LECTURE
Pemphigus as a paradigm of autoimmunity and cell adhesion
Masayuki Amagai
Department of Dermatology, School of Medicine, Keio University, Tokyo, Japan(Received for publication on April 15, 2002)

Abstract. Pemphigus is a group of autoimmune blistering diseases of the skin and mucous membranes
that are characterized histologically by intraepidermal blisters due to the loss of cell-cell adhesion of
keratinocytes and immunopathologically by the ﬁnding of pathogenic IgG autoantibodies directedagainst the cell surface of keratinocytes. Identiﬁcation of the target antigens has redeﬁned pemphigus
as an autoimmune disease against desmosomal cadherin or desmoglein. The IgG autoantibodymediated functional inhibition of desmoglein which plays an important role in the cell-cell adhesion of
keratinocytes results in blister formation. Patients with pemphigus vulgaris and pemphigus foliaceus
have IgG autoantibodies against desmoglein3 and desmoglein1, respectively. Even complex clinicalvariations of pemphigus vulgaris and foliaceus are now logically explained by the desmoglein compensation theory. As an extension of this theory, the exfoliative toxin produced by Staphylococcus
aureus, which causes staphylococcal scalded skin syndrome and bullous impetigo, was found to specifically cleave desmoglein1 and induce the identical histology to pemphigus foliaceus. Another recent
innovation has been the development of an active disease mouse-model for pemphigus using autoantigen knockout mice, in which self-tolerance of the defective gene product is not acquired. When
splenocytes from desmoglein3 knockout mice are adoptively transferred into mice expressing desmoglein3, anti-desmoglein3 IgG is stably produced in the recipient mice that develop the phenotype of
pemphigus vulgaris. This model will be valuable not only for dissecting the cellular and molecularmechanisms in pathogenic antibody production but also for developing novel therapeutic strategies.
(Keio J Med 51 (3): 133–139, September 2002)
Key words: cadherin, autoantibody, mouse model, desmoglein

Pemphigus as an Autoimmune Disease Against
Desmosomal Cadherin
The term pemphigus stems from the Greek pemphix
meaning blister or bubble and describes a group ofchronic blistering skin diseases in which autoantibodies
are directed against the cell surface of keratinocytes,
resulting in the loss of cell-cell adhesion of keratinocytes through a process called acantholysis.1 Pemphigus
can be divided into three major forms; pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus (Table 1).
In pemphigus vulgaris, essentially all patients havemucosal membrane erosions and more than half ofthem also have skin blisters and erosions. The blistersof pemphigus vulgaris develop in the deeper part of theepidermis, just above the basal cell layer. In pemphigus

foliaceus, patients have only cutaneous involvement
without mucosal lesions and the splits occur in the superﬁcial part of the epidermis, mostly at the granularlayer. Pemphigus vegetans is a vegetative variant of
pemphigus vulgaris, and pemphigus erythematosus andfogo selvagem are localized and endemic variants ofpemphigus erythematosus, respectively. Paraneoplastic
pemphigus was more recently recognized as a disease
distinct from the classic forms of pemphigus.2 Patientswith paraneoplastic pemphigus have a known or occult
associated neoplasm, usually of lymphoid tissue. Painful
severe oral and conjunctival erosions are a prominent
feature of paraneoplastic pemphigus.
The hallmark of pemphigus is the ﬁnding of IgG
autoantibodies against the cell surface of keratinocytes.3
The pemphigus autoantibodies found in patients’ sera
play a primary pathogenic role in inducing the loss ofPresented at the 2001 Keio Medical Science Prize Symposium, November 30, 2001.
Reprint requests to: Dr. Masayuki Amagai, Department of Dermatology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan, e-mail: amagai@sc.itc.med.keio.ac.jp
133

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Table 1

Amagai M: Anti-cadherin autoimmune disease
Target Autoantigens in Pemphigus

Subtypes
Pemphigus vulgaris
Mucosal dominant type
Mucocutaneous type
Pemphigus foliaceus
Paraneoplastic pemphigus

Antigens

desmoglein3
desmoglein3
desmoglein1
desmoglein1
desmoglein3
desmoglein1
plectin/HD1
desmoplakinI
desmoplakinII
BPAG1
envoplakin
periplakin?

Desmoglein Compensation Theory as an Explanation
for Localization of Blisters
MW

130 kD130 kD160 kD160 kD130 kD160 kD
500 kD250 kD
210 kD
230 kD
210 kD
190 kD
170 kD* Pemphigus vegetans is a variant of pemphigus vulgaris. Pempigus
erythematosus and Brazilian pemphigus (fogo selvagem) is a variantof pemphigus foliaceus.

cell adhesion of keratinocytes with resultant blister
formation. Immunochemical characterization of pemphigus antigens by immunoprecipitation or immunoblotting with extracts from cultured keratinocytes or
epidermis has demonstrated that the pemphigus vulgaris and foliaceus antigens are 130 kDa and 160 kDa
transmembrane glycoproteins, respectively (Table 1).4–8
Molecular cloning of cDNA encoding pemphigus antigens indicates that both these molecules are membersof the cadherin supergene family.9,10 Pemphigus foliaceus and vulgaris antigens are termed desmoglein1(Dsg1) and desmoglein 3 (Dsg3), respectively. Thus,
pemphigus was discovered to be an anti-cadherin autoimmune disease. The basic pathophysiology of pemphigus is that autoantibodies inhibit the adhesive functionof desmogleins and lead to the loss of cell-cell adhesionof keratinocytes with resultant blister formation.
Compelling evidence has accumulated that IgG
autoantibodies against Dsg1 and Dsg3 are pathogenic
and play a primary role in inducing the blister formation in pemphigus. IgG that is afﬁnity-puriﬁed frompemphigus vulgaris sera on the extracellular domain of
Dsg3 can cause suprabasilar acantholysis, the typical
histologic ﬁnding of pemphigus vulgaris, when injected
into neonatal mice.11 Furthermore, when anti-Dsg3
IgG is immunoadsorbed with the extracellular domainsof Dsg3 from pemphigus vulgaris sera, those sera nolonger have the pathogenic activity to cause blisters inneonatal mice.12 Similarly, immunoadsorption of pemphigus foliaceus sera with the extracellular domains of
Dsg1 eliminates the pathogenic activity of those sera
and anti-Dsg1 IgG bound on the column can cause superﬁcial blisters in neonatal mice.13

The disruption of desmoglein-dependent cell adhesion by autoantibodies is the basic pathophysiology inblister formation of pemphigus, but the clinical spectrum of pemphigus is more complex than this. Splits
associated with pemphigus foliaceus occur in the superﬁcial layer of the epidermis, while those of pemphigus vulgaris occur deep in the epidermis. Oral erosions
are developed in patients with pemphigus vulgaris, but
not in patients with pemphigus foliaceus. Some patientswith pemphigus vulgaris have only oral involvement,but others have extensive lesions on both skin and mucous membranes. These complex clinical features ofpemphigus are explained logically by the desmoglein
compensation theory: i.e. Dsg1 and Dsg3 compensates
for their adhesive function when they are coexpressedin the same cell (Fig. 1).14–16
When pemphigus vulgaris is divided into two subgroups, the mucosal dominant type which is demonstrated by mucosal lesions with minimal skininvolvement and the mucocutaneous type which isdemonstrated by extensive skin blisters and erosionsin addition to mucosal involvement, each subtype of
pemphigus has its own anti-desmoglein antibody proﬁle(Table 1). Patients with pemphigus foliaceus have only
anti-Dsg1 IgG autoantibodies. Patients with themucosal dominant type of pemphigus vulgaris have
only anti-Dsg3 IgG autoantibodies, while the mucocutaneous type of pemphigus vulgaris has both anti-Dsg3
and anti-Dsg1 IgG autoantibodies.17 The intraepithelial
expression pattern of Dsg1 and Dsg3 are different between skin and the mucous membranes. In the skin,Dsg1 is expressed throughout the epidermis, but more
intensely in the superﬁcial layers, while Dsg3 isexpressed in the lower part of the epidermis, mainlyin the basal and parabasal layers.18 In contrast, inthe mucous membranes, Dsg1 and Dsg3 are expressed
throughout the squamous mucosal epithelia, but Dsg1 isexpressed at a much lower level than Dsg3.14
When sera contain only anti-Dsg1 IgG which interferes with the function of Dsg1, those sera cause blisters
only in the superﬁcial epidermis because that is the only
area in which Dsg1 is present without coexpression of
Dsg3 (Fig. 1A). In the unaffected deep epidermis, thepresence of Dsg3 compensates for the loss of function of Dsg1. Although the anti-Dsg1 IgG binds to themucosa, no blisters are formed because of the coexpression of Dsg3. Thus, sera containing only antiDsg1 IgG cause superﬁcial blisters in the skin without
mucosal involvement as seen in patients with pemphigus foliaceus. When sera contain only anti-Dsg3 IgG,
those sera do not effectively cause blisters in theskin because the co-expressed Dsg1 compensates forKeio J Med 2002; 51 (3): 133–139

135

Fig. 1 Explanation of the sites of blisters in pemphigus by the desmoglein compensation theory. The triangles represent the distribution ofdesmoglein1 (Dsg1) and desmoglein3 (Dsg3) in the skin and mucous membranes. Pemphigus foliaceus sera contain only anti-Dsg1 IgG andcause superﬁcial blisters in the skin because Dsg3 functionally compensates for the impaired Dsg1 in the lower part of the epidermis, whilethese sera do not cause blisters in the mucous membrane because cell-cell adhesion is mainly mediated by Dsg3 (A). Sera containing only antiDsg3 IgG cause no or only limited blisters in the skin because Dsg1 compensates for the loss of the Dsg3-mediated adhesion, whereas those sera
induce separation in the mucous membrane where the low expression of Dsg1 will not compensate for the loss of the Dsg3-mediated adhesion(B). When sera contain both anti-Dsg1 and anti-Dsg3 IgG, the function of both Dsgs are compromised and blisters occur both in the skin andmucous membranes (C).

the impaired function of Dsg3, resulting in no or only
limited skin blisters (Fig. 1B). In contrast, in mucous
membranes, Dsg1 cannot compensate for the impaired
Dsg3 function because of its low expression. Therefore,
sera containing only anti-Dsg3 IgG cause oral erosions
without apparent skin involvement as seen in patientswith the mucosal dominant type of pemphigus vulgaris.
When sera contain both anti-Dsg1 and anti-Dsg3 IgG,
they interfere with the function of both Dsg1 and Dsg3,
resulting in extensive blisters and erosions in the skin as
well as the mucous membranes, as seen in patients withthe mucocutaneous type of pemphigus vulgaris (Fig.
1C). It is not clear why splits occur just above the basal
layer instead of the whole keratinocyte falling apart, it
is however speculated that the cell-cell adhesion between the basal and parabasal layers might be weaker
than the other parts of the epidermis because there arefewer desmosomes. In addition, the lower part of theepidermis might offer better access for autoantibodies
penetrating from the dermis.
In pregnant women with pemphigus, autoantibodies
cross the placenta and bind to the fetal epidermis.
Neonates develop blisters from mothers with pemphigus vulgaris, but very rarely from mothers with
pemphigus foliaceus. The reason for this paradoxical
observation is also explained by the desmoglein compensation theory.19 The distribution of Dsg3 in the
neonatal epidermis is unlike that in the adult epidermis
and is found on the surface of keratinocytes throughout
the epidermis, which is more like the distribution in
mucous membranes because the neonatal skin was inamnio. Therefore, pemphigus foliaceus sera containing
only anti-Dsg1 IgG cannot induce blisters in neonatal
skin.

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Amagai M: Anti-cadherin autoimmune disease

Staphylococcus Aureus Exfoliative Toxin Directly
Digests Desmoglein1 in SSSS And Bullous Impetigo
Staphylococcal scalded skin syndrome (SSSS) is a
generalized, conﬂuent, superﬁcially exfoliative disease
that is caused by the exfoliative toxin (ET, also known
as epidermolytic toxin, epidermolysin, and exfoliatin)of Staphylococcus aureus. The splits occur in the superﬁcial epidermis, at the level of the granular layer. ET
has two major serotypes: A and B (ETA and ETB,
respectively). In SSSS, S. aureus is present at a distantfocus, such as the pharynx, nose, ear, or conjunctiva,
and ET produced by S. aureus enters the circulationand causes exfoliation at remote sites, while in bullous
impetigo, a localized form of SSSS, S. aureus is present
in the lesions. In 1970, Melish and Glasgow identiﬁed
the toxin responsible by injecting newborn mice withbroth cultures of S. aureus isolated from patients with
SSSS, resulting in blister formation.20 However, itsmode of action in vivo remained an unanswered question for more than three decades.
One day, we realized that SSSS and pemphigus
foliaceus share many similar features. Both diseases
involve only the skin, and not mucous membranes orother tissues. The histology of both diseases shows
superﬁcial epidermal separation where Dsg3 is not coexpressed. Pathology textbooks actually say that thehistology of both diseases is indistinguishable. WhenIgG from PF is injected into neonatal mice, the micedevelop blisters. When ET is injected into neonatal
mice, the mice also develop blisters. The histology inboth mice is essentially identical. These similarities
caused us to consider whether the molecular mechanism of blister formation in SSSS was actually similar
to that in PF, and we started to investigate the fate of
Dsg1 after ET treatment.21
We ﬁrst stained Dsg1 and Dsg3 in mouse skin one
hour after injecting ETA into neonatal mice. ETA
caused substantial changes in Dsg1 staining, which wasmuch less intense on keratinocyte cell surfaces, while
there was no apparent change in Dsg3 staining. We
next examined whether Dsg1 is degraded after ETA
treatment. We performed an immunoblot analysis for
Dsg1, Dsg3, and E-cadherin on extracts of skin fromthe mice that developed blisters. The 160-kDa Dsg1
was degraded into a peptide of approximately 113 kDa,
while there was no degradation of Dsg3 or E-cadherin.
To demonstrate direct proteolysis of the extracellulardomain of Dsg1 by ETA, we incubated a soluble
recombinant form of the extracellular domains of
Dsg1 and Dsg3 with ETA in vitro (Fig. 2). ETA cleaved
the recombinant mouse and human Dsg1 in a dosedependent fashion, while ETA did not cleave Dsg3 at
all. Combined, these ﬁndings indicate that ETA speciﬁcally recognizes and cleaves the extracellular domain ofFig. 2 In vitro digestion of the recombinant extracellular domainsof human Dsg1 by exfoliative toxin. Dsg1 and Dsg3 extracellulardomains produced in baculovirus were incubated with or without
exfoliative toxin A (ET) and subjected to immunoblotting to visualize
Dsg1 and Dsg3. The toxin cleaved the extracellular domain of Dsg1,
but not that of Dsg3. The arrowhead and arrow indicate intact
recombinant Dsg1 and the cleaved product, respectively.

both mouse and human Dsg1. Subsequently, we also
demonstrated that ETB, another major serotype ofET, speciﬁcally cleaved Dsg1 in a manner identical toETA.22
These ﬁndings provide an important framework tounderstand the molecular mechanism of blister formation in these diseases, as well as cell-to-cell adhesion of
keratinocytes in the epidermis. By bringing dermatological tools to bear on our observations we were thus
able to clarify of the molecular mechanism of an exfoliative toxin, which had remained unsolved for three
decades after its identiﬁcation.
A Novel Autoimmune Mouse Model Using the
Autoantigen Knockout Mouse
To investigate the pathophysiological mechanisms
and to develop therapeutic strategies, animal diseasemodels have been playing important roles in the study

Keio J Med 2002; 51 (3): 133–139

Fig. 3 Methods to develop an active disease mouse models for
autoimmune diseases. In the conventional approach (A), various
strains of wild type mice are repeatedly immunized with various adjuvants to break their immunological tolerance. In a novel approach(B), splenocytes of autoantigen knockout mice which do not acquire
tolerance against the defective gene product are adoptively transferred to mice that express the autoantigen.

of various conditions including autoimmune diseases.
To examine the cellular mechanisms of autoantibody
production in pemphigus, specimens from patientsare naturally the best clinical material, but it is noteasy to obtain sufﬁcient amounts with proper controls.
To overcome this problem an active disease model isrequired. The conventional approach to develop an
autoimmune mouse model is forced immunization of
autoantigens in various strains of mice (Fig. 3A). However, this approach is empirical and immune responses
are largely dependent on the strains of mice or types ofadjuvant used. Furthermore, any autoimmune reactionin those mice may be transient, unlike that found inpatients, and the immune system is systemically stimulated.
The major difﬁculty in the development of an autoimmune reaction in mice is because of the self-tolerance
factor inherent in homeostasis, which prevents the immune system from reacting destructively against selfcomponents. When lymphocytes are exposed to selfcomponents during the development of the immune
system, auto-reacting lymphocytes are eliminated orinactivated. We have taken a novel approach to overcome this problem. Because self-tolerance is a technicalbarrier to the development of autoimmune mousemodels we thought of generating a condition whereself-tolerance is not established in an antigen-speciﬁcway. If it were possible to remove the antigen during

137

the development of the immune system, or if were notpresent from the start, tolerance against the removed
or absent molecule would not be acquired (Fig. 3B).
In the autoantigen knockout mouse, lymphocytes are
not exposed to the defective gene product, and selftolerance against that particular autoantigen is notestablished. Upon immunization with the autoantigen,the autoantigen knockout mice should elicit an immune
reaction against the autoantigen. However, in the immunized knockout mice, the antigen-antibody reaction is not expected because the mice lack the target
antigen. Therefore, lymphocytes from the immunizedautoantigen knockout mice are adoptively transferred
to wild type mice that express the autoantigen. The
transferred lymphocytes from the autoantigen knockout mice should be persistently stimulated by the endogenous autoantigen in the recipient mice and should
therefore produce antibodies against the autoantigen
with resultant phenotypes of the human disease.
Pemphigus Mouse Model with Persistent Pathogenic
Antibody Production
To develop an active disease mouse model for pemphigus vulgaris, we took this novel approach of using
autoantigen knockout mice, in the case of pemphigus vulgaris, Dsg3= mice.23 When we immunizedDsg3= mice with mouse recombinant Dsg3, anti-Dsg3
IgG was indeed produced. These sera were able to bindto the cell surfaces of living cultured mouse keratinocytes, indicating that the anti-Dsg3 IgG produced in
Dsg3= mice is capable of binding to the native Dsg3
on living keratinocytes. In contrast, sera from Dsg3þ=
littermates or wild type mice failed to bind to the surface of living keratinocytes. These ﬁndings conﬁrmedthat Dsg3= mice and mice expressing Dsg3 have aclear difference in their ability to produce anti-Dsg3
IgG that can bind to the native Dsg3.24
Despite the production of anti-Dsg3 IgG, no autoimmune reaction is expected in the immunized Dsg3=
mice because they lack the target antigen. To allow theanti-Dsg3 IgG to be exposed to the antigen, we isolated
splenocytes from the immunized Dsg3= mice andtransferred them into Rag-2= immunodeﬁcient micethat do express Dsg3. Rag-2= mice have no mature
T or B cells due to the inability to rearrange T cell
receptors or immunoglobulin genes and thus are unable
to produce antibodies or reject the transferred splenocytes. Circulating anti-Dsg3 IgG was detected in thesera of recipient Rag-2= mice as early as day 4 after
the transfer of Dsg3= splenocytes, and its titer increased rapidly without further boosting by recombinant Dsg3, and reached a plateau around day 21. The
circulating anti-Dsg3 IgG was detected for as long as 6

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Amagai M: Anti-cadherin autoimmune disease

Fig. 4 Phenotype of active disease model mice for pemphigus vulgaris. Recipient mice with Dsg3= splenocytes show in vivo mouse IgG deposition on keratinocyte cell surfaces (A) and suprabasilar acantholysis (B) just as in patients with pemphigus vulgaris. The recipient mice with
Dsg3= splenocytes (the lower mouse in C) are smaller than control mice with Dsg3þ= splenocytes (the upper mouse in C) because oral
erosions inhibit food intake. Some recipient mice with Dsg3= splenocytes show crusted erosions around the snout and cheeks, where micenormally scratch (D).

months or more. No signiﬁcant reactivity against Dsg1,
another desmosomal cadherin targeted in pemphigus
foliaceus, was observed in these recipient mice during
this period. In contrast, no circulating anti-Dsg3 IgG
was detected in Rag-2= mice given Dsg3þ= splenocytes. The persistent anti-Dsg3 IgG production indicates that endogenous Dsg3 in the recipient micestimulated the transferred Dsg3-speciﬁc lymphocytes
from the immunized Dsg3= mice in vivo.
In recipient mice with Dsg3= splenocytes, in vivo
IgG deposition was found on keratinocyte cell surfaces
in stratiﬁed squamous epithelia, including the skin andoral and esophageal mucous membranes, just as seen inpatients with pemphigus vulgaris (Fig. 4A). In thesemice, no IgG deposition was found in other tissues,
including heart, lung, liver, kidney, stomach, and small
and large intestines. These IgG binding sites correspond to the known tissue distribution of Dsg3. Histological examination of the recipient mice revealed an
intraepithelial loss of cell-cell adhesion just above thebasal layers, i.e., suprabasilar acantholysis, in the buccal
mucosa, hard palate, oropharyngeal areas, and the upper part of the esophagus, just as in human patients(Fig. 4B). These oral erosions likely inhibited food intake, resulting in the weight loss (Fig. 4C). Some of therecipient mice developed crusted erosions on the skinaround the snout, an area that is normally traumatizedby scratching (Fig. 4D). Close histological examination

revealed that the recipient mice with Dsg3= splenocytes also exhibited eosinophilic spongiosis which isoften found in patients with early lesions.25 We also
observed patchy hair loss in the recipient mice with
Dsg3= splenocytes. This hair loss phenotype also
persisted for over 6 months. Skin biopsy showed intense
IgG deposition on the cell surface of keratinocytes
surrounding the telogen hair club. Cleft formation wasobserved between the cells surrounding the telogen
club and the basal layer of the outer root sheath epithelium. In contrast, no phenotypic or pathologicalchanges were observed in recipient mice with Dsg3þ=
splenocytes. These results indicate that the Rag-2=
recipient mice given immunized Dsg3= splenocytes
developed clinical, histologic and immunopathologic
phenotypes similar to those of patients with pemphigus
vulgaris.24
A major hurdle in developing animal models of
autoimmune diseases has been overcoming the selftolerance component of the homeostatic system. We
circumvented this problem by immunizing autoantigen
knockout mice with the autoantigen, then transferring
their splenocytes to Rag-2= mice that expressed the
autoantigen. Although this model does not reﬂect theactual triggers of autoimmune diseases, it does provide
a means to investigate the roles of T and B lymphocytes
in perpetuating autoantibody production in the autoimmune response.26 We are also attempting to isolate

Keio J Med 2002; 51 (3): 133–139

a panel of monoclonal anti-Dsg3 IgG antibodies frompemphigus model mice, and investigate their pathogenic strength to clarify what factor(s) determines theseverity of the disease. In addition, this active animalmodel should be beneﬁcial for evaluating various therapeutic strategies that could modulate the autoimmune
response. Finally, our approach is widely applicable tovarious antibody-mediated and T cell-mediated autoimmune diseases, unless the relevant autoantigen
knockout mice are embryonicaly lethal or show grossabnormalities in their immune systems.
Acknowledgements: I acknowledge a deep debt of gratitude to Dr.
Takeji Nishikawa for his generous support and guidance and Dr. John
R. Stanley for his collaboration and stimulating discussion throughout
the course of the studies mentioned in this manuscript. The pemphigus mouse model was developed with collaboration with Dr. Shigeo
Koyasu. The works mentioned in this article were supported by Keio
Gijuku Academic Development Funds, Health Sciences Research
Grants for Research on Speciﬁc Diseases from Ministry of Health,Labour and Welfare, and a Grant-in-Aid for Scientiﬁc Research from
the Ministry of Education, Culture, Sports, Science and Technology ofJapan.

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