Pemphigoid diseases: Pathogenesis, diagnosis, and treatment

MICHAEL KASPERKIEWICZ1, DETLEF ZILLIKENS1, & ENNO SCHMIDT1,2

1Department of Dermatology, University of Lubeck, Lubeck, Germany, and 2Comprehensive Center for Inflammation Medicine,

University of Lubeck, Lubeck, Germany

(Submitted 25 June 2011; accepted 12 July 2011)

AbstractPemphigoid diseases (including bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgAdermatosis, lichen planus pemphigoides, and anti-p200 pemphigoid) are a subgroup of autoimmune bullous skin diseasescharacterized by an autoantibody response toward structural components of the hemidesmosome resulting in subepidermalblistering. By the use of different in vitro systems and experimental animal models, the pathogenic relevance of theseautoantibodies has been demonstrated. Recent advances in the understanding of autoantibody responses have led to noveldiagnostic tools and a more differentiated therapeutic approach for these disorders. This review covers the most recentunderstanding of the pathophysiology, diagnosis, and treatment of this group of autoimmune diseases.

Keywords: Pemphigoid, skin, antibody, antigen

Introduction

The pemphigoid group of diseases is characterized by

subepidermal blisters due to autoantibody-induced

disruption of the components of the dermal–

epidermal anchoring complex. Pemphigoid diseases

include bullous pemphigoid (BP), mucous membrane

pemphigoid (MMP), pemphigoid gestationis (PG),

linear IgA dermatosis (LAD), lichen planus pemphi-

goides (LPP), and anti-p200 pemphigoid. In particu-

lar, disorders with anti-BP180 (type XVII collagen)

reactivity, including BP, PG, LAD, LPP, and a

subgroup of MMP may form a continuous spectrum

of subepidermal autoimmune blistering dermatoses.

BP is not only the most common disorder within

the pemphigoid group, but also represents the most

frequent autoimmune blistering disease in general

[1,2]. The incidence of BP has been estimated between

4.5 and 14 new cases/million/year in central Europe

[1–5]. A higher incidence of 42.8/million/year has

recently been reported in Great Britain based on a

data registry established on the general practitioner

level [6]. Interestingly, in Germany and Great Britain,

it has been shown that the incidence of BP has

considerably increased within the last 10 years (2-fold

and 4.8-fold, respectively) [1,6]. This development

may be due to the increasing age of the general

population and/or an increased awareness leading to

further diagnostic steps. MMP and PG have been

identified as the second most frequent pemphigoid

diseases in central Europe with an incidence of two

new patients/million/year [1].

For the correct diagnosis of pemphigoid diseases,

the detection of tissue-bound and circulating auto-

antibodies is pivotal [7]. Although direct immuno-

fluorescence (IF) microscopy differentiates pemphigus

from pemphigoid disorders, serological analyses are

necessary to separate pemphigoid diseases from each

other and from epidermolysis bullosa acquisita (EBA).

In fact, while direct IF microscopy is still the gold

standard for the diagnosis of pemphigoid diseases, in

the great majority of patients, diagnosis can be made

serologically today [7].

By indirect IF microscopy on 1 M NaCl-split

human skin, anti-laminin 332 MMP and anti-p200

pemphigoid can be distinguished from BP, LAD, PG,

and anti-BP180 MMP, but final diagnosis can only

be made by more sophisticated methods, i.e. use

of cell-derived or recombinant forms of the target

antigens (Figure 1). In recent years, various novel

detection systems for serum antibodies have been

Correspondence: M. Kasperkiewicz, Department of Dermatology,University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany.Tel: 0049-451-500-5844. Fax: 0049-451-500-5162. E-mail: michael.kasperkiewicz@uk-sh.de

Autoimmunity, February 2012; 45(1): 55–70q Informa UK, Ltd.ISSN 0891-6934 print/1607-842X onlineDOI: 10.3109/08916934.2011.606447

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developed, some of which are also commercially avail-

able. These now allow for a more accurate diagnosis,

which is becoming increasingly important to guide

treatment decisions, while our knowledge about the

therapeutic arsenal of these disorders has also

expanded. In this review, we focus on recent progress

in our understanding of the pathogenesis, diagnosis,

and treatment of the different pemphigoid diseases.

Bullous pemphigoid

Pathogenesis

Two hemidesmosomal proteins, the 230 kDa protein

(BP230 or BPAG1), and 180 kDa antigen (BP180,

BPAG2, or type XVII collagen) have been identified

as the major antigenic targets of BP autoantibodies

[8–10]. BP230 is an intracellular plakin protein member

showing homology with plectin and desmoplakins I

and II and promotes the association of hemidesmo-

somes with keratin intermediate filaments [11–13].

In contrast, BP180 is a transmembrane protein with a

type II orientation that spans the lamina lucida and

projects into the lamina densa of the epidermal basal

membrane zone (BMZ). The extracellular region

consists of 15 collagen domains separated from one

another by noncollagen sequences [14,15].

The noncollagenous 16A domain (NC16A),

located at the membrane-proximal region of BP180,

is considered to harbor major pathogenically relevant

epitopes in BP and is recognized by autoantibodies in

80–90% of BP patients [16–19]. The importance of

anti-BP180 NC16A reactivity is further highlighted

by the observation that serum levels of BP180

NC16A-specific antibodies correlate with the disease

activity in BP patients [20].

In addition, it was reported that autoantibodies

preferentially recognize the phosphorylated BP180

ectodomain [21,22]. Recent studies have identified

the presence of memory B cells specific for the NC16A

domain, which can be induced in vitro to synthesize

autoantibodies [23]. These cells belong to the short-

lived plasma blast population [24]. The BP180

NC16A-specific autoantibodies are not only of the

IgG isotype (mainly IgG1 and IgG4 subclasses), but

also of the IgE class [25–27]. In fact, patients with

BP frequently have IgE autoantibodies binding to the

NC16A domain of BP180 [28].

The presence of IgE autoantibodies has recently

been correlated with a severe form of BP, and BP

patients, positive for IgE anti-BP180 antibodies,

required longer duration for remission, higher dosage

of prednisolone, and more intensive therapies for

remission [29]. Interestingly, one study showed that a

recombinant NC16A fusion protein degranulated

basophils opsonized with IgE from patients with BP

[30], further supporting the pathophysiological role

of IgE antibodies in BP. In addition, other antigenic

sites exist on both the extracellular and intracellular

BP180, BP230Lichen planuspemphigoides

BP180, BP230Linear IgA dermatosis

BP180, BP230Pemphigoid gestationis

BP180, BP230,α6β4 integrin

Mucous membranepemphigoid

BP180, BP230Bullous pemphigoid

(a)

(b)

Main target antigensDisease

Laminin γ1Anti-p200pemphigoid

Laminin 332Mucous membrane

pemphigoid

Main target antigensDisease

Figure 1. Indirect IF microscopy on 1 M NaCl split human skin and main target autoantigens of pemphigoid diseases. Differentiation of

the diseases and target molecules is based on the binding pattern with either (a) epidermal or (b) dermal binding of circulating autoantibodies

on the artificial split.

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domain of BP180, which are recognized by IgE and

IgG autoantibodies in BP patients [16–18,31–34].

BP patients also exhibit significant reactivity with

BP230, which is thought not to be involved in the

initiation of the inflammatory response in BP due to

its intracellular localization [8,35–40]. Currently, it is

unclear whether anti-BP230 autoantibodies in BP

patients directly contribute to blister formation or

whether they are just a result of keratinocyte injury

and determinant spreading of the autoimmune

response. Very recently, two retrospective studies with

a large series of 138 and 190 patients with active BP,

respectively, have determined the outcome of BP230

autoantibody detection using commercial enzyme-

linked immunosorbent assays (ELISAs) [39,40].

In the first-mentioned study, 59% of patients had a

positive BP230 ELISA result and 86% had a positive

BP180 ELISA result, while only 5% had anti-BP230

autoantibodies without anti-BP180 autoantibodies

[39]. In the second study, anti-BP230 and anti-

BP180 antibodies were detected in 61 and 79% of BP

patients serum samples, respectively, while 8% had

anti-BP230 autoantibodies without anti-BP180 auto-

antibodies [40]. Although the study by Charneux et al.

found no relationship between a positive BP230

ELISA result and disease extent or presence of

mucosal involvement [39], with regard to this specific

finding, the study by Roussel et al. [40] showed the

opposite finding. Two other studies suggested that

anti-BP230 antibodies may be preferentially associ-

ated with localized types of BP [37,38].

In contrast to the humoral immune response, the

cellular immune response has been less widely studied

in human BP. Autoreactive T and B cells are almost

constantly found in BP patients. These cells react with

the same regions of BP180 and BP230 that are

recognized by IgG autoantibodies. The differential

epitope recognition of BP180 seems to be associated

with distinct clinical severity: T- and B-cell reactivity

against the NH2-terminal portion of the BP180

ectodomain is associated with severe BP, while the

central portion is more frequently recognized in

patients with limited disease.

In contrast, combined T- and B-cell response against

the COOH- and NH2-terminal globular domains of

BP230 was found in less than 50% [41]. The response

to the BP180 ectodomain is restricted by certain HLA

class II alleles, such as the DQb1*0301 allele [42,43].

Autoreactive T cells in BP patients produce a Th1/Th2

mixed cytokine profile. We and others have detected

elevated levels of IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8,

IL-10, IL-15, IL-16, eotaxin, MCP-4, tumor necrosis

factor a (TNFa), and CCL18 in the sera and/or blister

fluids of BP patients [44–55].

Serum levels of TNFa, IL-6, IL-8, IL-15, and

CCL18 correlated with patients’ disease activity [47–

49,54], pointing to a pathological relevance of these

mediators. The observation that Th2-type cytokines

are important in human BP is supported by the

increased frequency of cutaneous lymphocyte-associ-

ated antigen-positive IL-4- and IL-13-producing cells

in the peripheral blood [56]. Furthermore, analysis of

cell subsets with immunoregulatory functions in

BP patients has shown that while the number of

circulating CD4 þ CD25 þ FOXP3 þ regulatory T

cells, natural killer T cells, and natural killer cells are

normal, gd T cells are reduced in BP patients [57,58].

Our knowledge about the functionally relevant

pathogenic mechanisms in BP is based on in vitro

studies using cultured human keratinocytes, ex vivo

studies using cryosections of human skin as well as

various mouse models [59,60]. When cultured human

keratinocytes were treated with anti-BP180 IgG, dose-

and time-dependent increases of both mRNA and

protein levels of IL-6 and IL-8 were observed,

pointing to a signal-transducing event via BP180

[61]. In the same model, decreased expression of

BP180 and weakening of keratinocyte attachment in

response to anti-BP180 IgG were seen [62].

Using cryosections of human skin, BP patients’ sera

were shown to generate dermal–epidermal separation

when co-incubated with leukocytes and complement

from healthy volunteers [63]. Characterizing the

specificity of pathogenically relevant autoantibodies,

we were later able to demonstrate that IgG antibodies

to human BP180, purified from sera of BP patients

and from rabbits immunized against recombinant

human BP180, induce dermal–epidermal separation

in this model. This effect was shown to be mediated by

binding of autoantibodies to the NC16A domain of

human BP180 and to be dependent on the Fc portion

of autoantibodies [64].

Passive transfer of rabbit IgG, raised against the

murine homolog of the human BP180 NC16A

domain, into neonatal wild-type mice produced

clinical, histologic, and immunopathologic alterations

like those seen in patients with BP [65]. In this model,

blister formation is dependent on the activation of

complement, degranulation of mast cells, and recruit-

ment of neutrophils [65–68].

Blister fluid and lesional/perilesional biopsies from

BP patients have been shown to contain high levels of

proteolytic enzymes, including neutrophil elastase

(NE), cathepsin G, collagenase, plasminogen activa-

tors, plasmin, matrix metalloproteinase-2 (MMP-2,

gelatinase A), MMP-9 (gelatinase B), and MMP-13

[69–77]. These enzymes, particularly the neutrophil-

and eosinophil-derived MMP-9 and NE, are secreted

into the extracellular space upon cell activation

and are thought to proteolytically degrade various

extracellular matrix proteins, including the extracellu-

lar domain of BP180 [76,78,79]. Mice genetically

deficient in NE or MMP-9 have been shown to be

resistant to experimental BP [80,81].

An interaction between MMP-9, NE, and the

plasminogen/plasmin system was demonstrated to

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occur during proteolytic events in experimental BP: in

the early stages of blistering, MMP-9 is mainly

activated by plasmin, which is formed from plasmino-

gen by tissue plasminogen activator (tPA) and/or

urokinase plasminogen activator (uPA) [82]. Further-

more, an elevated expression and release of tPA from

normal human keratinocytes upon stimulation with

antibodies to human BP180 has been reported [83].

In addition to plasmin, the mast cell-specific serine

protease MCP-4 (chymase) is also able to activate

MMP-9 [84]. Activated MMP-9 is believed to

proteolytically inactivate a1-proteinase inhibitor, the

physiological inhibitor of NE, which allows unrest-

rained activity of NE [85]. These findings demon-

strate that loss of cell-matrix adhesion within the

dermal-epidermal junction (DEJ) is directly mediated

by proteinases released by inflammatory cells.

In a first attempt to explore the functional relevance

of human anti-BP180 antibodies reacting with the

human target antigen, human skin was transplanted

onto Severe Combined Immunodeficiency (SCID)

mice. The injection of BP IgG into the transplant did,

however, not result in blister formation within the

observation period of 48 h [86]. Recently, additional

“humanized” mouse models have been established.

Olasz et al. generated a novel transgenic mouse

expressing human BP180 in murine epidermal BMZ

by the use of a keratin 14 promoter construct. They

showed that wild-type or MHC I2/2 , but not MHC

II2/2 , mice grafted with transgenic skin elicited IgG

that bound human epidermal BMZ and BP180.

Transgenic grafts on wild-type mice developed

neutrophil-rich leukocyte infiltrates and subepidermal

blisters [87]. Nishie et al. [88] used the same BP180

transgenic mice to rescue the blistering phenotype

of BP1802/2 mice by backcrossing experiments.

Clinical, histological, and immunopathologic features

of BP were achieved by passive transfer of IgG from

patients or IgG1 monoclonal antibodies against

humanized BP180 NC16A into these BP180-huma-

nized mice [88,89]. To show that pathogenic anti-

BP180 autoantibodies act in combination with key

innate immune system players also in the humanized

BP mouse model, Liu et al. generated a humanized

mouse strain, in which murine BP180 NC14A was

replaced by the homologous human BP180 NC16A

epitope [90]. These BP180 humanized mice pre-

treated with mast cell activation blocker or depleted of

complement or neutrophils become resistant to BP

after passive transfer of human BP autoantibodies.

More recently, an active mouse model for BP has been

developed by transferring splenocytes from wild-type

mice that had been immunized by grafting of human

BP180-transgenic mouse skin onto Rag-22/2 /BP180-

humanized mice. The recipient mice produced

anti-human BP180 IgG antibodies in vivo and

developed blisters and erosions corresponding

to clinical, histological, and immunopathological

features of BP [91].

In two other mouse models, the pathogenic effect of

IgE anti-BP180 antibodies has been elucidated,

demonstrating that an IgE hybridoma to LABD97

antigen or purified IgE from BP patients was able to

induce BP-characteristic inflammatory skin changes

and partly subepidermal blistering in human skin

grafts on nude mice [92,93].

Diagnosis

Clinically, BP is characterized by tense blisters predo-

minantly on flexural aspects of the limbs and abdomen

and associated with severe itching (Figure 2a). BP

typically affects the elderly with an average age at

diagnosis between 75 and 81 years [1,2,94,95]. Before

blisters arise, BP is typically preceded by a prodromal,

non-bullous stage, in which excoriated, eczematous,

papular, and/or urticarial lesions are found that may

persist for several weeks or even months.

Light microscopy of lesional skin from patients with

BP typically demonstrates a subepidermal blister with

an eosinophil- and/or neutrophil-rich leukocytic

infiltrate within the papillary dermis and along the

epidermal BMZ (Figure 2b). By direct IF microscopy

of perilesional skin linear deposits of IgG and/or C3

can be found at the epidermal BMZ (Figure 2c).

In approximately 80% of the cases, patient IgG

autoantibodies react with the epidermal side of 1 M

NaCl split human skin by indirect IF microscopy

(Figure 2d) [96].

Based on the finding that NC16A is the immuno-

dominant region of BP180 [17,18], two highly specific

and sensitive BP180 NC16A-specific ELISAs for

detection of circulating autoantibodies in BP have

been commercialized [19,97]. When these assays are

combined with other detection systems, including

those using BP180 fragments outside the NC16A

domain and BP230, the sensitivity of these tests can be

increased to even 100% [38,41,98,99]. In contrast to

serum levels of antibodies to BP230, BP180 NC16A-

specific autoantibodies correlate closely with disease

activity and may thus be not only of diagnostic use, but

also allow the monitoring of circulating autoantibody

levels during the course of the disease, helping to

guide treatment decisions [19,20,36].

BP must be differentiated from pemphigus and

other subepidermal blistering autoimmune derma-

toses, including EBA and dermatitis herpetiformis.

In contrast to BP, blister formation in pemphigus

results from intraepithelial cell separation and shows

an intercellular pattern of IgG between keratinocytes.

Differentiation of BP especially from EBA, anti-p200

pemphigoid, and MMP, however, presents a more

difficult task. The mechanobullous, non-inflamma-

tory form of EBA is characterized by the appearance

of skin fragility and tense blisters at anatomic

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areas subjected to trauma, healing of lesions with

scarring and milia formation as well as subepidermal

split formation with an only scattered dermal

inflammatory infiltrate. In contrast, the inflammatory

subtype of EBA may mimic clinical, histological, and

routine direct IF microscopy findings of BP.

Using higher magnifications of direct IF micro-

scopy, EBA can be sometimes differentiated from BP

by distinctly shaped IgG deposits at the epidermal

BMZ, i.e. EBA revealing an u-serrated pattern and BP

a n-serrated configuration [100]. In addition, as

autoantibodies in EBA are directed against type VII

collagen, sera from these patients do not bind to the

epidermal, but to the dermal side of 1 M NaCl split

human skin. Similarly, patients with anti-p200

pemphigoid show autoantibody reactivity to a dermal

antigen. This immunopathological finding may be of

major importance since clinically, anti-p200 pemphi-

goid and BP may not be distinguishable. In contrast

to BP, MMP is predominantly confined to mucous

membranes.

If blisters appear on the skin of MMP patients, they

are commonly smaller, transient, and of limited

extent. Indirect IF microscopy of sera from MMP

patients may reveal epidermal, dermal, or combined

staining patterns of IgG on 1 M NaCl split human

skin. Some forms of LAD clinically resemble BP or

dermatitis herpetiformis. Continuous linear immuno-

deposits of IgA, most often in the absence of IgG and

C3, together with circulating IgA anti-BMZ auto-

antibodies, can distinguish LAD from these other

immunobullous diseases.

Treatment

BP is generally a self-limited disease that may remit

within a few months or some years. However, the

mortality rate in the first year has been shown to be as

high as 11–40% [95,101–103], and was related to old

age, poor general condition, and use of high doses of

oral corticosteroids rather than to the extent of the

disease itself [94,102]. Systemic and topical cortico-

steroids have been widely used in clinical practice

[104]. Initially, daily morning doses of prednisolone in

the range of 0.5 mg/kg/day usually control the disease

within a few weeks. An initial dose higher than

0.75 mg/kg/day has been shown to be not beneficial in

a controlled prospective trial [105].

A large, randomized controlled trial showed that

initial disease control and 1-year survival were

significantly better when treating severe BP with

clobetasol propionate cream 40 mg/day compared with

oral prednisolone 1 mg/kg/day, while in moderate BP,

outcomes using clobetasol cream and prednisolone

Figure 2. Clinical, histologic, and immunopathologic findings in BP as representative pemphigoid disease. (a) Tense blisters and erosion on

erythematous base on the leg. (b) Histophathology of lesional skin demonstrating a subepidermal blister and a mixed dermal inflammatory

infiltrate containing numerous granulocytes. (c) Direct IF microscopy of perilesional skin showing continuous linear deposits of IgG at the

epidermal BMZ. (d) Indirect IF microscopy on 1 M NaCl split human skin revealing reactivity of circulating IgG against the epidermal side

of the artificial split.

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0.5 mg/kg/day were comparable [106]. Furthermore, a

mild regimen with clobetasol propionate cream 10–

30 g/day tapering over 4 months has been shown to be

not inferior to the high-dose topical regimen with

clobetasol propionate 40 g/day [107].

Considering other randomized controlled trials in

BP, no differences in disease control were seen for

azathioprine plus prednisone compared with predni-

sone alone [108], for prednisolone plus azathioprine

compared with prednisolone plus plasma exchange

[108], for prednisolone plus mycophenolate mofetil or

plus azathioprine [109], and for tetracycline plus

nicotinamide compared with prednisolone [110].

Reports have also described successful treatment of

BP patients with dapsone [111,112], methotrexate

[113], high-dose intravenous immunoglobulins

(IVIG) [114], rituximab [115–117], omalizumab

[118], and immunoadsorption [119].

Mucous membrane pemphigoid

Pathogenesis

BP180 is the target antigen in about 70% of MMP

patients [120]. However, unlike in BP, only about

half of the patients’ sera contain antibodies to BP180

NC16A, and C-terminal epitopes of BP180 are

preferentially targeted [120–122]. In addition,

patients with MMP may exhibit IgG and/or IgA

autoantibodies of other specificity that recognize

BP230 [123,124], the 97/120 kDa LAD antigen,

laminin 332 (laminin 5), laminin 331 (laminin 6)

[125,126], type VII collagen [127], or the a6 and

b4 integrin subunit [128]. Considering the latter

target antigens, it has been shown that sera from

patients with generalized MMP and ocular MMP

recognize the b4 integrin subunit, while sera from

patients with oral MMP recognize the a6 integrin

subunit [129].

The pathogenicity of anti-laminin 332 antibodies

has been documented in vivo. Passive transfer of anti-

laminin 332 IgG to neonatal or adult mice induced

subepidermal blisters of skin and mucous membranes

that mimicked clinical, histological, and immuno-

pathologic features seen in MMP patients [130]. The

same findings were seen in mice injected with Fab

fragments directed against laminin 332 as well as in

mice lacking complement, mast cells or T cells,

suggesting that such antibodies may elicit epidermal

detachment in vivo in a non-inflammatory and direct

manner [130,131].

The pathogenicity of patients’ autoantibodies was

further confirmed in an experimental human skin

graft model, in which human anti-laminin 332

autoantibodies induced subepidermal blisters [132].

Additionally, accumulating evidence indicates that

fibrogenic cytokines, matrix metalloproteinases, and

collagen type I secreted in high amounts by

pemphigoid fibroblasts may actively be involved in

ocular MMP-associated scarring processes [133,134].

Diagnosis

MMP is a chronic autoimmune blistering disease

of mucous membranes and skin. An international

consensus conference defined the predominant invol-

vement of mucous membranes as the major clinical

diagnosis criterion of MMP [135]. The oral mucosa

is the most common site affected by MMP followed

by ocular disease (Figure 3). It may also involve nasal,

pharyngeal, laryngeal, esophageal, and anogenital

mucous membranes. Progressive scarring potentially

may lead to serious complications, such as blindness

or asphyxiation. Histologically, MMP is characterized

by subepidermal blisters with a chronic inflammatory

infiltrate in the lamina propria that is composed of

lymphocytes, histiocytes, scattered neutrophils, and

eosinophils. Anti-BP180 and anti-laminin 332

MMP cannot be differentiated from each other by

histology [136].

Direct IF microscopy shows linear IgG and C3

deposits at the BMZ. Indirect IF microscopy using

1 M NaCl split human skin distinguishes between

antigens on the epithelial side of the split (BP180,

BP230, and a6b4 integrin) and those of the dermal

side (laminin 332). However, as only about one-half of

sera are reactive in indirect IF microscopy, ELISA and

Western blotting using relevant target antigens are

important additional diagnostic methods in MMP.

Although only half of the MMP patients develop

antibodies to the NC16A domain of BP180, the other

patients with BP180 reactivity react with LAD-1 or

the C-terminal portion of BP180 by Western blotting

[130]. Importantly, testing for IgA anti-BP180

antibodies in addition to the IgG isotype will further

increase the detection rate [130,137].

Assaying for anti-laminin 332 reactivity is of

particular importance as 25% of patients with laminin

332-specific antibodies develop a malignancy. In these

Figure 3. Clinical presentation of MMP. Ocular involvement with

symblepharon formation.

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patients, a tumor search is indicated [138,139].

Immunoprecipitation with human keratinocytes has

been reported to be the most sensitive technique for

the detection of serum autoantibodies against laminin

332, whereas immunoblotting with extracellular

matrix of cultured HaCaT cells was found to be the

most practical alternative [140]. The term cicatricial

pemphigoid, previously applied for patients with MMP,

is currently only used for the rare clinical variant in

which mucous membranes are not predominantly

affected and skin lesions heal with scarring [135].

Brunsting–Perry pemphigoid is a rare variant of

cicatricial pemphigoid first described in 1957 [141].

It is characterized clinically by blisters, hemorrhagic

crusts and atrophic scars confined to the head and

neck without mucosal involvement. It probably

represents a heterogeneous disorder with several

target antigens. Most patients with this type of

pemphigoid disease have been reported to have

autoantibodies against type VII collagen, therefore,

representing a localized form of EBA [142]. Although

the clinical features of Brunsting–Perry pemphigoid

are completely different from those of MMP, it has

recently been reported that they may share the same

target antigens, e.g. the C-terminal domain of BP180

and laminin 332 [143,144].

Treatment

Treatment of MMP is largely tempered by its severity

and sites of involvement. A consensus conference on

this disease differentiated high-risk and low-risk

patients. Although in low-risk patients, lesions are

limited to the oral cavity and the skin and are more

amenable to treatment, patients with conjunctival

involvement usually require aggressive management to

avoid blindness. Mild lesions of the oral mucosa and

skin can sometimes be effectively treated with topical

glucocorticoids or topical calcineurin inhibitors

combined with good oral hygiene. For more severe

lesions in low-risk patients, initial treatment may

include dapsone (1.0–1.5 mg/kg/day) and predniso-

lone (0.5–1.0 mg/kg/day).

An alternative for these patients may also be

tetracyclines combined with nicotinamide. Predniso-

lone (1.0–1.5 mg/kg/day) in combination with oral

cyclophosphamide (1.0–2.0 mg/kg/day) may be tried

in patients at high risk (ocular, nasopharyngeal,

genital, and esophageal involvement) [145,146].

Alternatively, i.v. dexamethasone pulses (100 mg on

3 consecutive days) combined with i.v. cyclopho-

sphamide pulses (500–1000 mg) in 2- to 4-week

intervals can be given. In patients who do not tolerate

cyclophosphamide, other immunosuppressants such

as azathiorpine, mycophenolate mofetil, and metho-

trexate can be applied [145,146].

Good therapeutic efficacy of IVIG has been

reported in patients with MMP. IVIG therapy, usually

given at 2 g/kg/cycle initially every 4 weeks, avoided

progression of the disease and was more effective than

conventional immunosuppressive treatment [104].

In one study, IVIG given as monotherapy halted

progression of scarring and visual deterioration during

the study period, and serological and clinical remis-

sion was sustained for several months after cessation of

IVIG infusions [147]. Recent case reports also

described the beneficial use of rituximab and TNF-a

inhibitors for severe and treatment-resistant cases of

MMP [105,107,148].

Pemphigoid gestationis

Pathogenesis

PG, formerly referred to as herpes gestationis, is

another disease in which BP180 has been identified as

the major target [149]. Occasionally, PG is associated

with a trophoblastic tumor, hydatidiform mole or

choriocarcinoma. The disease may appear for the first

time during any pregnancy, but then rarely skips

subsequent gestations [149]. The immunopathologic

hallmark of PG is linear deposits of C3 and, to a lesser

extent, of IgG along the DEJ in perilesional skin

biopsies. Circulating-complement fixing autoanti-

bodies “HG factor” can be detected by indirect IF

on intact or NaCl split skin.

The autoantibodies react with BP180 and, less

frequently, with BP230 [16,150]. IgG autoantibodies

in most PG sera target the NC16A domain of BP180

[16,32,151–153]. However, antigenic sites outside

NC16A have also been identified both extra- and

intracellularly [153]. Epitope mapping studies ident-

ified two well-defined antigenic sites within a 22 amino

acid segment of BP180 (NC16A2 and NC16A2.5) as

major antigenic targets for PG sera [152]. In addition,

using overlapping synthetic peptides, PG autoanti-

bodies were shown to bind to two defined epitopes

within the NC16A domain (aa 500–514 and aa 511–

523). Importantly, preadsorption using an affinity

matrix containing these epitopes completely abolished

dermal–epidermal separation ex vivo induced by PG

autoantibodies [154].

In contrast to findings in BP [155], reactivity to

NC16A is dominated by IgG1 and IgG3 antibodies in

PG patients [152]. As IgG1 and IgG3 are the IgG

subclasses with the strongest complement fixing

properties, these observations may well explain

complement deposition at the DEJ, which is the

most consistent immunopathological feature in PG. In

PG patients tested for T-cell autoreactivity, BP180-

specific T cells exclusively reacted with the NC16A2

domain. Proliferative responses of these cells were

restricted to HLA-DR and cells expressed a CD4 þ

Th1-type memory phenotype [156]. These results

underline other findings that PG is strongly associated

with HLA-DR3 and -DR4 haplotypes [149].

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Diagnosis

PG usually presents during the second or third

trimester of pregnancy or in the immediate postpartum

period with a pruritic urticarial, papulovesicular

eruption. Skin lesions often start around the umbilicus

and then spread over abdomen and thighs [149]. PG

frequently presents as a nonbullous disease with

eczematous lesions, erythema multiforme-like

changes or erythematous papules and plaques.

Diagnosis is based on detection of C3 deposits in

perilesional skin biopsies as well as circulating

autoantibodies by the complement binding test and

ELISA using recombinant BP180 NC16A [19,157].

Treatment

Treatment is aimed at suppression of new blister

formation and relief of the intense pruritus. In milder

cases, this can be achieved by the use of topical

corticosteroids in combination with oral antihista-

mines. In more severe cases, the administration of

prednisolone at an initial dose of 0.3–0.5 mg/kg/day

is generally sufficient. This dose can usually be

decreased during the course of the disease. Flares

postpartum may require a temporary increase in the

corticosteroid dose [149].

Linear IgA dermatosis

Pathogenesis

LAD is an autoimmune subepidermal blistering

disease characterized by circulating IgA anti-BMZ

autoantibodies. Autoantibodies in LAD were shown

to target antigens with various molecular weights,

including 97-, 120-, 180-, 200-, 230-, 280-, 285- and

290-kDa proteins [158–160]. The two most charac-

teristic target antigens are the protein of 97 kDa and

the 120 kDa protein, termed the LABD antigen 1

(LABD97) and LAD-1, respectively [159,161]. These

proteins present a cleaved portion of the extracellular

domain of BP180 [160,162–165]. Recently, the

sheddases ADAM 9 and 10 have been reported to be

involved in generation of LAD-1 from BP180, while

formation of LABD97 has been shown to be

dependent on plasmin [166,167].

In contrast to BP, only 20% of sera of patients with

LAD react with the NC16A domain [168]. In

addition, IgA antibodies to BP230, type VII collagen

and laminin 332 have been reported [169–171]. Since

the majority of LAD sera also contain IgG antibodies

against BP180 and in most BP sera, IgA anti-BP180

antibodies can be detected, LAD and BP may be

regarded as different ends of a continuous spectrum

[172]. In fact, the isotype of anti-BMZ reactivity was

associated with the age of the patients: in younger

patients, IgA autoantibodies predominated, whereas

in older patients, predominantly IgG anti-BMZ

antibodies were found [173].

LAD may be either idiopathic or drug-induced (e.g.

vancomycin). The mechanism for blister formation

is not fully understood, but is likely to involve IgA-

and complement-mediated neutrophil chemotaxis.

The pathogenic relevance of LAD-associated auto-

antibodies has been shown by the passive transfer of

IgA murine monoclonal antibodies against LAD

autoantigen to SCID mice bearing human skin grafts.

In some of these challenged mice, the transferred

autoantibodies produced neutrophil-rich infiltrates

and subepidermal vesicles [174].

Diagnosis

LAD mainly shows vesicobullous lesions affecting the

skin and mucosal surfaces, sometimes forming

characteristic collarettes of vesicles or blisters as new

lesions arise in the periphery of old lesions (Figure 4).

On histopathology, the bullae are subepidermal, with

collections of neutrophils along the epidermal BMZ

and occasionally in the dermal papillary tips. Direct IF

microscopy of perilesional skin shows linear depo-

sition of IgA at the epidermal BMZ, sometimes in

combination with linear IgG deposits. Patients have

Figure 4. Clinical presentation of LAD. Erythema multiforme-like

lesions with partly clustered annular tense blisters on proximal lower

extremity.

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circulating IgA autoantibodies that mostly bind the

epidermal side of 1 M NaCl split human skin on

indirect IF microscopy (lamina lucida type), but

combined epidermal and dermal staining as well as

dermal labeling alone (sublamina densa type) has also

been observed. Autoantibodies to LAD-1 in the

lamina lucida type of LAD are detected by immuno-

blotting with conditioned concentrated medium of

cultured human keratinocytes [159].

Treatment

Skin lesions in LAD commonly respond when treated

with dapsone. As dapsone may cause hemolytic

anemia, decreased hemoglobin values or even methe-

moglobinemia, glucose-6-phosphate dehydrogenase

deficiency should be excluded before the drug is

initiated. An alternative treatment is Sulfapyridine,

usually given at a dose of 15–60 mg/kg/day [175].

Some patients may require low-dose prednisone

initially to suppress blister formation. In unresponsive

patients, erythromycin, colchicine, flucloxacillin,

IVIG, and immunoadsorption have been administered

successfully [176].

Lichen planus pemphigoides

Pathogenesis

Regarding the pathogenesis of LPP, it is most likely

that the lymphocytic inflammatory process directed

against basal keratinocytes in lichen planus leads to a

release of hidden antigenic determinants within the

DEJ, resulting in an autoimmune response against

hemidesmosomal structures [177–180]. Immuno-

blotting studies have identified BP180 and BP230 as

target molecules but also a new antigen of 200 kDa of

keratinocyte derivation. The latter finding reinforces

the hypothesis that LPP might have a unique antigen

and thus represent a distinct entity from BP

[178,179]. In line with this assumption, it has been

shown that the epitope within the C-terminal NC16A

domain of BP180 antigen, targeted in LPP, differs

from BP, localizing to NC16A4 as opposed to

NC17A1 through NC16A3 [180].

Diagnosis

Most patients with LPP have typical lichenified

plaques or papules of lichen planus initially, followed

after weeks to months by tense vesicles and blisters

which arise, in contrast to bullous lichen planus,

independent of the lichenoid lesions (Figure 5).

Histologically, blisters resemble those in BP [177].

Direct IF microscopy of a papule shows Civatte

bodies, but when a blister is evaluated, IgG and C3 are

present as in BP. Indirect IF microsocopy on salt split

skin shows binding of IgG to the epidermal side.

By immunoblotting, reactivity is primarily directed

against BP180 with NC16A being the immunodomi-

nant domain [180]. Less often, antibodies against

BP230 or other yet uncharacterized antigens are

found [177–179]. The following observations suggest

that LPP is not a coincidental association of BP and

lichen planus: (i) the average age of BP patients is 77

years, whereas in LPP it is 44 years; (ii) lichenoid

papules are not seen in BP; (iii) autoantibodies in LPP

react with C-terminal epitopes of NC16A, which is

very uncommon in BP; and (iv) LPP is usually a

milder disease and more therapy-responsive than BP.

Therapy

It is important to treat existing lichen planus to avoid

further immunostimulation. In this context, acitretin

has proven valuable. Otherwise, treatment is the same

as in BP.

Anti-p200 pemphigoid

Anti-p200 pemphigoid is a subepidermal blistering

skin disease characterized by circulating autoanti-

bodies against a 200-kDa molecule (p200 protein) of

the lower lamina lucida of the BMZ [181]. Recently, it

has been shown that 90% of the anti-p200 pemphi-

goid sera react with the C-terminus of laminin g1

[182]. Subsequently, the term anti-laminin g1

Figure 5. Clinical presentation of LPP. Lichenified plaques and

tense blisters on the foot.

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pemphigoid was proposed for this disease. Because

not all anti-p200 pemphigoid sera react with laminin

g1 [182,183], we suggest not applying the two terms

synonymously and only diagnosing an anti-laminin g1

pemphigoid when reactivity with laminin g1 has

actually been identified.

Pathogenesis

Anti-p200 pemphigoid shows organ-specific patho-

genicity, although laminin g1 is expressed not only at

the DEJ but also in the BMZ of dermal blood vessels

[184]. This has been explained by the assumption that

laminin g1 in the epidermal BMZ has different

posttranslational modifications, such as glycosylation,

compared with laminin g1 expressed in blood vessels

[185]. However, the pathogenicity of anti-p200/lami-

nin g1 antibodies has hardly been studied yet, with the

exception of a single patient whose IgG, in contrast to

BP IgG, did not induce IL-8 secretion following

incubation with human cultured keratinocytes [186].

Diagnosis

Patients with anti-p200 pemphigoid typically

develop tense blisters and urticarial eruptions, some-

times with itching, closely resembling those of BP

(Figure 6). Usually, patients with anti-p200 pemphi-

goid can only be clinically differentiated from BP by

their considerably younger age with an average of 61

years at diagnosis [187]. Histopathologically, skin

biopsy specimens demonstrate subepidermal blister-

ing and a linear infiltrate of neutrophils, and some-

times eosinophils, along the epidermal BMZ.

With this method, anti-p200 pemphigoid cannot be

differentiated from other pemphigoid disorders [188].

Direct IF microscopy of perilesional skin biopsies from

patients with p200 pemphigoid demonstrate linear

deposits of IgG and C3 along the epidermal BMZ.

Typically, autoantibodies bind to the floor of the

artificial blister by indirect IF microscopy on 1 M

NaCl split human skin [181]. Classically, autoanti-

bodies in anti-p200 pemphigoid react with a 200-kDa

protein in extracts of human dermis by Western blot-

ting. Recently, laminin g1-specific antibodies could

be detected by Western blotting or ELISA using the

recombinant C-terminus of laminin g1 [182,183].

Treatment

Anti-p200 pemphigoid can be treated in a similar

way as BP and typically shows a prompt response

to topical class IV corticosteroids and dapsone (1.0–

1.5 mg/kg/day). In more severe cases, prednisolone

(0.5 mg/kg/day) may be added [187]. Recently, adju-

vant immunoadsorption has been successfully applied

in a severe case of anti-p200 pemphigoid with

concomitant active gastric ulceration [189].

Conclusion

Considerable progress has been made in the last years

regarding our understanding of pemphigoid diseases.

Experimental animal models of these diseases and

advances in translational research provided essential

insight into the pathophysiology of these disorders.

Intense scientific research on the autoantibody

response has led to new diagnostic techniques,

allowing the serological diagnosis in the great majority

of patients. Novel, more specific therapeutic avenues

are, however, needed to further reduce the long-term

adverse effects of the currently available immuno-

suppressants.

Declaration of interest: This work was supported by

grant EXC 306/1 Inflammation at Interfaces (Research

Areas E and H) from the Deutsche Forschungge-

meinschaft to E.S. and D.Z. The authors report no

conflicts of interest. The authors alone are responsible

for the content and writing of the paper.

References

[1] Bertram F, Brocker EB, Zillikens D, Schmidt E. Prospective

analysis of the incidence of autoimmune bullous disorders in

Lower Franconia, Germany. J Dtsch Dermatol Ges 2009;7:

434–440.

[2] Marazza G, Pham HC, Scharer L, Pedrazzetti PP, Hunziker

T, Trueb RM, Hohl D, Itin P, Lautenschlager S, Naldi L,

Borradori L. Autoimmune bullous disease Swiss study

group. Incidence of bullous pemphigoid and pemphigus in

Switzerland: A 2-year prospective study. Br J Dermatol 2009;

161:861–868.

[3] Cozzani E, Parodi A, Rebora A, Delmonte S, Barile M, Nigro

A, Priano L, Troiano G, Patri PL, Gruppo Ligure di Studi in

Dermatologia (GLISID). Bullous pemphigoid in Liguria:

A 2-year survey. J Eur Acad Dermatol Venereol 2001;15:

317–319.

[4] Gudi VS, White MI, Cruickshank N, Herriot R, Edwards SL,

Nimmo F, Ormerod AD. Annual incidence and mortality of

Figure 6. Clinical presentation of anti-p200 pemphigoid. Tense

blisters and erosions on the palms.

M. Kasperkiewicz et al.64

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y G

oteb

orgs

Uni

vers

ity o

n 11

/20/

12Fo

r pe

rson

al u

se o

nly.

bullous pemphigoid in the Grampian Region of North-east

Scotland. Br J Dermatol 2005;153:424–427.

[5] Serwin AB, Bokiniec E, Piascik M, Masny D, Chodynicka B.

Epidemiological and clinical analysis of pemphigoid patients

in northeastern Poland in 2000–2005. Med Sci Monit 2007;

13:CR360–CR364.

[6] Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ,

West J. Bullous pemphigoid and pemphigus vulgaris—

incidence and mortality in the UK: Population based cohort

study. BMJ 2008;337:160–163. doi: 10.1136/bmj.a180.

[7] Schmidt E, Zillikens D. Modern diagnosis of autoimmune

blistering skin diseases. Autoimmun Rev 2010;10:84–89.

[8] Stanley JR, Hawley-Nelson P, Yuspa SH, Shevach EM,

Katz SI. Characterization of bullous pemphigoid antigen: A

unique basement membrane protein of stratified epithelia.

Cell 1981;24:897–903.

[9] Mutasim DF, Takahashi Y, Labib RS, Anhalt GJ, Patel HP,

Diaz LA. A pool of bullous pemphigoid antigen(s) is

intracellular and associated with the basal cell cytoskeleton-

hemidesmosome complex. J Invest Dermatol 1985;84:

47–53.

[10] Labib RS, Anhalt GJ, Patel HP, Mutasim DF, Diaz LA.

Molecular heterogeneity of bullous pemphigoid antigens as

detected by immunoblotting. J Immunol 1986;136:

1231–1235.

[11] Tanaka M, Hashimoto T, Amagai M, Shimizu N, Ikeguchi N,

Tsubata T, Hasegawa A, Miki K, Nishikawa T. Character-

ization of bullous pemphigoid antibodies by use of

recombinant bullous pemphigoid antigen proteins. J Invest

Dermatol 1991;97:725–728.

[12] Sawamura D, Li K, Chu ML, Uitto J, Human bullous

pemphigoid antigen (BPAG1). Amino acid sequences

deduced from cloned cDNAs predict biologically important

peptide segments and protein domains. J Biol Chem 1991;

266:17784–17790.

[13] Green KJ, Virata ML, Elgart GW, Stanley JR, Parry DA.

Comparative structural analysis of desmoplakin, bullous

pemphigoid antigen and plectin: Members of a new gene

family involved in organization of intermediate filaments. Int

J Biol Macromol 1992;14:145–153.

[14] Giudice GJ, Emery DJ, Diaz LA. Cloning and primary

structural analysis of the bullous pemphigoid autoantigen

BP180. J Invest Dermatol 1992;99:243–250.

[15] Li K, Tamai K, Tan EM, Uitto J, Cloning of type XVII

collagen. Complementary and genomic DNA sequences of

mouse 180-kilodalton bullous pemphigoid antigen (BPAG2)

predict an interrupted collagenous domain, a transmembrane

segment, and unusual features in the 50-end of the gene and

the 30-untranslated region of the mRNA. J Biol Chem 1993;

268:8825–8834.

[16] Giudice GJ, Emery DJ, Zelickson BD, Anhalt GJ, Liu Z, Diaz

LA. Bullous pemphigoid and herpes gestationis autoanti-

bodies recognize a common non-collagenous site on the

BP180 ectodomain. J Immunol 1993;151:5742–5750.

[17] Zillikens D, Rose PA, Balding SD, Liu Z, Olague-Marchan

M, Diaz LA, Giudice GJ. Tight clustering of extracellular

BP180 epitopes recognized by bullous pemphigoid autoanti-

bodies. J Invest Dermatol 1997a;109:573–579.

[18] Zillikens D, Mascaro JM, Rose PA, Liu Z, Ewing SM, Caux F,

Hoffmann RG, Diaz LA, Giudice GJ. A highly sensitive

enzyme-linked immunosorbent assay for the detection of

circulating anti-BP180 autoantibodies in patients with

bullous pemphigoid. J Invest Dermatol 1997b;109:679–683.

[19] Sitaru C, Dahnrich C, Probst C, Komorowski L, Blocker I,

Schmidt E, Schlumberger W, Rose C, Stocker W, Zillikens D.

Enzyme-linked immunosorbent assay using multimers of the

16th non-collagenous domain of the BP180 antigen for

sensitive and specific detection of pemphigoid autoanti-

bodies. Exp Dermatol 2007;16:770–777.

[20] Schmidt E, Obe K, Brocker EB, Zillikens D. Serum levels of

autoantibodies to BP180 correlate with disease activity in

patients with bullous pemphigoid. Arch Dermatol 2000;136:

174–178.

[21] Zimina EP, Fritsch A, Schermer B, Bakulina AY,

Bashkurov M, Benzing T, Bruckner-Tuderman L.

Extracellular phosphorylation of collagen XVII by ecto-

casein kinase 2 inhibits ectodomain shedding. J Biol Chem

2007;282:22737–22746.

[22] Zimina EP, Hofmann SC, Fritsch A, Kern JS, Sitaru C,

Bruckner-Tuderman L. Bullous pemphigoid autoantibodies

preferentially recognize phosphoepitopes in collagen XVII.

J Invest Dermatol 2008;128:2736–2739.

[23] Leyendeckers H, Tasanen K, Bruckner-Tuderman L,

Zillikens D, Sitaru C, Schmitz J, Hunzelmann N. Memory

B cells specific for the NC16A domain of the 180 kDa bullous

pemphigoid autoantigen can be detected in peripheral blood

of bullous pemphigoid patients and induced in vitro to

synthesize autoantibodies. J Invest Dermatol 2003;120:

372–378.

[24] Laszlo S, Neumann S, Hertl M, Hunzelmann N. Generation

of increased numbers of HLA-DR(high) IgG þ plasma cells

in the peripheral blood of patients with bullous pemphigoid:

NC16a-specific cells belong to the short-lived plasma blast

population. J Invest Dermatol 2010;130:2838–2841.

[25] Bernard P, Aucouturier P, Denis F, Bonnetblanc JM.

Immunoblot analysis of IgG subclasses of circulating

antibodies in bullous pemphigoid. Clin Immunol Immuno-

pathol 1990;54:484–494.

[26] Dopp R, Schmidt E, Chimanovitch I, Leverkus M, Brocker

EB, Zillikens D. IgG4 and IgE are the major immunoglobu-

lins targeting the NC16A domain of BP180 in Bullous

pemphigoid: Serum levels of these immunoglobulins reflect

disease activity. J Am Acad Dermatol 2000;42:577–583.

[27] Laffitte E, Skaria M, Jaunin F, Tamm K, Saurat JH, Favre B,

Borradori L. Autoantibodies to the extracellular and

intracellular domain of bullous pemphigoid 180, the putative

key autoantigen in bullous pemphigoid, belong predomi-

nantly to the IgG1 and IgG4 subclasses. Br J Dermatol 2001;

144:760–768.

[28] Dimson OG, Giudice GJ, Fu CL, Van den Bergh F, Warren

SJ, Janson MM, Fairley JA. Identification of a potential

effector function for IgE autoantibodies in the organ-specific

autoimmune disease bullous pemphigoid. J Invest Dermatol

2003;120:784–788.

[29] Iwata Y, Komura K, Kodera M, Usuda T, Yokoyama Y,

Hara T, Muroi E, Ogawa F, Takenaka M, Sato S. Correlation

of IgE autoantibody to BP180 with a severe form of bullous

pemphigoid. Arch Dermatol 2008;144:41–48.

[30] Fairley JA, Fu CL, Giudice GJ. Mapping the binding sites of

anti-BP180 immunoglobulin E autoantibodies in bullous

pemphigoid. J Invest Dermatol 2005;125:467–472.

[31] Giudice GJ, Wilske KC, Anhalt GJ, Fairley JA, Taylor AF,

Emery DJ, Hoffman RG, Diaz LA. Development of an

ELISA to detect anti-BP180 autoantibodies in bullous

pemphigoid and herpes gestationis. J Invest Dermatol 1994;

102:878–881.

[32] Perriard J, Jaunin F, Favre B, Budinger L, Hertl M, Saurat JH,

Borradori L. IgG autoantibodies from bullous pemphigoid

(BP) patients bind antigenic sites on both the extracellular

and the intracellular domains of the BP antigen 180. J Invest

Dermatol 1999;112:141–147.

[33] Di Zenzo G, Grosso F, Terracina M, Mariotti F, De Pita O,

Owaribe K, Mastrogiacomo A, Sera F, Borradori L,

Zambruno G. Characterization of the anti-BP180 autoanti-

body reactivity profile and epitope mapping in bullous

pemphigoid patients. J Invest Dermatol 2004;122:103–110.

Update on pemphigoid 65

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y G

oteb

orgs

Uni

vers

ity o

n 11

/20/

12Fo

r pe

rson

al u

se o

nly.

[34] Dresow SK, Sitaru C, Recke A, Oostingh GJ, Zillikens D,

Gibbs BF. IgE autoantibodies against the intracellular

domain of BP180. Br J Dermatol 2009;160:429–432.

[35] Skaria M, Jaunin F, Hunziker T, Riou S, Schumann H,

Bruckner-Tuderman L, Hertl M, Bernard P, Saurat JH,

Favre B, Borradori L. IgG autoantibodies from bullous

pemphigoid patients recognize multiple antigenic reactive

sites located predominantly within the B and C subdomains

of the COOH-terminus of BP230. J Invest Dermatol 2000;

114:998–1004.

[36] Kromminga A, Sitaru C, Hagel C, Herzog S, Zillikens D.

Development of an ELISA for the detection of autoantibodies

to BP230. Clin Immunol 2004;111:146–152.

[37] Thoma-Uszynski S, Uter W, Schwietzke S, Hofmann SC,

Hunziker T, Bernard P, Treudler R, Zouboulis CC, Schuler

G, Borradori L, Hertl M. BP230- and BP180-specific auto-

antibodies in bullous pemphigoid. J Invest Dermatol 2004;

122:1413–1422.

[38] Di Zenzo G, Thoma-Uszynski S, Fontao L, Calabresi V,

Hofmann SC, Hellmark T, Sebbag N, Pedicelli C, Sera F,

Lacour JP, Wieslander J, Bruckner-Tuderman L, Borradori

L, Zambruno G, Hertl M. Multicenter prospective study of

the humoral autoimmune response in bullous pemphigoid.

Clin Immunol 2008;128:415–426.

[39] Charneux J, Lorin J, Vitry F, Antonicelli F, Reguiai Z, Barbe

C, Tabary T, Grange F, Bernard P. Usefulness of BP230 and

BP180-NC16a enzyme-linked immunosorbent assays in the

initial diagnosis of Bullous Pemphigoid: A retrospective study

of 138 patients. Arch Dermatol 2011;147:286–291.

[40] Roussel A, Benichou J, Randriamanantany ZA, Gilbert D,

Drenovska K, Houivet E, Tron F, Joly P. Enzyme-linked

immunosorbent assay for the combination of bullous

pemphigoid antigens 1 and 2 in the diagnosis of bullous

pemphigoid. Arch Dermatol 2011;147:293–298.

[41] Thoma-Uszynski S, Uter W, Schwietzke S, Schuler G,

Borradori L, Hertl M. Autoreactive T and B cells from

bullous pemphigoid (BP) patients recognize epitopes

clustered in distinct regions of BP180 and BP230. J Immunol

2015;176:2015–2023.

[42] Budinger L, Borradori L, Yee C, Eming R, Ferencik S,

Grosse-Wilde H, Merk HF, Yancey K, Hertl M. Identifi-

cation and characterization of autoreactive T cell responses to

bullous pemphigoid antigen 2 in patients and healthy

controls. J Clin Invest 1998;102:2082–2089.

[43] Lin MS, Fu CL, Giudice GJ, Olague-Marchan M, Lazaro

AM, Stastny P, Diaz LA. Epitopes targeted by bullous

pemphigoid T lymphocytes and autoantibodies map to the

same sites on the bullous pemphigoid 180 ectodomain.

J Invest Dermatol 2000;115:955–961.

[44] Schmidt E, Ambach A, Bastian B, Brocker EB, Zillikens D.

Elevated levels of interleukin-8 in blister fluid of bullous

pemphigoid compared with suction blisters of healthy control

subjects. J Am Acad Dermatol 1996;34:310–312.

[45] Schmidt E, Bastian B, Dummer R, Tony HP, Brocker EB,

Zillikens D. Detection of elevated levels of IL-4, IL-6, and IL-

10 in blister fluid of bullous pemphigoid. Arch Dermatol Res

1996;288:353–357.

[46] Schmidt E, Mittnacht A, Schomig H, Dummer R, Brocker

EB, Zillikens D. Detection of IL-1 alpha, IL-1 beta and IL-1

receptor antagonist in blister fluid of bullous pemphigoid.

J Dermatol Sci 1996;11:142–147.

[47] Ameglio F, D’Auria L, Bonifati C, Ferraro C, Mastroianni A,

Giacalone B. Cytokine pattern in blister fluid and serum of

patients with bullous pemphigoid: Relationships with disease

intensity. Br J Dermatol 1998;138:611–614.

[48] Inaoki M, Takehara K. Increased serum levels of interleukin

(IL)-5, IL-6 and IL-8 in bullous pemphigoid. J Dermatol Sci

1998;16:152–157.

[49] D’Auria L, Bonifati C, Cordiali-Fei P, Leone G, Picardo M,

Pietravalle M, Giacalone B, Ameglio F. Increased serum inter-

leukin-15 levels in bullous skin diseases: Correlation with

disease intensity. Arch Dermatol Res 1999;291:354–356.

[50] Wakugawa W, Nakamura K, Hino H, Toyama K, Hattori N,

Okochi H, Yamada H, Hirai K, Tamaki K, Furue M. Elevated

levels of eotaxin and interleukin-5 in blister fluid of bullous

pemphigoid: Correlation with tissue eosinophilia. Br J

Dermatol 2000;143:112–116.

[51] Frezzolini A, Teofoli P, Cianchini G, Barduagni S, Ruffelli M,

Ferranti G, Puddu P, Pita OD. Increased expression of

eotaxin and its specific receptor CCR3 in bullous pemphi-

goid. Eur J Dermatol 2002;12:27–31.

[52] Frezzolini A, Cianchini G, Ruffelli M, Cadoni S, Puddu P,

De Pita O. Interleukin-16 expression and release in bullous

pemphigoid. Clin Exp Immunol 2004;137:595–600.

[53] Gounni Abdelilah S, Wellemans V, Agouli M, Guenounou

M, Hamid Q, Beck LA, Lamkhioued B. Increased expression

of Th2-associated chemokines in bullous pemphigoid

disease: Role of eosinophils in the production and release of

these chemokines. Clin Immunol 2006;120:220–231.

[54] Gunther C, Carballido-Perrig N, Kopp T, Carballido JM,

Pfeiffer C. CCL18 is expressed in patients with bullous

pemphigoid and parallels disease course. Br J Dermatol 2009;

160:747–755.

[55] Ludwig RJ, Schmidt E. Cytokines in autoimmune bullous

skin diseases: Epiphenomena or contribution to pathogen-

esis? G Ital Dermatol Venereol 2009;144:339–349.

[56] Teraki Y, Hotta T, Shiohara T. Skin-homing interleukin-4

and -13-producing cells contribute to bullous pemphigoid:

Remission of disease is associated with increased frequency of

interleukin-10-producing cells. J Invest Dermatol 2001;117:

1097–1102.

[57] Rensing-Ehl A, Gaus B, Bruckner-Tuderman L, Martin SF.

Frequency, function and CLA expression of CD4 þ CD25 þ

FOXP3 þ regulatory T cells in bullous pemphigoid.

Exp Dermatol 2007;16:13–21.

[58] Oswald E, Fisch P, Jakob T, Bruckner-Tuderman L, Martin

SF, Rensing-Ehl A. Reduced numbers of circulating

gammadelta T cells in patients with bullous pemphigoid.

Exp Dermatol 2009;18:991–993.

[59] Kasperkiewicz M, Zillikens D. The pathophysiology of

bullous pemphigoid. Clin Rev Allergy Immunol 2007;33:

67–77.

[60] Bieber K, Sun S, Ishii N, Kasperkiewicz M, Schmidt E,

Hirose M, Westermann J, Yu X, Zillikens D, Ludwig RJ.

Animal models for autoimmune bullous dermatoses.

Exp Dermatol 2010;19:2–11.

[61] Schmidt E, Reimer S, Kruse N, Jainta S, Brocker EB,

Marinkovich MP, Giudice GJ, Zillikens D. Autoantibodies to

BP180 associated with bullous pemphigoid release inter-

leukin-6 and interleukin-8 from cultured human keratino-

cytes. J Invest Dermatol 2000;115:842–848.

[62] Iwata H, Kamio N, Aoyama Y, Yamamoto Y, Hirako Y,

Owaribe K, Kitajima Y. IgG from patients with bullous

pemphigoid depletes cultured keratinocytes of the 180-kDa

bullous pemphigoid antigen (type XVII collagen) and

weakens cell attachment. J Invest Dermatol 2009;129:

919–926.

[63] Gammon WR, Merritt CC, Lewis DM, Sams WM, Jr, Carlo

JR, Wheeler CE, Jr. An in vitro model of immune complex-

mediated basement membrane zone separation caused by

pemphigoid antibodies, leukocytes, and complement. J Invest

Dermatol 1982;78:285–290.

[64] Sitaru C, Schmidt E, Petermann S, Munteanu LS, Brocker

EB, Zillikens D. Autoantibodies to bullous pemphigoid

antigen 180 induce dermal-epidermal separation in cryosec-

tions of human skin. J Invest Dermatol 2002;118:664–671.

M. Kasperkiewicz et al.66

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y G

oteb

orgs

Uni

vers

ity o

n 11

/20/

12Fo

r pe

rson

al u

se o

nly.

[65] Liu Z, Diaz LA, Troy JL, Taylor AF, Emery DJ, Fairley JA,

Giudice GJ. A passive transfer model of the organ-specific

autoimmune disease, bullous pemphigoid, using antibodies

generated against the hemidesmosomal antigen, BP180.

J Clin Invest 1993;92:2480–2488.

[66] Liu Z, Giudice GJ, Swartz SJ, Fairley JA, Till GO, Troy JL,

Diaz LA. The role of complement in experimental bullous

pemphigoid. J Clin Invest 1995;95:1539–1544.

[67] Liu Z, Giudice GJ, Zhou X, Swartz SJ, Troy JL, Fairley JA,

Till GO, Diaz LA. A major role for neutrophils in

experimental bullous pemphigoid. J Clin Invest 1997;100:

1256–1263.

[68] Chen R, Ning G, Zhao ML, Fleming MG, Diaz LA, Werb Z,

Liu Z. Mast cells play a key role in neutrophil recruitment in

experimental bullous pemphigoid. J Clin Invest 2001;108:

1151–1158.

[69] Oikarinen AI, Zone JJ, Ahmed AR, Kiistala U, Uitto J.

Demonstration of collagenase and elastase activities in the

blister fluids from bullous skin diseases: Comparison between

dermatitis herpetiformis and bullous pemphigoid. J Invest

Dermatol 1983;81:261–266.

[70] Welgus HG, Bauer EA, Stricklin GP. Elevated levels of

human collagenase inhibitor in blister fluids of diverse

etiology. J Invest Dermatol 1986;87:592–596.

[71] Jensen PJ, Baird J, Morioka S, Lessin S, Lazarus GS.

Epidermal plasminogen activator is abnormal in cutaneous

lesions. J Invest Dermatol 1988;90:777–782.

[72] Grando SA, Glukhenky BT, Drannik GN, Kostromin AP,

Chernyavsky AI. Cytotoxic proteases in blister fluid of

pemphigus and pemphigoid patients. Int J Tissue React 1989;

11:195–201.

[73] Grando SA, Glukhenky BT, Drannik GN, Epshtein EV,

Kostromin AP, Korostash TA. Mediators of inflammation in

blister fluids from patients with pemphigus vulgaris and

bullous pemphigoid. Arch Dermatol 1989;125:925–930.

[74] Gissler HM, Simon MM, Kramer MD. Enhanced association

of plasminogen/plasmin with lesional epidermis of bullous

pemphigoid. Br J Dermatol 1992;127:272–277.

[75] Kramer MD, Reinartz J. The autoimmune blistering skin

disease bullous pemphigoid: The presence of plasmin/alpha

2-antiplasmin complexes in skin blister fluid indicates

plasmin generation in lesional skin. J Clin Invest 1993;92:

978–983.

[76] Stahle-Backdahl M, Inoue M, Guidice GJ, Parks WC. 92-kD

gelatinase is produced by eosinophils at the site of blister

formation in bullous pemphigoid and cleaves the extracellular

domain of recombinant 180-kD bullous pemphigoid auto-

antigen. J Clin Invest 1994;93:2022–2030.

[77] Niimi Y, Pawankar R, Kawana S. Increased expression of

matrix metalloproteinase-2, matrix metalloproteinase-9

and matrix metalloproteinase-13 in lesional skin of

bullous pemphigoid. Int Arch Allergy Immunol 2006;139:

104–113.

[78] Verraes S, Hornebeck W, Polette M, Borradori L, Bernard P.

Respective contribution of neutrophil elastase and matrix

metalloproteinase 9 in the degradation of BP180 (type XVII

collagen) in human bullous pemphigoid. J Invest Dermatol

2001;117:1091–1096.

[79] Shimanovich I, Mihai S, Oostingh GJ, Ilenchuk TT,

Brocker EB, Opdenakker G, Zillikens D, Sitaru C.

Granulocyte-derived elastase and gelatinase B are required

for dermal-epidermal separation induced by autoantibodies

from patients with epidermolysis bullosa acquisita and

bullous pemphigoid. J Pathol 2004;204:519–527.

[80] Liu Z, Shipley JM, Vu TH, Zhou X, Diaz LA, Werb Z, Senior

RM. Gelatinase B-deficient mice are resistant to experimental

bullous pemphigoid. J Exp Med 1998;188:475–482.

[81] Liu Z, Shapiro SD, Zhou X, Twining SS, Senior RM,

Giudice GJ, Fairley JA, Diaz LA. A critical role for neutrophil

elastase in experimental bullous pemphigoid. J Clin Invest

2000;105:113–123.

[82] Liu Z, Li N, Diaz LA, Shipley M, Senior RM, Werb Z.

Synergy between a plasminogen cascade and MMP-9 in

autoimmune disease. J Clin Invest 2005;115:879–887.

[83] Schmidt E, Wehr B, Tabengwa EM, Reimer S, Brocker EB,

Zillikens D. Elevated expression and release of tissue-type,

but not urokinase-type, plasminogen activator after binding

of autoantibodies to bullous pemphigoid antigen 180 in

cultured human keratinocytes. Clin Exp Immunol 2004;135:

497–504.

[84] Coussens LM, Raymond WW, Bergers G, Laig-Webster M,

Behrendtsen O, Werb Z, Caughey GH, Hanahan D.

Inflammatory mast cells up-regulate angiogenesis during

squamous epithelial carcinogenesis. Genes Dev 1999;13:

1382–1397.

[85] Liu Z, Zhou X, Shapiro SD, Shipley JM, Twining SS,

Diaz LA, Senior RM, Werb Z. The serpin alpha1-proteinase

inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo.

Cell 2000;102:647–655.

[86] Zillikens D, Schmidt E, Reimer S, Chimanovitch I,

Hardt-Weinelt K, Rose C, Brocker EB, Kock M, Boehncke

WH. Antibodies to desmogleins 1 and 3, but not to BP180,

induce blisters in human skin grafted onto SCID mice.

J Pathol 2001;193:117–124.

[87] Olasz EB, Roh J, Yee CL, Arita K, Akiyama M, Shimizu H,

Vogel JC, Yancey KB. Human bullous pemphigoid antigen 2

transgenic skin elicits specific IgG in wild-type mice. J Invest

Dermatol 2007;127:2807–2817.

[88] Nishie W, Sawamura D, Goto M, Ito K, Shibaki A,

McMillan JR, Sakai K, Nakamura H, Olasz E, Yancey KB,

Akiyama M, Shimizu H. Humanization of autoantigen. Nat

Med 2007;13:378–383.

[89] Li Q, Ujiie H, Shibaki A, Wang G, Moriuchi R, Qiao HJ,

Morioka H, Shinkuma S, Natsuga K, Long HA, Nishie W,

Shimizu H. Human IgG1 monoclonal antibody against

human collagen 17 NC16A induces blisters via complement

activation in experimental bullous pemphigoid model.

J Immunol 2010;185:7746–7755.

[90] Liu Z, Sui W, Zhao M, Li Z, Li N, Thresher R, Giudice GJ,

Fairley JA, Sitaru C, Zillikens D, Ning G, Marinkovich MP,

Diaz LA. Subepidermal blistering induced by human

autoantibodies to BP180 requires innate immune players in

a humanized bullous pemphigoid mouse model. J Auto-

immun 2008;31:331–338.

[91] Ujiie H, Shibaki A, Nishie W, Sawamura D, Wang G, Tateishi

Y, Li Q, Moriuchi R, Qiao H, Nakamura H, Akiyama M,

Shimizu H. A novel active mouse model for bullous

pemphigoid targeting humanized pathogenic antigen.

J Immunol 2010;184:2166–2174.

[92] Zone JJ, Taylor T, Hull C, Schmidt L, Meyer L. IgE basement

membrane zone antibodies induce eosinophil infiltration and

histological blisters in engrafted human skin on SCID mice.

J Invest Dermatol 2007;127:1167–1174.

[93] Fairley JA, Burnett CT, Fu CL, Larson DL, Fleming MG,

Giudice GJ. A pathogenic role for IgE in autoimmunity:

Bullous pemphigoid IgE reproduces the early phase of lesion

development in human skin grafted to nu/nu mice. J Invest

Dermatol 2007;127:2605–2611.

[94] Joly P, Benichou J, Lok C, Hellot MF, Saiag P, Tancrede-

Bohin E, Sassolas B, Labeille B, Doutre MS, Gorin I,

Pauwels C, Chosidow O, Caux F, Esteve E, Dutronc Y, Sigal

M, Prost C, Maillard H, Guillaume JC, Roujeau JC.

Prediction of survival for patients with bullous pemphigoid:

A prospective study. Arch Dermatol 2005;141:691–698.

[95] Parker SR, Dyson S, Brisman S, Pennie M, Swerlick RA,

Khan R, Manos S, Korman BD, Xia Z, Korman NJ.

Mortality of bullous pemphigoid: An evaluation of 223

patients and comparison with the mortality in the general

Update on pemphigoid 67

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y G

oteb

orgs

Uni

vers

ity o

n 11

/20/

12Fo

r pe

rson

al u

se o

nly.

population in the United States. J Am Acad Dermatol 2008;

59:582–588.

[96] Kelly SE, Wojnarowska F. The use of chemically split tissue in

the detection of circulating anti-basement membrane zone

antibodies in bullous pemphigoid and cicatricial pemphigoid.

Br J Dermatol 1988;118:31–40.

[97] Kobayashi M, Amagai M, Kuroda-Kinoshita K, Hashimoto

T, Shirakata Y, Hashimoto K, Nishikawa T. BP180 ELISA

using bacterial recombinant NC16a protein as a diagnostic

and monitoring tool for bullous pemphigoid. J Dermatol Sci

2002;30:224–232.

[98] Hofmann S, Thoma-Uszynski S, Hunziker T, Bernard P,

Koebnick C, Stauber A, Schuler G, Borradori L, Hertl M.

Severity and phenotype of bullous pemphigoid relate to

autoantibody profile against the NH2- and COOH-terminal

regions of the BP180 ectodomain. J Invest Dermatol 2002;

119:1065–1073.

[99] Yoshida M, Hamada T, Amagai M, Hashimoto K, Uehara R,

Yamaguchi K, Imamura K, Okamoto E, Yasumoto S,

Hashimoto T. Enzyme-linked immunosorbent assay using

bacterial recombinant proteins of human BP230 as a

diagnostic tool for bullous pemphigoid. J Dermatol Sci

2006;41:21–30.

[100] Vodegel RM, Jonkman MF, Pas HH, de Jong MC.

U-serrated immunodeposition pattern differentiates type

VII collagen targeting bullous diseases from other subepi-

dermal bullous autoimmune diseases. Br J Dermatol 2004;

151:112–118.

[101] Roujeau JC, Lok C, Bastuji-Garin S, Mhalla S, Enginger V,

Bernard P. High risk of death in elderly patients with

extensive bullous pemphigoid. Arch Dermatol 1998;134:

465–469.

[102] Rzany B, Partscht K, Jung M, Kippes W, Mecking D, Baima

B, Prudlo C, Pawelczyk B, Messmer EM, Schuhmann M,

Sinkgraven R, Buchner L, Budinger L, Pfeiffer C, Sticherling

M, Hertl M, Kaiser HW, Meurer M, Zillikens D, Messer G.

Risk factors for lethal outcome in patients with bullous

pemphigoid: Low serum albumin level, high dosage of

glucocorticosteroids, and old age. Arch Dermatol 2002;138:

903–908.

[103] Colbert RL, Allen DM, Eastwood D, Fairley JA. Mortality

rate of bullous pemphigoid in a US medical center. J Invest

Dermatol 2004;122:1091–1095.

[104] Kirtschig G, Middleton P, Bennett C, Murrell DF,

Wojnarowska F, Khumalo NP. Interventions for bullous

pemphigoid. Cochrane Database Syst Rev 2010;CD002292.

[105] Morel P, Guillaume JC. Treatment of bullous pemphigoid

with prednisolone only: 0.75 mg/kg/day versus 1.25 mg/kg/

day. A multicenter randomized study. Ann Dermatol

Venereol 1984;111:925–928.

[106] Joly P, Roujeau JC, Benichou J, Picard C, Dreno B,

Delaporte E, Vaillant L, D’Incan M, Plantin P, Bedane C,

Young P, Bernard P, Bullous Diseases French Study Group.

A comparison of oral and topical corticosteroids in patients

with bullous pemphigoid. N Engl J Med 2002;346:321–327.

[107] Joly P, Roujeau JC, Benichou J, Delaporte E, D’Incan M,

Dreno B, Bedane C, Sparsa A, Gorin I, Picard C, Tancrede-

Bohin E, Sassolas B, Lok C, Guillaume JC, Doutre MS,

Richard MA, Caux F, Prost C, Plantin P, Chosidow O,

Pauwels C, Maillard H, Saiag P, Descamps V, Chevrant-

Breton J, Dereure O, Hellot MF, Esteve E, Bernard P. A

comparison of two regimens of topical corticosteroids in the

treatment of patients with bullous pemphigoid: A multicenter

randomized study. J Invest Dermatol 2009 July;129(7):

1681–1687.

[108] Guillaume JC, Vaillant L, Bernard P, Picard C, Prost C,

Labeille B, Guillot B, Foldes-Pauwels C, Prigent F, Joly P,

Cordoliani F, Salagnac V, Machet L, Aldigier JC, Crickx B,

Roujeau JC. Controlled trial of azathioprine and plasma

exchange in addition to prednisolone in the treatment of

bullous pemphigoid. Arch Dermatol 1993;129:49–53.

[109] Beissert S, Werfel T, Frieling U, Bohm M, Sticherling M,

Stadler R, Zillikens D, Rzany B, Hunzelmann N, Meurer M,

Gollnick H, Ruzicka T, Pillekamp H, Junghans V, Bonsmann

G, Luger TA. A comparison of oral methylprednisolone plus

azathioprine or mycophenolate mofetil for the treatment of

bullous pemphigoid. Arch Dermatol 2007;143:1536–1542.

[110] Fivenson DP, Breneman DL, Rosen GB, Hersh CS, Cardone

S, Mutasim D. Nicotinamide and tetracycline therapy of

bullous pemphigoid. Arch Dermatol 1994;130:753–758.

[111] Schmidt E, Kraensel R, Goebeler M, Sinkgraven R, Brocker

EB, Rzany B, Zillikens D. Treatment of bullous pemphigoid

with dapsone, methylprednisolone, and topical clobetasol

propionate: A retrospective study of 62 cases. Cutis 2005;76:

205–209.

[112] Gurcan HM, Ahmed AR. Efficacy of dapsone in the

treatment of pemphigus and pemphigoid: Analysis of current

data. Am J Clin Dermatol 2009;10:383–396.

[113] Gurcan HM, Ahmed AR. Analysis of current data on the use

of methotrexate in the treatment of pemphigus and

pemphigoid. Br J Dermatol 2009;161:723–731.

[114] Ishii N, Hashimoto T, Zillikens D, Ludwig RJ. High-dose

intravenous immunoglobulin (IVIG) therapy in autoimmune

skin blistering diseases. Clin Rev Allergy Immunol 2010;38:

186–195.

[115] Schmidt E, Brocker EB, Goebeler M. Rituximab in

treatment-resistant autoimmune blistering skin disorders.

Clin Rev Allergy Immunol 2008;34:56–64.

[116] Hertl M, Zillikens D, Borradori L, Bruckner-Tuderman L,

Burckhard H, Eming R, Engert A, Goebeler M, Hofmann S,

Hunzelmann N, Karlhofer F, Kautz O, Lippert U,

Niedermeier A, Nitschke M, Pfutze M, Reiser M, Rose C,

Schmidt E, Shimanovich I, Sticherling M, Wolff-Franke S.

Recommendations for the use of rituximab (anti-CD20

antibody) in the treatment of autoimmune bullous skin

diseases. J Dtsch Dermatol Ges 2008;6:366–373.

[117] Kasperkiewicz M, Shimanovich I, Ludwig RJ, Rose C,

Zillikens D, Schmidt E. Rituximab for treatment-refractory

pemphigus and pemphigoid: A case series of 17 patients.

J Am Acad Dermatol 2011;65:552–558.

[118] Fairley JA, Baum CL, Brandt DS, Messingham KA.

Pathogenicity of IgE in autoimmunity: Successful treatment

of bullous pemphigoid with omalizumab. J Allergy Clin

Immunol 2009;123:704–705.

[119] Schmidt E, Zillikens D. Immunoadsorption in dermatology.

Arch Dermatol Res 2010;302:241–253.

[120] Schmidt E, Skrobek C, Kromminga A, Hashimoto T, Messer

G, Brocker EB, Yancey KB, Zillikens D. Cicatricial

pemphigoid: IgA and IgG autoantibodies target epitopes on

both intra- and extracellular domains of bullous pemphigoid

antigen 180. Br J Dermatol 2001;145:778–783.

[121] Bedane C, McMillan JR, Balding SD, Bernard P, Prost C,

Bonnetblanc JM, Diaz LA, Eady RA, Giudice GJ. Bullous

pemphigoid and cicatricial pemphigoid autoantibodies react

with ultrastructurally separable epitopes on the BP180

ectodomain: Evidence that BP180 spans the lamina lucida.

J Invest Dermatol 1997;108:901–907.

[122] Oyama N, Setterfield JF, Powell AM, Sakuma-Oyama Y,

Albert S, Bhogal BS, Vaughan RW, Kaneko F, Challacombe

SJ, Black MM. Bullous pemphigoid antigen II (BP180) and

its soluble extracellular domains are major autoantigens in

mucous membrane pemphigoid: The pathogenic relevance to

HLA class II alleles and disease severity. Br J Dermatol 2006;

154:90–98.

[123] Bernard P, Prost C, Lecerf V, Intrator L, Combemale P,

Bedane C, Roujeau JC, Revuz J, Bonnetblanc JM, Dubertret

L. Studies of cicatricial pemphigoid autoantibodies using

M. Kasperkiewicz et al.68

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y G

oteb

orgs

Uni

vers

ity o

n 11

/20/

12Fo

r pe

rson

al u

se o

nly.

direct immunoelectron microscopy and immunoblot anal-

ysis. J Invest Dermatol 1990;94:630–635.

[124] Calabresi V, Carrozzo M, Cozzani E, Arduino P, Bertolusso

G, Tirone F, Parodi A, Zambruno G, Di Zenzo G. Oral

pemphigoid autoantibodies preferentially target BP180

ectodomain. Clin Immunol 2007;122:207–213.

[125] Domloge-Hultsch N, Gammon WR, Briggaman RA, Gil SG,

Carter WG, Yancey KB. Epiligrin, the major human

keratinocyte integrin ligand, is a target in both an acquired

autoimmune and an inherited subepidermal blistering skin

disease. J Clin Invest 1992;90:1628–1633.

[126] Chan LS, Majmudar AA, Tran HH, Meier F, Schaumburg-

Lever G, Chen M, Anhalt G, Woodley DT, Marinkovich MP.

Laminin-6 and laminin-5 are recognized by autoantibodies in

a subset of cicatricial pemphigoid. J Invest Dermatol 1997;

108:848–853.

[127] Luke MC, Darling TN, Hsu R, Summers RM, Smith JA,

Solomon BI, Thomas GR, Yancey KB. Mucosal morbidity in

patients with epidermolysis bullosa acquisita. Arch Dermatol

1999;135:954–959.

[128] Tyagi S, Bhol K, Natarajan K, Livir-Rallatos C, Foster CS,

Ahmed AR. Ocular cicatricial pemphigoid antigen: Partial

sequence and biochemical characterization. Proc Natl Acad

Sci USA 1996;93:14714–14719.

[129] Rashid KA, Gurcan HM, Ahmed AR. Antigen specificity in

subsets of mucous membrane pemphigoid. J Invest Dermatol

2006;126:2631–2636.

[130] Lazarova Z, Yee C, Darling T, Briggaman RA, Yancey KB.

Passive transfer of anti-laminin 5 antibodies induces

subepidermal blisters in neonatal mice. J Clin Invest 1996;

98:1509–1518.

[131] Lazarova Z, Hsu R, Briggaman RA, Yancey KB.

Fab fragments directed against laminin 5 induce subepider-

mal blisters in neonatal mice. Clin Immunol 2000;95:26–32.

[132] Lazarova Z, Hsu R, Yee C, Yancey KB. Human anti-laminin

5 autoantibodies induce subepidermal blisters in an

experimental human skin graft model. J Invest Dermatol

2000;114:178–184.

[133] Razzaque MS, Foster CS, Ahmed AR. Tissue and molecular

events in human conjunctival scarring in ocular cicatricial

pemphigoid. Histol Histopathol 2001;16:1203–1212.

[134] Saw VP, Schmidt E, Offiah I, Galatowicz G, Zillikens D,

Dart JK, Calder VL, Daniels JT. Profibrotic phenotype

of conjunctival fibroblasts from mucous membrane pemphi-

goid. Am J Pathol 2011;178:187–197.

[135] Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD,

Elder MJ, Fine JD, Foster CS, Ghohestani R, Hashimoto T,

Hoang-Xuan T, Kirtschig G, Korman NJ, Lightman S,

Lozada-Nur F, Marinkovich MP, Mondino BJ, Prost-

Squarcioni C, Rogers RS, 3rd, Setterfield JF, West DP,

Wojnarowska F, Woodley DT, Yancey KB, Zillikens D, Zone

JJ. The first international consensus on mucous membrane

pemphigoid: Definition, diagnostic criteria, pathogenic

factors, medical treatment, and prognostic indicators. Arch

Dermatol 2002;138:370–379.

[136] Rose C, Schmidt E, Kerstan A, Thoma-Uszynski S,

Wesselmann U, Kasbohrer U, Zillikens D, Shimanovich I.

Histopathology of anti-laminin 5 mucous membrane

pemphigoid. J Am Acad Dermatol 2009;61:433–440.

[137] Horvath B, Niedermeier A, Podstawa E, Muller R,

Hunzelmann N, Karpati S, Hertl M. IgA autoantibodies in

the pemphigoids and linear IgA bullous dermatosis.

Exp Dermatol 2010;19:648–653.

[138] Leverkus M, Schmidt E, Lazarova Z, Brocker EB, Yancey

KB, Zillikens D. Antiepiligrin cicatricial pemphigoid:

An underdiagnosed entity within the spectrum of scarring

autoimmune subepidermal bullous diseases? Arch Dermatol

1999;135:1091–1098.

[139] Egan CA, Lazarova Z, Darling TN, Yee C, Cote T, Yancey

KB. Anti-epiligrin cicatricial pemphigoid and relative risk for

cancer. Lancet 2001;357:1850–1851.

[140] Lazarova Z, Sitaru C, Zillikens D, Yancey KB. Comparative

analysis of methods for detection of anti-laminin 5 autoanti-

bodies in patients with anti-epiligrin cicatricial pemphigoid.

J Am Acad Dermatol 2004;51:886–892.

[141] Brunsting LA, Perry HO. Benign pemphigoid? A report of

seven cases with chronic, scarring, herpetiform plaques about

the head and neck. Arch Dermatol 1957;75:489–501.

[142] Kurzhals G, Stolz W, Meurer M, Kunze J, Braun-Falco O,

Krieg T. Acquired epidermolysis bullosa with the clinical

feature of Brunsting–Perry cicatricial bullous pemphigoid.

Arch Dermatol 1991;127:391–395.

[143] Daito J, Katoh N, Asai J, Ueda E, Takenaka H, Ishii N,

Hashimoto T, Kishimoto S. Brunsting–Perry cicatricial

pemphigoid associated with autoantibodies to the C-terminal

domain of BP180. Br J Dermatol 2008;159:984–986.

[144] Jedlickova H, Niedermeier A, Zgazarova S, Hertl M.

Brunsting–Perry pemphigoid of the scalp with antibodies

against laminin 332. Dermatology 2011;222:193–195.

[145] Meyer-ter-Vehn T, Schmidt E, Zillikens D, Geerling G.

Mucous membrane pemphigoid with ocular involvement.

Part II: Therapy. Ophthalmologe 2008;105:405–419.

[146] Knudson RM, Kalaaji AN, Bruce AJ. The management of

mucous membrane pemphigoid and pemphigus. Dermatol

Ther 2010;23:268–280.

[147] Sami N, Letko E, Androudi S, Daoud Y, Foster CS, Ahmed

AR. Intravenous immunoglobulin therapy in patients

with ocular-cicatricial pemphigoid: A long-term follow-up.

Ophthalmology 2004;111:1380–1382.

[148] O’Neill ID. Off-label use of biologicals in the management of

inflammatory oral mucosal disease. J Oral Pathol Med 2008;

37:575–581.

[149] Shimanovich I, Brocker EB, Zillikens D. Pemphigoid

gestationis: New insights into the pathogenesis lead to novel

diagnostic tools. BJOG 2002;109:970–976.

[150] Morrison LH, Labib RS, Zone JJ, Diaz LA, Anhalt GJ.

Herpes gestationis autoantibodies recognize a 180-kD

human epidermal antigen. J Clin Invest 1988;81:2023–2026.

[151] Murakami H, Amagai M, Higashiyama M, Hashimoto K,

Chorzelski TP, Bhogal BS, Jenkins RE, Black MM, Zillikens

D, Nishikawa T, Hashimoto T. Analysis of antigens

recognized by autoantibodies in herpes gestationis: Useful-

ness of immunoblotting using a fusion protein representing

an extracellular domain of the 180 kD bullous pemphigoid

antigen. J Dermatol Sci 1996;13:112–117.

[152] Chimanovitch I, Schmidt E, Messer G, Dopp R, Partscht K,

Brocker EB, Giudice GJ, Zillikens D. IgG1 and IgG3 are the

major immunoglobulin subclasses targeting epitopes within

the NC16A domain of BP180 in pemphigoid gestationis.

J Invest Dermatol 1999;113:140–142.

[153] Di Zenzo G, Calabresi V, Grosso F, Caproni M, Ruffelli M,

Zambruno G. The intracellular and extracellular domains

of BP180 antigen comprise novel epitopes targeted by

pemphigoid gestationis autoantibodies. J Invest Dermatol

2007;127:864–873.

[154] Herrero-Gonzalez JE, Brauns O, Egner R, Ronspeck W,

Mascaro JM, Jr, Jonkman MF, Zillikens D, Sitaru C.

Immunoadsorption against two distinct epitopes on human

type XVII collagen abolishes dermal-epidermal separation

induced in vitro by autoantibodies from pemphigoid

gestationis patients. Eur J Immunol 2006;36:1039–1048.

[155] Dopp R, Schmidt E, Chimanovitch I, Leverkus M, Brocker

EB, Zillikens D. IgG4 and IgE are the major immunoglobu-

lins targeting the NC16A domain of BP180 in bullous

pemphigoid: Serum levels of these immunoglobulins reflect

disease activity. J Am Acad Dermatol 2000;42:577–583.

Update on pemphigoid 69

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y G

oteb

orgs

Uni

vers

ity o

n 11

/20/

12Fo

r pe

rson

al u

se o

nly.

[156] Lin MS, Gharia MA, Swartz SJ, Diaz LA, Giudice GJ.

Identification and characterization of epitopes recognized

by T lymphocytes and autoantibodies from patients with

herpes gestationis. J Immunol 1999;162:4991–4997.

[157] Sitaru C, Powell J, Messer G, Brocker EB, Wojnarowska F,

Zillikens D. Immunoblotting and enzyme-linked immuno-

sorbent assay for the diagnosis of pemphigoid gestationis.

Obstet Gynecol 2004;103:757–763.

[158] Wojnarowska F, Whitehead P, Leigh IM, Bhogal BS,

Black MM. Identification of the target antigen in chronic

bullous disease of childhood and linear IgA disease of adults.

Br J Dermatol 1991;124:157–162.

[159] Marinkovich MP, Taylor TB, Keene DR, Burgeson RE,

Zone JJ. LAD-1, the linear IgA bullous dermatosis

autoantigen, is a novel 120-kDa anchoring filament protein

synthesized by epidermal cells. J Invest Dermatol 1996;106:

734–738.

[160] Zone JJ, Taylor TB, Meyer LJ, Petersen MJ. The 97 kDa

linear IgA bullous disease antigen is identical to a portion of

the extracellular domain of the 180 kDa bullous pemphigoid

antigen, BPAg2. J Invest Dermatol 1998;110:207–210.

[161] Zone JJ, Taylor TB, Kadunce DP, Meyer LJ. Identification

of the cutaneous basement membrane zone antigen and

isolation of antibody in linear immunoglobulin A bullous

dermatosis. J Clin Invest 1990;85:812–820.

[162] Pas HH, Kloosterhuis GJ, Heeres K, van der Meer JB,

Jonkman MF. Bullous pemphigoid and linear IgA dermatosis

sera recognize a similar 120-kDa keratinocyte collagenous

glycoprotein with antigenic cross-reactivity to BP180. J Invest

Dermatol 1997;108:423–429.

[163] Hirako Y, Usukura J, Uematsu J, Hashimoto T, Kitajima Y,

Owaribe K. Cleavage of BP180, a 180-kDa bullous

pemphigoid antigen, yields a 120-kDa collagenous extra-

cellular polypeptide. J Biol Chem 1998;273:9711–9717.

[164] Schacke H, Schumann H, Hammami-Hauasli N, Raghunath

M, Bruckner-Tuderman L. Two forms of collagen XVII in

keratinocytes: A full-length transmembrane protein and a

soluble ectodomain. J Biol Chem 1998;273:25937–25943.

[165] Hirako Y, Nishizawa Y, Sitaru C, Opitz A, Marcus K, Meyer

HE, Butt E, Owaribe K, Zillikens D. The 97-kDa (LABD97)

and 120-kDa (LAD-1) fragments of bullous pemphigoid

antigen 180/type XVII collagen have different N-termini.

J Invest Dermatol 2003;121:1554–1556.

[166] Franzke CW, Bruckner-Tuderman L, Blobel CP. Shedding of

collagen XVII/BP180 in skin depends on both ADAM10 and

ADAM9. J Biol Chem 2009;284:23386–23396.

[167] Hofmann SC, Voith U, Schonau V, Sorokin L, Bruckner-

Tuderman L, Franzke CW. Plasmin plays a role in the in vitro

generation of the linear IgA dermatosis antigen LADB97.

J Invest Dermatol 2009;129:1730–1739.

[168] Zillikens D, Herzele K, Georgi M, Schmidt E, Chimanovitch I,

Schumann H, Mascaro JM, Jr, Diaz LA, Bruckner-Tuderman

L, Brocker EB, Giudice GJ. Autoantibodies in a subgroup of

patients with linear IgA disease react with the NC16A domain

of BP180. J Invest Dermatol 1999a;113:947–953.

[169] Zambruno G, Manca V, Kanitakis J, Cozzani E, Nicolas JF,

Giannetti A. Linear IgA bullous dermatosis with autoanti-

bodies to a 290 kDa antigen of anchoring fibrils. J Am Acad

Dermatol 1994;31:884–888.

[170] Ghohestani RF, Nicolas JF, Kanitakis J, Claudy A. Linear

IgA bullous dermatosis with IgA antibodies exclusively

directed against the 180- or 230-kDa epidermal antigens.

J Invest Dermatol 1997;108:854–858.

[171] Natsuga K, Nishie W, Shinkuma S, Moriuchi R, Shibata M,

Nishimura M, Hashimoto T, Shimizu H. Circulating IgA and

IgE autoantibodies in antilaminin-332 mucous membrane

pemphigoid. Br J Dermatol 2010;162:513–517.

[172] Kromminga A, Scheckenbach C, Georgi M, Hagel C, Arndt

R, Christophers E, Brocker EB, Zillikens D. Patients with

bullous pemphigoid and linear IgA disease show a dual IgA

and IgG autoimmune response to BP180. J Autoimmun

2000;15:293–300.

[173] Mulyowa GK, Jaeger G, Kabakyenga J, Brocker EB, Zillikens

D, Schmidt E. Autoimmune subepidermal blistering diseases

in Uganda: Correlation of autoantibody class with age of

patients. Int J Dermatol 2006;45:1047–1052.

[174] Zone JJ, Egan CA, Taylor TB, Meyer LJ. IgA autoimmune

disorders: Development of a passive transfer mouse model.

J Investig Dermatol Symp Proc 2004;9:47–51.

[175] Guide SV, Marinkovich MP. Linear IgA bullous dermatosis.

Clin Dermatol 2001;19:719–727.

[176] Kasperkiewicz M, Meier M, Zillikens D, Schmidt E. Linear

IgA disease: Successful application of immunoadsorption

and review of the literature. Dermatology 2010;220:

259–263.

[177] Willsteed E, Bhogal BS, Das AK, Wojnarowska F, Black MM,

McKee PH. Lichen planus pemphigoides: A clinicopatholo-

gical study of nine cases. Histopathology 1991;19:147–154.

[178] Davis AL, Bhogal BS, Whitehead P, Frith P, Murdoch ME,

Leigh IM, Wojnarowska F. Lichen planus pemphigoides: Its

relationship to bullous pemphigoid. Br J Dermatol 1991;125:

263–271.

[179] Bouloc A, Vignon-Pennamen MD, Caux F, Teillac D,

Wechsler J, Heller M, Lebbe C, Flageul B, Morel P,

Dubertret L, Prost C. Lichen planus pemphigoides is a

heterogeneous disease: A report of five cases studied by

immunoelectron microscopy. Br J Dermatol 1998;138:

972–980.

[180] Zillikens D, Caux F, Mascaro JM, Wesselmann U, Schmidt E,

Prost C, Callen JP, Brocker EB, Diaz LA, Giudice GJ.

Autoantibodies in lichen planus pemphigoides react with a

novel epitope within the C-terminal NC16A domain of

BP180. J Invest Dermatol 1999b;113:117–121.

[181] Zillikens D, Kawahara Y, Ishiko A, Shimizu H, Mayer J, Rank

CV, Liu Z, Giudice GJ, Tran HH, Marinkovich MP, Brocker

EB, Hashimoto T. A novel subepidermal blistering disease

with autoantibodies to a 200-kDa antigen of the basement

membrane zone. J Invest Dermatol 1996;106:1333–1338.

[182] Dainichi T, Kurono S, Ohyama B, Ishii N, Sanzen N,

Hayashi M, Shimono C, Taniguchi Y, Koga H, Karashima T,

Yasumoto S, Zillikens D, Sekiguchi K, Hashimoto T. Anti-

laminin gamma-1 pemphigoid. Proc Natl Acad Sci U S A

2009;106:2800–2805.

[183] Groth S, Recke A, Vafia K, Ludwig RJ, Hashimoto T,

Zillikens D, Schmidt E. Development of a simple enzyme-

linked immunosorbent assay for the detection of autoanti-

bodies in anti-p200 pemphigoid. Br J Dermatol 2011;164:

76–82.

[184] Timpl R, Rohde H, Robey PG, Rennard SI, Foidart JM,

Martin GR. Laminin — A glycoprotein from basement

membranes. J Biol Chem 1979;254:9933–9937.

[185] Dainichi T, Koga H, Tsuji T, Ishii N, Ohyama B, Ueda A,

Natsuaki Y, Karashima T, Nakama T, Yasumoto S, Zillikens

D, Hashimoto T. From anti-p200 pemphigoid to anti-

laminin gamma1 pemphigoid. J Dermatol 2010;37:231–238.

[186] Iwata H, Hiramitsu Y, Aoyama Y, Kitajima Y. A case of anti-

p200 pemphigoid: Evidence for a different pathway in

neutrophil recruitment compared with bullous pemphigoid.

Br J Dermatol 2009;160:462–464.

[187] Dilling A, Rose C, Hashimoto T, Zillikens D, Shimanovich I.

Anti-p200 pemphigoid: A novel autoimmune subepidermal

blistering disease. J Dermatol 2007;34:1–8.

[188] Rose C, Weyers W, Denisjuk N, Hillen U, Zillikens D,

Shimanovich I. Histopathology of anti-p200 pemphigoid.

Am J Dermatopathol 2007;29:119–124.

[189] Kasperkiewicz M, Hoppe U, Zillikens D, Schmidt E.

Relapse-associated autoantibodies to BP180 in a patient with

anti-p200 pemphigoid. Clin Exp Dermatol 2010;35:614.

M. Kasperkiewicz et al.70

Aut

oim

mun

ity D

ownl

oade

d fr

om in

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ahea

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/20/

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