely resembles
© 2013 Wiley Periodicals, Inc.
the eccrine duct. It consists of a double or triple layer of
rather similar cuboidal cells, those of the inner layer
exhibiting a faint luminal fringe. The peripheral basal
layer contains numerous mitochondria and microvilli.
The apocrine sweat is scanty and sticky in consistency.
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Sweat gland immunohistochemistry
. F No€el et al.
(a)
(b)
(c)
(d)
Figure 4 Lysosomal antigen immunoreactivity in sweat glands. (a, b, c, d) CD63.
It is considered that the different portions of the ESG
contain a cytoskeleton made of several distinct CK.33,34
They include CK 7, CK 8, CK 14, CK 18, and CK 19,
as well as EMA and CEA.22 It was reported that the
expression intensity of CK 7, CK 18, and CD 19 was
stronger than that of CK 8 and CK 14.22 A controversy exists about the presence of CK 10.22,34 The
present findings using the CAM 5.2 antibody are in
line with the current concepts. A positivity was found
in both the ESG and ASG, and in the presumed apoeccrine glands. By contrast, the S100-B immunoreactivity appeared restricted to the cytoplasm of eccrine
secretory coils.35 Any S100-B immunoreactivity in larger sweat glands in axillary skin could be tentatively
used to reveal apoeccrine glands.
Epithelial membrane antigen (EMA) is present in the
luminal coating of ESG. EMA immunoreactivity was
found in ASG as well.24 The anti-EMA antibody is thus
unlikely helpful in the identification of apoeccrine
sweat glands.
Carcinoembryonic antigen (CEA) is a glycoprotein
found in diverse organs. In the skin, it is exclusively
present in sweat glands. The CEA gene family belongs
to the immunoglobulin superfamily. CEA has been presented as an immunologic marker of ESG.22,24 It possibly plays a role in the innate immune defense.26 CEA
possibly binds and traps micro-organisms at the cell
surface. Epidermal growth factor receptors are
expressed as well.22,36 The secretory portion of ASG do
184
not exhibit CEA immunoreactivity. Any positivity
in large acini could therefore represent a clue for
apoeccrine differentiation.
Lectins represent a group of proteins and glycoproteins distinct from enzymes and antibodies. UEA-1
binds to a-fucose moiety with a high specificity
through complementary sugar-binding sites. Lectins
were used to demonstrate the presence of complex carbohydrate moieties at the cell surface or in cytoplasmic
organelles in skin appendages. However, little is known
about the precise composition and distribution of glycoconjugates in the normal skin and skin appendages.
Only few reports deal with the application of lectins to
the determination of sweat gland differentiation. UEA-1
was shown to be present on the plasma membranes of
the eccrine dark and clear cells, as well as in apocrine
cells.27 Similarly, granules of the ESG and lysosomal
granules in apoecrine cells were reported to contain
binding sites for the UEA-1 lectin.27 Our findings are
in line with previous works and suggest that UEA-1
immunoreactivity does not help identifying apoeccrine
glands.
CD138 antigen corresponding to syndecan is a cell
surface proteoglycan, playing a prominent role in tissue remodeling and homeostasis. It binds to growth
factors and interstitial matrix molecules. It modulates
the effect of the primary ligand–receptor interaction at
the cell membrane by increasing the affinity of cell–
ligand interactions. Additionally, it influences the
© 2013 Wiley Periodicals, Inc.
Sweat gland immunohistochemistry
strength of cell–cell and cell–matrix interactions. Under
physiologic conditions, CD138 expression is restricted
to the epidermis, the outer root sheath of the anagen
hair follicle, and the sweat gland epithelium. The present study confirms the presence of CD138 in sweat
glands. In addition, we stress the fact that the luminal
part of the acrosyringium is not immunoreactive in
normal conditions.
Cells showing diffuse CD63 positivity indicate an unusual structure of lysosomes. CD63 was originally offered
as a melanoma antigen, but it was subsequently shown
to be directed against a probable lyzosomal antigen. The
present study highlights the CD63 immunoreactivity in
sweat glands. We did not find any specific report about
that sweat gland immunoreactivity in the literature.
The apical pole of the eccrine secretory coils was labeled.
In apocrine secretory cells, the cytoplasmic immunoreactivity was faint to absent, but a thin luminal lining
was clearly evidenced. Such different patterns of immunoreactivity possibly help identifying apoeccrine sweat
glands. Of note contrasting with the CD63 immunoreactivity, CD68, another lysosomial marker, was not
disclosed in both ESG and ASG.
In conclusion, a multipronged immunohistochemical
approach is helpful in the study of human sweat
glands. Although the excretory ducts appear phenotypically similar in the distinct sweat glands, the deep
secretory coils show distinctive differentiation patterns.
The present findings suggest that the immunoreactivity
to the S100-B protein, CEA, and CD63 may help
identifying some apoeccrine sweat glands.
Acknowledgments
This work was supported by a grant from the “Fonds
d’Investissement de la Recherche Scientifique” of the
University Hospital of Liege. No other sources of funding were used to assist in the preparation of this manuscript. The authors have no conflict of interest that
are directly relevant to the content of this review.
The authors wish to thank Mrs. Jennifer EspinosaPerez, Mr. Pierrick Malengreaux, and Mr. Fabian
Mattiuz for their skillful technical assistance. We appreciate the excellent secretarial assistance of Mrs. Ida
Leclercq and Marie Pugliese.
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