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Ana Maria ABREU VELEZ
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Antibodies to pilosebaceous units along their neurovascular supply routes in a new variant of
endemic pemphigus foliaceus in Colombia, South America
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European Journal of Dermatology, 2011, Volume 21, Numéro 3
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© John Libbey Eurotext, 2011
Eur J Dermatol 2011; 21(3): 371-5
Investigative report
Antibodies to pilosebaceous units along their
neurovascular supply routes in a new variant
of endemic pemphigus foliaceus in Colombia,
South America
t
of
Reprints: A.M. Abreu Velez
<abreuvelez@yahoo.com>
Senear Usher syndrome is a variant of pemphigus foliaceus, confined
to seborrheic sites and considered to be a clinical overlap syndrome,
with features of both pemphigus foliaceus and lupus erythematosus.
We recently described autoantibodies to skin eyelid meibomian glands
in patients with a new variant of endemic pemphigus foliaceus (El
Bagre EPF) in South America. We tested for El Bagre EPF patient
sera autoreactivity to pilosebaceous units utilizing direct and indirect
immunofluorescence, confocal microscopy, immunohistochemistry and
immunoelectron microscopy. Hematoxylin and eosin staining of skin
biopsies revealed that one third of the patients affected by El Bagre-EPF
demonstrated some histologic alteration of the pilosebaceous units. By
immunohistochemistry, most El Bagre EPF biopsies demonstrated evidence of an autoimmune response along the neural and vascular supply
routes of the pilosebaceous units. An active immune response was seen
with antibodies such as anti-human mast cell tryptase, myeloid/histoid
antigen, CD8, CD20, CD68, CD117/c-kit, ZAP-70 and vimentin.
Immunoelectron microscopy demonstrated autoantibodies within the
hair follicle and at the basement membrane area of the sebaceous glands.
El Bagre-EPF patients have autoantibodies to pilosebaceous units and
to their surrounding neurovascular packages. Our results warrant further
characterization and may explain the loss of hair described in severe
endemic pemphigus foliaceus before the therapeutic steroid era.
rin
1 Georgia Dermatopathology Associates,
Atlanta,
Georgia,
USA
2 Robert P. Apkarian Integrated Electron
Microscopy Core,
Emory University Medical Center,
Atlanta,
Georgia
3 Department of Ophthalmology,
Emory University Medical Center,
Atlanta,
Georgia
4 Department of Pathology,
University of Arkansas for Medical
Sciences,
Little Rock,
Arkansas,
USA
fp
Ana Maria ABREU VELEZ1
Hong YI2
Weiqing GAO3
Bruce R. SMOLLER4
Hans E. GROSSNIKLAUS3
Michael S. HOWARD1
S
or
th
Article accepted on 2/17/2011
enear-Usher syndrome (SUS), also known as pemphigus erythematosus (PE), seborrheic pemphigus
(SP), or pemphigus erythematodes of Pusey, is
known to be a variant of pemphigus foliaceus (PF) confined to seborrheic sites (e.g., face, scalp, upper chest, ears
and neck). PE is an overlap syndrome with features of
both lupus erythematosus (LE) and PF [1-9]. Pemphigus
foliaceus is characterized by epidermal acantholysis, and
immunoglobulin deposits in an intercellular staining pattern
(ICS) between epidermal keratinocytes [1-9]. The lupus
erythematosus component is demonstrated by circulating
antinuclear antibodies in about one third of the patients, and
sometimes by immunoglobulin and complement deposits
at the dermal/epidermal basement membrane zone (BMZ)
[1-9]. PE and pemphigus foliaceus are commonly present in
cats and dogs in the endemic areas of human fogo selvagem
(FS) [10].
Although absent on the palms and soles, sebaceous glands
are generally found over most of the body [11-17]. We
Au
doi:10.1684/ejd.2011.1310
Key words: pilosebaceous units, endemic pemphigus foliaceus,
velo-cardio-facial syndrome (ARVCF), desmoplakins I and II,
plakophilin 4 (p0071) antibody
described an endemic form of pemphigus foliaceus (El
Bagre-EPF) that resembles seborrheic pemphigus, where
patients predominantly show clinical lesions in the seborrheic areas [18-24]. The disease presents in middle-aged
and older men and postmenopausal women from rural areas
[18-24].
Before the therapeutic steroid era, several authors reported
that severely affected patients with FS developed hair thinning, hair loss, and ectropic, friable eyelids [25].
Given that El Bagre-EPF mainly affects seborrheic areas,
and also given our recent discovery of autoantibodies to
the meibomian glands in patients affected by El Bagre-EPF
[26], we decided to test for autoreactivity to pilosebaceous
units and sebaceous glands utilizing direct and indirect
immunofluorescence (DIF and IIF), immunohistochemistry
(IHC), confocal microscopy (CFM) and immunoelectron
microscopy (IEM) assays. We also searched for histologic
alterations involving these structures utilizing hematoxylin
and eosin (H&E) staining.
371
EJD, vol. 21, n◦ 3, May-June 2011
To cite this article: Abreu Velez AM, Yi H, Gao W, Smoller BR, Grossniklaus HE, Howard MS. Antibodies to pilosebaceous units along their neurovascular supply routes
in a new variant of endemic pemphigus foliaceus in Colombia, South America. Eur J Dermatol 2011; 21(3): 371-5 doi:10.1684/ejd.2011.1310
© John Libbey Eurotext, 2011
Materials and methods
Immunoabsorption of autoreactivity using commercial
peptides directed against desmogleins 1 and 3 (Dsg 1
and 3)
Subjects
t
In order to evaluate the reactivity seen within the hair follicles and/or sebaceous glands, we pre-incubated the sera
of the patients with commercial peptides directed against
the ectodomains of both Dsg1 and Dsg3 for one hour at
differential volumes, as previously described [19]. We then
titrated the sera reactivities via IIF until reaching a point
where the intercellular staining between keratinocytes was
not detected [19]. We then used these pre-adsorbed sera
against Dsg1 and Dsg3 to conduct further investigative
assays.
rin
Image analysis of co-localization of El Bagre-EPF
autoantibodies in sebaceous glands utilizing confocal
microscopy (CFM)
fp
To further study possible reactivity and co-localization of
the patients’ autoantibodies with sebaceous glands, we utilized confocal microscopy examinations with standard 20×
and 40× objective lenses; each photoframe included an area
of approximately 440 × 330 ␮m. Image data was converted
to TIF format, and interpreted with EZ 1 Viewer image
analysis software.
Indirect immunoelectron microscopy (IEM)
Testing was performed as previously described [20].
Statistical methods
H&E
or
of
A case control study was performed. We studied twenty
patients who fulfilled the diagnosis of El Bagre-EPF
based upon clinical, epidemiological, histopathological and
immunological criteria formerly reported by us and others
[18-24]. Skin biopsies were taken from the patients’
seborrheic areas, and examined by H&E, DIF, IIF, CFM,
IHC and IEM. El Bagre-EPF was considered to have the
clinical following features: patients lived in the endemic
area, and demonstrated 1) intercellular staining between
keratinocytes as detected by DIF and IIF utilizing antihuman total IgG and/or IgG4 antibodies, and 2) positive
staining of the BMZ of the dermal/epidermal junction with
either IgG, IgM or Complement/C3 as previously described
by us and others [18-24]. In addition, to be considered a
case of El Bagre-EPF, the patient sera had to immunoprecipitate the ectodomain of desmoglein 1 (Dsg1), utilizing a Concanavalin-A affinity purified bovine tryptic
fragment of 45 kDa [18-24]. Sera from all patients and
controls from the endemic area were also tested by
immunoblotting for reactivity against skin extracts. In order
to be considered a case of El Bagre-EPF, it was necessary
to show positivity to Dsg1, to desmoglein 3 (Dsg3), desmoplakin, periplakin and to other, unknown antigens [18-24].
To be considered a case of El Bagre EPF, the samples were
also required to test positive in the El Bagre-EPF ELISA test
previously reported [18-24]. Sera from sporadic PF cases
and two paraneoplastic pemphigus patients were utilized
as positive controls. We also tested the sera and skin of
twenty control patients from the endemic area matched by
age, sex, work activity and living area. Twenty normal sera
from the United States were used as negative controls. We
obtained informed consent from all patients and complied
with Institutional Review Board requirements.
DIF, IIF
th
Staining was performed as previously described [23]. In
the El Bagre-EPF cases the biopsies were taken from active
lesions, predominately from the upper chest. Normal control biopsies were also taken from the upper chest.
Au
Studies were performed as previously described [22-24].
In addition, we tested for the anti-armadillo repeat deleted
gene in velo-cardio-facial syndrome (ARVCF) antibody,
the antibody against combined desmoplakins I and II (DPIDPII) and plakophilin 4 (p0071) antibody (all from Progen,
Heidelberg, Germany). These molecules were all conjugated with Texas red. Our autometallographic studies were
performed as previously described [21].
IHC
IHC studies were performed as previously described
[22-24]. We utilized anti-human mast cell tryptase (MCT),
myeloid/histoid antigen, CD8, CD20, CD68, CD117/c-kit,
ZAP-70 and vimentin antibodies.
372
Autoantibodies to the sebaceous glands were statistically
analyzed using Student’s t-test to evaluate differences in
morphology, and to interpret the images. We considered
a correlation a p-value of 0.05 or less, utilizing a normal
distribution of the samples.
Results
Clinical lesions
The physical examination in all El Bagre-EPF patients
revealed lesions typically involving the scalp, face, upper
part of the chest, neck, periumbilical area and inside the
ears. Often, we detected hyperkeratotic plaques in the seborrheic areas; occasionally we observed small, flaccid bullae
with scaling, crusting, and hyperpigmentation. Selected
cases demonstrated a thick, greasy, yellowish scale crust.
Of note, alopecia of the scalp was noticed in two cases,
characterized by extensive and generalized lesions.
H&E of the skin biopsies revealed that about one third of the
patients affected by El Bagre-EPF showed some degree of
alteration of either the pilosebaceous units, or of histologically solitary sebaceous glands. The alterations included a
lymphohistiocytic infiltrate at the edges of hair follicular
units, and hyalinization of dermal collagen around these
structures (figure 1). The hyalinization was particularly
noticed on periodic acid Schiff (PAS) staining, and also
highlighted with IHC utilizing anti-human vimentin antibody. Follicular plugging of the pilosebaceous units was
also noted. The changes in the sebaceous glands consisted
of focal degeneration of the sebocytes. The blood vessels
around the hair follicular units were dilated, and distended
© John Libbey Eurotext, 2011
EJD, vol. 21, n◦ 3, May-June 2011
I
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N
K
L
O
P
Figure 2. CFM images (A, B and O). A) and B) Positive CFM
staining utilizing rhodamine conjugated Complement/C1q
(red staining, yellow arrows) around the BMZ of the sebaceous
glands. Sebocyte nuclei were counterstained with Dapi (blue
staining). C) Positive DIF staining of FITC conjugated Complement/C1q around sebaceous gland peripheral areas using
polarized light microscopy (yellow staining, red arrows). D)
IHC staining fibrinogen around the sebaceous glands (brown
staining, blue arrows). E) IIF positive staining with FITC conjugated anti-human IgM at the BMZ of the sebaceous glands
and some intrasebaceous structures (yellow staining, white
arrow). In F), similar to E), but utilizing FITC conjugated
anti-human IgG (faint yellow staining, white arrows); nuclei
are counterstained with TO-PRO® -3/DNA in orange. G) Positive staining with MCT around blood vessels surrounding
sebaceous glands (brown staining, blue arrows). H) IHC showing positive anti-human IgE staining around the sebaceous
gland (brown staining, blue arrows). I) Positive myeloid histoid around sebaceous glands (brown staining, red arrows).
J) Positive staining for HAM 56, antibody, clustered around
sebaceous glands (brown staining, black arrows). K) Positive
staining for albumin, clustered around a hair follicular unit
(brown staining, blue arrow). L) Positive staining for Complement/C4 around sebaceous glands and surrounding blood
vessels (brown staining, blue arrows). M) Positive staining for
CD68 around a pilosebaceous unit and surrounding blood vessels (brown staining, black arrows). N) Positive staining for
CD20 around sebaceous glands and surrounding blood vessels (brown staining, black arrows). O) CFM showing positive
staining around a sebaceous gland utilizing FITC conjugated
anti-human IgM (green staining, yellow arrow). Sebaceous
glands nuclei were counterstained with TO-PRO® -3/DNA in
red. P) Positive staining around the BMZ area of the sebaceous
glands utilizing anti-human fibrinogen (dark brown staining,
black arrow).
or
of
Figure 1. A) Clinical lesions around the ear. In B), A perisebaceous lymphohistocytic infiltrate is noted by H&E, without
evidence of collagen alteration (black arrow). C) IHC staining
with MCT around blood vessels surrounding the hair follicle (brown staining, black arrows). D) Gomori Trichrome
stain shows accentuation of blue collagen staining around a
sebaceous glands (blue arrows). E) H&E of accentuated collagen and inflammatory infiltration around a pilosebaceous unit
(black arrow). F) Compartmentalization of vimentin around
the hair follicular unit (brown staining, red arrow). G) CFM
showing IgG positive staining around sebaceous glands (yellow staining, white arrow). The nuclei of the sebaceous glands
are represented in the center of the image in the blue-green area.
H) DIF staining of FITC conjugated Complement/C3 on the
deep edge of a sebaceous gland (green staining, white arrow).
I) Stain of a BMZ of a sebaceous gland with FITC conjugated Complement/C3c (green-white staining, white arrows).
J) Staining with anti-human IgM antibody on the periphery of
a sebaceous gland, and clustered around a nearby blood vessel
(brown staining, blue arrows). K) Staining around a sebaceous
glands utilizing anti-human IgG (brown staining, blue arrows).
L) ZAP 70 positive staining at the BMZ of the sebaceous glands
and inside (brown stain) (blue arrows).
t
H
G
J
D
D
C
F
C
rin
E
B
B
fp
A
A
Au
th
with a lymphohistiocytic infiltrate (figures 1, 2). Occasionally, the sebaceous glands were partially or completely
destroyed and in some, we noticed an infundibular folliculitis. No alterations in the sebaceous glands were seen
in the controls. Classic EPF acantholysis was detected in
new and active lesions, but not in biopsies taken from the
controls.
Utilizing DIF and IIF, were able to visualize a polyclonal immune response to the pilosebaceous structures,
most commonly with IgG, IgM, Complement/C1q, C3c,
C3d, and C4. IgE, fibrinogen, albumin, and IgA were
also noticed. In all slides demonstrating IgE positivity, mast cell tryptase and CD117/c-kit antibodies were
also present, clustered around the neurovascular bundles
surrounding solitary sebaceous glands and pilosebaceous
units (figures 1, 2).
Moreover, we noted that most primary reactivity near the
sebaceous glands was directed against their neurovascular packages. In figure 3A, we found positive staining
EJD, vol. 21, n◦ 3, May-June 2011
© John Libbey Eurotext, 2011
373
A
B
E
F
to be a more common type of autoimmune blistering disease in cats and dogs, due to their higher concentrations of
sebaceous glands and/or pilosebaceous units [10]. In Brazil,
where FS is common, a large reference laboratory at the
University of São Paulo has compiled large numbers of
cases of canine PF and PE, and a few of feline PF and PE
[10]. The number of animals affected by Brazilian PF is
high in comparison with the prevalence of the disease in
other countries [10].
The sebaceous glands play an important role in the
metabolism and control of sex hormones, human growth
hormone, melanocyte stimulating factor, adrenocorticotropic hormone and additional pituitary hormones,
including prolactin [11-14]. High temperatures also induce
changes in these glands, and the El Bagre-EPF endemic
area is one of high temperature and humidity [18]. In addition, we have shown that people living in the endemic area
of El Bagre EPF are exposed to high levels of mercuric
selenides and iodides; [21] we were further able to observe
the presence of these metals within the sebaceous glands
[21].
Before the therapeutic steroid era, histologic alterations
of sebaceous glands were found in patients affected with
FS. The alterations included atrophy and reabsorption,
as described above. In addition to the sebaceous glands,
mammary atrophy and several endocrinopathies were documented [25].
Of importance, El Bagre EPF displays features of both
lupus erythrematosus and pemphigus [18]. In patients with
lupus erythematosus on the face, especially on the nose,
removal of scaly skin lesions may yield the peculiar finding
of numerous projecting processes on their inner surfaces,
which represent widened mouths of sebaceous gland follicles [27]. Dr Ferdinand Hebra (1816-1880), reasoning from
the finding of these distended and plugged sebaceous gland
follicles, suggested a connection of the disease with these
glands [27]. Thus, in lupus erythematosus, as in El Bagre
EPF, there seems to be anatomically selective pathologic
changes, with these changes being found in and around the
sweat and sebaceous glands [27-29].
The sebaceous glands are richly innervated, largely via
sympathetic nerves. We recently reported the presence of
autoantibodies directed against nerves and mechanoreceptors in the skin, as corroborated in this study [20]. In
addition, we suggest that since sebaceous glands also have
receptors for sex hormones, this may explain why El BagreEPF does not affect children, and rarely affects selected
post-menopausal females [18-24].
Further, we had previously demonstrated the presence of
several autoantibodies to plakins (e.g. DPI, DPII, periplakin
and envoplakin) in El Bagre EPF [19, 20]. These plakin
molecules are in turn embedded within the sebaceous
glands, and interact with ceramides [17]. Thus, this interaction may lead to epitope spreading on some lipid-related
antigens [30]. Other research indicates that involucrin,
envoplakin and periplakin serve as substrates for ester linkage attachments of ceramides to the cornified envelope,
enhancing the barrier function quality of human epidermis
[30]. Finally, we found positive staining within the sebaceous glands in proximity to the inflammatory infiltrate.
Zeta-chain-associated protein (ZAP-70) is adaptor protein
that acts quickly after T cell activation to propagate signals from the TCR: CD3 complex [32]. ZAP-70 is essential
for a proper and complete T cell immune response [31, 32],
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t
D
C
200 nm
H
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Figure 3. Shows colocalization of El Bagre-EPF patient sera
with some molecules of the p120 catenin family, and with DPI
and DPII. Also, we demonstrate autoantibodies in the sebaceous glands utilizing IEM. (See Results section for detailed
captions).
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or
against the neurovascular supply of a sebaceous gland utilizing FITC conjugated anti-human IgG antibody (yellow
staining, white arrow), with simultaneous staining at the
BMZ of the sebaceous gland (yellow staining, light blue
arrow). In figure 3B, we demonstrate exact colocalization
of El Bagre-EPF antibodies with p0071 antibody (orange
dots, white arrows). In figure 3C, we also show exact colocalization of El Bagre-EPF patient sera with the reactivity of
Texas red conjugated DP-I and DP-II antibodies, in areas
surrounding the neurovascular package of the gland (red
staining, yellow arrow). The sebaceous gland nuclei are
counterstained in blue with Dapi. In figure 3D, we show an
IEM at 200 kV demonstrating the presence of a single 10
nanometer Gold particle in the BMZ of the sebaceous gland
(red arrow). In figure 3E, we present a 10kV IEM image of
the same gland. In figure 3F, we show positive staining to
Texas red conjugated ARVCF antibody, colocalizing with
El Bagre-EPF patient sera inside a sebaceous gland (red
staining, yellow arrow). Finally, in figure 3G and figure 3H,
an IEM of the skin at low and high magnification, respectively, in an area surrounding the hair follicle. The red arrow
in figure 3G (50 kV) indicates the area (near the lower right
hair follicle) where in figure 3H (150kV), 10 nm Gold particles are found close to a desmosome (green arrow) and
within myxoid connective tissue (red arrow).
Discussion
Seborrheic pemphigus and pemphigus foliaceus are rare in
humans [1-8]. However, these two kinds of pemphigus seem
374
© John Libbey Eurotext, 2011
EJD, vol. 21, n◦ 3, May-June 2011
and thus our data may highlight a specific immune response
against pilosebaceous units in this new variant of El
Bagre-EPF. t
Disclosure. Declaration of funding sources: All work
was performed with funding from Georgia Dermatopathology Associates (GDA) (Dr. Howard). The El Bagre-EPF
samples were collected through previous grants from the
Embassy of Japan in Colombia, Mineros de Antioquia SA,
Hospital Nuestra Senora del Carmen, Medellin, Colombia,
South America (Dr. Abreu Velez). Conflict of interest: none.
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References
EJD, vol. 21, n◦ 3, May-June 2011
© John Libbey Eurotext, 2011
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