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Autoimmunity, February 2012; 45(1): 5570

q Informa UK, Ltd.


ISSN 0891-6934 print/1607-842X online
DOI: 10.3109/08916934.2011.606447

Pemphigoid diseases: Pathogenesis, diagnosis, and treatment

MICHAEL KASPERKIEWICZ1, DETLEF ZILLIKENS1, & ENNO SCHMIDT1,2


1
Department 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)


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Abstract
Pemphigoid diseases (including bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA
dermatosis, lichen planus pemphigoides, and anti-p200 pemphigoid) are a subgroup of autoimmune bullous skin diseases
characterized by an autoantibody response toward structural components of the hemidesmosome resulting in subepidermal
blistering. By the use of different in vitro systems and experimental animal models, the pathogenic relevance of these
autoantibodies has been demonstrated. Recent advances in the understanding of autoantibody responses have led to novel
diagnostic tools and a more differentiated therapeutic approach for these disorders. This review covers the most recent
understanding of the pathophysiology, diagnosis, and treatment of this group of autoimmune diseases.
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Keywords: Pemphigoid, skin, antibody, antigen

Introduction may be due to the increasing age of the general


population and/or an increased awareness leading to
The pemphigoid group of diseases is characterized by
further diagnostic steps. MMP and PG have been
subepidermal blisters due to autoantibody-induced
disruption of the components of the dermal identified as the second most frequent pemphigoid
epidermal anchoring complex. Pemphigoid diseases diseases in central Europe with an incidence of two
include bullous pemphigoid (BP), mucous membrane new patients/million/year [1].
pemphigoid (MMP), pemphigoid gestationis (PG), For the correct diagnosis of pemphigoid diseases,
linear IgA dermatosis (LAD), lichen planus pemphi- the detection of tissue-bound and circulating auto-
goides (LPP), and anti-p200 pemphigoid. In particu- antibodies is pivotal [7]. Although direct immuno-
lar, disorders with anti-BP180 (type XVII collagen) fluorescence (IF) microscopy differentiates pemphigus
reactivity, including BP, PG, LAD, LPP, and a from pemphigoid disorders, serological analyses are
subgroup of MMP may form a continuous spectrum necessary to separate pemphigoid diseases from each
of subepidermal autoimmune blistering dermatoses. other and from epidermolysis bullosa acquisita (EBA).
BP is not only the most common disorder within In fact, while direct IF microscopy is still the gold
the pemphigoid group, but also represents the most standard for the diagnosis of pemphigoid diseases, in
frequent autoimmune blistering disease in general the great majority of patients, diagnosis can be made
[1,2]. The incidence of BP has been estimated between serologically today [7].
4.5 and 14 new cases/million/year in central Europe By indirect IF microscopy on 1 M NaCl-split
[1 5]. A higher incidence of 42.8/million/year has human skin, anti-laminin 332 MMP and anti-p200
recently been reported in Great Britain based on a pemphigoid can be distinguished from BP, LAD, PG,
data registry established on the general practitioner and anti-BP180 MMP, but final diagnosis can only
level [6]. Interestingly, in Germany and Great Britain, be made by more sophisticated methods, i.e. use
it has been shown that the incidence of BP has of cell-derived or recombinant forms of the target
considerably increased within the last 10 years (2-fold antigens (Figure 1). In recent years, various novel
and 4.8-fold, respectively) [1,6]. This development 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
56 M. Kasperkiewicz et al.

(a) Disease Main target antigens


Bullous pemphigoid BP180, BP230
Mucous membrane BP180, BP230,
pemphigoid 64 integrin

Pemphigoid gestationis BP180, BP230

Linear IgA dermatosis BP180, BP230

Lichen planus
BP180, BP230
pemphigoides

(b)
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Disease Main target antigens


Mucous membrane
Laminin 332
pemphigoid
Anti-p200
Laminin 1
pemphigoid

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

developed, some of which are also commercially avail- epitopes in BP and is recognized by autoantibodies in
able. These now allow for a more accurate diagnosis, 80 90% of BP patients [16 19]. The importance of
which is becoming increasingly important to guide anti-BP180 NC16A reactivity is further highlighted
treatment decisions, while our knowledge about the by the observation that serum levels of BP180
therapeutic arsenal of these disorders has also NC16A-specific antibodies correlate with the disease
expanded. In this review, we focus on recent progress activity in BP patients [20].
in our understanding of the pathogenesis, diagnosis, In addition, it was reported that autoantibodies
and treatment of the different pemphigoid diseases. preferentially recognize the phosphorylated BP180
ectodomain [21,22]. Recent studies have identified
Bullous pemphigoid the presence of memory B cells specific for the NC16A
domain, which can be induced in vitro to synthesize
Pathogenesis autoantibodies [23]. These cells belong to the short-
Two hemidesmosomal proteins, the 230 kDa protein lived plasma blast population [24]. The BP180
(BP230 or BPAG1), and 180 kDa antigen (BP180, NC16A-specific autoantibodies are not only of the
BPAG2, or type XVII collagen) have been identified IgG isotype (mainly IgG1 and IgG4 subclasses), but
as the major antigenic targets of BP autoantibodies also of the IgE class [25 27]. In fact, patients with
[810]. BP230 is an intracellular plakin protein member BP frequently have IgE autoantibodies binding to the
showing homology with plectin and desmoplakins I NC16A domain of BP180 [28].
and II and promotes the association of hemidesmo- The presence of IgE autoantibodies has recently
somes with keratin intermediate filaments [1113]. been correlated with a severe form of BP, and BP
In contrast, BP180 is a transmembrane protein with a patients, positive for IgE anti-BP180 antibodies,
type II orientation that spans the lamina lucida and required longer duration for remission, higher dosage
projects into the lamina densa of the epidermal basal of prednisolone, and more intensive therapies for
membrane zone (BMZ). The extracellular region remission [29]. Interestingly, one study showed that a
consists of 15 collagen domains separated from one recombinant NC16A fusion protein degranulated
another by noncollagen sequences [14,15]. basophils opsonized with IgE from patients with BP
The noncollagenous 16A domain (NC16A), [30], further supporting the pathophysiological role
located at the membrane-proximal region of BP180, of IgE antibodies in BP. In addition, other antigenic
is considered to harbor major pathogenically relevant sites exist on both the extracellular and intracellular
Update on pemphigoid 57

domain of BP180, which are recognized by IgE and are important in human BP is supported by the
IgG autoantibodies in BP patients [16 18,31 34]. increased frequency of cutaneous lymphocyte-associ-
BP patients also exhibit significant reactivity with ated antigen-positive IL-4- and IL-13-producing cells
BP230, which is thought not to be involved in the in the peripheral blood [56]. Furthermore, analysis of
initiation of the inflammatory response in BP due to cell subsets with immunoregulatory functions in
its intracellular localization [8,35 40]. Currently, it is BP patients has shown that while the number of
unclear whether anti-BP230 autoantibodies in BP circulating CD4 CD25 FOXP3 regulatory T
patients directly contribute to blister formation or cells, natural killer T cells, and natural killer cells are
whether they are just a result of keratinocyte injury normal, gd T cells are reduced in BP patients [57,58].
and determinant spreading of the autoimmune Our knowledge about the functionally relevant
response. Very recently, two retrospective studies with pathogenic mechanisms in BP is based on in vitro
a large series of 138 and 190 patients with active BP, studies using cultured human keratinocytes, ex vivo
respectively, have determined the outcome of BP230 studies using cryosections of human skin as well as
autoantibody detection using commercial enzyme- various mouse models [59,60]. When cultured human
linked immunosorbent assays (ELISAs) [39,40]. keratinocytes were treated with anti-BP180 IgG, dose-
In the first-mentioned study, 59% of patients had a and time-dependent increases of both mRNA and
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positive BP230 ELISA result and 86% had a positive protein levels of IL-6 and IL-8 were observed,
BP180 ELISA result, while only 5% had anti-BP230 pointing to a signal-transducing event via BP180
autoantibodies without anti-BP180 autoantibodies [61]. In the same model, decreased expression of
[39]. In the second study, anti-BP230 and anti- BP180 and weakening of keratinocyte attachment in
BP180 antibodies were detected in 61 and 79% of BP response to anti-BP180 IgG were seen [62].
patients serum samples, respectively, while 8% had Using cryosections of human skin, BP patients sera
anti-BP230 autoantibodies without anti-BP180 auto- were shown to generate dermal epidermal separation
antibodies [40]. Although the study by Charneux et al. when co-incubated with leukocytes and complement
found no relationship between a positive BP230 from healthy volunteers [63]. Characterizing the
ELISA result and disease extent or presence of specificity of pathogenically relevant autoantibodies,
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mucosal involvement [39], with regard to this specific we were later able to demonstrate that IgG antibodies
finding, the study by Roussel et al. [40] showed the to human BP180, purified from sera of BP patients
opposite finding. Two other studies suggested that and from rabbits immunized against recombinant
anti-BP230 antibodies may be preferentially associ- human BP180, induce dermal epidermal separation
ated with localized types of BP [37,38]. in this model. This effect was shown to be mediated by
In contrast to the humoral immune response, the binding of autoantibodies to the NC16A domain of
cellular immune response has been less widely studied human BP180 and to be dependent on the Fc portion
in human BP. Autoreactive T and B cells are almost of autoantibodies [64].
constantly found in BP patients. These cells react with Passive transfer of rabbit IgG, raised against the
the same regions of BP180 and BP230 that are murine homolog of the human BP180 NC16A
recognized by IgG autoantibodies. The differential domain, into neonatal wild-type mice produced
epitope recognition of BP180 seems to be associated clinical, histologic, and immunopathologic alterations
with distinct clinical severity: T- and B-cell reactivity like those seen in patients with BP [65]. In this model,
against the NH2-terminal portion of the BP180 blister formation is dependent on the activation of
ectodomain is associated with severe BP, while the complement, degranulation of mast cells, and recruit-
central portion is more frequently recognized in ment of neutrophils [65 68].
patients with limited disease. Blister fluid and lesional/perilesional biopsies from
In contrast, combined T- and B-cell response against BP patients have been shown to contain high levels of
the COOH- and NH2-terminal globular domains of proteolytic enzymes, including neutrophil elastase
BP230 was found in less than 50% [41]. The response (NE), cathepsin G, collagenase, plasminogen activa-
to the BP180 ectodomain is restricted by certain HLA tors, plasmin, matrix metalloproteinase-2 (MMP-2,
class II alleles, such as the DQb1*0301 allele [42,43]. gelatinase A), MMP-9 (gelatinase B), and MMP-13
Autoreactive T cells in BP patients produce a Th1/Th2 [69 77]. These enzymes, particularly the neutrophil-
mixed cytokine profile. We and others have detected and eosinophil-derived MMP-9 and NE, are secreted
elevated levels of IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, into the extracellular space upon cell activation
IL-10, IL-15, IL-16, eotaxin, MCP-4, tumor necrosis and are thought to proteolytically degrade various
factor a (TNFa), and CCL18 in the sera and/or blister extracellular matrix proteins, including the extracellu-
fluids of BP patients [44 55]. lar domain of BP180 [76,78,79]. Mice genetically
Serum levels of TNFa, IL-6, IL-8, IL-15, and deficient in NE or MMP-9 have been shown to be
CCL18 correlated with patients disease activity [47 resistant to experimental BP [80,81].
49,54], pointing to a pathological relevance of these An interaction between MMP-9, NE, and the
mediators. The observation that Th2-type cytokines plasminogen/plasmin system was demonstrated to
58 M. Kasperkiewicz et al.

occur during proteolytic events in experimental BP: in to clinical, histological, and immunopathological
the early stages of blistering, MMP-9 is mainly features of BP [91].
activated by plasmin, which is formed from plasmino- In two other mouse models, the pathogenic effect of
gen by tissue plasminogen activator (tPA) and/or IgE anti-BP180 antibodies has been elucidated,
urokinase plasminogen activator (uPA) [82]. Further- demonstrating that an IgE hybridoma to LABD97
more, an elevated expression and release of tPA from antigen or purified IgE from BP patients was able to
normal human keratinocytes upon stimulation with induce BP-characteristic inflammatory skin changes
antibodies to human BP180 has been reported [83]. and partly subepidermal blistering in human skin
In addition to plasmin, the mast cell-specific serine grafts on nude mice [92,93].
protease MCP-4 (chymase) is also able to activate
MMP-9 [84]. Activated MMP-9 is believed to Diagnosis
proteolytically inactivate a1-proteinase inhibitor, the
physiological inhibitor of NE, which allows unrest- Clinically, BP is characterized by tense blisters predo-
rained activity of NE [85]. These findings demon- minantly on flexural aspects of the limbs and abdomen
strate that loss of cell-matrix adhesion within the and associated with severe itching (Figure 2a). BP
dermal-epidermal junction (DEJ) is directly mediated typically affects the elderly with an average age at
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by proteinases released by inflammatory cells. diagnosis between 75 and 81 years [1,2,94,95]. Before
In a first attempt to explore the functional relevance blisters arise, BP is typically preceded by a prodromal,
of human anti-BP180 antibodies reacting with the non-bullous stage, in which excoriated, eczematous,
human target antigen, human skin was transplanted papular, and/or urticarial lesions are found that may
onto Severe Combined Immunodeficiency (SCID) persist for several weeks or even months.
mice. The injection of BP IgG into the transplant did, Light microscopy of lesional skin from patients with
however, not result in blister formation within the BP typically demonstrates a subepidermal blister with
observation period of 48 h [86]. Recently, additional an eosinophil- and/or neutrophil-rich leukocytic
infiltrate within the papillary dermis and along the
humanized mouse models have been established.
epidermal BMZ (Figure 2b). By direct IF microscopy
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Olasz et al. generated a novel transgenic mouse


of perilesional skin linear deposits of IgG and/or C3
expressing human BP180 in murine epidermal BMZ
can be found at the epidermal BMZ (Figure 2c).
by the use of a keratin 14 promoter construct. They
In approximately 80% of the cases, patient IgG
showed that wild-type or MHC I2/2 , but not MHC
autoantibodies react with the epidermal side of 1 M
II2/2 , mice grafted with transgenic skin elicited IgG
NaCl split human skin by indirect IF microscopy
that bound human epidermal BMZ and BP180.
(Figure 2d) [96].
Transgenic grafts on wild-type mice developed
Based on the finding that NC16A is the immuno-
neutrophil-rich leukocyte infiltrates and subepidermal
dominant region of BP180 [17,18], two highly specific
blisters [87]. Nishie et al. [88] used the same BP180
and sensitive BP180 NC16A-specific ELISAs for
transgenic mice to rescue the blistering phenotype detection of circulating autoantibodies in BP have
of BP1802/2 mice by backcrossing experiments. been commercialized [19,97]. When these assays are
Clinical, histological, and immunopathologic features combined with other detection systems, including
of BP were achieved by passive transfer of IgG from those using BP180 fragments outside the NC16A
patients or IgG1 monoclonal antibodies against domain and BP230, the sensitivity of these tests can be
humanized BP180 NC16A into these BP180-huma- increased to even 100% [38,41,98,99]. In contrast to
nized mice [88,89]. To show that pathogenic anti- serum levels of antibodies to BP230, BP180 NC16A-
BP180 autoantibodies act in combination with key specific autoantibodies correlate closely with disease
innate immune system players also in the humanized activity and may thus be not only of diagnostic use, but
BP mouse model, Liu et al. generated a humanized also allow the monitoring of circulating autoantibody
mouse strain, in which murine BP180 NC14A was levels during the course of the disease, helping to
replaced by the homologous human BP180 NC16A guide treatment decisions [19,20,36].
epitope [90]. These BP180 humanized mice pre- BP must be differentiated from pemphigus and
treated with mast cell activation blocker or depleted of other subepidermal blistering autoimmune derma-
complement or neutrophils become resistant to BP toses, including EBA and dermatitis herpetiformis.
after passive transfer of human BP autoantibodies. In contrast to BP, blister formation in pemphigus
More recently, an active mouse model for BP has been results from intraepithelial cell separation and shows
developed by transferring splenocytes from wild-type an intercellular pattern of IgG between keratinocytes.
mice that had been immunized by grafting of human Differentiation of BP especially from EBA, anti-p200
BP180-transgenic mouse skin onto Rag-22/2 /BP180- pemphigoid, and MMP, however, presents a more
humanized mice. The recipient mice produced difficult task. The mechanobullous, non-inflamma-
anti-human BP180 IgG antibodies in vivo and tory form of EBA is characterized by the appearance
developed blisters and erosions corresponding of skin fragility and tense blisters at anatomic
Update on pemphigoid 59
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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.

areas subjected to trauma, healing of lesions with dermatitis herpetiformis. Continuous linear immuno-
scarring and milia formation as well as subepidermal deposits of IgA, most often in the absence of IgG and
split formation with an only scattered dermal C3, together with circulating IgA anti-BMZ auto-
inflammatory infiltrate. In contrast, the inflammatory antibodies, can distinguish LAD from these other
subtype of EBA may mimic clinical, histological, and immunobullous diseases.
routine direct IF microscopy findings of BP.
Using higher magnifications of direct IF micro-
Treatment
scopy, EBA can be sometimes differentiated from BP
by distinctly shaped IgG deposits at the epidermal BP is generally a self-limited disease that may remit
BMZ, i.e. EBA revealing an u-serrated pattern and BP within a few months or some years. However, the
a n-serrated configuration [100]. In addition, as mortality rate in the first year has been shown to be as
autoantibodies in EBA are directed against type VII high as 11 40% [95,101 103], and was related to old
collagen, sera from these patients do not bind to the age, poor general condition, and use of high doses of
epidermal, but to the dermal side of 1 M NaCl split oral corticosteroids rather than to the extent of the
human skin. Similarly, patients with anti-p200 disease itself [94,102]. Systemic and topical cortico-
pemphigoid show autoantibody reactivity to a dermal steroids have been widely used in clinical practice
antigen. This immunopathological finding may be of [104]. Initially, daily morning doses of prednisolone in
major importance since clinically, anti-p200 pemphi- the range of 0.5 mg/kg/day usually control the disease
goid and BP may not be distinguishable. In contrast within a few weeks. An initial dose higher than
to BP, MMP is predominantly confined to mucous 0.75 mg/kg/day has been shown to be not beneficial in
membranes. a controlled prospective trial [105].
If blisters appear on the skin of MMP patients, they A large, randomized controlled trial showed that
are commonly smaller, transient, and of limited initial disease control and 1-year survival were
extent. Indirect IF microscopy of sera from MMP significantly better when treating severe BP with
patients may reveal epidermal, dermal, or combined clobetasol propionate cream 40 mg/day compared with
staining patterns of IgG on 1 M NaCl split human oral prednisolone 1 mg/kg/day, while in moderate BP,
skin. Some forms of LAD clinically resemble BP or outcomes using clobetasol cream and prednisolone
60 M. Kasperkiewicz et al.

0.5 mg/kg/day were comparable [106]. Furthermore, a pemphigoid fibroblasts may actively be involved in
mild regimen with clobetasol propionate cream 10 ocular MMP-associated scarring processes [133,134].
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]. Diagnosis
Considering other randomized controlled trials in
BP, no differences in disease control were seen for MMP is a chronic autoimmune blistering disease
azathioprine plus prednisone compared with predni- of mucous membranes and skin. An international
sone alone [108], for prednisolone plus azathioprine consensus conference defined the predominant invol-
compared with prednisolone plus plasma exchange vement of mucous membranes as the major clinical
[108], for prednisolone plus mycophenolate mofetil or diagnosis criterion of MMP [135]. The oral mucosa
plus azathioprine [109], and for tetracycline plus is the most common site affected by MMP followed
nicotinamide compared with prednisolone [110]. by ocular disease (Figure 3). It may also involve nasal,
Reports have also described successful treatment of pharyngeal, laryngeal, esophageal, and anogenital
BP patients with dapsone [111,112], methotrexate mucous membranes. Progressive scarring potentially
[113], high-dose intravenous immunoglobulins may lead to serious complications, such as blindness
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(IVIG) [114], rituximab [115 117], omalizumab or asphyxiation. Histologically, MMP is characterized
[118], and immunoadsorption [119]. by subepidermal blisters with a chronic inflammatory
infiltrate in the lamina propria that is composed of
lymphocytes, histiocytes, scattered neutrophils, and
Mucous membrane pemphigoid eosinophils. Anti-BP180 and anti-laminin 332
MMP cannot be differentiated from each other by
Pathogenesis histology [136].
BP180 is the target antigen in about 70% of MMP Direct IF microscopy shows linear IgG and C3
patients [120]. However, unlike in BP, only about deposits at the BMZ. Indirect IF microscopy using
half of the patients sera contain antibodies to BP180 1 M NaCl split human skin distinguishes between
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NC16A, and C-terminal epitopes of BP180 are antigens on the epithelial side of the split (BP180,
preferentially targeted [120 122]. In addition, BP230, and a6b4 integrin) and those of the dermal
patients with MMP may exhibit IgG and/or IgA side (laminin 332). However, as only about one-half of
autoantibodies of other specificity that recognize sera are reactive in indirect IF microscopy, ELISA and
BP230 [123,124], the 97/120 kDa LAD antigen, Western blotting using relevant target antigens are
laminin 332 (laminin 5), laminin 331 (laminin 6) important additional diagnostic methods in MMP.
[125,126], type VII collagen [127], or the a6 and Although only half of the MMP patients develop
b4 integrin subunit [128]. Considering the latter antibodies to the NC16A domain of BP180, the other
target antigens, it has been shown that sera from patients with BP180 reactivity react with LAD-1 or
patients with generalized MMP and ocular MMP the C-terminal portion of BP180 by Western blotting
recognize the b4 integrin subunit, while sera from [130]. Importantly, testing for IgA anti-BP180
patients with oral MMP recognize the a6 integrin antibodies in addition to the IgG isotype will further
subunit [129]. increase the detection rate [130,137].
The pathogenicity of anti-laminin 332 antibodies Assaying for anti-laminin 332 reactivity is of
has been documented in vivo. Passive transfer of anti- particular importance as 25% of patients with laminin
laminin 332 IgG to neonatal or adult mice induced 332-specific antibodies develop a malignancy. In these
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 Figure 3. Clinical presentation of MMP. Ocular involvement with
collagen type I secreted in high amounts by symblepharon formation.
Update on pemphigoid 61

patients, a tumor search is indicated [138,139]. given at 2 g/kg/cycle initially every 4 weeks, avoided
Immunoprecipitation with human keratinocytes has progression of the disease and was more effective than
been reported to be the most sensitive technique for conventional immunosuppressive treatment [104].
the detection of serum autoantibodies against laminin In one study, IVIG given as monotherapy halted
332, whereas immunoblotting with extracellular progression of scarring and visual deterioration during
matrix of cultured HaCaT cells was found to be the the study period, and serological and clinical remis-
most practical alternative [140]. The term cicatricial sion was sustained for several months after cessation of
pemphigoid, previously applied for patients with MMP, IVIG infusions [147]. Recent case reports also
is currently only used for the rare clinical variant in described the beneficial use of rituximab and TNF-a
which mucous membranes are not predominantly inhibitors for severe and treatment-resistant cases of
affected and skin lesions heal with scarring [135]. MMP [105,107,148].
Brunsting Perry pemphigoid is a rare variant of
cicatricial pemphigoid first described in 1957 [141].
It is characterized clinically by blisters, hemorrhagic Pemphigoid gestationis
crusts and atrophic scars confined to the head and
Pathogenesis
neck without mucosal involvement. It probably
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represents a heterogeneous disorder with several PG, formerly referred to as herpes gestationis, is
target antigens. Most patients with this type of another disease in which BP180 has been identified as
pemphigoid disease have been reported to have the major target [149]. Occasionally, PG is associated
autoantibodies against type VII collagen, therefore, with a trophoblastic tumor, hydatidiform mole or
representing a localized form of EBA [142]. Although choriocarcinoma. The disease may appear for the first
the clinical features of Brunsting Perry pemphigoid time during any pregnancy, but then rarely skips
are completely different from those of MMP, it has subsequent gestations [149]. The immunopathologic
recently been reported that they may share the same hallmark of PG is linear deposits of C3 and, to a lesser
target antigens, e.g. the C-terminal domain of BP180 extent, of IgG along the DEJ in perilesional skin
and laminin 332 [143,144]. biopsies. Circulating-complement fixing autoanti-
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bodies HG factor can be detected by indirect IF


on intact or NaCl split skin.
Treatment
The autoantibodies react with BP180 and, less
Treatment of MMP is largely tempered by its severity frequently, with BP230 [16,150]. IgG autoantibodies
and sites of involvement. A consensus conference on in most PG sera target the NC16A domain of BP180
this disease differentiated high-risk and low-risk [16,32,151 153]. However, antigenic sites outside
patients. Although in low-risk patients, lesions are NC16A have also been identified both extra- and
limited to the oral cavity and the skin and are more intracellularly [153]. Epitope mapping studies ident-
amenable to treatment, patients with conjunctival ified two well-defined antigenic sites within a 22 amino
involvement usually require aggressive management to acid segment of BP180 (NC16A2 and NC16A2.5) as
avoid blindness. Mild lesions of the oral mucosa and major antigenic targets for PG sera [152]. In addition,
skin can sometimes be effectively treated with topical using overlapping synthetic peptides, PG autoanti-
glucocorticoids or topical calcineurin inhibitors bodies were shown to bind to two defined epitopes
combined with good oral hygiene. For more severe within the NC16A domain (aa 500 514 and aa 511
lesions in low-risk patients, initial treatment may 523). Importantly, preadsorption using an affinity
include dapsone (1.0 1.5 mg/kg/day) and predniso- matrix containing these epitopes completely abolished
lone (0.5 1.0 mg/kg/day). dermal epidermal separation ex vivo induced by PG
An alternative for these patients may also be autoantibodies [154].
tetracyclines combined with nicotinamide. Predniso- In contrast to findings in BP [155], reactivity to
lone (1.0 1.5 mg/kg/day) in combination with oral NC16A is dominated by IgG1 and IgG3 antibodies in
cyclophosphamide (1.0 2.0 mg/kg/day) may be tried PG patients [152]. As IgG1 and IgG3 are the IgG
in patients at high risk (ocular, nasopharyngeal, subclasses with the strongest complement fixing
genital, and esophageal involvement) [145,146]. properties, these observations may well explain
Alternatively, i.v. dexamethasone pulses (100 mg on complement deposition at the DEJ, which is the
3 consecutive days) combined with i.v. cyclopho- most consistent immunopathological feature in PG. In
sphamide pulses (500 1000 mg) in 2- to 4-week PG patients tested for T-cell autoreactivity, BP180-
intervals can be given. In patients who do not tolerate specific T cells exclusively reacted with the NC16A2
cyclophosphamide, other immunosuppressants such domain. Proliferative responses of these cells were
as azathiorpine, mycophenolate mofetil, and metho- restricted to HLA-DR and cells expressed a CD4
trexate can be applied [145,146]. Th1-type memory phenotype [156]. These results
Good therapeutic efficacy of IVIG has been underline other findings that PG is strongly associated
reported in patients with MMP. IVIG therapy, usually with HLA-DR3 and -DR4 haplotypes [149].
62 M. Kasperkiewicz et al.

Diagnosis in older patients, predominantly IgG anti-BMZ


antibodies were found [173].
PG usually presents during the second or third
LAD may be either idiopathic or drug-induced (e.g.
trimester of pregnancy or in the immediate postpartum
vancomycin). The mechanism for blister formation
period with a pruritic urticarial, papulovesicular
is not fully understood, but is likely to involve IgA-
eruption. Skin lesions often start around the umbilicus
and complement-mediated neutrophil chemotaxis.
and then spread over abdomen and thighs [149]. PG
The pathogenic relevance of LAD-associated auto-
frequently presents as a nonbullous disease with
antibodies has been shown by the passive transfer of
eczematous lesions, erythema multiforme-like
IgA murine monoclonal antibodies against LAD
changes or erythematous papules and plaques.
autoantigen to SCID mice bearing human skin grafts.
Diagnosis is based on detection of C3 deposits in
In some of these challenged mice, the transferred
perilesional skin biopsies as well as circulating
autoantibodies produced neutrophil-rich infiltrates
autoantibodies by the complement binding test and
and subepidermal vesicles [174].
ELISA using recombinant BP180 NC16A [19,157].

Diagnosis
Treatment
Autoimmunity Downloaded from informahealthcare.com by Goteborgs University on 11/20/12

LAD mainly shows vesicobullous lesions affecting the


Treatment is aimed at suppression of new blister
skin and mucosal surfaces, sometimes forming
formation and relief of the intense pruritus. In milder
characteristic collarettes of vesicles or blisters as new
cases, this can be achieved by the use of topical
lesions arise in the periphery of old lesions (Figure 4).
corticosteroids in combination with oral antihista-
On histopathology, the bullae are subepidermal, with
mines. In more severe cases, the administration of
collections of neutrophils along the epidermal BMZ
prednisolone at an initial dose of 0.3 0.5 mg/kg/day
and occasionally in the dermal papillary tips. Direct IF
is generally sufficient. This dose can usually be
microscopy of perilesional skin shows linear depo-
decreased during the course of the disease. Flares
sition of IgA at the epidermal BMZ, sometimes in
postpartum may require a temporary increase in the
For personal use only.

combination with linear IgG deposits. Patients have


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 Figure 4. Clinical presentation of LAD. Erythema multiforme-like
associated with the age of the patients: in younger lesions with partly clustered annular tense blisters on proximal lower
patients, IgA autoantibodies predominated, whereas extremity.
Update on pemphigoid 63

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
Autoimmunity Downloaded from informahealthcare.com by Goteborgs University on 11/20/12

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].
For personal use only.

Lichen planus pemphigoides Figure 5. Clinical presentation of LPP. Lichenified plaques and
tense blisters on the foot.
Pathogenesis
Regarding the pathogenesis of LPP, it is most likely By immunoblotting, reactivity is primarily directed
that the lymphocytic inflammatory process directed against BP180 with NC16A being the immunodomi-
against basal keratinocytes in lichen planus leads to a nant domain [180]. Less often, antibodies against
release of hidden antigenic determinants within the BP230 or other yet uncharacterized antigens are
DEJ, resulting in an autoimmune response against found [177 179]. The following observations suggest
hemidesmosomal structures [177 180]. Immuno- that LPP is not a coincidental association of BP and
blotting studies have identified BP180 and BP230 as lichen planus: (i) the average age of BP patients is 77
target molecules but also a new antigen of 200 kDa of years, whereas in LPP it is 44 years; (ii) lichenoid
keratinocyte derivation. The latter finding reinforces papules are not seen in BP; (iii) autoantibodies in LPP
the hypothesis that LPP might have a unique antigen react with C-terminal epitopes of NC16A, which is
and thus represent a distinct entity from BP very uncommon in BP; and (iv) LPP is usually a
[178,179]. In line with this assumption, it has been milder disease and more therapy-responsive than BP.
shown that the epitope within the C-terminal NC16A
domain of BP180 antigen, targeted in LPP, differs
Therapy
from BP, localizing to NC16A4 as opposed to
NC17A1 through NC16A3 [180]. It is important to treat existing lichen planus to avoid
further immunostimulation. In this context, acitretin
has proven valuable. Otherwise, treatment is the same
Diagnosis as in BP.
Most patients with LPP have typical lichenified
plaques or papules of lichen planus initially, followed
Anti-p200 pemphigoid
after weeks to months by tense vesicles and blisters
which arise, in contrast to bullous lichen planus, Anti-p200 pemphigoid is a subepidermal blistering
independent of the lichenoid lesions (Figure 5). skin disease characterized by circulating autoanti-
Histologically, blisters resemble those in BP [177]. bodies against a 200-kDa molecule (p200 protein) of
Direct IF microscopy of a papule shows Civatte the lower lamina lucida of the BMZ [181]. Recently, it
bodies, but when a blister is evaluated, IgG and C3 are has been shown that 90% of the anti-p200 pemphi-
present as in BP. Indirect IF microsocopy on salt split goid sera react with the C-terminus of laminin g1
skin shows binding of IgG to the epidermal side. [182]. Subsequently, the term anti-laminin g1
64 M. Kasperkiewicz et al.

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-
Figure 6. Clinical presentation of anti-p200 pemphigoid. Tense vant immunoadsorption has been successfully applied
Autoimmunity Downloaded from informahealthcare.com by Goteborgs University on 11/20/12

blisters and erosions on the palms. in a severe case of anti-p200 pemphigoid with
concomitant active gastric ulceration [189].
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 Conclusion
synonymously and only diagnosing an anti-laminin g1
Considerable progress has been made in the last years
pemphigoid when reactivity with laminin g1 has
regarding our understanding of pemphigoid diseases.
actually been identified.
Experimental animal models of these diseases and
advances in translational research provided essential
insight into the pathophysiology of these disorders.
For personal use only.

Pathogenesis
Intense scientific research on the autoantibody
Anti-p200 pemphigoid shows organ-specific patho-
response has led to new diagnostic techniques,
genicity, although laminin g1 is expressed not only at
allowing the serological diagnosis in the great majority
the DEJ but also in the BMZ of dermal blood vessels
of patients. Novel, more specific therapeutic avenues
[184]. This has been explained by the assumption that
are, however, needed to further reduce the long-term
laminin g1 in the epidermal BMZ has different
adverse effects of the currently available immuno-
posttranslational modifications, such as glycosylation,
suppressants.
compared with laminin g1 expressed in blood vessels
[185]. However, the pathogenicity of anti-p200/lami-
Declaration of interest: This work was supported by
nin g1 antibodies has hardly been studied yet, with the
grant EXC 306/1 Inflammation at Interfaces (Research
exception of a single patient whose IgG, in contrast to
Areas E and H) from the Deutsche Forschungge-
BP IgG, did not induce IL-8 secretion following
meinschaft to E.S. and D.Z. The authors report no
incubation with human cultured keratinocytes [186].
conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
Diagnosis
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