Piloerector ARVCF MYZAP DP I-II P0071

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CED
Original article
Clinical and Experimental Dermatology
Patients with a new variant of endemic pemphigus foliaceus have
autoantibodies against arrector pili muscle, colocalizing with
MYZAP, p0071, desmoplakins 1 and 2 and ARVCF
A. M. Abreu-Velez,1
C. A. Valencia-Yepes,2 Y. A. Upegui-Zapata,3 E. Upegui-Quiceno,3
4,5
N. R. Mesa-Herrera, J. E. Velazquez-Velez6,7 and M. S. Howard1
1
Georgia Dermatopathology Associates, Atlanta, GA, USA; 2Department of Education, University of Antioquia, Medellin, Colombia; 3Pecet Group,
University of Antioquia, Medellin, Colombia; 4Biogemo Institute, Medellin, Colombia; 5Department of Physiology and Biochemistry, School of Medicine,
University of Antioquia, Medellin, Colombia; 6Department of Cardiology, Hospital General de Medellin, Medellin, Antioquia, Colombia; and 7Clinica CES
Medellin, Medellin, Colombia
doi:10.1111/ced.13214
Summary
Background. We identified a new variant of endemic pemphigus foliaceus in El
Bagre, Colombia, South America, which we term El Bagre-EPF, and observed reactivity
to arrector pili muscle (APM), thus we tested for autoimmunity to APM.
Methods. We took skin biopsies from 30 patients with El Bagre-EPF and 30
healthy controls (HCs) matched by age, sex and occupation, who were all from the
endemic area, and tested these using direct immunofluorescence (DIF), confocal
microscopy, immunohistochemistry and immunoblotting (IB).
Results. Of the 30 patients with El Bagre-EPF, 27 had autoantibodies to APM that
colocalized with commercial antibodies to myocardium-enriched zonula occludens-1associated protein (MYZAP), desmoplakin (DP)1 and DP2, plakophilin 4, and Armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF) (P < 0.001, Fisher
exact test). The positive staining also colocalized with Junctional Adhesion Molecule 1
(JAM-A), a control antibody for gap cell junctions. No HC samples were positive. In 27
of the 30 patients, serum that was APM-positive also displayed IB colocalization of their
autoantibody molecular weights with the Progen antibodies (P < 0.001, Fisher exact test).
Conclusions. Patients affected by El Bagre-EPF have autoantibodies to APM, colocalizing with the antibodies MYZAP, ARVCF, p0071, DP1 and DP2, suggesting
that these molecules are El Bagre-EPF antigens. Further, all of these antigens represent components of cell junctions, indicating that the immune response is directed,
at least partially, against cell junctions. The immune response in patients affected by
El Bagre-EPF is polyclonal, and it includes B and T lymphocytes, mast cells, IgG,
IgA, IgM, IgD, IgE, fibrinogen, albumin, complement/C1q, C3c and C4.
Introduction
Endemic pemphigus foliaceus (EPF) is a group of
autoimmune blistering diseases considered variants of
PF, but presenting in an endemic fashion.1–4 EPF was
Correspondence: Dr Ana Maria Abreu-Velez, Georgia Dermatopathology
Associates, 1534 North Decatur Road NE, Suite 206, Atlanta, GA, 303071000, USA
E-mail: [email protected]
Conflict of interest: the authors declare that they have no conflicts of
interest.
Accepted for publication 29 December 2016
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Clinical and Experimental Dermatology (2017) 42, pp874–880
originally documented in recently deforested and mining areas near rivers; this presentation is particularly
true in areas of Brazil, where mining and road construction have increased over the past century. EPF
foci have also been described in Central American and
other South American countries, as well as in Africa
(Tunisia).1–5 Recently, the incidence and prevalence of
EPF has decreased significantly, especially in Brazil.3,4
We have identified a new variant of EPF in El Bagre,
Colombia, which we term El Bagre-EPF, and found
that people with this disease have autoantibodies to
desmoglein (Dsg)1 Dsg3, periplakin, envoplakin and
ª 2017 British Association of Dermatologists
Autoantibodies in a new variant of endemic pemphigus foliaceus A. M. Abreu-Velez et al.
bullous pemphigoid antigen 1, and also to other, as
yet unknown antigens.6 These patients also have
autoantibodies to pilosebaceous units and associated
neurovascular supply structures.7 In routine direct
and indirect immunofluorescence (DIF and IIF) of
these patients, we noticed a pattern of autoantibody
deposits directed against arrector pili smooth muscle
(APM). In the current study, we aimed to test for reactivity to the APM, using multiple antibodies, complement and other immunological activation markers.
Methods
A human quality assurance review board approved
the studies at the Hospital Nuestra Se~
nora del Carmen
in El Bagre, and all participants provided signed
informed consent.
Patients
We tested 30 patients with El Bagre-EPF and 30
healthy controls (HCs) from the endemic area,
matched by age, sex and employment activities. The
patients were evaluated clinically, and biopsy samples
were assessed by haematoxylin and eosin (H&E)
histology, direct immunofluorescence (DIF), immunohistochemistry, confocal microscopy (CFM), ELISA,
immunoblotting (IB) and immunoprecipitation (IP), as
previously described.7–10 For DIF, biopsies were taken
from perilesional skin on the chest; control biopsies
were also obtained from the chest.
Patients were included only after these tests were
performed and if they fulfilled full diagnostic criteria
for El Bagre-EPF: (i) the patient had the clinical and
epidemiological features described for this disease; (ii)
they lived in the endemic area; (iii) their serum displayed intercellular staining of the cell junctions
(desmosomes) between epidermal keratinocytes (ICS)
by DIF, and to the basement membrane zone (BMZ)
of the skin by either DIF or indirect immunofluorescence (IIF), using fluorescein isothiocyanate (FITC)conjugated monoclonal antibodies to human total IgG
or to IgG4, as previously described;11,12 (iv) their
serum was positive by IB for reactivity against Dsg1
and plakin molecules, as previously described;6 (v)
their serum immunoprecipitated a concanavalin A
affinity-purified antigen bovine tryptic 45 kDa fragment of Dsg1;13 and (vi) the patient serum yielded a
positive result using an ELISA when screening for
autoantibodies to pemphigus foliaceus (PF) antigens.14 HC sera were assessed by the same tests.
ª 2017 British Association of Dermatologists
Direct immunofluorescence
DIF was performed as previously described.7–10 The
slides were counterstained with 4,6-diamidino-2phenylindole (DAPI) (Pierce, Rockford, IL, USA).
Several years ago, the first author discovered new
autoantigens to several organs other than the skin.
Because of the complexity of the immune response
in these patients, we contacted other experts including Dr E. H. Beutner in the USA, Dr T. Hashimoto
in Japan and a scientist at the University of Heidelberg in Germany. All agreed that our data indicated
new autoantigens. We sent identical serum for study
to these scientists; all agreed this disorder was
unique. A few months later, the primary owner of
Progen Biotechnik (Heidelberg, Germany) commercialized these antibodies. Thus, we used the following antibodies from Progen: anti-ARCVF (Armadillo
repeat gene deleted in velo-cardio-facial syndrome;
cat. no. GP155), anti-desmoplakin (DP)1 and DP2
(cat. no. 65146), anti-p0071 (cat. no. 651166), and
anti-MYZAP (myocardium-enriched zonula occludens1-associated protein; cat. no. 651169).
Secondary antibodies were obtained from ThermoFisher Scientific (Waltham, MA, USA), for ARCVF we
used Alexa Fluor 555 goat anti-guinea pig, while for
DP1 DP2, p0071 and MYZAP, we used goat antimouse Texas Red-conjugated IgG.
We also used rabbit anti-junctional adhesion molecule 1 (JAM-A) (ThermoFisher Scientific), as this antibody is positive against gap junctions present in APM.
All experiments were performed with positive and negative control samples.
Immunohistochemistry
Immunohistochemistry performed as previously
described.7–11 We tested for mouse anti-human ribosomal protein s6-ps240 (RIBO), and anti-metallothionein
(both Dako, Carpinteria, CA, USA). We also used antihuman IgG antibody (Dako) as it is specific for APM.
To confirm the identity of the APM, we used an antibody to smooth muscle antigen (SMA) (Dako), which
stains APM.
Immunoblotting
For IB substrates, we used normal human skin from
reduction plastic surgeries. For control samples, we
used antibodies against DP1, DP2 and Dsg1.6,12–14 IB
was performed using an enhanced chemiluminescence
set (SuperSignal; ThermoFisher Scientific) on 4%, 7%
Clinical and Experimental Dermatology (2017) 42, pp874–880
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Autoantibodies in a new variant of endemic pemphigus foliaceus A. M. Abreu-Velez et al.
and 14% precast gels (Invitrogen, Carlsbad, CA, USA).
Samples were separated by both 4% and 7% SDSPAGE according to the Laemmli method, and transferred
to
PVDF
membranes
as
previously
described.6,12–14
Colocalization of the patient autoantibodies with
commercial antibodies under confocal microscopy
CFM colocalization analysis is often used to determine
whether two molecules associate with the same cell
structures; for example, to determine whether two particular proteins or molecules both display intracellular
colocalization to a specific organelle. CFM was performed as previously described.10,11 In brief, we used
standard 9 20 and 9 40 objective lenses; each photo
frame
included
an
area
of
approximately
440 9 330 lm. Images were obtained using image
analysis software (EZ-1; Nikon, Tokyo, Japan). For
colocalization experiments with serum autoantibodies,
we used the aforementioned Progen antibodies to D1,
D2, ARVCF, p0071 and MYZAP.
Statistical analysis
Statistical analysis was performed using GraphPad
QuickCalcs (GraphPad Software Inc., La Jolla, CA,
USA). We used the Fisher exact test to compare two
nominal variables (e.g. positive and negative) of antibody response. P < 0.05 was considered statistically
significant.
Immunohistochemistry showed positivity against
RIBO in 27 of the 30 patients (90%), whereas negative staining was noted in all the HCs (P < 0.001,
Fisher exact test). In addition, 25 of the patients displayed reactivity to anti-metallothionein, which was
negative in all HCs (83.3% vs. 0%) (P < 0.001, Fisher
exact test). The identity of the APM was verified using
anti-SMA (Fig. 1).
Using histopathological examination with H&E
stain, no noticeable changes were seen in the APM,
with the exception of a few lymphocytes and histiocytes around these muscles (Fig. 1f).
Immunoblotting
All patient sera that had positive DIF results for APM also
displayed IB colocalizations of their autoantibody molecular weights with the antibodies (all Progen) to DP1
(360 kDa), DP2 (260 kDa), p0071 (135 kDa) ARVCF
(105 kDa) and MYZAP (54 kDa) (P < 0.001) (Fig. 1).
Confocal microscopy
CFM showed that in 27 of the 30 patient sera, the
patient autoantibodies colocalized exactly with the
antibodies to MYZAP, ARVCF, DP1, DP2 and p0071
(P < 0.001, Fisher exact test). The positive staining
also colocalized with the JAM-A control antibody for
gap cell junctions (100% vs. 10% respectively,
P < 0.001, Fisher exact test) (Fig. 2).
Discussion
Results
Staining results
DIF results are shown in Table 1 and Fig. 1. Positive
staining for all the antibodies also colocalized with the
JAM-A control antibody for gap cell junctions. No control tissues were positive.
During our previous DIF studies on patients with El
Bagre-EPF,6,7 we observed disease reactivity to APM.
In the current study, we specifically tested for APM
reactivity and found a polyclonal immune response.
We had previously documented a polyclonal response
against other structures.6–11 APM is composed of
smooth muscle and has many gap junctions. For the
Figure 1 Colocalization of antibodies from patients with El Bagre endemic pemphigus foliaceus (EPF) and the commercial antibodies to
Armadillo repeat gene deleted in velo-cardio-facial syndrome (ARCVF), desmoplakin (DP), p0071 and myocardium-enriched zonula
occludens-1-associated protein (MYZAP) in arrector pili muscle (APM). (a) Direct immunofluorescence (DIF) shows colocalization of
p0071 (red/yellow staining) and fluorescein isothiocyanate (FITC)-conjugated anti-human IgG patient antibodies (green staining) (black
arrow) (original magnification 9 400). (b) Immunohistochemistry (IHC) shows positive (brown) staining for IgG in patient APM (black
arrow) (original magnification 9 200). (c) DIF shows positive (green) with FITC-conjugated anti-human IgG in patient APM (white
arrows) (original magnification 9 100). (d) IHC shows positive (brown) staining for human ribosomal protein s6-ps240 (RIBO), in
APM (black arrow) (original magnification 9 400). (e) Histology showing a lymphohistiocytic infiltrate around a patient APM (black
arrows) (haematoxylin and eosin, original magnification 9 40). (f) Immunoblotting results: Lanes A and B progressing right indicate
sera from a patient with El Bagre-EPF; lane C, negative control; lane D, positive controls Note the positive staining from top to bottom:
360 kDa (DP1) 260 kDa (DP2), 160 kDa (Dsg1), 135 kDa (p0071), 105 kDa (ARVCF), 67 kDa (unknown), 54 kDa (MYZAP) and
47 KDa (unknown).
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Clinical and Experimental Dermatology (2017) 42, pp874–880
ª 2017 British Association of Dermatologists
Autoantibodies in a new variant of endemic pemphigus foliaceus A. M. Abreu-Velez et al.
(a)
(c)
(e)
ª 2017 British Association of Dermatologists
(b)
(d)
(f)
Clinical and Experimental Dermatology (2017) 42, pp874–880
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Autoantibodies in a new variant of endemic pemphigus foliaceus A. M. Abreu-Velez et al.
Table 1 Results of direct immunofluorescence staining of arrector pili muscle.
Marker
Positive cases, n*
IgG
Fibrinogen
Albumin
Complement/C3c
Complement/C1q
IgA
IgD
IgE
27
20
13
9
8
9
9
0
Staining strength
++++
++++
+++
+++
++
++
++
–
*Out of 30.
disease fogo selvagems, the Portuguese medical literature prior to the introduction of steroids includes postmortem studies documenting pathological findings in
smooth muscle of the stomach, intestine, ocular ciliary
muscles, urinary bladder and blood vessels.15,16 Our
findings are thus in agreement with these early fogo
selvagem results regarding smooth muscle reactivity.
At least one-third of patients with El Bagre-EPF have
systemic autoreactivity, and we are in the process of
documenting these new data. In the current study, we
found that 90% of the patients with El Bagre-EPF displayed autoantibodies to APM. APM is responsible for
piloerection, and we previously showed that patients
with El Bagre-EPF have autoantibodies to the pilosebaceous units and that these antibodies colocalize
with ARVCF, p0071, DP1 and DP2 antibodies, which
are all present in the cell junctions.7 At the time we
reported those findings, our samples did not display significant APM reactivity; we later collected additional
samples. In the current study, we found autoantibodies
Figure 2 (a) Direct immunofluorescence (DIF) using fluorescein isothiocyanate (FITC)-conjugated anti-human IgG (green), epidermal
intercellular staining (red arrow) and staining along the basement membrane zone (BMZ) (yellow arrow) and in arrector pili muscle
(APM) (black arrow) (original magnification 9 100). (b) DIF using FITC-conjugated anti-human IgG (green staining) colocalizing with
myocardium-enriched zonula occludens-1-associated protein (MYZAP) (red/yellow staining) in patient APM (black arrow). (c) Immunohistochemistry shows positive (brown) staining with IgG against patient APM (red arrow) (original magnification 9 400). (d) Verification that this tissue was APM was performed using smooth muscle antigen antibody (brown staining) (original magnification 9 400).
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Clinical and Experimental Dermatology (2017) 42, pp874–880
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Autoantibodies in a new variant of endemic pemphigus foliaceus A. M. Abreu-Velez et al.
to APM in patients with El Bagre-EPF. We are not
aware of any clinical implications of our current findings.
We had also shown previously that these commercial antibodies from Progen colocalized exactly with
structures in the heart, including the Purkinje system
and heart cell junctions.8 These findings suggested
that the specific molecules that belong to the 120
(catenin)/plakophilin subfamily of Armadillo-like proteins (i.e. ARVCF and p0071) are El Bagre-EPF
autoantigens. ARVCF, DP1, DP2, and p0071MYZAP
are components of cell junctions in most parts of the
body. This is supported by our results here, as their
reactivity colocalized with the JAM-A control antibody
for gap junctions; these colocalizations were confirmed
by confocal microscopy, and the molecular weight of
these proteins was similar to those of El Bagre-EPF
autoantigens.
In the current study, we also found that RIBO and
metallothionein were overexpressed in APM, indicating a pathological process.17 Metallothioneins represent a family of cysteine-rich, low molecular weight
proteins18 that bind both pathological and xenobiotic
heavy metals through the thiol group of their cysteine
residues. We previously reported that patients with El
Bagre-EPF live in an area with high levels of xenobiotics such as mercuric selenides, iodine, heavy metals and metalloids, and they are also exposed to
materials used in cocaine processing, such as permanganate, sulphuric acid, caustic sodium ammonium sulphate and lime.18 APM are rich in enzymes; some,
including acetylcholinesterase, are inhibited by mercury. Acetylcholine is one of the primary neurotransmitters of nerves in the autonomic nervous system.19
We previously documented that patients with El
Bagre-EPF are exposed to high environmental levels of
mercury,18 and in other studies, that autoantibodies
in patients with El Bagre-EPF were present in smooth
muscle areas, nerve receptors and pilosebaceous unit
tissue.7–9
In a previous study of 72 patients with dermatitis
herpetiformis, IgA was observed in 19 cases in the
APM, and, in a few cases, complement/C3, IgM, and
IgG were also identified.20 This indicates that the
auto-reactivity to APM is important in other autoimmune blistering diseases.
We have previously shown that DP1, DP2 and
members of the p120 (ctn)/plakophilin subfamily of
Armadillo-like proteins (ARVCF and p0071) are recognized by the autoantibodies from patients with El
Bagre-EPF.7,8 All these molecules are part of cell junctions in multiple human organs.19,21 MYZAP has
ª 2017 British Association of Dermatologists
recently been identified as a component of the cytoplasmic plaques of the area composita of myocardial
intercalated disks, and in the adherens junctions in
vascular endothelia. Most patients with El Bagre-EPF
have autoantibodies to these structures.
We have also previously demonstrated that the
immune response in patients with El Bagre-EPF is
polyclonal, and that it includes B and T lymphocytes,
mast cells, IgG, IgA, IgM, IgD, IgE, fibrinogen, albumin, complement/C1q, C3c, and C4.7–14 The El
Bagre–EPF disease focus differs from other foci of EPF.
Patients with El Bagre-EPF are exposed to tropical and
parasitic disease agents including malaria (both Plasmodium vivax, and Plasmodium falciparum), tuberculosis, Hirudinea spp., Haementeria spp., Glossiphoniidae
spp., Oxytychus ornatus, Enterobacter cloacae, Bordetella
bronchiseptica, Enterococcus faecalis, Klebsiella oxytoca
and Klebsiella pneumoniae. They are also exposed to
multiple metals and metalloids, which may explain
the polyclonal immune response. In the current study,
we found that patients with El Bagre-EPF had reactivity to APM, which colocalized with the commercial
antibodies DP1, DP2, ARVCF, MYZAP and p0071;
these may represent putative new antigens in patients
with El Bagre-EPF. All these molecules are components of cell junctions, indicating that the immune
response is possibly directed, at least partially, against
these structures. As noted previously, APM contain
multiple enzymes, including acetylcholinesterase.
Moreover, these enzymes may be altered by mercury
and other metals and metalloids that prevail in the
endemic area; these enzymes may also be altered by
chemicals used in cocaine processing.
Conclusion
We have identified a new variant of EPF in El Bagre,
Colombia, South America, which we term El BagreEPF (also called pemphigus Abreu–Manu) and detected
a polyclonal reactivity to APM and its cell junctions,
indicating that the immune response in this variant of
pemphigus is not only directed to the desmosomal
antigens but also to smooth muscle cells and their
junctions. The implications of these results for immune
response triggers still remain unsolved and warrant
further study.
Acknowledgements
We thank J. S. Jones, HT (ASCP), Georgia Dermatopathology Associates, for excellent technical assistance. This study was supported financially by Georgia
Clinical and Experimental Dermatology (2017) 42, pp874–880
879
Autoantibodies in a new variant of endemic pemphigus foliaceus A. M. Abreu-Velez et al.
Dermatopathology Associates (Atlanta, GA, USA);
Mineros SA (Antioquia, Colombia); Embassy of Japan
(Colombia) Municipality of El Bagre (Antioquia,
Colombia) and Hospital Nuestra Se~
nora de El Bagre
(Antioquia, Colombia).
What’s already known about this topic?
10
11
• Patients with EPF have autoantibodies to epi-
dermal keratinocyte cell junctions.
12
What does this study add?
13
• Patients with El Bagre-EPF have autoantibodies
to APM.
• These antibodies colocalize with antibodies to
ARVCF, DP1, DP2, p0071 and MYZAP.
14
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ª 2017 British Association of Dermatologists
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