LECTURE
BP180 as the common autoantigen in blistering diseases
with different clinical phenotypes
Detlef Zillikens
Department of Dermatology, University of Würzburg, Würzburg, Germany(Received for publication on November 19, 2001)

Abstract. Bullous pemphigoid antigen 180 (BP180, type XVII collagen) is a transmembrane hemidesmosomal glycoprotein of basal keratinocytes that spans the lamina lucida of the dermal-epidermal
junction. Five autoimmune subepidermal blistering diseases are associated with an immune response toBP180, including bullous pemphigoid (BP), pemphigoid gestationis (PG), cicatricial pemphigoid (CP),lichen planus pemphigoides (LPP), and linear IgA disease (LAD). The BP180 ectodomain consists of
15 interrupted collagen domains. The largest non-collagenous (NC) 16A domain is located next to thecell membrane. In BP, autoantibodies are directed to a tightly clustered set of epitopes located at the
N-terminal 45 amino acids of the NC16A domain. However, some BP sera also react with other portions of the BP180 ectodomain or with the intracellular region of this protein. In PG, antibodies appear
to exclusively recognize the immunodominant BP180 NC16A region. In CP, autoantibodies are
directed to both the NC16A domain and the C-terminus of BP180 that projects into the lamina lucida/lamina densa interface of the dermal-epidermal junction. In LPP, autoantibodies react with an epitope
located at the C-terminus of NC16A, that is not targeted by BP or PG sera. Finally, the epidermal 97
kDa and the keratinoctye-derived 120 kDa autoantigens of LAD (LABD97 and LAD-1, respectively)
have recently been identiﬁed as portions of the BP180 ectodomain. These observations demonstratethat different clinical phenotypes are associated with an autoimmune response to the same autoantigen
yet the immunoglobulin subclass of the autoantibody and the epitope that is recognized may be different. (Keio J Med 51 (1): 21–28, March 2002)
Key words: autoantigen, basement membrane zone, hemidesmosome, linear IgA disease, pemphigoid

target of autoantibodies is BP180. BP180 is a memberof the collagen protein family and is also referred to as
type XVII collagen. It is a transmembrane glycoproteinwith a type II orientation, i:e:, the N-terminus localizes
to the cytoplasm, whereas the C-terminal ectodomain
consisting of about 1,000 amino acids projecting into
the extracellular space.2,3 Rotary shadowing revealed
that BP180 contains an intracellular globular head, an
extracellular rigid rod corresponding to the 16th noncollagenous (NC) A and the 15th collagenous domain
spanning the lamina lucida, and a ﬂexible tail extending into the lamina densa of the DEJ (Fig. 1).2,3 The
extracellular domain of BP180 forms a homotrimer.4
BP180 was identiﬁed and characterized independently
using a biochemical approach5 and by screening an epi-

Adhesion of basal keratinocytes to the underlying
dermis is maintained by various structural proteins ofhemidesmosomes, including the 230 kD bullous pemphigoid antigen (BP230), plectin, a6 b4 integrin, BP180,
and laminin 5. Directly or through other proteins thesehemidesmosomal components associate with anchoring ﬁbrils which originate in the lamina densa of thedermal-epidermal junction (DEJ) and extend into thesubjacent connective tissue. The major component ofanchoring ﬁbrils is type VII collagen.1
Mutations for the different components of thisanchoring complex as well as formation of autoantibodies against these structures result in split formation at the level of the DEJ. A major component of
the dermal-epidermal anchoring complex and a major

Presented at the 1190th Meeting of the Keio Medical Society in Tokyo, December 5, 2000.
Detlef Zillikens was supported by grants from the Wilhelm Sander-Stiftung (98.073.2) and the Deutsche Forschungsgemeinschaft (Zi 439/4-1).
Reprint requests to: Dr. Detlef Zillikens, Department of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany, e-mail: zillikens-d.derma@mail.uni-wuerzburg.de
21

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Zillikens D: BP180 as autoantigen in blistering skin diseases

Fig. 1 Schematic diagram of BP180, soluble forms of its ectodomain, and recombinant fragments of the NC16A domain. BP180 is a transmembrane hemidesmosomal protein of basal keratinocytes with a type II orientation, i:e:, the NH2 terminus localizes to the cytoplasm while the
COOH terminus projects into the extracellular space. LABD97 and LAD-1 are generated by proteolytic cleavage of the BP180 ectodomain.
The BP180 molecule consists of a series of alternating collagenous (C, light grey) and non-collagenous (NC, dark grey) domains. The extracellular portion of the 16th non-collagenous domain (NC16A) is the major target of autoantibodies in patients with BP and PG. NC16A has
been subdivided into 6 fragments (NC16A1 through NC16A5) each approximately 15 amino acids in length (boxes). Amino acid residue
numbers are shown above the boxes. C15, 15th collagenous domain of BP180; HP, hemidesmosomal plaque; MCW, Medical College of
Wisconsin.

dermal cDNA library using patients’ autoantibodies.6,7
Chromosomal mapping studies localized the BP180 geneto the long arm of chromosome 10, locus 10q24.3.8
The biological importance of BP180 is demostrated
by the observation that mutations in the COL17A1
gene encoding BP180 may result in generalized atrophic benign epidermolysis bullosa (GABEB). Patientswith this hereditary disease are characterized by subepidermal blisters of skin and mucous membranes resulting in skin atrophy, alopecia, nail dystrophy, toothanomalies, and pigmentary changes.9
Recent work from different laboratories demonstrated that BP180 may function as the common autoantigen in autoimmune subepidermal blistering diseases
with different clinical phenotypes (Table 1). These include bullous pemphigoid, pemphigoid (herpes) gestationis, lichen planus pemphigoides, linear IgA disease,and cicatricial pemphigoid.

Bullous Pemphigoid
Bullous pemphigoid (BP) mainly affects the elderly
and is by far the most common of the diseases associated with autoantibodies to BP180, followed by cicatricial pemphigoid, pemphigoid gestationis, linear IgA
disease, and lichen planus pemphigoides.10,11 Although

Table 1 Autoimmune Blistering Diseases Associated with Autoantibodies to BP180
Bullous pemphigoid
Pemphigoid (herpes) gestationis
Lichen planus pemphigoides
Linear IgA disease
Cicatricial pemphigoid

Keio J Med 2002; 51 (1): 21–28

Fig. 2 Direct immunoﬂuorescence microscopy of a perilesional skinbiopsy from a patient with bullous pemphigoid. Linear deposits of C3
at the dermal-epidermal junction.

the incidence of BP in persons younger than 60 years is
0.7 new cases/1,000,000 people/year, this incidence
increases to 158 new cases/1,000,000 residents/year
in patients 90 years and older.12 Clinically, patientswith BP have tense blisters arising on erythematousor normal skin. In the premonitory stage, for weeks,months, or even years the disease may present witherythematous macules, eczematous lesions, papules,
and urticarial plaques. By direct immunoﬂuorescence(IF) microscopy of perilesional skin biopsies, the patients
reveal linear deposits of C3 and/or IgG along the DEJ(Fig. 2). By the use of 1 mol/L NaCl-split normal humanskin as a substrate for indirect IF analysis, in about
90% of patients, circulating serum autoantibodies aredetected that bind to the epidermal side of the artiﬁcial
split (Fig. 3).
Through the use of immunoprecipitation and immunoblotting techniques, BP230 and BP180 wereidentiﬁed as targets of circulating autoantibodies in
BP patients.13–16 Cloning of corresponding epidermal
cDNAs revealed that BP230 and BP180 are products ofdistinct and unrelated genes.6,7,17,18 The BP230 genemaps to the short arm of the chromosome 6, locus
6p11–12.19 BP230 is a constituent of the hemidesmosomal plaque and belongs to the plakin family ofproteins.
Whereas BP230 is located intracellularly, BP180 is atransmembrane protein. The NC16A domain adjacentto the cell membrane of basal keratinocytes has been
identiﬁed as an immunodominant region of BP180 thatis targeted by approximately 90% of BP sera (Fig.
4).20–23 Within this stretch of 76 amino acids, BP autoantibodies bind to four well-deﬁned epitopes (MCW-0
through MCW-3) located at the N-terminal 45 aminoacids (Fig. 1).21

23

Fig. 3 IgG from a serum of a patient with bullous pemphigoid binds
to the epidermal side of 1 mol/L NaCl-split human skin by indirect
immunoﬂuorescence microscopy.

Fig. 4 Sera from patients with ﬁve different autoimmune subepidermal blistering diseases react with the immunodominant NC16A
domain of BP180. Recombinant GST-NC16A was fractionated by
15% SDS-PAGE, transferred to nitrocellulose, and reacted with serum from patients with bullous pemphigoid (BP, lane 1), pemphigoid
gestationis (PG, lane 2), lichen planus pemphigoides (LPP, lane 3),
linear IgA disease (LAD, lane 4), and cicatricial pemphigoid (CP, lane
5). Sera had been preadsorbed against recombinant GST to abolishunspeciﬁc reactivity with this portion of the fusion protein. Serum of ahealthy control (NHS; lane 6) shows no speciﬁc labeling. The migration positions of molecular weight markers are shown to the left.

Based on these epitope mapping data, an ELISA
system was developed utilizing a recombinant form of
the entire BP180 NC16A domain as the target.22 This
ELISA turned out to be highly sensitive and speciﬁc forthe detection of autoantibodies to BP180 in patients24with BP. No correlation has been reported between
disease activity in BP and anti-DEJ antibody titers as
detected by indirect IF microscopy. However, when we
studied levels of autoantibodies to BP180 NC16A inpatients with BP during the course of the disease, we
detected a correlation between disease activity and serum levels of antibodies to NC16A.24 In addition, thisstudy conﬁrmed the lack of correlation of disease activity with titers of indirect IF microscopy which may be
explained by the observation that IF staining predominantly reﬂects the activity with BP230 and to a lesser
extent with BP180.25 Reactivity to BP180 NC16A wasfurther found to be mediated mainly by IgG4 and IgE,
and less frequently by IgG1 , IgG2 , or IgG3 .26 Serumlevels of IgE and IgG subclasses to BP180 NC16A also
reﬂected disease activity, and no change was observedwith regard to immunoglobulin subclass reacting predominantly with BP180 NC16A or the speciﬁc epitopes
within this domain during the course of the disease.26
Several investigations have been aimed at unequivocally demonstrating the pathogenic relevance of antibodies to BP180 in patients with BP. These attempts
have been hindered by the fact that murine BP180
shows a lack of homology within the region that is homologous with the NC16A domain of human BP180.27
However, when neonatal mice were injected with antibodies from a rabbit that had been immunized withmurine BP180, the skin of the mice developed an inﬂammatory blistering disease mimicking BP.27 Further
studies demonstrated that, in addition to anti-BP180
antibodies, complement activation and neutrophil inﬁltration are prerequisites for disease induction inthis experimental model.28,29 In another attempt, werecently grafted human skin onto the back of severe
combined immunodeﬁcient (SCID) mice. However, although antibodies to desmoglein 1 and desmoglein 3
from patients with pemphigus foliaceus and pemphigus vulgaris reproduced the clinical, histological, andimmunopathological ﬁndings of these diseases, antibodies to BP180 from patients with BP did not induce
blisters.30
Various cytokines and mediators have been implicated in the inﬂammatory reaction in BP patients.31 In
blister ﬂuid of these patients, elevated levels of several
cytokines and chemokines, including TNFa, IL-1a, IL1b, IL-4, IL-5, IL-6, IL-8, and IL-10 have been detectedcompared to levels in suction blisters induced in healthy
controls.32–36 To investigate the functional relevanceof anti-BP180 autoantibodies, we recently tested therelease of various cytokines from cultured human kertinocytes after treatment with IgG to BP180 puriﬁed
from the serum of BP patients. We detected a dose- andtime-dependent secretion of IL-6 and IL-8, but not of
TNFa, IL-1a, IL-1b, IL-10, or MCP-1 on stimulation
with IgG from patients compared to healthy controls.37

Zillikens D: BP180 as autoantigen in blistering skin diseases

This effect was abolished by depleting immunoreactivity to the N-terminal 30 amino acids of BP180
NC16A. Upregulation of IL-6 and IL-8 after incubationof keratinocytes with IgG from patients was also foundat the mRNA level. These data demonstrate that BPassociated autoantibodies to well-deﬁned epitopes on
the human BP180 ectodomain may trigger a signaltransduction event that leads to the expression and secretion of IL-6 and IL-8 from human keratinocytes.37
Treatment of the cells with dapsone inhibited the release of IL-6 and IL-8 from cells incubated with human
IgG, but did not affect the mRNA levels for these two
inﬂammatory mediators. The effect of dapsone on thesecretion of IL-6 and IL-8 by keratinocytes stimulatedwith antibodies to BP180 may well contribute to improvement of the skin disease in patients treated withthis drug.38
Pemphigoid Gestationis
Pemphigoid gestationis (PG), formerly referred to as
herpes gestationis, most commonly presents during thesecond or third trimester of pregnancy or in the immediate post-partum period, often as a non-bullous disease. Skin lesions include erythematous papules as wellas urticarial, eczematous, and erythema multiforme-likelesions. Less frequently, papulo-vesicles and blisters areencountered in PG (Fig. 5). The autoimmune response
in PG is directed against BP180 and, less frequently,
BP230.20,39 Like in BP, the NC16A domain has been
identiﬁed as the major target of autoantibodies and isrecognized by more than 80% of PG sera (Fig. 4).20,40
Recent epitope mapping studies identiﬁed two welldeﬁned antigenic sites within a 22 amino acid segment
of BP180 (NC16A2 and NC16A2.5) as the major antigenic targets of PG sera.41 In contrast to ﬁndings in
BP,26 reactivity to NC16A is dominated by IgG1 andIgG3 in PG patients.41 As IgG3 and IgG1 are the IgG
subclasses with the strongest complement-ﬁxing properties, these observations may well explain complement
deposition at the DEJ which is the most consistentimmunopathological ﬁnding in the skin of PG patients.
Lichen Planus Pemphigoides
In contrast to bullous lichen planus, in which blisters
are conﬁned to lichen planus lesions, in lichen planus
pemphigoides (LPP), blister formation usually follows
the appearance of papules and plaques associated with
LP and may arise on both lichen planus lesions andunaffected skin. In addition, the ﬁnding of linear deposits of C3 and IgG along the DEJ by direct IF microscopy differentiates LPP from bullous lichen planus.42
Several observations speak against a simple associationof lichen planus and BP in LPP patients. LPP is seen inKeio J Med 2002; 51 (1): 21–28

25

Fig. 6 Tense blisters on the back of a 2-year-old boy with linear IgA
disease of childhood (chronic bullous disease of childhood).

Fig. 5 Urticarial plaques on the trunk of a patient with pemphigoid
gestationis.

younger patients and the clinical course is less severe
compared to BP. This concept is substantiated by recent ﬁndings that autoantibodies in LPP sera react with
BP180 NC16A4 (MCW-4), an epitope that is not recognized by antibodies in BP.42 Therefore, LPP can be
distinguished from BP not only clinically but also immunologically.
Linear IgA Disease
Linear IgA disease (LAD) is characterized by linear
IgA deposits at the DEJ. Clinically, considerable variations are seen with respect to the age of disease onset,
morphology of bullous lesions, and mucosal involvement. LAD of childhood, also referred to as chronicbullous disease of childhood, is the most common autoimmune bullous disorder in children (Fig. 6).43 By
immunoelectron microscopy, most LAD sera bind within the lamina lucida, others label the lamina densa, andstill others react with both locations.44,45 Similarly, by
indirect IF microscopy on salt-split skin, most LAD sera
label the epidermal side of the split, some show dermalbinding, and others stain both sides.46 Different target
antigens of the lamina lucida-type of LAD have beenreported, including a 97 kD protein (LABD97) extracted from epidermis47 and a 120 kD polypeptide(LAD-1) secreted into the medium of cultured humankeratinocytes.48,49 Based on biochemical studies andpeptide sequence analyses, it now appears that LABD97
and LAD-1 are generated as proteolytic cleavage products of the BP180 ectodomain.50–52 Some LAD sera
also contain autoantibodies to full-length BP180 as
detected by immunoblotting of epidermal or keratinocyte extracts.53–54 When we tested 50 LAD sera forreactivity with BP180 NC16A, the immunodominantregion of BP180 in BP and PG, antibodies to this domain were found in 20% of LAD patients. However,when reactivity to NC16A was abolished, the sera continued to react with LAD-1 or BP180. These results
suggest that LAD sera, in contrast to the majority of BP
sera, target epitopes on the entire BP180 ectodomain.54
In another subset of patients, a combined IgA andIgG response was detected.55–57 For this disease, theterm linear IgA/IgG bullous dermatosis was proposed.55
Interestingly, in addition to LAD patients, a large
number of BP sera has been found to react with the 120
kD soluble ectodomain of BP180 (LAD-1).49,58 In a
recent study, we investigated the hypothesis that there
is a signiﬁcant overlap in the autoimmune isotype proﬁles associated with BP and LAD. For this study, several new recombinant forms of BP180 were generated
in the baculovirus expression system, including the fulllength protein. IgG reactivity with full-length BP180 or
portions of it was detected in 39 of 40 (98%) of BP
sera; interestingly, 88% of BP sera also contained IgA

26

Zillikens D: BP180 as autoantigen in blistering skin diseases

anti-BP180 autoantibodies. Similarly, anti-BP180 reactivity in LAD sera was also attributed to both an
IgA (68%) and IgG (76%) autoantibody response. IgA
and IgG autoantibodies to the intracellular portion of
BP180 were found in 14% and 28% of BP sera, respectively, and 8% of LAD sera (same percentage forboth isotypes). These ﬁndings demonstrate that both
BP and LAD patients have a dual IgG and IgA autoimmune response to BP180 which is directed not only
to the ectodomain but also to the intracellular portionof this protein.59
Cicatricial Pemphigoid
Cicatricial pemphigoid (CP) is a chronic blistering
disease of the mucous membranes and skin. It may
involve the oral, ocular, nasal, pharyngeal, laryngeal,
esophageal, and anogenital mucous membranes (Fig.
7). Skin lesions appear in about 30% of CP patients. CP
is a heterogeneous disease with respect to the clinicalsite of involvement, the isotype of autoantibodies (IgA,
IgG, or the combination of IgA and IgG), the site of
autoantibody binding by indirect IF microscopy on saltsplit skin (epidermal, dermal, or both), and the target
antigens (BP180, laminin 5, laminin 6, b4 integrin, type
VII collagen).60 About 30% of patients with the clinicalphenotype CP reveal autoantibodies to laminin 5.61,62
In a recent study on 26 patients with the clinical phenotype of CP, we found reactivity with laminin 5 in 7
sera and with BP180 in the remaining 19 patients.
Thirty-two percent of the BP180 reactive sera only
showed IgA reactivity to this protein. By the combined
use of the soluble BP180 ectodomain (LAD-1) andrecombinant BP180 NC16A, 84% of the BP180 reactive
sera were positive. IgG reactivity was preferentiallyfound against NC16A, whereas IgA antibodies pre-Fig. 7 Conjuctivitis and synechiae of the conjunctivae of the left eye
in a patient with cicatricial pemphigoid.

dominantly recognized LAD-1. Thirty-two percent of
the BP180 reactive sera revealed reactivity with theintracellular domain of this protein. These ﬁndings
demonstrate that autoantibodies in CP target epitopes
on both the extra- and intracellular domains of BP180
and underline the importance of testing for both IgG
and IgA reactivity in CP sera.62
Conclusion
The observations outlined above demonstrate thatﬁve autoimmune diseases with different clinical phenotypes are associated with an autoimmune response to
the same autoantigen, yet the immunoglobulin subclassand the sites on the autoantigen that are targeted are
different. Future studies will have to identify the pathogenically relevant epitopes on BP180 that mediate subepidermal blister formation in these diseases.
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