Report
Autoantibodies to full body vascular cell junctions colocalize
with MYZAP, ARVCF, desmoplakins I and II and p0071 in
endemic pemphigus in Colombia, South America
Ana M. Abreu Velez1, MD, PhD, DSc
Michael S. Howard1, MD
1
Georgia Dermatopathology Associates,
Atlanta, GA, USA, 2Robert P. Apkarian
Integrated Electron Microscopy Core,
Emory University Medical Center, Atlanta,
GA, USA, and 3Department of Oral
€
Pathology, Faculty of Odontology, Malmo
€, Sweden
University, Malmo
, Hong Yi2, MS, Gunnar Warfvinge3, OD, and
Abstract
Background We previously described a new variant of endemic pemphigus foliaceus in El
Bagre, Colombia (El Bagre-EPF).
Methods Here we aimed to investigate disease autoreactivity to vessels in all body
organs/systems. We compared 57 patients and 57 controls from the endemic area,
matched by demographics, age, sex, and work activity. We performed
immunofluorescence, immunohistochemistry, confocal microscopy, immunoblotting, indirect
Correspondence
Ana M. Abreu-Velez, MD, PHD
Georgia Dermatopathology Associates
1534 North Decatur Rd. NE, Suite 206
Atlanta, GA 30307-1000
USA
E-mail: [email protected]
Funding: Our work was performed with
funding from Georgia Dermatopathology
Associates(GDA); Mineros, SA, Medellin,
Colombia, South America; Department of
Oral Pathology, Faculty of Odontology,
€ University, 205 06, Malmo
€, Sweden,
Malmo
~ora del Carmen, El
Hospital Nuestra Sen
Bagre, Colombia, South America, and the
El Bagre Mayoral Office.
immune electron microscopy studies, and autometallographic studies. We performed
ultrasonography on large patient arteries, investigating for vascular anomalies. In addition,
we reviewed autopsies on seven patients who died affected by El Bagre-EPF. We
immunoadsorbed any positive vessel immunofluorescence with desmoglein (Dsg1),
investigating for new autoantigens.
Results Overall, 57/57 patients affected by El Bagre-EPF displayed autoantibodies to
vessels in all the organs/systems of the body via all methods (P < 0.01). The autoreactivity
was polyclonal, and the patient’s antibodies colocalized with commercial antibodies to
desmoplakins I and II, p0071, ARVCF, and MYZAP (all from Progen Biotechnik, Germany;
P < 0.01; all present at cell junctions). Immunoadsorption with Dsg1 on positive vessel
immunofluorescence showed that the immune response against the vessels was directed
against non-Dsg1 antigen(s). Autometallographic studies showed deposits of metals and
metalloids in vessel cell junctions and in erythrocytes of 85% of patients (P < 0.01).
Conclusions Immune response to these vascular antigens is likely altering endothelial
cells and vessel shapes, thus disturbing hemodynamic flow. The flow alterations likely lead
Conflicts of interest: None.
to inflammation and may play a role in the atherogenesis often seen in these patients.
doi: 10.1111/ijd.13827
A new focus of EPF was described in El Bagre, Colombia,
Introduction
South America.3 Furthermore, studies in the endemic area con-
Endemic pemphigus foliaceus (EPF) is an autoimmune disease
firmed a new clinicopathologic variant of EPF (pemphigus
characterized by the presence of cutaneous vesicles and blis-
Abreu-Manu).5 The new variant shares features with Senear-
ters, and well-documented autoantibodies to desmoglein 1
Usher Syndrome. As in lupus, a localized form accounts for
about 30% of the cases; a systemic form accounts for about
(Dsg1).1,2 By direct immunofluorescence (DIF) and indirect
30% of the cases, affecting multiple organs.5–12 The patients
immunofluorescence (IIF), the “hallmark” of pemphigus and
EPF has been focused on the autoantibodies that create inter-
are primarily gold miners who also work in agricultural activi-
cellular staining (ICS) between epidermal keratinocytes.1–3
ties.5,6 The endemic area is in the tropics and rich in metals,
primarily
metalloids, and xenobiotics such as mercury and cyanide.5,6
documented in rural areas of South and Central America, and
We have previously reported El Bagre EPF autoantibodies to
in Tunisia, Africa.1–4 In Latin America, the disease affects
sebaceous and Meibomian glands, hair follicular units, nerves,
Indians and colonos, descendants of workers brought to these
areas for gold, nickel and other metal mining activities and road
neural receptors, neurovascular bundles, melanocytes, heart,
smooth and skeletal muscle, and kidney.7–12 The aim of this
construction.1–3
study was to confirm the presence of autoantibodies against
Endemic
pemphigus
foliaceus
has
ª 2017 The International Society of Dermatology
been
International Journal of Dermatology 2017
1
2
Report
Abreu Velez et al.
Autoantibodies to vessel in endemic pemphigus
vessels in multiple organ/systems, utilizing differential techniques in a case–control study.
Materials and methods
We tested 57 patients affected by El Bagre-EPF and 57
controls from the endemic area matched by age, gender, and
work activities, clinical history, and physical examination. The
patients and controls were evaluated by hematoxylin and eosin
(H&E), DIF, IIF, confocal microscopy (CFM), immunoblotting
Statistical analysis
We used Fisher’s exact test to compare two nominal variables
(e.g., positive and negative) of the antibody response. We also
compared the differences when evaluating (i) positivity of the El
Bagre-EPF autoantibodies between patient cases and controls,
and (ii) patient antibody results versus the commercial
antibodies to MYZAP, p0071, DP I-II, and ARVCF. P < 0.05
with a 95% of confidence or more was considered statistically
significant. We used the software GraphPad QuickCalcs from
GraphPad Software Inc. (La Jolla, CA, USA).
(IB) using skin and vessels as antigens, indirect immune
electron microscopy (IEM), and autometallography studies (see
File S1 for these methods). We used cow, mouse, rat, and
Results
human tissues including musculoskeletal (including bone and
The H&E results showed perivascular inflammation (primarily by
cartilage); central and peripheral nervous; cardiovascular and
lymphohistiocytic cells) in all cases of El Bagre-EPF, compared with
lymphatic; digestive, respiratory, and urinary systems;
none in the controls (P < 0.01). In addition, most dermal vessels
(especially those under the blisters) were either dilated and/or chan-
reproductive organs (male and female); and sensory organs
and endocrine glands in both cases and controls.
ged in shape (e.g., tortuosity), and/or revealed a rouleaux phe-
We also tested the patients and controls using B-Mode two-
nomenon compared with none of these changes in the controls
dimensional ultrasound imaging. Autometallographic studies in
(P < 0.01). Less often, a mild vasculitis was present in some skin
skin biopsies of cases and controls were also performed
biopsies of the El Bagre-EPF patients (13/57). Our testing demon-
(Table S1). Only patients meeting diagnostic criteria for El
strated positive staining with multiple antibodies on vessels and
Bagre-EPF were included, specifically: (i) patients displayed
their cell junctions, confirmed via several immunological methods
clinical and epidemiologic features described for this disease;5–14
including immune electron microscopy. In the skin, the autoantibodies were noted on all vessels in the dermal neurovascular vascular
(ii) patients lived in the endemic area; and (iii) patient serum
displayed intercellular staining (ICS) between epidermal
plexus, around all skin appendices, and in neural/mechanoreceptor
keratinocytes and to the basement membrane zone of the skin,
areas. The autoantibodies were also present in all organs/systems
via either DIF or IIF using fluorescein isothiocyanate (FITC)-
reviewed, including the heart, kidney, brain, meninges, oral, muscu-
conjugated monoclonal antibodies to human total IgG, as
loskeletal, and intervertebral disks (Figs. 1 and 2). Overall, 57/57
described elsewhere.5,6 Furthermore, (iv) each patient’s serum
patients affected by El Bagre EPF demonstrated autoantibodies to
was positive by IB for reactivity against Dsg1, as well as for
vessels, primarily in their cell junctions (including lymphatics)
plakin molecules as previously described5,6; (v) each patient’s
(P < 0.01) utilizing DIF, IIF, IHC, IB, CFM, and IEM. We found no
differences in the staining in all the organs/systems examined in all
serum immunoprecipitated (IP) a Concanavalin A (Con A)
affinity-purified 45 kDa fragment of Dsg1;3 and (vi) each
the animal and human tissues reviewed. The reactivity was poly-
patient’s serum yielded a positive result ELISA14 test when
clonal, with IgG (57/57), IgM (53/57), C1q (53/57), C3c (53/53),
screening for autoantibodies to pemphigus foliaceus (PF)
kappa (57/57), lambda (54/57), fibrinogen (50/57), albumin (50/57),
antigens. Written consents were obtained from all patients and
and IgE (37/57) observed. Fewer cases stained with IgA (37/57)
controls, and Institutional Review Board permission from the
~ora de El Carmen, in El Bagre, Colombia,
Hospital Nuestra Sen
and IgD (28/57) (P < 0.01) (CI 98%) (Table S1). A few control
was obtained. All the cases and controls were tested via the
sels in the skin by DIF for IgG (6/57) and fibrinogen (6/57), kappa
(6/57), and lambda (6/57); these control cases were all genetically
same methods and conditions.
cases from the endemic area (6/57) showed some reactivity to ves-
related to the El Bagre-EPF patients. For IIF, rat bladder epithelium
B-mode two-dimensional ultrasound imaging
We tested for any possible vascular abnormalities in the clinical
setting, especially for atherosclerosis. We utilized a
VisualSonics ultrasound from Fujifilm, Toronto, Ontario,
Canada, and the testing was performed as described.15 We
classified carotid artery plaques into four categories:
echolucent, predominantly echolucent, predominantly
echogenic, or echogenic.
Autopsies were reviewed from seven deceased patients with
El Bagre-EPF. These represented El Bagre-EPF patients not
included as cases in this study.
International Journal of Dermatology 2017
(a substrate) also displayed positive staining with all the El BagreEPF sera because of the desmoplakins present there.
In all the organs we studied, the patient autoantibodies perfectly colocalized with the commercial antibodies to desmoplakins
I and II, p0071, ARVCF, and MYZAP (P < 0.01, CI 98%). The
patient autoantibodies also colocalized with our vascular markers
and the JAM-A gap cell junction marker. Specifically, colocalizations were noted with CD31, CD34, von Willebrand Factor/VWF
and D2-40 by DIF, IIF, and IHC staining (P < 0.01, CI 98%). Furthermore, we noted positive staining on mesenchymal-endothelial
cell junctions in the dermis.
ª 2017 The International Society of Dermatology
Abreu Velez et al.
Autoantibodies to vessel in endemic pemphigus
Report
Figure 1 Clinical features, histology, and
detection of autoantibodies to vessels. (a) A
clinical picture of one El Bagre-EPF patient
with plaque lesions on his back (white
arrow). (b) H&E staining demonstrates
dilated upper dermal plexus vessels,
surrounded by a lymphohistiocytic infiltrate
(black arrows) (2009). (c) DIF of negative
controls using anti-human IgG FITC
conjugated showing non specific selffluorescence of the dermal vessels (white
arrows). (d) DIF of the skin showing positive
light green staining on a dermal vessel
using FITC conjugated anti-human IgG
(+++) (overlapping with orange staining from
MYZAP) (white arrows) (2009). (e) IIF,
showing light green positive staining on a
network of bovine cardiac vessels utilizing
FITC conjugated anti-human IgM (+++),
colocalizing with orange staining for p0071
(white arrow) (4009). (The muscle in
fuchsia) (f) IHC, demonstrating positive
staining of an El Bagre-EPF patient skin
biopsy with C3c on vessels in the papillary
dermis (brown staining; red arrow)
Immunoadsorption of the skin cell junction
autoantibodies, and testing with the vascular
autoantibodies
Original patient serum, affinity tryptic purified to remove desmoglein antibodies and eluted from the affinity columns was tested.
We preincubated then tested this serum via DIF and IIF on El
Bagre-EPF patient tissue. We observed positive reactivity to the
ª 2017 The International Society of Dermatology
vessels; the vascular reactivity persisted, indicating that the vessel antigens are different than Dsg1.
CFM studies
The CFM studies also demonstrated 100% colocalization of the
patient autoantibodies and all the antibodies from Progen
(P < 0.01), and with JAM-A (Fig. 2).
International Journal of Dermatology 2017
3
4
Report
Abreu Velez et al.
Autoantibodies to vessel in endemic pemphigus
Figure 2 Detection of autoantibodies to vessels cell junctions, and colocalizations with MYZAP, ARVCF, DP I-II and p0071. (a) An IEM
photograph of rat cardiac tissue, showing El Bagre-EPF serum labeled with 10 nm Gold-conjugated protein A antibodies and reacting with
endothelial cell junctions (red arrows; black dots) (100 kV). (b) IIF, showing positive staining of splenic vessels using FITC conjugated antihuman IgG and anti-fibrinogen antibodies (light green staining), that colocalized with yellow-red-orange staining for MYZAP (white arrow)
(4009). (c) A CFM data image showing perfect colocalization of the peaks of fluorescence (white arrow), indicating that the antibodies to
MYZAP (red staining) colocalized with the patient antibodies (green staining). The blue peaks represent DAPI nuclear counterstaining. (d) A
series of IBs show colocalization of patient autoantibodies via molecular weight with commercial antibodies. Upper left shows the
colocalization of the patient antibodies (Lane 2) with the commercial antibody to p0071 (Lane 3) (at P, 105 kDa). Lane 1, a negative control.
Lower left shows the colocalization of DP I-II (250 and 215 kDa, respectively) and a patient’s antibodies (Lane 1 is a representative patient
serum, and Lane 2 is the commercial DP I-II antibody). The right panel shows the colocalizations of control markers (Lane 1) with patient
antibodies; Lanes 2 and 3 are two patient sera, both colocalizing with ARVCF (A; 105 kDa) and MYZAP (M, 54 kDa). Full IB correlation was
found between these commercial antibodies from Progen and the patient autoantibodies (P < 0.001; 98% CI)
IEM and IB studies
Immune electron microscopy showed positive staining for
patient autoantibodies on vascular endothelial cells and their
cell junctions (Fig. 2). The IB confirmed multiple antigens
detected by patient sera, that also perfectly colocalized with the
Progen antibodies (P < 0.01, CI 98%) (Fig. 2).
cardiovascular
valves,
some
system
showed
atheromatous
some
plaques
enlarged
ranging
cardiac
between
classes III and IV, several vessels with dilations and
inflammation, and congestion in the pial and lung vessels.
The spleens were very congested (P < 0.01). The H&E
staining showed a lymphohistiocytic infiltrate around most
vessels.
Patient autopsies
All the autopsies showed vascular alterations. The most frequent cause of death in our study patients was cardiovascular. Patient autopsy data for the vessels and the
International Journal of Dermatology 2017
In Figure 3 and in Table S1, we show a summary of our
patient DIF testing (and the percentage of positive findings for
immunoglobulins, complement, fibrinogen, and albumin). IB data
(including 320, 260, 200, 160, 126, 116, 105, 97, 80, 67, 66,
ª 2017 The International Society of Dermatology
Abreu Velez et al.
45, 48, and 31–34 kDa bands) (P < 0.01) is summarized, as
well as the IP and ELISA assay data.
Autoantibodies to vessel in endemic pemphigus
Report
vessels, and in erythrocytes (Fig. 3). We observed these metals/metalloids in three genetically related controls for the El
Bagre-EPF patients.
B-mode two-dimensional ultrasound imaging
We detected early and advanced carotid artery atherosclerotic
plaques in 40/57 of the El Bagre-EPF patients (P < 0.01) and in
three male controls from the endemic area suffering from psoriasis at ages 53, 57, and 63. We confirmed atherosclerotic
lesions as protrusions of the intima media; we recorded the
number of visualized plaques, as well as total plaque area or
total plaque volume. Some plaques contained a large lipid core
and appeared echolucent; other plaques with fibrosis and calcification tended to appear echogenic. We found multiple types of
carotid plaques, displaying echolucent, predominantly echolucent, and predominantly echogenic features. These findings are
consistent with flow alterations in the vessels.
Autometallography assay
Mercury and amalgamations of other metals and metalloids
were present in 85% (P < 0.01) of the El Bagre-EPF patient
vessel cell junctions and endothelia (including lymphatics, arteries, and veins of all sizes) (Fig. 3). We also detected the presence of these metals/metalloids in the plasma inside the
Discussion
We document for the first time autoantibodies to vessels and
their cell junctions (different from Dsg1) in all organs/systems,
and colocalizing with MYZAP, ARVCF, p0071, and desmoplakins 1 and 2 in El Bagre EPF. These autoantibodies also
colocalize with mercury/metalloids and within erythrocytes.
As confirmed here, MYZAP, desmoplakins I-II, ARVCF, and
p0071 are components of vascular cell junctions in blood vessels, arteries, veins, lymphatics, and capillaries. The multiple
organ/system reactivity to the vessel cell junctions may account
for the multi-organ clinical lesions seen in 30% of El Bagre-EPF
patients. Vasculitis is one of the complications of lupus; in El
Bagre-EPF, only a few cases present a mild vasculitis.
Our findings may explain the enlargement, atherosclerosis,
vascular shape alterations, and rouleaux we previously reported
in these patients, as well in patients with other autoimmune blistering diseases.16 The autoantibodies to the vessels may also
result in histologic tissue edema and inflammation.16,17 In El
Figure 3 Autometallographic studies on
vessels. In (a) and (b), we show positive
staining with metals and metalloids at the
small dermal blood vessel and lymphatic cell
junctions, respectively (dark staining; red
arrows). In (c) and (d), we show the same
staining in larger vessels (red arrows), as
well as in plasma and erythrocytes (black
arrows)
ª 2017 The International Society of Dermatology
International Journal of Dermatology 2017
5
6
Report
Abreu Velez et al.
Autoantibodies to vessel in endemic pemphigus
Bagre-EPF and in other autoimmune blistering diseases including PF, bullous pemphigoid (BP), pemphigus vulgaris (PV), epi-
We found immunohistologic abnormalities in the vessels, and
autoantibodies mainly directed against their cell junctions. We also
dermolysis bullosa acquisita, linear IgA disease, and dermatitis
detected atherosclerotic plaques in the El Bagre-EPF patients of
herpetiformis, we have noted patient vessels overexpressing
differential echolucencies, which were indicative of alterations in
HLA-DPDQDR antigen, ribosomal protein s6-ps240, cyclo-oxy-
vessel flow. The alterations may be because of a direct deposition
genase 2, and C5-b9/MAC. These patient biopsies also
of the antibodies in vascular cell junctions, likely changing confor-
revealed vascular rouleaux phenomenon and other vascular
mations of molecules. Alterations could then occur in vessel
inflammatory markers, including CD3, CD20, CD1a, HAM56,
shape, attracting immune cells around the vessels and inflamma-
CD68, and S100, and autoantibodies to the vessels.16,18–25 We
confirmed our data by IHC, which prevents the “autofluores-
tory markers and altering flow dynamics.20 It is possible that the
autoantibodies stimulate endothelial cells to express adhesion
cence” possible when using DIF/IIF. In most skin biopsies on all
molecules and various chemokines; this may lead to a recruitment
autoimmune skin blistering diseases, dilated vessels and papil-
of monocytes, leukocyte recruitment with the secretion of cytoki-
lary dermal edema are noted under the blisters, with additional
nes and other inflammatory markers. Deposition of fibrin, fibrino-
mild dermal perivascular inflammation.16,18–26
gen and activated platelets on damaged endothelium may
Of interest, the largest histopathology series on Brazilian
expresses tissue and von Willebrand factor, creating a prothrom-
EPF demonstrated that most cases have dilated capillaries in
botic milieu and leading to clinical vascular disorders.21,24 The
the dermal papillae and upper dermis; there was a variable
degree of edema, with an inflammatory infiltrate that could be
polyclonality of the immune response may partially result from pollution by metals and metalloids in the endemic area, as well as
diffuse, or present a perivascular and periadnexal distribution.27
patient exposure to tropical and parasitic diseases.20,21,24,25
It was often composed of neutrophils, eosinophils, and lympho-
Other authors have reported in BP, PV, and PF patients that
cytes, which were variably represented in small or moderate
soluble E-selectin was found to be significantly increased; in
numbers.27
addition, autoreactivity to dermal vessels was noted involving
For the DIF, IIF, CFM, and immunoadsorption experiments,
fibrin and C3c.31–33
we partially solubilized the cell membranes with Triton X and
Of interest, all of the patient autoantibodies perfectly colocal-
blocked with normal goat serum. These methods helped to
allow permeation of the antibodies into the cells, including their
ized with the Progen antibodies p0071, ARVCF, MYZAP, and
DP I-II.34–38 These molecules are located in cell junctions in all
membranes and cell junctions. We also blocked any nonspecific
organs/systems; some are members of the armadillo protein
immune responses that can be seen when IIF or DIF are per-
family and represent specific components of dermal microvas-
formed on vascular tissues. El Bagre-EPF has autoantibodies
cular endothelial intercellular junctions.
to multiple organs as likely occurs in Senear-Usher syndrome
Our data correlates with a recent study demonstrating cardio-
that may require further studies investigating cross-reactivity or
vascular alterations in patients with inflammatory skin diseases
multiple autoimmunity.28
(including pemphigus and pemphigoid) versus controls; 2002–
The autometallographic technique detects silver sulfides/selenides, metallic silver, and gold in addition to mercuric sulfides/
2012 US national inpatient hospitalizations (n = 72 108, 077
adults) were reviewed and correlated with cardiovascular and
selenides.9,29,30 To differentiate between mercury, silver, and
cerebrovascular associated diseases.39 In our current and previ-
gold, additional steps were performed (Table S1). In our study,
ous studies, we present evidence for vascular alterations in
we clearly demonstrate the presence of mercury and other met-
most autoimmune skin diseases.16,18–25
alloids located in the cell junctions of the vessels, including the
lymphatics (where the main autoantigens were found in this
study) as well as in erythrocytes. Once absorbed in the body,
Conclusion
the metals/metalloids may exist in the circulation as an ionic
species, or bound to serum proteins or erythrocytes. Inorganic
Patients affected by El Bagre-EPF have autoantibodies to most
of the tested vascular cell junctions in most tissues. Autometal-
mercury will bind to serum proteins, and methylmercury will bind
lographic studies show deposits of metals and metalloids in
to erythrocytes. Erythrocytes and plasma are typically the main
these cell junctions. These findings may explain the clinical and
transport routes of metals and or metalloids. These metals bind
histologic edema in their tissues and observed alterations in
to protein sites by displacing original metals from their natural
vessel morphology. The chronic inflammation of the vascular
binding sites, causing malfunctioning of the molecule and ulti-
endothelial cells and observed atherosclerosis suggest that the
mately toxicity. In our cases, these metals/metalloids likely
autoantibodies are causing and/or potentiating hemodynamic
changed the conformations of proteins, possibly triggering
autoimmunity. Three relatives of El Bagre-EPF patients showed
alterations in these patients. Moreover, the antibodies to the
vessels and their cell junctions perfectly colocalize with multiple
metal/metalloid deposits similar to the El Bagre-EPF patients;
commercial antibodies from Progen. Further research to detect
we speculate that this finding could indicate a genetic predispo-
autoantibodies against vessels in autoimmune blistering dis-
sition toward the deposits.
eases is encouraged.
International Journal of Dermatology 2017
ª 2017 The International Society of Dermatology
Abreu Velez et al.
Acknowledgments
We thank Jonathan Jones, HT (ASCP) at GDA for excellent
technical assistance.
References
1 Abreu-Velez AM, Messias-Reason LJ, Howard MS, et al.
Endemic pemphigus foliaceus over a century: part 1. N Am J
Med Sci 2010; 2: 51–59.
2 Castro RM, Proencßa NG. Similarities and differences between
Brazilian wild fire and pemphigus foliaceus Cazenave. Hautarzt
1982; 33: 574–577.
3 Robledo MA, Prada S, Jaramillo D, et al. South American
pemphigus foliaceus: study of an epidemic in El Bagre and
Nechi, Colombia 1982 to 1986. Br J Dermatol 1988; 118:
737–744.
4 Morini JP, Jomaa B, Gorgi Y, et al. Pemphigus foliaceus in
young women. An endemic focus in the Sousse area of Tunisia.
Arch Dermatol 1993; 129: 69–73.
u-Velez AM, Hashimoto T, Bollag WB, et al. A unique form
5 Abre
of endemic pemphigus in Northern Colombia. J Am Acad
Dermatol 2003; 49: 599–608.
u-Velez AM, Beutner EH, Montoya F, et al. Analyses of
6 Abre
autoantigens in a new form of endemic pemphigus foliaceus in
Colombia. J Am Acad Dermatol 2003; 49: 609–614.
7 Abreu-Velez AM, Howard MS, Hashimoto K, et al.
Autoantibodies to sweat glands detected by different methods in
serum and in tissue from patients affected by a new variant of
endemic pemphigus foliaceus. Arch Dermatol Res 2009; 301:
711–718.
8 Abreu-Velez AM, Howard MS, Smoller BR. 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; 3: 371–375.
u Ve
lez AM, Warfvinge G, Herrera WL, et al. Detection of
9 Abre
mercury and other undetermined materials in skin biopsies of
endemic pemphigus foliaceus. Am J Dermatopathol 2003; 25:
384–391.
10 Abreu-Velez AM, Zhe J, Howard MS, et al. Cardiac
autoantibodies from patients affected by a new variant of
endemic pemphigus foliaceus in Colombia, South America.
J Clin Immunol 2011; 31: 985–987.
11 Abreu-Velez AM, Howard MS, Grossniklaus HE, et al. Neural
system antigens are recognized by autoantibodies from patients
affected by a new variant of endemic pemphigus foliaceus in
Colombia. Clin Immunol 2011; 31: 356–358. https://doi.org/10.
1007/s10875-010-9495.
12 Abreu-Velez AM, Howard MS, Hashimoto T. Palms with a
polyclonal autoimmune response in patients affected by a new
variant of endemic pemphigus foliaceus in Colombia, South
America. Eur J Dermatol 2010; 20: 74–81.
u-Ve
lez AM, Patin
~o PJ, Montoya F, et al. The tryptic
13 Abre
cleavage product of the mature form of the bovine desmoglein 1
ectodomain is one of the antigen moieties immunoprecipitated
by all sera from symptomatic patients affected by a new variant
of endemic pemphigus. Eur J Dermatol 2003; 13: 359–346.
u-Ve
lez AM, Yepes MM, Patin
~o PJ, et al. A cost effective,
14 Abre
sensitive and specific enzyme linked immunosorbent assay
useful for detecting a heterogeneous antibody population in sera
from people suffering a new variant of endemic pemphigus.
Arch Dermatol Res 2004; 295: 434–441.
ª 2017 The International Society of Dermatology
Autoantibodies to vessel in endemic pemphigus
Report
15 Steinl DC, Kaufmann BA. Ultrasound imaging for risk
assessment in atherosclerosis. Int J Mol Sci 2015; 16:
9749–9769.
16 Abreu-Velez AM, Smoller BR, Howard MS. Rouleaux and
autoagglutination of erythrocytes associated with fibrin-like
material in skin biopsies form patients with autoimmune
blistering diseases. Our Dermatol Online 2013; 4: 613–615.
17 Howard MS, Yepes MM, Maldonado JG, et al. Broad
histopathologic patterns of non-glabrous skin and glabrous skin
from patients with a new variant of endemic pemphigus
foliaceus (Part 1). J Cutan Pathol 2010; 2: 222–230.
18 Abreu-Velez AM, Calle-Isaza J, Howard MS. HLA-DPDQDR is
expressed in lesional skin from patients with autoimmune skin
diseases. Our Dermatol Online 2014; 2: 125–128.
19 Abreu-Velez AM, Googe PB Jr, Howard MS. Ribosomal protein
s6-ps240 is expressed in lesional skin from patients with
autoimmune skin blistering diseases. N Am J Med Sci 2010; 5:
604–608.
20 Abreu-Velez AM, Howard MS, Hashimoto T, et al. Human eyelid
meibomian glands and tarsal muscle are recognized by
autoantibodies from patients affected by a new variant of
endemic pemphigus foliaceus in El-Bagre, Colombia, South
America. J Am Acad Dermatol 2010; 62: 437–447.
21 Abreu-Velez AM, Calle-Isaza J, Howard MS. Cyclo-oxygenase 2
is present in the majority of lesional skin from patients with
autoimmune blistering diseases. Our Dermatol Online 2013; 4:
4476–4478.
22 Abreu-Velez AM, Calle-Isaza J, Howard MS. CD1a, HAM56,
CD68 and S-100 are present in lesional skin biopsies from
patients affected by autoimmune blistering diseases. Our
Dermatol Online 2014; 5: 113–117.
23 Abreu-Velez AM, Yepes-Naranjo MM, Avila IC, et al. Tissue
inhibitor of metalloproteinase 1, Matrix metalloproteinase 9,
alpha-1 antitrypsin, metallothionein and urokinase type
plasminogen activator receptor in skin biopsies from patients
affected by autoimmune blistering diseases. Our Dermatol
Online 2013; 4: 275–280.
24 Abreu-Velez AM, Googe PB Jr, Howard MS.
Immunohistochemistry versus immunofluorescence in the
diagnosis of autoimmune blistering diseases. Our Dermatol
Online 2013; 4: 585–595.
25 Abreu-Velez AM, Googe PB Jr, Howard MS. In situ immune
response in skin biopsies from patients affected by autoimmune
blistering diseases. Our Dermatol Online 2013; 4: 606–612.
26 Lever WF. Pemphigus and pemphigoid. A review of the
advances made since 1964. J Am Acad Dermatol 1979; 1:
2–31.
27 Furtado TA. Histopathology of pemphigus foliaceus. AMA Arch
Derm 1959; 80: 66–71.
rez-Pe
rez ME, Avalos-Dıaz E, Herrera-Esparza R.
28 Pe
Autoantibodies in Senear-Usher syndrome: cross-reactivity or
multiple autoimmunity? Autoimmune Dis 2012; 2012: 1–7.
29 Danscher G, Møller-Madsen B. Silver amplification of mercury
sulphides and selenides. A histochemical method for light and
electron microscopic localization of mercury in tissue.
J Histochem Cytochem 1985; 31: 219–228.
30 Danscher G, Rungby J. Differentiation of histochemically
visualized mercury and silver. Histochem J 1986; 18: 109–114.
31 D’Auria L, Cordiali Fei P, Pietravalle M, et al. The serum levels
of sE-selectin are increased in patients with bullous pemphigoid
or pemphigus vulgaris. Correlation with the number of skin
lesions and recovery after corsticosteroid therapy. Br J Dermatol
1997; 137: 59–64.
International Journal of Dermatology 2017
7
8
Report
Abreu Velez et al.
Autoantibodies to vessel in endemic pemphigus
32 Ameglio F, D’Auria L, Cordiali-Fei P, et al. Bullous pemphigoid
and pemphigus vulgaris: correlated behavior of serum VEGF,
sE selectin and TNF-alpha levels. J Biol Regul Homeost Agents
1997; 11: 148–153.
33 Peterson JD, Worobec SM, Chan LS. An erythrodermic variant
of pemphigus foliaceus with puzzling histologic and
immunopathologic features. J Cutan Med Surg 2007; 11:
179–184.
34 Pieperhoff S, Rickelt S, Heid H, et al. The plaque protein
myozap identified as a novel major component of adhering
junctions in endothelia of the blood and the lymph vascular
systems. J Cell Mol Med 2012; 16: 1709–1719.
35 Franke WW, Rickelt S, Barth M, et al. The junctions that don’t
fit the scheme: special symmetrical cell-cell junctions of their
own kind. Cell Tiss Res 2009; 338: 1–17.
36 Calkins CC, Hoepner BL, Law CM, et al. The Armadillo family
protein p0071 is a VE-cadherin- and desmoplakin-binding
protein. J Biol Chem 2003; 278: 1774–17783.
37 Schmelz M, Franke WW. Complexus adhaerentes, a new group
of desmoplakins containing junctions in endothelial cells: the
syndesmos connecting retothelial cells of lymph nodes.
Eur J Cell Biol 1993; 61: 274–289.
International Journal of Dermatology 2017
38 Andreeva ER, Pugach IM, Gordon D, et al. Continuous
subendothelial network formed by pericyte-like cells in human
vascular bed. Tissue Cell 1998; 30: 127–135.
39 Kwa MC, Silverberg JI. Association between inflammatory skin
disease and cardiovascular and cerebrovascular co-Morbidities
in US adults: analysis of Nationwide Inpatient Sample Data. Am
J Clin Dermatol 2017; https://doi.org/10.1007/s40257-0170293-x. [Epub ahead of print].
Supporting Information
Additional Supporting Information may be found in the online
version of this article:
Table S1. Shows a summary of the autoantibodies detected by
different methods in the patients and controls.
File S1. In all the cases and controls, skin biopsies were taken
for H&E, PAS, DIF, IHC, CFM, EM and autometallographic
studies
ª 2017 The International Society of Dermatology
Download

Vessesl El Bagre-EPF

epfvesseslbagre