Journal of Dermatological Science (2003) 32, 33 /41
www.elsevier.com/locate/jdermsci
Comparative study of autoantigen profile between
Colombian and Brazilian types of endemic
pemphigus foliaceus by various biochemical and
molecular biological techniques
Yoshiko Hisamatsua,c,1, Ana Maria Abreu Velezb,1, Masayuki Amagaid,
Marilia M. Ogawae, Tamotsu Kanzakic, Takashi Hashimotoa,*
a
Department of Dermatology, Kurume University School of Medicine, 67 Asahimachi, Kurume, 830-0011
Fukuoka, Japan
b
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA, USA
c
Department of Dermatology, Kagoshima University School of Medicine, Kagoshima, Japan
d
Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
e
Department of Dermatology, Paulista College of Medicine, Sao Paulo, Brazil
Received 30 October 2002; received in revised form 15 January 2003; accepted 16 January 2003
KEYWORDS
Autoimmune bullous
disease;
Endemic pemphigus
foliaceus;
Enzyme-linked immunosorbent assay;
Immunoblotting;
Desmoglein;
Desmocollin;
Desmosome;
Plakin family protein
Summary Background: Besides Brazilian endemic pemphigus foliaceus (EPF), we
have described another focus of EPF in Colombia. Our previous study suggested that
Colombian EPF seemed to react various plakin family proteins, such as envoplakin,
periplakin and BP230. Objective: To further characterize the Colombian EPF and
study the difference from Brazilian EPF, we examined the antigen profile of the two
types of EPF. Methods and results: Immunoblotting using normal human epidermal
extracts revealed that 38% Colombian EPF sera and 25% Brazilian EPF sera showed IgG
antibodies reactive with desmoglein (Dsg) 1, pemphigus foliaceus antigen. The sera of
both types of EPF showed protein bands co-migrating with plakin family proteins,
particularly periplakin. Immunoblotting analyses using recombinant proteins of
various domains of envoplakin, periplakin and BP230 revealed that a considerable
number of Colombian EPF sera reacted with recombinant proteins of periplakin, while
only few Brazilian sera reacted with some of the recombinant proteins of any plakins.
Enzyme-linked immunosorbent assay (ELISA) for Dsg1 and Dsg3 showed that Dsg1 was
reacted by almost all sera of both types of EPF. However, unexpectedly, while none of
Colombian EPF sera reacted with Dsg3, about half of Brazilian EPF sera reacted with
Dsg3. Conclusion: These results suggested that the Colombian EPF is basically similar
to Brazilian EPF in terms that major antigen is Dsg1, but there were some different
antigen profiles between the two types of EPF.
– 2003 Japanese Society for Investigative Dermatology. Published by Elsevier Science
Ireland Ltd. All rights reserved.
Abbreviations: ELISA, enzyme-linked immunosorbent assay; EPF, endemic pemphigus foliaceus.
*Corresponding author. Tel.: /81-942-31-7571; fax: /81-942-34-2620.
E-mail address: [email protected] (T. Hashimoto).
1
Joint first authors.
0923-1811/03/$30.00 – 2003 Japanese Society for Investigative Dermatology. Published by Elsevier Science Ireland Ltd. All rights
reserved. doi:10.1016/S0923-1811(03)00034-3
34
Y. Hisamatsu et al.
1. Introduction
2.3. Immunoblotting studies
An endemic pemphigus foliaceus (EPF) was first
described in certain regions of Brazil more than a
century ago, which is also known as fogo selvagem
[1 /5]. Another type of EPF has been reported in
Tunisia [6,7]. Recently, we have also described
additional focus of EPF Colombia [8 /10] (two full
papers by Abreu Velez et al., in press). All types of
EPF were characterized histologically by acantholytic intraepidermal blisters and immunologically
by circulating IgG autoantibodies that react keratinocyte cell surfaces.
A remarkable feature of EPF is its epidemiological nature. Brazilian EPF is endemic to certain
states in Brazil, there are many familial cases
including child and young adult cases, most patients are dedicated to farming, and both sexes are
equally affected [2]. On the other hand, the
previous epidemiological studies revealed that
Colombian EPF affects predominantly males at an
age of 40 /60 years, as well as a few postmenopausal females [8 /10]. These findings suggest that Colombia EPF differ from Brazilian EPF.
Tunisian EPF also showed different features and
affected most frequently females of childbearing
age, although its epidemicity has not been well
characterized [6,7].
In this study, the Colombian EPF is further
characterized and the difference between Colombian and Brazilian EPF is studied; we examined
autoantigens in both diseases by various biochemical and molecular biological techniques, including
immunoblotting and enzyme-linked immunosorbent assay (ELISA) using various antigen sources.
We performed various immunoblotting procedures using different antigen sources to identify
possible autoantigens reacted by EPF sera. Immunoblotting of normal human epidermal extracts
was performed as described previously [4,11 /15].
Recently, we have successfully produced recombinant fusion proteins of envoplakin (EPL), periplakin
(PPL) and BP230, which are members of plakin
family protein [16,17]. All the plakin family proteins show similar molecular structures, consisting
of N-terminal globular domain (N), middle rod
domain (M) and C-terminal globular domain (C)
[18 /21]. It is now confirmed that these plakin
family proteins are autoantigens targeted by paraneoplastic pemphigus sera [22 /27]. We generated
domain-specific recombinant fusion proteins,
named EPL-N, M, C, PPL-N, M, C and BP230-N, M,
C [16,17]. Immunoblotting using these recombinant
proteins was performed as described previously
[16,17]. Because the fusion proteins of ENV-N, ENVM, PPK-N, PPK-M, BP230-N, BP230-M and BP230-C
could not be purified by glutathione /sepharose
column, the patients sera were pre-absorbed with
bacterial lysate to reduce background reactivity
due to non-specific antibodies to bacterial proteins
[16,17].
2.4. ELISA of desmoglein (Dsg) 1 and Dsg3
2. Materials and methods
ELISA of Dsg1 and Dsg3 for IgG antibodies was
performed as described previously [28 /30]. In this
ELISA for IgG antibodies, the index value above 20
was considered positive and the value between 10
and 20 was in the gray zone. We also performed
ELISA of Dsg1 and Dsg3 for IgA antibodies, which
has recently been developed [31].
2.1. Patients
2.5. ELISA of desmocollin (Dsc) 1, 2 and 3
In this study, we used sera from 29 Colombian
EPF patients and 20 Brazilian EPF patients, who
lived in the endemic areas for both diseases and
showed typical clinical and histological features
each of Colombia EPF and Brazil EPF. We also used
two sera each from typical cases of pemphigus
vulgaris, pemphigus foliaceus, paraneoplastic pemphigus and bullous pemphigoid as positive controls,
as well as 10 normal control sera.
We have recently produced recombinant proteins
of extracellular domains of human Dsc1 /3 using
baculovirus expression system (Hisamatsu et al.,
submitted for publication). Using the recombinant
proteins, we have developed a novel ELISA for
detecting antibodies of both IgG and IgA classes
against Dsc1 /3 (Hisamatsu et al., submitted for
publication). The details for the ELISA of Dsc1 /3
are described in a separate manuscript (Hisamatsu
et al., submitted for publication). Procedures are
almost the same as that for ELISA of Dsg1 and Dsg3
[28 /30], with some modifications. All the normal
control sera showed the value of OD490 less than
0.03. Therefore, we arbitrarily set the cut-off
value as 0.1 for both IgG and IgA antibodies. In
2.2. Immunofluorescence studies
Indirect immunofluorescence using sections of
normal human skin for both IgG and IgA antibodies
was performed as described previously [1,3].
Comparison of antigen between two types of endemic pemphigus foliaceus
general, none of the 45 sera of classic types of
pemphigus; i.e. pemphigus vulgaris and sporadic
pemphigus foliaceus, showed positive reactivity.
2.6. COS-7 cell transfection study using
human Dsc1 3 cDNA
/
cDNA transfection study to detect IgA antibodies
to Dsc1, 2, or 3 cDNAs was performed, as described
previously [32].
3. Results
The results of all experiments are summarized in
Table 1.
3.1. Immunofluorescence studies
By indirect immunofluorescence using sections
of normal human skin, the sera of all the 29
Colombia EPF and 20 Brazil EPF patients showed
IgG anti-cell surface antibodies (data not shown).
In addition, two Colombian EPF sera showed IgA
anti-cell surface antibodies reactivity with upper
epidermis, while none of Brazilian EPF showed IgA
antibodies.
3.2. Immunoblotting studies
By immunoblotting using normal human epidermal extracts, 11 (38%) of 29 Colombian EPF sera
and 5 (25%) of 20 Brazilian EPF sera showed a 160
kDa protein band, which co-migrated with Dsg1
detected by control non-endemic pemphigus foliaceus sera (Fig. 1a,b). However, numerous additional protein bands were seen in blots reacted by
both EPF sera (Fig. 1a,b). Particularly, 14 (48%) of
Colombian EPF sera reacted clearly with a 190 kDa
protein band, which co-migrated with periplakin
detected by control sera of paraneoplastic pemphigus (Fig. 1a). In addition, some patients weakly
reacted with 230 and 210 kDa protein bands, which
co-migrated with BP230 and envoplakin detected
by control sera of bullous pemphigoid and paraneoplastic pemphigus, respectively (Fig. 1a). These
protein bands co-migrating with various plakin
family proteins were also frequently detected by
Brazilian EPF sera (Fig. 1b).
In immunoblot analyses using recombinant proteins of EPL-N,M,C, PPL-N,M,C and BP230-N,M,C,
the most interesting result was that 13 /31% of
Colombian EPF sera reacted with various domains
of periplakin, particularly frequently with N- and Cterminal domains of the protein, whereas only few
35
Table 1 Summary of the results of all experiments
Colombian EPF
Brazilian EPF
Immunoblotting of epidermal extracts
230 kDa BP230
2/29 (7%)
1/20 (5%)
210 kDa envoplakin
2/29 (7%)
5/20 (25%)
190 kDa periplakin
14/29 (48%)
10/20 (50%)
160 kDa Dsg1
11/29 (38%)
5/20 (25%)
130 kDa Dsg3
0/29 (0%)
1/20 (5%)
Immunoblotting of recombinant proteins
EPL-N
2/29 (7%)
0/20 (0%)
EPL-M
4/29 (13%)
3/20 (15%)
EPL-C
0/29 (0%)
0/20 (0%)
PPL-N
PPL-M
PPL-C
9/29 (31%)
4/29 (13%)
8/29 (27%)
1/20 (5%)
1/20 (5%)
3/20 (15%)
1/29 (3%)
0/29 (0%)
0/29 (0%)
0/20 (0%)
1/20 (5%)
1/20 (5%)
ELISA
Dsg1 (IgG)
Dsg3 (IgG)
Dsg1 (IgA)
Dsg3 (IgA)
27/29 (93%)
0/29 (0%)
0/2 (0%)*
0/2 (0%)*
20/20 (100%)
12/20 (60%)
3/20 (15%)
1/20 (5%)
Dsc1 (IgG)
Dsc2 (IgG)
Dsc3 (IgG)
0/29 (0%)
0/29 (0%)
0/29 (0%)
3/20 (15%)
3/20 (15%)
3/20 (15%)
BP230-N
BP230-M
BP230-C
cDNA transfection to COS-7 cells
Dsc1 (IgA)
0/2 (0%)*
Dsc2 (IgA)
0/2 (0%)*
Dsc3 (IgA)
0/2 (0%)*
Not done
Not done
Not done
* Two cases with IgA anti-cell surface antibodies.
Brazilian EPF sera reacted with some of the
periplakin recombinant proteins (Fig. 2). In contrast with the results of periplakin recombinant
proteins, only a few (less than 15%) of sera of both
types EPF reacted with some of envoplakin recombinant proteins (Fig. 3). Furthermore, concerning
the recombinant proteins of BP230, any recombinant proteins were rarely detected by the sera of
both types of EPF (Fig. 4).
3.3. Results of ELISA of Dsg1 and Dsg3
Twenty-seven (93%) of 29 Colombia EPF sera and
all 20 Brazil EPF sera showed IgG antibodies to Dsg1
by ELISA. Interestingly, whereas none of Colombia
EPF sera reacted with Dsg3, seven Brazil EPF sera
reacted with Dsg3 and five Brazil EPF sera weakly
reacted with Dsg3 (in the gray zone) (Fig. 5).
In addition, we examined all 20 Brazilian EPF
sera by ELISA of Dsg1 and Dsg3 for IgA antibodies.
Three and one sera showed positive reactivity with
36
Y. Hisamatsu et al.
Fig. 1 The results of immunoblotting using normal human epidermal extracts. Two separate experiments were
performed for Colombian EPF (a) and for Brazilian EPF (b). In each panel, the lanes showed reactivity of EPF patients
(Pt), control PV serum (PV), control paraneoplastic pemphigus serum (PNP), control bullous pemphigoid serum (BP),
and monoclonal antibodies to Dsc (Dsc-mAb) and to desmoplakin (DPL-mAb). The positions of protein bands are shown
in the left of each panel.
Dsg1 and Dsg3, respectively. Because two Colombian EPF sera showed IgA anti-cell surface antibodies by indirect immunofluorescence, we also
examined the two sera by ELISA of Dsg1 and Dsg3
for IgA antibodies. However, neither serum reacted
with any Dscs.
3.4. Results of ELISA of Dsc1 3
/
As we mention in detail in a separate study
(Hisamatsu et al., submitted for publication), by
the ELISA of Dsc1 /3, 3 of the 20 Brazilian EPF sera
reacted with all Dsc1 /3 (Fig. 6). In contrast, no
Colombian EPF sera showed positive reactivity,
although a few sera showed a weak reactivity
within the gray zone (Fig. 6).
3.5. Results of cDNA transfection method
To study the antigens for IgA antibodies in the
two Colombian sera which showed IgA anti-cell
surface antibodies, we performed the cDNA transfection method. However, IgA antibodies in the two
sera did not show any positive reactivity with all
Dscs (data not shown).
4. Discussion
In our previous study, we showed that 12 of 27
Brazilian EPF sera reacted with Dsg1 by immunoblotting of epidermal extracts, which is consistent
with the results that about one-third of sporadic
pemphigus foliaceus sera react with Dsg1, suggest-
ing the similarity between the two diseases [4]. In
the present study, we further confirmed that all
the Brazilian EPF sera reacted with Dsg1 by ELISA,
which has been shown to be a highly sensitive and
specific method [28 /30]. The reason why only onethird of the sera of EPF and sporadic pemphigus
foliaceus reacted with Dsg1 by immunoblotting was
considered that the epitopes detected by the sera
are destroyed during the procedure of immunoblotting, while such epitopes are retained in the
ELISA.
In addition, 38% Colombian EPF sera reacted with
Dsg1 by immunoblotting, and almost all Colombian
EPF sera showed anti-Dsg1 antibodies by ELISA,
which was very similar to the results of Brazilian
EPF, suggesting that the Colombian and Brazilian
EPF have common nature as a subtype of pemphigus foliaceus.
However, a striking finding was that more than
half of Brazilian EPF showed antibodies to Dsg3,
pemphigus vulgaris antigen, by the ELISA. This
result is in contrast to the result of sporadic
pemphigus foliaceus, which showed no positive
reactivity with Dsg3 by this ELISA [28,30]. We could
not detect the reactivity with Dsg3 in any Brazilian
EPF by immunoblotting, which may be due to the
relatively low titer of anti-Dsg3 antibodies in the
sera.
Interestingly, none of Colombia EPF sera reacted
with Dsg3 by ELISA. This specific reactivity of
Brazilian EPF with Dsg3 is also in clear contrast to
the result that none of sporadic pemphigus foliaceus sera showed antibodies to Dsg3 by the same
ELISA [28 /30].
Comparison of antigen between two types of endemic pemphigus foliaceus
37
Fig. 2 The results of immunoblotting of recombinant
proteins of various domains of envoplakin. Left panel
shows the results of representative Colombian EPF sera
with recombinant proteins of EPL-N, EPL-M and EPL-C,
and right panel shows the results of representative
Brazilian EPF sera. The right lane in each panel showed
the reactivity of a control paraneoplastic pemphigus
serum (PNP). An arrow in the left in each panel indicates
the position of intact recombinant protein.
Fig. 3 The results of immunoblotting of recombinant
proteins of various domains of periplakin. Left panel
shows the results of representative Colombian EPF sera
with recombinant proteins of PPL-N, PPL-M and PPL-C,
and right panel shows the results of representative
Brazilian EPF sera. The right lane in each panel showed
the reactivity of a control paraneoplastic pemphigus
serum (PNP). An arrow in the left in each panel indicates
the position of intact recombinant protein.
The significance of the results that a few
Brazilian EPF sera showed IgA anti-Dsg antibodies
is at the present unknown.
In our previous study, we found that, in addition
to Dsg1, Colombian EPF sera reacted with many
other protein bands by various immunoblotting and
immunoprecipitation analyses, particularly, 230,
210 and 190 kDa proteins, which were considered
to be BP230, envoplakin an periplakin, respectively
(Abreu Velez et al., in press). In the present study,
we further found the reactivity of many Colombian
EPF sera with multiple proteins by immunoblotting
of human epidermal extracts, which was not used
in the previous study (Abreu Velez et al., in press).
To confirm the reactivity of Colombian EPF sera
with these plakin family proteins (also know as
paraneoplastic pemphigus antigens), we examined
sera of both Colombian and Brazilian EPF by
immunoblotting using various domain-specific recombinant proteins of these proteins. These studies further indicated that considerable number of
Colombian EPF sera reacted with various domains
of periplakin, while only few of Brazilian EPF sera
reacted with some of them. Recombinant proteins
of envoplakin were recognized by less number of
sera of both types of EPF. These results are similar
to those in our previous study [16], which indicated
that a few sera of non-paraneoplastic pemphigus
patients react with either envoplakin or periplakin.
However, the number of the Colombian EPF sera
reactive with envoplakin recombinant proteins are
significantly higher, indicating that the preferential
reactivity with periplakin may be characteristic of
Colombian EPF.
38
Y. Hisamatsu et al.
Fig. 5 The results of ELISA of Dsg1 and Dsg3 for IgG
antibodies. Upper and lower panels showed the results of
ELISA for Dsg1 and Dsg3, respectively. In each panel, the
results of Colombian EPF sera were shown in the left and
the results of Brazilian EPF sera in the right. The dashed
horizontal lines indicate the cut-off levels (index value
20).
Fig. 4 The results of immunoblotting of recombinant
proteins of various domains of BP230. Left panel shows
the results of representative Colombian EPF sera with
recombinant proteins of BP230-N, BP230-M and BP230-C,
and right panel shows the results of representative
Brazilian EPF sera. The right lane in each panel showed
the reactivity of a control bullous pemphigoid serum
(BP). An arrow in the left in each panel indicates the
position of intact recombinant protein.
In clear contrast, the sera of both types of EPF
rarely reacted with any BP230 recombinant proteins, which is consistent with the results of our
previous study [17], that any BP230 recombinant
proteins were detected by non-bullous pemphigoid
sera. Therefore, it seems likely that, although the
230 kDa protein band detected by some Colombian
EPF sera in our previous study (Abreu Velez et al.,
in press), the 230 kDa protein was other protein
with molecular weight of 230 kDa, but not BP230.
In our previous studies, we have found that some
Brazilian EPF sera showed IgG antibodies reactive
with bovine Dsc [33]. However, the significance of
these findings was not clear because none of these
sera reacted with human Dsc. In this study, a few
Brazilian EPF sera, but no Colombian EPF sera,
showed a positive IgG reactivity with Dsc1 /3 by
ELISA of Dsc1 /3. Although the specificity of this
reactivity could not be confirmed, the results with
this novel ELISA may further suggest that Brazilian
EPF sera, but not Colombian EPF sera, contain antiDsc antibodies.
Finally, we found that two Colombian EPF sera
showed IgA antibodies, which reacted with cell
surfaces in the upper epidermis. Because this
distribution is that of Dsc1, we considered that
these sera may contain IgA antibodies to Dsc1.
However, IgA antibodies in the sera did not react
with any Dsc by either ELISA of Dsc1 /3 or cDNA
transfection method for Dsc1 /3.
The results of the present study first indicate
that, although the both Colombian and Brazilian
EPF showed similar reactivity in terms of Dsg1,
there were several clear differences in immunoreactivity between the two EPF.
One finding was that, while more than half of
Brazilian EPF reacted with Dsg3 by ELISA, none of
Colombian EPF reacted with Dsg3. The next finding
was that, while Colombian EPF preferentially
reacted with the recombinant proteins of various
domains of periplakin, only few Brazilian EPF sera
reacted with them. Furthermore, some Brazilian
Comparison of antigen between two types of endemic pemphigus foliaceus
Fig. 6 The results of ELISA of Dsc1-Dsc3 for IgG
antibodies. Upper, middle and lower panels showed the
results of ELISA for Dsc1, Dsc2 and Dsc3, respectively. In
each panel, the results of Colombian EPF sera were
shown in the left and the results of Brazilian EPF sera in
the right. The dashed horizontal lines indicate the cutoff levels (OD 0.1).
EPF sera showed positive reactivity in ELISA of
Dsc1 /3 for IgG antibodies.
These results indicated that, although both
Colombian and Brazilian types of EPF seemed to
be subtypes of pemphigus foliaceus, there is a
considerable difference in their immunopathological features between the two EPF. These differences may be consistent with the different findings
in both clinical and epidemiological characteristics
between the two EPF, which were indicated by the
previous study (Abreu Velez et al., in press).
However, in contrast that sera of classic types of
pemphigus rarely react with antigens other than
Dsgs, both Colombian and Brazilian EPF sera
reacted with a variety of desmosomal proteins by
various techniques.
The reason why both types of EPF show such a
highly immunogenic condition in the patients is not
known. However, the previous study showed that
even the relatives both in Brazilian EPF and in
Colombian EPF (Abreu Velez et al., submitted for
publication). These results lead us to speculate
that, in conjunction with genetic predisposition,
39
some triggers, such as exposure to micro-organisms, may induce a highly immunogenic state in the
patients, resulting in production of antibodies to
many self antigens. Epitope spreading mechanism
may be involved in the production of multiple
autoantibodies [34].
In addition, because Colombian EPF sera preferentially reacted with paraneoplastic pemphigus
antigens, there may be a similar pathomechanism
in autoantigen production in Colombian EPF and
paraneoplastic pemphigus, although the two diseases are quite different clinically and epidemiologically.
The endemic autoimmune diseases are very rare,
and EPF is a typical example for this condition,
which should give us many clues to unravel the
pathomechanisms in development of autoimmunity. In this respect, the various interesting and
complex autoantigen profiles found in both Colombian and Brazilian EPF in this study should be
important to understanding the pathogenesis of
these diseases, although the significance of the
results is not clear at present.
In conclusion, the results of the present study
indicated that, although both Colombian and Brazilian EPF are similar diseases in terms of the
reactivity with Dsg1, there is considerable variability with reactivity with other desmosomal proteins, indicating some difference between the two
diseases. The significance of the complex autoantigen profile in these diseases should be clarified
in future studies.
Acknowledgements
We gratefully thank Dr. Marilia M. Ogawa for
generously providing us with the sera of Brazilian
EPF. We thank Miss Michiyo Noge, Miss Yuko
Kawano, and Miss Ayumi Suzuki for their technical
assistance, and Miss Akiko Tanaka for secretarial
assistance. This work was supported by Grant-inAid for Scientific Research from the Ministry of
Education, Science and Culture of Japan, and a
grant from the Ministry of Health and Welfare of
Japan. Dr. Hisamatsu was an awardee of the
Professor Klingman Award for travel expense for
the Annual Meeting for the Society of Investigative
Dermatology in 2001 (Washington, DC).
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Antigens comparison FS and El Bagre-EPF

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